My 5 year old child is having exon 45 deletion. Last year his cpk total was 18160 again we checked for the second time this week now it came to 244. What does this mean??
Currently he is on steroids defcort 12 mg.
Exon 45 skipping would restore the genetic code for this deletion. However, I do not know whether exon 45 skipping is available where you live. It is approved in the USA and tested in clinical trials at several locations in Europe and North-America.
Note that exon 45 skipping results in only low levels of dystrophin and that it is not known whether this results in functional effects yet. The currently ongoing clinical trials aim to test this.
In one of your comments below you’ve mentioned “it is possible that your body already spontaneously skips exon 45 at a low level”. That’s quite interesting and I would really appreciate if you would be able to share a bit more information or resources. Do you think that there is a way somehow to force the body to do that?
There is a way to specifically increase exon 45 skipping with antisense oligonucleotides.
There may also be other compounds (chemicals) that do this not specifically. This means they would increase exon 45 skipping, but likely also induce the skipping of other exons, which may have detrimental effects.
Exon 40 small deletion was observed gene sequencing
Our doctor suggested that 39 and 41 will automatically join up and BMD like symptoms will show up probably. As of there are no clear symptoms are age of 5. So he has told to wait and watch ? We are in dilemma should we go for exon skipping or not? Please rep soon
apologies for the delayed reply. The alert messages do not arrive in my inbox for some reason.
If exon 40 is deleted, indeed this is ‘in-frame’ so the code remains readable. So indeed we expect him to have Becker. The problem is that Becker is very variable, some patients have first symptoms at age 7 while others have first symptoms at a much later age (sometimes in the 40s or even 60s).
You should not go for exon skipping, because exon skipping is not going to help. The aim of exon skipping is to make the code readable. If the code is already readable, you cannot make it more readable.
None that I have heard since Kevin Flannigan’s presentation at PPMD meeting on the baby he treated with the exon 2 skipping gene therapy who had very good dystrophin restoration.
Hello.
I am writing to you because I have been following you on Twitter for a long time.
I’m impressed with your work on Duchenne’s disease.
Not to be too long, my 2 boys aged 10 and 6 have Duchenne muscular dystrophy, deletion of exon 7 (the mother does not have the gene).
Do you have any information on this type of deletion?
I use Google Translate, forgive me, we are from France.
Cordially
Apologies for the delayed reply. The email alert system did not work so I was not aware of your question.
What we know about exon 7 deletions is not a lot. Generally speaking Duchenne patients with deletions before exon 8 have a slower disease course than other Duchenne patients (but they still have Duchenne AND this is on average, so there is still variability).
For dystrophin restoration approaches this is not a good mutation, as microdystrophin is currently not possible due to the risk of an auto-immune response to the microdystrophin for patients with deletions in the beginning of the gene. Also for exon skipping this is not a good mutation as two exons need to be skipped (exon 6 and exon 8) and that is very challenging.
Greeting!
My son’s Duchenne muscular dystrophy is defective in exon 44. I would be interested in the skipping 45 therapy, where it is done, how to get into the program and try it out. Please write if you have any information. Thanks Nora
A deletion of exon 49-50 is out of frame, i.e. it disrupts the genetic code of the dystrophin gene. Since the dystrophin gene is located on the X-chromosome, and you have 2 of those, you are not sick. However, your boy has 50% chance of having this deletion. Then he would not be able to make dystrophin protein and he would have Duchenne.
Please note that as a carrier of this mutation, you CAN have symptoms (muscle cramps and weakness) and you are also at risk to develop heart problems. The heart problems can be treated if they do develop. however, it is important that they check you regularly (every 3 years and more frequent if problems do develop). There are guidelines available for this. For more information, see e.g. https://www.duchenneuk.org/study-paves-the-way-for-improved-detection-of-heart-disease-in-female-carriers-of-dmd/
Hi my son 5 years has hemizygous deletion of exon 52 out of frame .exon 51 and 53 are present in entirety. .ck is 18000.does it indicate dmd.how severe will it be and is exon skipping option available .thank you
This is indeed Duchenne. How severe it will be is difficult to predict as there is variation between Duchenne patients. however, Duchenne is sadly a severe disease.
Exon skipping is an option: both exon 51 skipping (eteplirsen) and exon 53 skipping (golodirsen and viltolarsen) are options. Since exon 53 skipping is more efficient so far than exon 51 skipping, if you have the option, I would recommend exon 53 skipping.
Hello,
We found out that my nephew, 7 years old, has deletion on exons 45-50. He is showing some weakness symptoms. Does this deletion lead to the serious DMD or to the milder one, BMD?
Thank you very much!
sadly a deletion of exon 45-50 leads to the serious DMD.
Depending on where you live a treatment may be available. Exon 51 skipping restores the genetic code for this mutation. In the USA exon 51 skipping drugs are approved (eteplirsen). They have only been shown to restore the missing protein (dystrophin) at low levels. It is not known if that is enough to slow down disease progression. The drug is approved in the USA, but trials to assess what the functional effects are, are ongoing at different locations. Also, other exon skipping drugs (that lead to hopefully more dystrophin restoration) are being evaluated in clinical trials. For more information see https://treat-nmd.org/resources-support/research-overview/dmd-research-overview/mutation-specific-approaches/#1555493313072-b6404a52-9df4
Unfortunately there is not cure for Duchenne.
Exon 51 skipping would restore the genetic code. However, this is only approved in the USA and is very inefficient. It is not yet known whether it slows down disease progression.
There is no way yet to restore the exons that are missing.
Hello Doctor Rus,
My Nephew is 9 year old and was detected DMD for 46-48 exon deletion.At present he is walking on his toe. we are very tensed about his health. kindly suggest the available treatment for him.is Exon 45 skipping is possible in his case? Kindly suggest us the possible way out for his treatment.
Indeed exon 45 skipping would restore the genetic code for this mutation and would restore dystrophin production.
Note that exon 45 skipping is approved in the USA (Casimersen) based on low levels of dystrophin restoration. It is not yet known whether this will slow down disease progression. Clinical trials to study this in more detail are ongoing.
I am sorry to hear about your nephew.
There is no treatment available for this mutation yet. IT requires the skipping of exon 45 AND of exon 53 both. While exon 45 and exon 53 skipping drugs have been approved in the USA, they have never been test in combination in humans. What we know from mice is that the skipping of two exons is very inefficient for the type of exon skipping drug that has been approved.
My nephew’s genetic test results indicate deletion in exons 45-47, and he was diagnosed with BMD. He doesn’t show any symptoms, apart from occasional mild pain in one of his legs after strenuous activity. I was wondering if you are aware of any treatment options/clinical trials for this specific mutation (anywhere in the world but especially in Europe).
It is indeed expected that this mutation results in Becker as it allows production of a partly functional dystrophin.
There are limited clinical trials ongoing for Becker patients. Edgewise and Italpharmaco are evaluating their treatments in both Duchenne and Becker patients. There may be others but I am not aware of them. Treatment developments for Becker are being discussed during annual meetings of the Italian Duchenne Parent Project and of the Parent Project Muscular Dystrophy.
There is currently no specific treatment for exon 44 duplications.
Trials for exon 44 skipping are in preparation. I do not know whether the inclusion criteria will allow patients with duplications to be included as well. The companies preparing exon 44 skipping trials are Entrada and Avidity.
Stem cell treatment to restore dystrophin will not help in this case or in any case. Thus far it has not been possible to achieve significant restoration of dystrophin with stem cell treatment.
Exon 45 skipping would restore the genetic code and restore dystrophin production – albeit at low levels so far. Exon 45 skipping is approved in the USA (casimersen) and tested in clinical trials in other countries.
Met Mustafa heb zelf dmd en ben 31 jaar oud. Wilde meer informatie over stem cell therapie wat is het precies en kom ik daarvoor in aanmerking. Heb je ook trails waar ik aan mee kan doen. Ik hoor graag van u.
Hoi,
Bij stamcel therapie voor Duchenne is het doel om spierstamcellen in het lichaam te brengen die gaan fuseren met de zieke spieren van Duchenne patienten. Dan zorgen die stamcellen ervoor dat de spieren herstellen en dat er dystrofine gemaakt kan worden
Klinkt heel mooi in theorie, maar helaas werkt het niet in de praktijk. Namelijk als je de stamcellen in de bloedbaan inbrengt gaan ze NIET naar de spier maar blijven ze in het bloed en gaan ze dood. Als je ze in spieren injecteert blijven ze rondom de injectieplek zitten en zou je dus miljarden injecties moeten doen en heel veel stamcellen nodig hebben (dan heb je meerdere mensen nodig die hun armen en benen afstaan hiervoor – dat gaat dus ook niet werken).
Ik ben wetenschapper en geen arts en heb dus zelf geen trials. Er zijn wel klinische studies gaande in Nederland (zie Duchenne Centrum Nederland). Echter, ik weet niet of patienten van 31 in aanmerking komen hiervoor.
37 Yrs old just found have deletion in Exons 45-53 guessing some from of BMD no family history of DMD mutation. What does it mean since I am not really showing any symptoms other than some minor calf hypertrophy and slight weakness in proximal muscles. Is there any options for treatment.
Please bear in mind that I am not a medical doctor so my information should not be interpreted as medical advice.
This is an in-frame deletion so it would indeed be expected to result in Becker muscular dystrophy. This disease is very variable with some patients not showing pathology until their 40s or even 60s, while others have pain and weakness from childhood. From what you describe you seem to be one of the milder cases.
Given the mildness of the symptoms it is possible that other family members are affected as well but never realized because the symptoms were not very severe.
Currently there is no treatment for Becker muscular dystrophy. Patients are usually followed by neuromuscular specialists who also assess heart function, as a subset of Becker patients develops cardiomyopathy.
There are clinical trials ongoing to study whether compounds that preserve muscle or improve muscle metabolism benefit Becker patients. However, as yet it is not clear if these are safe and effective.
During a routine test of my amniotic fluid I see that an in frame deletion of 48-51 was noticed.
I am absolutely terrified and scared. I am pregnant with twin boys and we are in week 24 already.
Can you please let me know if there is a chance to not have a disease with this sequence?
What does it mean?Can it result in a mild form of a disease?
Apologies for the delayed reply Ines.
This deletion is in frame and expected to lead to Becker muscular dystrophy. This is the milder form of the disease (if you compare it to Duchenne). Becker is variable with some patients having muscle problems in late childhood while others do not have any symptoms until later in life.
I am sorry I cannot give more detailed information.
Annemieke
Good evening,
my son has a deletion of exons 51 and 52. He is only 6 months old and not showing any symptoms yet. I was just wondering if you could tell me more about this particular deletion. I have just recently found out I am a carrier but no one in family has this desease (at least that we know). I know it is likely to be associated with Becker since it is an in frame deletion. But I was wondering how many documented cases of this deletion there are and how it has affected those individuals with it. I am in many Facebook and internet groups about MD but I have NOT found one single person with this deletion. Also, I was reading an article that it said it was pretty rare and one individual with this deletion is actually asymptomatic and with normal CK levels. Maybe I am just trying to be optimistic…or is there a chance this deletion is actually pretty rare and very very mild?
Dear Elisa,
This deletion is indeed expected to result in Becker muscular dystrophy. I checked the LOVD Duchenne/Becker database and discovered ~20 other individuals with this deletion. However, it was not indicated whether they have Duchenne or Becker so that is not very helpful. I have heard of an individual with very mild symptoms with this mutation in Israel on top of the publications. We also know that in a mouse with a deletion of exon 52, skipping exon 51 results in production of a functional dystrophin, further underlining that the exon 51-52 deleted dystrophin is partially to largely functional.
The challenge with Becker is that it is very variable and patients with the same deletions can have different severity. So there is never a guarantee that it will be very mild unfortunately.
Given that the mutation is very mild in some individuals, it is possible that your male relatives (e.g. your father, brother, or uncles) also carry it but are not aware because it is very mild. If it is severe it must be inherited via the mother if no one in the family has the disease. However, if it is mild it is possible that it was inherited via your father as well. If that is the case, that will of course tell you that it likely will be very mild in your son. However, it is also possible that the mutation started with you or was inherited via your mother.
Het skippen van duplicaties van meerdere exonen is heel erg lastig. Dit komt omdat bij een duplicatie sommige exonen dubbel aanwezig zijn. Er kunnen dan meerdere dingen gebeuren voor elk exon in de duplicatie: het originele exon wordt geskipt, het extra exon wordt geskipt, beide exonen worden geskipt of geen van beide exonen worden geskipt. En dat dan voor elk exon afzonderlijk. Het gevolg is dat je heel veel verschillende combinaties krijgt waarvan er maar een paar zijn wat je daadwerkelijk wilt (exon 24-29 skippen voor ofwel het origineel ofwel de duplicatie). Je krijgt dus een ernstige verdunning van het effect.
Dus hoewel het in theorie heel mooi lijkt (inderdaad je gaat terug naar een ‘intact/normaal’ dystrofine transcript), is de praktijk dat het al heel erg lastig is bij een duplicatie van 2 exonen, laat staan een duplicatie van 6 exonen).
We live in the UK. Our 2yr old son has just been diagnosed as having muscular dystrophy- Hemizygous duplication of Exon 46.
We are struggling to find any information on this particular variant.
Are you or your group familiar with single Exon 46 duplication? Am I correct in thinking that it is out of frame, as not divisible by 3?
Any information on phenotype or implications for therapies available or undergoing research would be greatly appreciated. I’ve read the website section on exon skipping for single duplications and note some success with 45 but 44 was more complex. Has any work been done on skipping 46 duplication?
The genetic report notes that the variant is associated with both Duchenne and Becker. Our son has a raised CK -9000, and proximal leg muscle weakness with a positive modified Gower sign. We’re assuming the phenotype will be more likely Duchenne while noting that genotypes do not always perfectly correlate with phenotype.
Dear Pete,
I am very sorry to hear you son has been diagnosed with muscular dystrophy. A duplication of exon 46 is quite rare. You are correct in your thinking: this duplication would be expected to lead to Duchenne as the length of exon 46 is not divisible by 3. Duplications are known for sometimes ‘misbehaving’, so in-frame duplications leading to Duchenne, and out-of-frame ones leading to Becker. However, sadly I agree with you that the symptoms your son presents at such an early age suggests that he has Duchenne indeed.
Exon skipping for single exon duplications is difficult when done in cultured cells. However, exon skipping in cultured cells is very easy – you “overdose” the cells with the exon skipping compound (ASO). This means there is so much ASO in each cell that instead of one ASO binding to an exon 46, two bind to both exons 46. You then end up with a deletion of exon 46 – which is also out-of-frame.
In a body this will not happen. Here actually it is very difficult to get the ASOs to go to the muscle fibers. So it is difficult to get even a single ASO into a cell – thus the chance of skipping both exons 46 is very low. As such we expect that exon skipping for single exon duplications will be feasible.
Sarepta is currently doing a clinical trial to test this for exon 45, 51 and 53 single exon duplications. This is because they have ASOs approved targeting those exons.
To my knowledge no one is working on developing an exon 46 skipping ASO at the moment.
I am sorry I do not have better news for you. If you have any questions please do not hesitate to contact me again.
While there is no treatment yet for your son, there is multidisciplinary care, which can achieve a lot.
Furthermore, there are patient organisations that can help you with emotional and logistic support if you need it.
My son 7 year old , recently diagnose with MD symptoms. He was tested for CKP 7800 and MLPA report says “a deletion in dystrophin gene involving multiple exon (8-16) was observed (exons 7 and 17 were present)”.
Please let me know its meaning if it is a case of DMD or BMD and how severe?
We really need your directions and treatment option available for him.
I am sorry to hear about your son having muscular dystrophy. For a deletion of exon 8-16 we would expect Duchenne, as the deletion disrupts the genetic code. However, whether someone has Duchenne or Becker mainly is determined by the symptoms. When did they start (for Duchenne signs are there at 2-4 years of age, difficulty climbing stairs and frequent falls and a waddling gate).
This must be a very difficult time for you. Note that patient groups are in place in many countries to help you with information and also to give emotional support.
If you have additional questions, please do not hesitate to ask here or on via email (a dot m dot rus ad lumc dot nl)
Annemieke
Respected Sir,
I have an eighteen years old son who is suffering from DMD ( Deletion of 45 exon ). Costly medicine Amondys can be given. Dr. in India does not want to prescribe it. What can I do to save the life of my son ?
Dinesh Kumar ( Punjab, India)
I am sorry to hear about your son having DMD. Amondys (casimersen) is a compound that is only approved in the USA. It aims to make the genetic code readable by patient with specific mutations through skipping exon 45. This would NOT apply to your son unfortunately. A deletion of exon 45 means the genetic code is disrupted because exon 45 is absent. To make the genetic code readable again exon 44 or exon 46 would have to be skipped. There is currently no exon 44 or exon 46 compound in clinical development.
I’m sorry I do not have better news for you
Hello dr my son is 5 year old and after test found exxon deletion 47-50 , exxon 46&51 were present, i am from india east coast, request treatment and any medication also if required would travel to us for treatment, please guide me am helpless at present due to my son illness
I’m very sorry to hear about your son having Duchenne. The mutation would be eligible for exon 51 skipping. There is an exon 51 skipping compound approved in the USA (eteplirsen). However, that is based only on small increases in dystrophin expression (less than 1% after weekly intravenous infusions for over 3 years). The question is whether this will slow down disease progression. This is still being studied.
Eteplirsen treatment is not available outside of the USA as far as I am aware.
I am sorry I cannot be of more help.
Annemieke
Dear John,
A deletion of exon 46-48 is expected to result in Duchenne, because the reading frame (genetic code) is disrupted. Note however, that whether someone has Duchenne or Becker is decided by the symptoms and when they appear.
Hi Annemieke, my son is 3 years old this nov-21 in Singapore , and he has been diagnosed with DMD with Exon 46 & 47 deletions on the same day. We can’t explain emotions. We really need your directions and option available. What is the process to enroll for trials or how to get the medication which is available in any other country like USA. Any links would help.
The therapies that are approved in Europe and the USA are mutation specific. The only applying to your son’s mutation is casimersen (exon 45 skipping). Please note that this therapy is approved based on the restoration of very low levels of dystrophin (~1%). It is not yet known whether those small increases will be enough to slow down disease progression. That is something that is currently being evaluated in clinical trials (see https://clinicaltrials.gov/ct2/show/NCT02500381?term=casimersen&draw=2&rank=4). I do not know whether that trial also occurs close to Singapore. That is something you could ask the company developing casimersen (Sarepta). I would contact them on their website to ask about this: https://www.sarepta.com/
I am sorry I cannot be of more help to you. I will be praying for you and your family.
I would love to make contact with Prof Dr Annemieke Aartsma-Rus. I have a 3 year old grandson with DMD . I live in South Africa where the only treatment is corticosteroids.
Thank you kindly.
Kind Regards
Carol Smit
Dear Carol,
I am sorry to hear your grandson has Duchenne. Please note that steroid treatment is what is available to most patients around the world. This slows down disease progression significantly but of course it is not without side effects.
There are drugs approved for Duchenne patients who carry specific mutations. In Europe and Russia: Translarna (ataluren) specifically for nonsense mutations.
In the USA and Japan: viltolarsen specifically for patients where the genetic code can become readable after skipping exon 53.
In the USA: eteplirsen, golodirsen and casimersen specifically for patients where the genetic code can become readable after skipping exon 51, 53 and 45, respectively.
Note that these drugs are not cures. They restore dystrophin production at a very low level and how much this will slow down disease progression is not yet clear.
To my knowledge these compounds are not approved or available in South Africa. Furthermore, whether your grandson would be eligible for these therapies depends on his mutation.
Thank you for answers and guidelines. I do have more questions than answers.
1. Regarding to steroid therapy. Obviously next step is to apply deflazacort (Calcort). My question is; what is better steroid prednisone or deflazacort? What is yours experience. What are side effects to each one.
2. Exon 44 skipping – is in progress NCT04129294 (Nippon Shinyaku Co., Ltd.). My question is: do you have any other information regarding to/from development from other Pharmaceutical company. Do we have any in EU or worldwide.
Thank you for you time and answers.
Best regards
Igor
I am not an MD so do not have personal experience with different steroids (deflazacort vs prednisone). I know there are MDs who prefer one over the other (both for prednisone and deflazacort). There is a clinical trial ongoing (FOR-DMD) that compares the efficacy and side effect profile – the trial has completed and data is currently being analyzed. Hopefully that will shed more light on this question. For now the answer is that we do not know whether one is better than the other with regards to efficacy and side effects. What we DO know is that using either of them slows down disease progression significantly compared to no steroids.
I was not aware of the exon 44 skipping trial by Nippon Shinyaku. As far as I am aware this is the only trial with exon 44 skipping ongoing at the moment. I know Sarepta mentioned preclinical work on exon 44 skipping at patient conferences. Some of the newer companies are mentioning exon 44 skipping as well (e.g. Entrada). However, I have not heard of any plans for clinical trials yet.
Hello dear dr.Annemieke
My 7-years -old son affected with Duchenne mascular dystrophy (deletion from exon 46 to 55, hemyzigote). Do you have any information about this mutation and avaliable treatments?
I am sorry to hear about your son having Duchenne.
Your son cannot make dystrophin because the gene code is unreadable. An approach called ‘exon skipping’ aims to make the code readable again. This allows patients to produce shorter dystrophins that are partially functional. This is not a cure but hopefully something to slow down disease progression. Exon skipping is ‘mutation specific’ Depending on which exons are missing, different exons have to be skipped. Your son would need ‘exon 45 skipping’. There is a drug approved in the USA that induces exon 45 skipping (casimersen). Note that this drug is approved based on very small increased in dystrophin in treated patients (~1% dystrophin after 1 year of treatment). What is not yet known is whether these low amounts are enough to slow down disease progression.
In other parts of the world casimersen is not approved.
Dear Prof. dr. Annemieke Aartsma-Rus,
We are from Slovenia (EU).
My son all so affected from Duchenne Muscular Dystrophy (DMD) Exon 45 deletion.
He is 7 years old. Do you have any information regarding to the treatment coming.
Best regards
Dear Igor,
I have recently updated the research overview (https://treat-nmd.org/research-overview/dmd-research-overview/). This explains how different therapeutic approaches work that are in or close to clinical trials and what the current stage of development is.
Currently there is no approved therapy available for your son in Europe. There are a number of clinical trials ongoing with compounds that aim to slow down disease progression. Givinostat and tamoxifen trials should have results shortly. We all hope that these results will be positive (the drugs are save and effective). However, clinical trials are conducted to evaluate this and unfortunately we have also seen clinical trials show that drugs were not effective or not safe.
With regards to mutation specific approaches: exon 44 skipping would restore the genetic code for your son. However, this is currently only in preclinical development.
I am sorry to hear about your son having Duchenne.
What is currently available is multidisciplinary care. This applies to all patients and slows down disease progression.
What is approved in the USA: exon skipping. This applies only to specific mutations and so far we do not know if and how much this slows down the disease. Your son’s mutation would required ‘exon 45 skipping’. Casimersen is a drug that induces exon 45 skipping. However, it has only been approved in the USA at the moment. In other countries it is not yet approved or available (except in clinical trials). Note that while caismersen is approved, this is only based on the fact that it can restore very tiny amounts of dystrophin (the protein missing in Duchenne). Whether these tiny amounts will slow down disease progression is not yet know.
greetings dr. im 25 affected by duchenne exon45 deletion at my age how effective is exon skipping ? and is there any skipping available for my mutation? i know there are comercial aons for 45 53 and 51. is it do Abble for 44 or 46?
Exon skipping restores very low levels of dystrophin. As yet it is not known whether these levels will slow down disease progression – that is currently being studied for exon 45, 53 and 51 exon skipping compounds. What is known is that muscle function that is lost will not return. There are currently no exon 44 skipping compounds available or tested in clinical trials
Zolgensma is only applicable for patients with Spinal Muscular Atrophy. It provides motorneurons with a gene for the protein that is missing in SMA patients. This will not be helpful for Duchenne or Becker muscular dystrophy patients.
Dear Dr.,
I am a carrier of muscolar dystrophy with a 51-52 deletion. My newborn son genetic screening was positive. What type of MD we can expect him to have and how severe?
Please I need answers as I am devastated and desperate…
A deletion of exon 51-52 does not disrupt the genetic code of the dystrophin gene. As such, it is expected to allow the production of a shorter, but partially functional dystrophy and be associated with Becker muscular dystrophy rather than the more severe Duchenne muscular dystrophy (which is caused by mutations that DO disrupt the genetic code). How severe the disease is is difficult to predict unfortunately – there is a lot of individual variation between patients with mutations that do not disrupt the genetic code from patients who experience the first symptoms in childhood or adolescence to those that experience first symptoms when they are in their forties or fifties.
I understand you would like to have more clear answers, but unfortunately I cannot give them to you. I’ll pray for strength for you and your family.
it´s any new result of exon2 skipping,clinical trial?, I´m trying to receive any updates, even if you think that is a same questions, it´s not because the DMD life depends of time, that´s why every month i make you the same question, sorry.
I am not aware of any updates on this trial. Hopefully there will be an update during the World Muscle Society meeting in September.
Don’t worry about asking this question again and again. I know time is of the essence for Duchenne.
We do not know this yet. Current givinostat is evaluated in clinical trials for Duchenne and Becker. These clinical trials will reveal whether givinostat has therapeutic effects in Duchenne and Becker patients. I hope it works, but we need to results of the trial to draw any conclusions.
Hello Dr.Aartsma-Rus,
My 10 year old is hemizygous for a-243.88kb deletion within the DMD (NM-004006.2)gene.Deletion includes exons 45 to 48 with breakpoints in introns44 and 48.
Please tell me If it is mild or severeand what can I do for him ?
Dear Shipra,
A deletion of exon 45-48 does not disrupt the genetic code of the dystrophin gene. As such one would expect this to be Becker muscular dystrophy (The milder form of the disease). However, there are exceptions. About 10% of patients with this type of mutations still develops Duchenne, the severe type of the disease.
Whether he has the mild or severe form depends on how his muscle function is. If he is 10 with Duchenne he would have great difficulty walking or be in a wheelchair.
Regardless of whether he has Duchenne or Becker, the best thing to do is to go to an expert clinic so he can receive the optimal care for Duchenne or Becker.
Indeed a deletion of exon 45-48 is in-frame. This means that in theory your son should be able to make a shorter dystrophin and as such one would expect him to have Becker muscular dystrophy. However, there are unfortunately exceptions to the in-frame means Becker rule. Whether your son has Duchenne or Becker or is intermediate depends on how he develops clinically. If he presents as a Duchenne, he has Duchenne, even with an in-frame mutation. I am not a clinician, so I cannot say if he has Duchenne or Becker – the treating clinician can do this. But it is based on his function and progression – not on his mutation.
The question is of course why your son has a more severe disease than would be expected. Western blotting is a technique that can measure if your son produces dystrophin and if so how much. For this a muscle biopsy is needed. This is painful and invasive – while knowing whether he makes dystrophin will not alter how he does clinically.
Since your son has an in-frame mutation, exon skipping is not an option. Exon skipping aims to make out-of-frame mutations in-frame on gene transcript level.
Stem cell treatment has been tried for many Duchenne patients but unfortunately so far without success. The problem is that muscle stem cells do not go to muscle when you inject them in the bloodstream and do not migrate far if you inject them into a muscle. If you use other stem cells, these can go to muscle from the bloodstream, but this is incredibly inefficient so you would get maybe a few stem cells in the diseases muscles – that is not enough to change the disease in those muscles.
Note that there are companies that claim that stem cells work for many diseases including Duchenne. There is no evidence whatsoever to support these claims so I would strongly advise against going for stem cell ‘therapy’.
Hello Professor My name is Ahmad I am 24 years old I was diagnosed with DMD at age 6. I have a deletion of 46-47. I just wanted to see what you thought I am using a wheelchair full time but I have very mild symptoms and still have strength to transfer and do most things my self and haven’t really progressed. Do you think it could be considered Severe Becker’s instead of Duchenne because we are still unsure. Also would Amondys 45 be beneficial in my case.
A deletion of exon 46-47 is quite rare. This deletion disrupts the genetic code. Indeed exon 45 skipping would restore the genetic code, so Amondys45 (casimersen) should restore dystrophin production. Note that this drug was approved based only on dystrophin restoration. It is as yet unknown whether it will also slow down disease progression / have an impact on muscle function. That is currently evaluated in ongoing clinical trials.
Since you have a relatively mild progression, it is possible that your body already spontaneously skips exon 45 at a low level. However, that does not make you ineligible for Amondys45. Amondys is currently only approved by the FDA, so only available in the USA outside of clinical trials.
A deletion of exon 46-53 would require the skipping of exon 45 AND exon 53. Only when both are skipped would the genetic code be restored. Exon 45 and exon 53 skipping drugs are approved in the USA (casimersen (exon 45) and golodirsen or viltolarsen (exon 53). However, double exon skipping is much more difficult than skipping a single exon. This is because only when both drugs make it to the same muscle fiber and even to the same dystrophin gene transcript will this be therapeutic.
The expected efficiecy of this would be very low – best case scenario it would be increasing dystrophin levels by 0.05% (1% (casimersen) of 5% (viltolarsen). Furthermore, the combination of both has never been tested so it is also not sure whether combining these drugs would be safe.
I am sorry I do not have a better answer for you. Hopefully one of the other therapeutic approaches in development (those that are not mutation specific) will be effective in slowing down disease progression.
Dear Prof. Annemieke
My boyfriend was diagnosed with BMD- in his case exon deletion 45,46,47 (in frame)
We live in Europe
He is 28 years old now, has to be cautious while walking upstairs
1.Are there any possible clinical trials which would be helpful here in Europe
2.Neurologist told him that he will remain walking with mild problems – Is there any real evidence for this opinion (probably he was talking about it because his symptoms around his age were mild?…)
3.What we know about his deletion in general?
Regards
Alexandra
Dear Alessandra,
Becker muscular dystrophy (BMD) presents with variable severity – even for the same mutation. I know Luca Bello has studied a lot of Becker patients and he found that some deletions are presenting milder than others. I would email him to ask if indeed a deletion of exon 45-47 is one of the mild deletions.
1. There is a clinical trial with givinostat for Becker patients.
2. I am not a clinician so I am unable to answer this question, I would ask Dr. Luca Bello what he thinks.
3. We know this is one of the more common Becker mutations and that it is not associated with severe Becker muscular dystrophy. For more details I would againd defer you to Dr. Luca Bello.
Finally not that every patient is a unique individual. So when we say milder or more severe this is based on averages.
Thank you for such feature helping us to understand further about DMD. I would like to know the feasibility of treating a DMD patient with Exon 1-2 deletion.
Currently approved therapies are mutation specifici. For a deletion of exon 1 or 2 the mutation specific approaches unfortunately would not work. Stop codon readthrough does not work for deletions. Exon skipping is not possible because exon 1 is deleted.
However, there are many approaches in clinical development that apply to all patients, e.g. micro-dystrophin gene therapy, improving muscle quality (with e.g. givinostat or tamoxifen). Should the clinical trials reveal these compounds are safe and effective, then they would apply to all patients.
Unfortunately there is currently no cure for DMD. There are treatments that can slow down progression, such as corticosteroids.
There are also mutation specific treatments in development for Duchenne that aim to restore dystrophin protein – however, for now these it is not yet fully clear whether they slow down disease progression.
With regards to the mutation:
I assume you mean a deletion of exon 53? Or does he have a mutation inside exon 53?
I am very sorry I cannot offer more to your brother.
Hello,
My son was diagnosed with DMD at the age 18 months and now he just turned 4 years. Exon deletion 45 46 47, is there any therapy for this deletion? Is this DMD or BMD
Thanks
Dear Arid,
I’m sorry to hear about your son. For a deletion of exon 45-46-47 the genetic code of the dystrophin gene is readable, so we would expect this to result in Becker. However, there are exceptions. What is leading in deciding whether someone has Duchenne or Becker is the clinical presentation. If a patient presents with symptoms at an early age (2-3 years), he has Duchenne, regardless of whether the code is readable or not. So the question is whether you son has symptoms or whether this was a chance finding?
Hello , my child has exons 44-45 deletion. We found it by genetically testing myself for something else and then also tested the child .Started walking at 10 months and now at 30 months old has no symptoms and the cpk levels are normal . Any predictions for the future ; I can not find others with this deletion .
Dear Maria,
First a disclaimer. I am not an MD, I am a researcher. I have a lot of experience with dystrophin and dystrophin mutations, but cannot give medical advice, only speculate based on what I know.
Is the child a boy or a girl? If it is a girl, I would not expect problems, since the dystrophin gene is located on the X-chromosome. That means she would have a backup copy (like you have). If it is a boy, this is the only copy he has, and there is a deletion in his only dystrophin gene. However, this deletion is expected to maintain the genetic code of the dystrophin gene. This means he would be able to produce a dystrophin protein that is partially functional. As such, one would expect Becker muscular dystrophy. This is a disease of varying severity, with some individuals having symptoms in childhood and others in midlife or even later. It is difficult to predict which type of Becker he would have, as sometimes there is variation even within a family.
In theory it is still possible to have Duchenne with a mutation that maintains the code – there are exceptions. However, if the CK is normal at 30 months, I think that can be ruled out.
I am sorry I cannot give more clear answers – hope you and your child stay well.
Annemieke
Hallo noch mal , bei letzte Email habe ich Medikamente geschrieben und bei schicken das Wörter hat sich selba gewechselt auf Folgen 🙂.
Ich habe noch Fragen, welche Vitamine kann man einnehmen für Unterstützung:
-BISPHOSPHONATE, CARNITIN, ARGININ, CALCIUM, CITRULLIN oder was anderes ? Was meinen Sie ?
-VITAMIN-COCTAIL für Mitochondrien:
aus Q10, Thiamin, Riboflavin, Biotin ? Was meinen Sie ?
Please note that I am not a medical doctor but a researcher. This means I cannot give medical advise.
What I know from presentations on clinical care:
Bisphosphonate is used in patients who show osteoporosis or problems with bones.
Carnitin, arginin, calcium, citrullin: this has been evaluated in animal models and some also in patients but this has not shown large effects as yet
Vitamin cocktails and supplements etc: note that supplements seem harmless. However, because they have to fullfil less strict criteria than medicines, the concentrations of the vitamins etc can very. Also overdosing of these compounds can result in health problems and sometimes there are also toxic impurities inside. So be careful with these.
Hallo noch mal Pr. Dr. Aartsma- Rus,
ich wollte noch was Fragen , welche Medikamenten passt für Unterstützung unsere Krankheit:
-METFORMIN und L- ARGININ- verbessert Muskelkraft, EnergieStoffwechsel ?
-METFORMIN und L-CITRULLIN- Baustein von Eiweiß ?
-UTROPHIN- kompensiert Dystrophin und unterdrückt Myostatin ?
-ELAMIPRETID-schütz die Membran der Mitochondrien ?
-TAMOXIFEN-verbessert Muskelkraft und erhöht MembranStabilität der Muskelfibrille ?
-GIVINOSTAT- reduziert Fibrose ?
-TADALAFIL ?
-ETEPLIRSEN oder GOLODIRSEN ?
-CASIMERSEN – Sie haben geschrieben , das passt für uns , aber wo kann man das kaufen ,wenn in Europa noch nicht zugelassen ? Und das ist Medikament oder Spritze ?
-Micro-dystrophin Therapie ?
Metmorfin and combinations are evaluated in clinical trials at the moment – we do not know whether they will have a therapeutic effect
Utrophin upregulation was tested in clinical trials but these were stopped because no therapeutic effects were found.
Elamipretid: I do not know but things that improve mitochondria for Duchenne have therapeutic potential. Other compounds that do this are in clinical trials so we do not know yet if they are safe and effective.
Tamoxifen: tested in clinical trials – we do not yet know if it is safe or effective
Givinotat: currently tested in clinical trials – hopefully later this year we will learn whether this was safe and effective.
Tadalafil: was tested and did not show therapeutic effects.
Eteplirsen and golodirsen: approved in the USA by the FDA – however these skip exon 51 and exon 53 – your son needs exon 45 skipping
Casimersen: skips exon 45 and is approved in the USA but not yet in Europe. This means you cannot buy it – it is not marketed in Europe. This is because it is not yet known whether the treatment will slow down disease progression – it is only known that treatment increases dystrophin levels in tiny amounts. It is tested in clinical trials that are ongoing in Europe to hopefully show functional effects – however it is possible that the tiny amounts produced do not result in functional effects.
Microdystrophin therapy: this is not a therapy yet – it is tetsed in clinical trials. Sarepta and Solid have trials only in the USA, however, Pfizer is also doing trials in Europe and Roche will also initiate this in Europe (with the Sarepta gene therapy product).
Hallo Liebe Dr. Pr. Aarstma- Rus,
vielen Dank für die Antwort, aber ich noch Frage . Welche Therapie passt für uns:
-PTC ?
-AONS ?
-AAV- Genabgabe von U7-Ribonukleoprotein(snRNPs) ?
-GEN- Therapie ?
-ASO- Leserahmewiederhergestellt ?
– READ-THROUGH-Therapie ?
-CRISPR-CAS9 – (Base-Editing oder Meilenstein) ?
-mRNA- molekulare Therapie ?
-Micro- Dystrophin ?
PTC/Ataluren does NOT work
AONs: exon 45 skipping would restore the genetic code and protein production (so this would apply)
AAV U7 would in theory work, but you would need AAV U7 genes that target exon 45 (these are currently not in clinical development)
Gene therapy (microdystrophin) applies to all patients independent of mutations, so that would also work
Readh-through is the same as PTC ataluren: would not work
CRISPR/Cas9: base editing would work in theory. One would have to edit the splice site of exon 45. However I do not know if this is possible (depends on genetic context).
mRNA: in theory would work – however producing dystrophin mRNA is very challenging because it is so long and delivering it to all muscles is also difficult
micro-dystrophin is the same as gene-therapy: would work.
NOTE that of the options you mention only ataluren and exon 45 skipping with AONs has received regulatory approval.
Gene therapy is tested in clinical trials so it is not yet know if it is safe and effective.
Crisper and mRNA are in the preclinical phase. So here it is not know if it will ever make the clinical stage.
While going through some readings found that their is something known as Gene therapy which is one time solution for DMD, how do we get to know more about it & how soon this would be available for patients.
Unfortunately gene therapy for Duchenne will not be a one time solution.
First gene therapy for Duchenne delivers a microdystrophin – this is a partially functional version of normal dystrophin. The gene is delivered to muscle fibers – it does not integrate into the DNA but floats around in the fibers and allows production of microdystrophin. What we do not know yet is how functional this will be in humans. We do know however that it is not fully functional. At best it will slow down disease progression.
Secondly, because the microdystrophin is not fully functional, with time muscle fibers will be lost and replaced by muscle stem cells. The viral vector used to deliver microdystrophin does not target the muscle stem cells. This means that with muscle turnover you will get less and less microdystrophin genes and less and less microdystrophin protein. What we do not know is how long this process will take.
Sorry to have to tell you this negative news.
Microdystrophin is currently tested in clinical trials for Duchenne by several companies (Pfizer, Sarepta and Solid). It is not known if and when it will be available. This depends on the results of the clinical trials.
What can you say about the positive results of the srp 9001 study announced by Sarepta in May? Also, I learned that there is a study in Japan for exon 44 skipping?
There is a clinical trial for exon 45 skipping ongoing in Japan. This is coordinated by Daiichi Sankyo. The early results showed exon skipping but no dystrophin restoration yet. However, these were obtained in biopsies after 12 weeks of treatment. Results after longer term treatments are not yet in.
The Gene Therapy studies from Sarepta in May show that with their viral vector it is possible to safely and effectively deliver a microdystrophin in young Duchenne patients (4-7 years old). The levels of microdystrophin are very good (both total levels and percent of positive fibers). However, what we do not know yet is how functional microdystrophin will be in humans – we are waiting to see if the expression of microdystrophin slows down disease progression (hopefully it does). Furthermore, we know that the microdystrophin will disappear with time due to muscle fiber turnover (it is a partially functional protein after all – cannot fully protect fibers against damage). What we do not know is how long this will take. Hopefully decades but we just do not know yet.
Hallo Dr. Annemieke
Frage : es gibt schon eine Therapie für Muskeldystrophie (Exon 46-47 out of frame deletation) neu Mutation ?
Und noch Frage : Medikament Idebenone hilft bei Muskeldystrophie oder ? kann man das einnehmen ? oder es gibt was anderes ?
Danke voraus.
Beste Grüsse .
Good morning,
I hope you do not mind me replying in English – I understand German but do not speak/write it well. For a deletion of exon 46-47 in theory the skipping of exon 45 would restore the genetic code and allow production of Becker-type dystrophin. Exon 45 skipping is approved in the USA (casimersen developed by Sarepta). This is based on very minor increases in dystrophin levels in treated patients – it is not yet known whether this will slow down disease progression. Casimersen is not approved in Europe.
Idebenone has been tested in placebo controlled clinical trial. Although early phase results seemed promising, larger clinical trials showed no therapeutic effect of idebenone treatment in Duchenne patients. This development has therefore been stopped by the company developing idebenone for Duchenne (Santhera).
My Son is 5 years old & is detected with Hemizygous deletion of exons 45 – 50 & is mentioned as Out-Of-Frame deletion in the report.
1)How severe it is.
2) Do we have any treatment for it, Does Exon skipping can reduce the issue or do we have any medication for this.
3) How can the progress of this be reduced.
We are very anxious & worries as a parents, looking for your response.
I am very sorry to hear about your son having a deletion. This deletion disrupts the genetic code, so it would be expected to lead to Duchenne (the severe form of the disease).
Exon 51 skipping would restore the genetic code and allow production of a partially functional protein, like those found in Becker patients. An exon 51 skipping drug has been approved in the USA (eteplirsen developed by Sarepta). Note that this drug has been approved based only on restoring dystrophin in patients and that it restored very low levels of dystrophin (<1%). Whether this is sufficient to slow down the disease progression is something that is currently being evaluated in additional clinical trials.
Thanks very much fir helping me
But i just have one other question
Can i use (Deflazacort) and (Prednisone) is that do any improvements to my muscles strength ?
Helloj,
A deletion of exon 3-4 is in-frame and therefore one would expect this to result in Becker muscular dystrophy. There is currently no cure for Becker. Recently treatment guidelines were developed in Italy and these are currently being translated. You would have to inquire with the Italian Parent Project about these (http://parentproject.it/). There are also several clinical trials ongoing in Becker patients, e.g. givinostat (Italfarmaco) and a compound to improve mitochondria (the energy producers of the cells) by Empirio. There were presentations about these trials at the Italian Parent Project meeting in February – the meeting was virtual and the presentations should still be viewable ( http://conferenza.parentproject.it/).
My Son, 4 year old has been diagnosed with Hemizygous deletion of Exon 45 Out of frame, How severe is that, what should I do right now ? Will Amondys 45 (casirmersen) be an option?
I am sorry about your son having a deletion in the dystrophn gene. A deletion of exon 45 will disrupt the genetic code of the dystrophin gene. Therefore this is expected to lead to Duchenne. Amondys45 will not be therapeutic – this is a drug that induces exon 45 skipping to restore the genetic code. In your son’s case, this exon is not present (deleted), so it cannot be skipped. Restoring the genetic code would require exon 44 skipping. Compounds for exon 44 skipping are in preclinical development but not yet tested in clinical trials.
Amongst all this bad news, also some good news: patients who need exon 44 skipping on average has a slower disease progression than ‘other Duchenne patients’, because of spontaneous exon 44 skipping at very low levels.
What you should do right now is make sure your son receives good care at an expert Duchenne center. You can find more information on care here: http://www.dmd-guide.org/
Please do not hesitate to ask if you have more questions.
My son, 10 years old, has been diagnosed with exon 2 duplication. How severe is that? What are the possible prognosis for his disease? What can be done to slow down the illnes? Any chances of an effective treatment? He is an active boy but signs of the illness are already starting to appear. He’s able to walk for a long time. He’s playful but has studying problems. He’s not able to concentrate for long periods and he’s been having problems such as not being able to memorize the multiplication table or learning his lessons. He has occasional anger issues for no apparent reasons. Besides that he’s bright minded and has lots of other interests where he’s learning quite well. I’ve been searching the internet for all possible information but would like to hear your opinion and advice. We live in Bulgaria and healthcare is not the best but we’re willing to do whatever it takes so that our boy has a normal life. Thank you in advance!
Regards, Peter
Dear Peter,
I am sorry to hear your son has a duplication of exon 2. Every patient with mutations in the dystrophin gene is unique and there is variation even between patients with the same mutations so it is difficult to give predictions or prognosis.
What you can do is make sure your son receives optimal care. There are care guidelines for Duchenne muscular dystrophy – you can find them here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/guide-for-families-in-different-languages/ This is a version that is accessible also to lay people and translations in many languages are available now.
There are currently a few treatments approved for DMD in Europe and the USA and Japan. However, they are all mutation specific and would not apply to an exon 2 duplication unfortunately. In the USA a clinical trial is ongoing specifically for exon 2 duplications – this one uses gene therapy to try and restore the readability of the dystrophin gene. I do not know whether this is open only for patients in the USA and what the inclusion criteria are. You can find more information about this here: https://clinicaltrials.gov/ct2/show/NCT04240314?term=exon+2&cond=Duchenne+Muscular+Dystrophy&draw=2&rank=1
Learning difficulties are common in Duchenne patients. Dystrophin is also present in the brain and lack of this causes amongst others the problems you describe (automization and focusing). So this is part of the disease. There are studies done into how to best deal with these learning difficulties. Jos Hendriksen is a Dutch neuropsychiatrist who has done work on this.
I am not a clinician so I cannot advise on medical treatments. However, what I’ve learned from Duchenne patients is that they appreciate it if their parents treat them like normal boys/men even if there may be impediments (e.g. also helping with chores, but then those that they could do).
If you look for inforation, I suggest also starting with the World Duchenne Organization. This is a collaborative effort of the Duchenne Parent orginisations around the world https://www.worldduchenne.org/. You will be able to find a lot of information there.
Take care and do not hesitate to ask other questions either here or via email (a dot m dot rus at lumc dot nl).
Hello Maam ,
I’ve heard of Gene therapy treatment for DMD. Which will be coming soon . I just want to know the status of it ? How long will it take for a common man to access it ? Is it a one time treatment ? My son is 4 yrs old . What should i do right now , go for a steroid as of now ? Go for exon skipping as well ?? Or wait till he gene therapy is been approved? Thank you Maam
Hello Madam ,
My son is 4 yrs old . He has been diagnosed with DMD. We have visit few doctors and they have suggested for the exodys 51 therapy as his deletion is 45-50. I just want to know how effective is this ? Are there many side effects ? When can i start my sons therapy as in, right now or when we see some symptoms in future ? How successful is this treatment in the world? Pls give me your opinions Doctor. Thank you
Dear Agnetta,
I am sorry to hear about your son being diagnosed with DMD.
Indeed for a deletion of exon 45-50, exon 51 skipping can restore the genetic code and dystrophin production. Exondys51 is a drug that induces exon 51 skipping. It is approved in the USA for all patients with eligible mutations (so no age specified), but not yet anywhere else. For now it is approved based only on the fact that the protein that is missing in Duchenne (dystrophin) is restored at very low levels. What is not yet known is whether these low levels are sufficient to slow down the disease progression. This is something that is still being evaluated in clinical trials around the world. As far as I am aware, exondys51 does not induce a lot of side effects. It needs to be delivered via intravenous infusion once weekly.
I am sorry I cannot give you more information than this. In summary: exondys51 is only approved in the USA, we know it restores dystrophin a minute amounts but we do not yet know whether this will have an effect on disease progression.
My son has exon 44 deletion out of frame, what is the treatment for him, though he is having defcort at present and he is 8 years old now, will exon 45 skipping be an option? if so how it will work? please give your valuable reply
First of all it is important to give your son optimal care – like you are doing, with corticosteroid treatment.
Duchenne is caused by the dystrophin gene being unreadable for the protein translation machinery. The exon skipping approach aims to make the code readable so a partially functional dystrophin can be produced rather than no dystrophin at all. For a deletion of exon 44, exon 45 skipping would restore the genetic code. Exon 45 skipping can be achieved by casimersen. This compound is approved by the FDA since last month. However, the approval was based only on dystrophin restoration. What is not yet clear is whether the low amounts of dystrophin restored by casimersen will slow down disease progression. Clinical trials are ongoing to evaluate this at the moment. If you live in the USA you could request casimersen treatment (with the caveat that it may not slow down disesae progression while it is a weekly intravenous infusion). Outside of the USA you could consider taking part in a clinical trial with the caveats that 1) it may not slow down disease progression 2) there are additional burdensome evaluations involved in clinical trial participation.
Hello.
My son has DMD gene duplication 18-44. He is 7 yrs now. We are still not taking steroide because of possible side effects, but we decided to start with DEFLAZACORT. Once Vomorolone is available in Slovenia, we could continue with that.
What is the prognosis for my son’s mutation I would like to ask You about gene therapies currently in clinical trials and whether any of this would be an option for him. Would CRISPR Cas9 be the option for him? Or exon skipping 45 Casimersen? I would also like to ask about dosing steroide, do you recommend more daily or weekend dose.
Thank You very much for your answers.
I am sorry to hear about your son having DMD. Hopefully vamorolone will turn out to be a safe and effective alternative to corticosteroids (it is currently tested in clinical trials).
It is difficult to say anything about the prognosis. Especially large duplications, such as the one your son has, are known to not follow the rules, meaning that it is possible he will have a slower progression but also that he will have typical DMD progression. The only way to find out is to see what happens when he grows older. I’m sorry I cannot say more about this.
For your questions:
I am not an MD so cannot give you a recommendation about the dosis regimen of corticosteroids. You have to discuss the pros and cons with your treating physician and then make your own decision I’m afraid.
Micro-dystrophin gene therapy would in principle apply to your son (it is not mutation specficic). Currently this is only tested in clinical trials.
Casimersen would in theory also work – however, because large duplications often do the unexpected in the process from gene to transcript to protein, and the exon skipping approach (casimersen) influences the process of transcript formation, it is not a guarantee that after exon skipping, your son would make dystrophin. Likely this is something that first would have to be tested. Note that casimersen is only approved in the USA and not in Europe. Clinical trials are ongoing worldwide though.
Finally the CRISPR Cas9 option: first note that CRISPR Cas9 is currently in preclinical studies as a whole. So there is no disease for which this technique has been approved. There are many unknowns for now about safety (because it causes irreversible changes in the DNA). In theory editing out the duplication would restore the normal dystrophin transcript and protein. However, because the duplication is so large, this would likely not be very efficient. Much more preclinical research is required for this.
I am sorry I cannot give you more positive answers.
Dear Annemieke ,my son is 6.5y old. He is in Vamorolone study and he is doing great. We have not seen any side effect so far. He has a frequently mutation, DELETION OF EXON 44.
I am wondering if you know what is prognosis of this mutation (deletion of exon 44) in Dystrophin gene? I am also interesting on Casimersen for my son, what is your opinion on this treatment?
Thank you very much for your ansvers.
Kind regards, Sanja
Happy to hear your son is doing so well! For a deletion of exon 44 I would expect typical DMD. However, you are probably aware that there is no such thing as typical DMD, but that there are patients who progress faster than others. Likely this is due to a combination of genetic factors – the majority of which we have no idea about. Sorry I am so vague, but this is the best answer I can give you.
Casimersen has been approved by the FDA for use in DMD patients with eligible mutations (such as indeed a deletion of exon 44). The approval is based only on dystrophin restoration (of ~1% after a year of treatment). What is not yet know is whether this low amount of dystrophin restoration is enough to slow down the progression of the disease. Currently ongoing clinical trials are done to test this. So we know the therapy works in that it restores dystrophin, but we do not know yet whether this will have a therapeutic effect (slower disease progression). Note that the treatment involves weekly intravenous infusions so this is more burdensome than vamorolone (tablet).
A deletion of exon 45-51 does not disrupt the genetic code. So this deletion is expected to result in Becker muscular dystropy. There are currently no approved drugs for Becker but several are in development. The Duchenne Parent Project Onlus from Italy recently had a session on Becker therapy development during their virtual meeting (see http://conferenza.parentproject.it/).
If the mutation is found in a patient with Duchenne (so severe symptoms already at 3-4 years old), something strange is happening to prevent this individual from making dystrophin. For mutation specific approaches, this first has to be elucidated. However, there are also approaches in clinical trials that are not mutation specific (e.g. AAV micro-dystrophin gene therapy, givinostat, vamorolone etc). You can find an overview of these approaches here: https://treat-nmd.org/research-overview/dmd-research-overview/ (I hope to soon be able to update this). Updates can also be seen using the link to the Italian parent project conference.
Dear Sheila,
A deletion of exon 46-47 disrupts the genetic code. The code can be made readable by exon 45 skipping. In the USA a drug for exon 45 skipping was approved on Feb 25 2021 (casimersen). Outside of the USA, Sarepta (the company developing casimersen) is conducting clinical trials with casimersen.
Note that the approval was only based on the ability of casimersen to restore very low amounts of dystrophin (1%). Currently ongoing trials are needed to see if this also results in a slower disease progression.
Please do not hesitate to ask me additional questions should you have them
Dear Sara,
Exon 44 skipping would restore the genetic code for an exon 43 deletion. Please note however that exon 44 skipping is currently in a preclinical development stage.
Dear Dr. Aartsma-Rus,
My son 15 year old is DMD. His exon 45 is deleted. I came to know that he is amenable to exon 44 skipping. I need to know about the progress of any research going on for 44 exon skipping
Regards Shilpa
Indeed exon 44 skipping would restore the genetic code for an exon 45 deletion. However, exon 44 skipping is currently not evaluated in clinical trials. During the most recent presentation by Sarepta at the Italian Duchenne Parent Project however, they mentioned that exon 44 skipping is in preclinical development: http://conferenza.parentproject.it/schedule/ The video should be available on youtube.
If and when exon 44 skipping compounds will be tested in clinical trials is not known yet.
No exon skipping is not an option. If we skip the exon with the nonsense mutation (exon 44), this will cause a frame-shift. In other words, skipping this exon will make the code unreadable. So that will not improve matters, because still no dystrophin can be produced.
However, ataluren/translarna is a drug that is approved to treat ambulant Duchenne patients with nonsense mutations in Europe and several other countries as well. Depending on where you live, this may be an option.
My son has a point deletion on exon 45 out of frame.
I would like to know if at the moment are any ongoing trials for his mutation and if there is any chance for him to be accepted, considering that he is not walking anymore and his arms become weaker every day.
Thank you!
Kind Regards
Camelia Marian, Ianis’s mum
Dear Camelia,
I am sorry to hear about your son having Duchenne. If he has a small mutation within exon 45 that disrupt the reading frame, he is unfortunately not eligible for mutation specific therapies that are currently in development. Translarna/ataluren only works for nonsense mutations (small mutations that maintain the reading frame). Exon skipping will not work either because if we skip the exon with the mutation (exon 45) that will not help, as skipping this exon will also be out of frame.
There are also approaches in development that are not mutation specific however. For some of them companies are planning trials also in non-ambulant patients. The most recent update on this was presented at the meeting of the Italian Parent Project. You can watch the presentations on youtube: http://conferenza.parentproject.it/schedule/
I am sorry I do not have a better answer for you
Annemieke
Dear Mr Singh,
I am sorry to hear your son has a mutation in his DMD gene. A duplication of exon 3-4 means these exons are present twice. The question is whether this mutation was found because your son has symptoms of Duchenne, or whether it was found by chance. The reason I ask is that duplications can cause Duchenne, but also Becker or no disease at all. If you want to provide me more information, you can also email me direction at a dot m dot rus at lumc dot nl.
Finally, I’ll explain what hemizygous means. Our genes are located on chromosomes. We have two copies of each chromosomes – one from our father and one from our mother. This means that we have two copies of each genes as well. When both genes are the same, we say this is ‘homozygous’, when they are different we say ‘heterozygous’. There is one exception: the sex chromosomes. Females have two X-chromosomes, while men have an X and a Y chromosome. This means that men have only one copy of each gene on the X-chromosome. The dystrophin gene is located on the X-chromosome. When there is a mutation or variation in the X-chromosome in a man, this is called hemizygous.
My family member (male, 9.5 years) has been diagnosed with DMD very recently. His deletions are exons 10-43.
1) Do these deletions mean that he is amenable to exon 44 skipping only?
2) Are there any current treatment options (besides steroids) or trials in the foreseeable future that he may qualify for?
3) We have come across some research that indicates that patients that are amenable to exon 44 skipping may have delayed loss of ambulation as compared to patients that are amenable to certain other types of exon skipping. What are your thoughts on that?
As you can imagine, we are very eager to better understand this disease and explore all treatment options.
1. When considering exon skipping, indeed only exon 44 skipping would restore the genetic code.
2. There are many different therapeutic approaches in clinical development that do not depend on the mutation. e.g. AAV-microdystrophin gene therapy and compounds to improve muscle quality. See this overview that I hope to update soon – still it will give you an idea of the different approaches currently in clinical trials. https://treat-nmd.org/treat-nmd-diseases/duchenne-muscular-dystrophy/#research-overview-link
3. The finding that exon 44 skippable patients have on average a slower disease progression has been found in different independent cohorts in different countries. So I am convinced this is a true thing. However, these analyses look at averages. On average exon 44 skippable patients have a slower disease progression than those that have other mutations. That means it is still possible that a poor performing exon 44 skippable patient does worse than a good performing ‘other’ patient. Hopefully your family member is a good performing exon 44 skippable patient though.
Apologies for not updating the DMD research page. It is on the to do list. What has been presented at meetings is that 2 DMD patients have been treated with the AAV U7snRNP (the exon 2 skipping antisense ‘gene’). Biopsies were taken and dystrophin was seen at low levels (~2% in one and ~8% in the other patient). This was presented last October at the WMS meeting and I have not heard of an update since.
This is an in-frame deletion, meaning that it does not disrupt the code. As such, Becker muscular dystrophy would be the expected disease. However, exceptions do occur, so if the disease looks like Duchenne (difficulty with walking and stair climbing from 2-3 years of age), he would have Duchenne. Depending on the disease, care would very. For Duchenne guidelines for care are in place. For Becker this is not the case to my knowledge. In either case, he should be seen by a neuromuscular specialist.
Therapies for Duchenne that are approved are all mutation specific. Unfortunately, there is no specific treatment for this mutation.
Dear Professor!
My 7 month old grandchild was diagnosed with DMD( 45 exon deletio).
I know we have a few good years, but we need a safty trial for a future.
I heard about Viltolarsen to exon 53 skipping.
Wich exon skipping is working for 45 exon deletio?
Thank you for your answer
Best regards
Susanna
Dear Susanna,
I am sorry to hear your grandchild was diagnosed with DMD. With optimal care, there will be many good years. However, I understand you are also looking into treatment options.
The exon skipping approach aims to make the genetic code for the dystrophin protein readable. In DMD, this code is mutated making it unreadable. By making it readable the muscle can produce a shorter but partially functional dystrophin protein, which is better than no dystrophin protein at all.
This approach is however mutation specific. So depending on where the code is mutated, different exons have to be skipped to make the code readable.
Viltolarsen (exon 53 skipping) will not work for an exon 45 deletion. Rather, exon 53 skipping for a patient with an exon 45 deletion, will make the code even more unreadable.
There are two other exon skipping drugs approved in the US: golodirsen (also exon 53 skipping so same story) and eteplirsen (exon 51 skipping, which unfortunately also does not work for an exon 45 deletion).
Casimersen is in development for exon 45 skipping. FDA will discuss the approval (or not) of this compound in February this year. Exon 45 skipping will unfortunately also not help for your grandchild’s mutation. He does not have exon 45, so it is not possible to skip it.
To make the code readable for an exon 45 deletion, exon 44 OR exon 46 should be skipped. I know Sarepta is working on preclinical studies for exon 44 skipping but I have not heard them present plans to move this into clinical trials. Other exon skipping companies may also work on exon 44 skipping.
I am sorry I cannot give you more positive news. Please note that there are also many therapeutic approaches evaluated in trials that do are not mutation specific. These target all Duchenne patients.
Warm regards and do not hesitate to contact me if you have any further questions
I’m from Tunisia, I was diagnosed when I was 10 years old as having DMD (and now I’m 21) , and they said that I don’t have any deleted or duplicated exons, I just have a mutation in some of them (one or more)
but they don’t know exactly which one, because they couldn’t continue their analysis back then.
So, now after I heard about the recently approved method (which is “exon skipping”) I wanted to ask you if you can guide me so I can reach an hospital in any country to take this method (the government of my country will take care of the price if it very high, so you just have to guide me, if you want)
Exon skipping is a mutation specific approach. Duchenne is caused by mutations that make the genetic code of dystrophin unreadable. Exon skipping aims to make the code readable again. Which exon needs to be skippend and whether exon skipping will work at all depends on where the mutation is. For now exon skipping is used only for patients with deletions and duplications. So for your mutation this will unfortonately not work.
There is another approach, nonsense codon read through, that works for a subset of small mutations (i.e. those that are nonsense mutations). However, to know whether you would be eligible it is crucial that you know your excact mutation is. So my first advise would be to have them identify this. Note that 10 years ago finding small mutations was challenging, while now it is easier. Also for laboratories that cannot do this analyisis themselves, there are opportunities to send the DNA to other labs that can do this type of analysis.
Dear Suniel,
I am sorry to hear about your son’s friend being diagnosed with Duchenne. This disesae is caused by mutations in the dystrophin gene that make the code unreadable. Therefore no dystrophin protein can be produced. Since dystrophin has a stabilizing function in muscle during contraction, muscle lacking dystrophin are very sensitive to damage and this results in Duchenne patients gradually losing their muscle tissue and function.
In addition, therapies are in development for Duchenne and some are already approved. You can find an overview here: https://treat-nmd.org/research-overview/dmd-research-overview/(I hope te be able to update this soon). The currently approved therapies are all mutation specific. This means they only work for some mutaitons. Unfortuantely, none of these approved therapies work for a deletion of exon 51.
Eteplirsen is a compound that induces exon 51 skipping and that way makes the dystrophin gene code readable again. However, because your friends’ son does not have exon 51, this exon cannot be skipped (it is already missing). Golodirsen and viltolarsen induce exon 53 skipping. However, exon 53 skipping does not make the code readable for a deletion of exon 51. Finally, ataluren makes the cell ignore premature stop signals. This works only for a specific type of mutation (premature nonsense mutations), and not for exon deletions.
Hi, my son has been diagnosed with DMD. He is 11 month old. He’s exon missing is exon 51. Is there any treatment for this ? On the letter is saying loss, encompassing 51. What dose this exactly means? Is an exon missing and is there anything I can do?
Please help
Dear Andreea,
I am sorry to hear about your son being diagnosed with Duchenne. This disesae is caused by mutations in the dystrophin gene that make the code unreadable. Therefore no dystrophin protein can be produced. In your son’s case, the code becomes unreadable because one of the coding pieces (exons) is missing. The exons fit together like puzzle pieces normally. Due to exon 51 missing, they do not ‘fit’ and the code becomes unreadable and the muscles cannot translate the code into dystrophin protein.
In addition, therapies are in development for Duchenne and some are already approved. You can find an overview here: https://treat-nmd.org/research-overview/dmd-research-overview/(I hope te be able to update this soon). The currently approved therapies are all mutation specific. This means they only work for some mutations. Unfortuantely, none of these approved therapies work for a deletion of exon 51.
Eteplirsen is a compound that induces exon 51 skipping and that way makes the dystrophin gene code readable again. However, because your son does not have exon 51, this exon cannot be skipped (it is already missing). Golodirsen and viltolarsen induce exon 53 skipping. However, exon 53 skipping does not make the code readable for a deletion of exon 51. Finally, ataluren makes the cell ignore premature stop signals. This works only for a specific type of mutation (premature nonsense mutations), and not for exon deletions.
I am sorry I cannot be of more help. If you have additional questions, please do not hesitate to ask.
sorry, my question last December 22 was if anybody knows something a results of a two child’s already inoculate with the solution of an exon 2 duplication.
In October 2020, Megan Waldrop said the encourage results but since them, nothing else was said by the nationwide children´s.
I have only heard the results that were presented at the World Muscle Society meeting, where they found dystrophin restoration in two patients treated with the ‘exon 2 skip antisense gene therapy’. Low dystrophin levels were found in both patients (1-2% in one and 6% in the other patient).
My 3 year old son was diagnosed with DMD we were advised he has a hemicigote genotype for a pathogenic variant of point-transition type and that eliminates to the Intron 5 splicing accepting canon site of the DMD gene. Do you have any info on this particular deletion?
I am sorry to hear about your son being diagnosed with DMD.
DMD is caused by changes in the DNA that cause the dystrophin gene code to become unreadable. Therefore, the dystrophin protein cannot be translated from the DMD gene.
The pieces of the gene that contain the genetic information for the dystrophin protein are called exons. These exons are recognized by the cells via specific ‘signals’, which are called splice donor and splice acceptor site. In case of you son’s mutation, one of these signals is not functionig, i.e. the spilce acceptor site in intron 5. This intron is located between exon 5 and exon 6. The splice acceptor site of intron 5 in involved in the recognition of exon 6. When the acceptor site does not function properly, the exon involved is not recognized by the cell. Therefore, when the exons are joined together by the cell, in case of your son, exon 6 is not included. This causes the protein code to become unreadable and therefore no dystrophin is produced by your son’s muscle cells.
There are many therapies in development for DMD. Some are approved already – however, these are ‘mutation specific’ therapies, meaning they only work for specific variants. There is no specific therapy for your son’s particular variant. However, there are therapies in development that apply to all variants. You can find an overview here: https://treat-nmd.org/research-overview/dmd-research-overview/
por favor alguien puede decirme los resultados de la investigación que se está haciendo en dos niños en el nationwide children´s de ohio para la eliminación de la duplicación del exon 2 del gen de la distrofina
Our son was diagnosed with BMD last year at almost 9 years old. We were advised he has a deletion of exon 3-4 in the DMD gene.
I have read conflicting information on the progression of this deletion, and if there are any treatments on the horizon to ease symptoms. Do you have any info on this particular deletion?
I am sorry to hear about your son’s diagnosis. Based on the genetic properties of exon 3 and 4, indeed Becker would be expected. This deletion does not disrupt the genetic code, so the transcript remains readable for the protein translation system and this will produce a dystrophin that is slightly shorter than normal, but has its crucial domains.
I have looked in our online database (www.dmd.nl) and found only two reports of this deletion – and they were very old. No information on the disease progression was given unfortunately.
From a dystrophin protein perspective I would expect this mutation to be associated with a more severe type of Becker (i.e. milder than Duchenne, but more severe than ‘typical’ Becker). The dystrophin protein connects two proteins in the muscle fiber, actin and dystroglycan. In this way the ‘skeleton’ of the fiber is connected to the protective layer surrounding each muscle fiber. For dystrophin to be functional it needs to be able to bind to these two proteins. Dystroglycan binding happens at the end of the protein (encoded by exons 64-70). Actin binding happens via 3 parts, encoded by exon 2-8 (part 1 and 2) and exon 32-45 (part 3). As long as you have 1 actin binding part the dystrophin is functional. However, the first 2 actin binding parts are most important (they bind best so to say). Your son’s mutation disrupts at least one of these actin binding parts – and it is possible that due to this the second part will also not work optimally (part 1 and 2 work together). This is why patients who have mutations affecting the first 2 actin binding parts generally have a more severe Becker disease and this is why I would expect this for a deletion of exon 3-4.
Having said all this: every patient is unique and everything is relative. There are examples of patients with mutations in the first 2 actin binding parts who have very mild Becker and there are patients who have mutations that leave all three actin binding parts in tact who still have severe Becker. We know what happens ‘on average’, but as I said each patient is unique and not ‘an average patient’. So it is always difficult to predict what will happen.
I’m sorry I am unable to provide you with more clear information about the disease progression.
Dear Prof. Aartsma-Rus,
I am a mother of a 10-month-old boy, while I was still pregnant, it turned out that my son has duplications of exons 45-48. I am a carrier. I searched the databases and found nothing. My son had CK levels and liver parameters checked and everything was normal so far. Can I ask you for help in understanding a few things: what can we expect? How could the location and type of our mutation theoretically affect the production of dystrophin? Are there any attempts to treat such mutations? Thank you for your answer and best regards from Poland
Unfortunately I am unable to tell you what to expect. There are several possibilities.
1. The duplication is located within the dystrophin gene. In this case this will disrupt the production of dystrophin. There are two ways in which mutations (genetic mistakes) can do this. First they can make the code unreadable. Then no dystrophin can be formed and individuals will develop Duchenne. Secondly, the code can remain readable. Then individuals can still form a dystrophin, only it is altered from what is normal. These altered dystrophins are partially functional and found in individuals with Becker.
A duplication of exon 45-48 is expected to keep the code readable. So Becker would be expected. There are however, exceptions to the rule (patients where the code is unreadable who still develop Becker and vice versa). However, based on what you describe, Duchenne is not likely. Duchenne patients have elevated CK levels from birth onwards. Note that the liver parameters you mention are not actually liver parameters. Rather these enzymes exist in liver but also in muscle. Normally they are a sign of liver damage (which is more common than muscle damage). however, in case of muscle damage they are also leaking into the blood. So when they are elevated and CK is elevated in the blood this is a sign of muscle damage. Regardless, so far there seem to be no signs of muscle damage in your son – which is of course good.
Becker is a very variable disease. Some individuals develop the first symptoms in midlife, while other develop them in adolesence. Sometimes there is even variation within the same family with the same mutation.
2. For duplications only: it is possible that the duplicated region is not located in the dystrophin gene, but somewhere else in the genome. With generally used techniques (e.g. MLPA) this cannot be detected (whether it is in dystrophin or not). Most commonly the duplication will be within the dystrophin gene but there are examples where the duplicated part is somewhere else completely. In that case, dystrophin production is not affected at all.
I am sorry I cannot give a more definitive answer. I hope you and your son stay well
In addition, many therapies are in development and some are even approved in some countries. An overview can be found here: https://treat-nmd.org/research-overview/dmd-research-overview/
Shortly, the approved drugs are mutation specific and unfortunately do not apply to your son’s mutation.
Finally, it has been found that patients with a deletion of exon 45 on average have a slower disease progression than most other patients. They still have Duchenne but compared to other patients, major disease milestones like loss of ambulation occur later.
I am sorry I can not be more helpful than this.
Annemieke
Hello Prof.dr.Annemieke Aartsma-Rus,
I’ d like to request if an exon skipping therapy for Exon 18 and 19 in the Dystrophin gene is available, since our 6y and 8 months old son was diagnosed with DMD 5 months ago. We are originally from Bulgaria but we are considering participating in every treatment that will hopefully improve our son’s quality of life. We started Deflazacort therapy 2 ago months and we are observing improvement in his motor functions.
Do I understand correctly that your son has a deletion of exon 18 and 19? Unfortunately this is a deletion that is very difficult to restore the genetic code for. It would require skipping of at least 10 exons – this is not feasible with current techniques. I am sorry to be the bearer of bad news. Note that there are many therapies in development that do not rely on the mutation.
My son has deletion of exon 45. Are there any ongoing trials or medicine in progress for exon skipping 44? As i understood the group who are missing exon 45 are large. Why cant i find any ongoing projects skipping 44?
Dear Daniel,
Currently there are no exon 44 skipping trials ongoing. They have occurred in the past (Prosensa/BioMarin). This was with an exon skipping compound that had the same chemistry as drisapersen (exon 51 skipper). FDA did not approve drisapersen because they were unconvinced about the therapeutic effects and there were safety concerns. BioMarin then decided to stop the development of all exon skipping compounds with the same chemistry that were in clinical trials at that point (exon 44, exon 45 and exon 53) in addition to drisapersen (exon 51).
Exon 51, exon 45 and exon 53 are the three most applicable exons (respectively 14%, 8% and 8% of patients) – exon 44 is next in line (6% of patients). I know that companies that work on exon skipping are doing preclinical work for exon 44 skipping (e.g. Sarepta Therapeutics), but I do not know if and when this will move into clinical development.
I am writing you in the name of a family ( I am Godfather of the kid ) that has a young boy with duchenne Exon deletion 44. The boy´s name is Angel Mercado, whose mother name is Euridisis Jimenez. ( Copied on this email )
We are really interested to get him into this hopeful trial, thinking about his future.
Let us know if he has the chance, and if we could contact you to talk about it.
Thanks in advance for any information you could provide us.
There are currently many clinical trials ongoing for Duchenne patients. You can find an overview e.g. here: https://treat-nmd.org/research-overview/
Some of these approaches are mutation specific, stop codon readthrough (ataluren) and exon skipping. Ataluren would not be applicable for a deletion. Exon skipping would be an option – a deletion of exon 44 requires the skipping of exon 45 to make the code readable again. Exon 45 skipping is currently tested in clinical trials in the US, Europe and Japan. You can find more information about that also in the research overview.
I´m a father of a 7 years old boy, he have DMD because of exon2 duplication’, is any solution available today to solve this kind of mutation, in July 2018 I wrote you and the answer was very rapidly, I knew that Dr. Kevin Flanigan with Audentes Therapeutics is working in a AT’702 to skip the exon2 duplication, it is any update about the results of a two boys inoculated in January 2020?
Hallo.
Thank You very much for answer. I have one more question. What is currently available in the Netherlands for a 5-year-old boy? He has deletion 46,47. How we can help him now? What we can do that he will be longer efficient?
Greetings.
Hallo.
I have a questions about terapie exon skipping 45, because my son has deletion 46,47. We leave now in Nederland, will be this therapy also available in the Netherlands in the near future? Please Let me know.
Greetings
Dear Ewelina,
Exon 45 skipping is currently tested in clinical trials. These are done to assess whether the compound to induce exon 45 skipping (casimersen) is effective and safe. Whether this therapy will be available in the Netherlands depends first on the outcome of the clinical trial. If it is unsafe or not effective it will of course not be approved. If it is deemed sufficiently effective and safe by the regulators (European Medicines Agency for Europe), it will be approved. Then, the drug will have to be marketed in each European country individually. So even if it is approved, there is no guarantee that it will be available in the Netherlands, because this depends on whether the company wants to market it in the Netherlands and how the Dutch Zorg Instituut Nederlands evaluates the drug. Regardless, all these processes (clinical trial, analysis of trial data, regulatory application, marketing in different countries) take time. So unfortunately, it will not be available in the near future.
My son was recently diagnosed with mild form of Becker. He’s results show 48-49. He is 13 years old very active and no signs. This was accidental finding as he’s active playing competitive soccer and we noticed hamstring tightness no more than 3 times a year (plays about 125/games practice a year) after sports doctor recommended ck. Three ck tests highest one was over 2000. His heart test came perfect. Mother is the carrier, no noticeable signs. We do know which grandparents came from yet, but both are alive around 60s. Fully functional and no signs of muscle or health issues.
What is the function of 48-49. Can other Exons fill in to continue providing muscle support needed.
Is there a medicine/treatment?
What kind of activities make it worse?
What kind of activities make it better?
We just found out about this before corona virus, which has stopped us from continuing doctors visits for additional info until further notice.
Thank you!
I am sorry to hear your son was diagnoses with Becker but of course I’m happy that the signs are very minimal.
I am not a medical doctor or a rehabilitation specialist. As such I cannot recommend treatments or activities for your son. Is it possible to have a digital meeting with the specialists who diagnosed your son? They are probably better qualified to address your questions.
Dear Parimita,
There is currently no therapy and there are currently no specific trials for an exon 2 duplication.
However, Audentes and Prof Kevin Flanigan/Dr Nicolas Wein are preparing for a therapy for exon 2 duplications.
Dear Annemieke,
My son is 7 years old, a genetic test confirmed the diagnosis of Duchenne myodystrophy – a deletion of 45 exon. At the moment, from the symptoms of the disease: it is difficult to climb the stairs, but he copes with it on his own, he runs in a peculiar, slow, jumping way, but also with difficulty. In general, a very active child, goes to school. Could there be a milder form of Duchenne or Becker with our deletion, despite the rule of violating the reading frame? I read some sources that spoke about exceptions to the reading frame rule, which included patients with a deletion of one45 exon in particular. It was an endogenous exon skipping, and this is somehow related to 44.
And what do you think about the fate of research related to microdystrophin – will we live to see the medicine? We are from Russia, and, unfortunately, we do not have knowledgeable doctors, rehabilitation centers, or financial support for families. We are ready to go for treatment, or participation in trials to any part of the world.
I’m sorry to hear about your son. Indeed, a deletion of exon 45 can be milder than ‘typical’ Duchenne. This is because exon 44 is spontaneously skipped in all of us at a very low level. For healthy individuals this means that they make slightly less dystrophin. However, for a deletion of exon 45, skipping exon 44 makes the genetic code readable again, so this would mean your son can make a little bit of dystrophin. Not enough to prevent the disease and generally also not enough to have Becker, but slightly more than other Duchenne patients – and enough to have a slightly slower disease progression.
For therapeutic approaches, I refer you to an overview available on the TREAT-NMD website: https://treat-nmd.org/research-overview/dmd-research-overview/
For microdystrophin specifically: this is still tested in clinical trials. We do not know if it works and whether it is safe. What we know is that some patients develop a severe immune response after treatment with the virusses that carry microdystrophin. We also know that treated patients will produce the microdystrophin. What we do not know is whether the microdystrophin is functional – it is very small – much smaller than the dystrophin Becker patients produce. We know it is functional in mice – but unfortunately that is no guarantee it will be functional in humans. We do know it is not a cure – it is a very small dystrophin – it will be less functional than the ‘regular’ dystrophin.
We do not know whether exon skipping will help. For now we know that exon 51 skipping and exon 53 skipping can restore minute amounts of dystrophin. Whether this has functional effects we do not know yet – this is something Sarepta Therapeutics is currently establishing in phase 3 clinical trials. For exon 48 skipping we have no clinical evidence yet that it will restore dystrophin (or slow down disease progression).
For translarna we know that it slows down disease progression in ambulant DMD patients – however, here the functional data was not yet sufficient for full approval. So in Europe translarna is conditionally approved and PTC Therapeutics is currently conducting a confirmatory phase 3 clinial trial.
In summary, there is unfortunately no certainty yet.
My sons is tested positive for DMD, and his report results are mentioned below, can you kindly help me understand whether this is a non-sense mutation,
What could be the possible treatment ahead?
“A hemizygous nonsense variation in exon 48 of the DMD gene (chrX:g.31893448G>A; Depth: 218x)
that results in a stop codon and premature truncation of the protein at codon 2319 (p.Gln2319Ter; ENST00000357033.4) was detected (Table). The observed variation has reported as pathogenic in the ClinVar database [18]. The p.Gln2319Ter variant has not been reported in the 1000 genomes, ExAC and our internal databases. ”
Dear Sebastian,
This is indeed a nonsense mutation. A nonsense mutation changes the code for an animo acit into a stop code (this is what the p.Gln2319Ter means – on position 2319 of the protein there is normally a glutamine, but due to the mutation there is a stop – Ter(mination).
In Europe there is an approved treatment for ambulant patients aged 2 and up with nonsense mutations. It is called Translarna (or ataluren – same thing). Translarna is available in several European countries, as well as some other countries. It is conditionally approved based on trials that suggest it slows down disease progression in Duchenne patients to some extent.
Dear Navin,
There is currently no mutation specific therapy approved for this mutation. Exon 45 skipping would restore the genetic code. This is currently tested in clinical trials.
Note that multiple additional therapies are in clinical development (not mutation specific) and also that good care is important to keep patients is as optimal a condition as possible.
Hello,
I have a 12 week old son who has deletions 51-52. I was found to be a carrier with the same deletions during the third month of my pregnancy. Our doctors have been unable to find record of deletions 51-52 in 2 US databases and 1 in France. There is no known family history. We do know it is an in frame deletion and they suspect it is Becker. We continue to research but have been unsuccessful in finding really anything.
If you have any information to share about deletions 51-52, please let me know. Thank you.
I am sorry to hear about this story – must be very stressful for you.
I have checked the DMD Leiden Open Variation Database and also there, there is no record of a deletion of exon 51-52. So based on humans we cannot make a comparison, only a prediction that likely this will be Becker.
What I do know is that in a mouse model with a deletion of exon 52, skipping exon 51 restores production of dystrophin. This dystrophin lacks the parts encoded by exon 51 and exon 52 – like your son. This treatment is beneficial for this mouse, suggesting that at least in mouse a dystrophin lacking the parts encoded by exon 51 and exon 52 is partially functional.
Humans and mice differ, so this is not a definitive answer. However, it makes it more likely that your son has of Becker muscular dystrophy.
I´m a father of a 7 years old boy, he have DMD because of exon2 duplication’, is any solution available today to solve this kind of mutation, in July 2018 I wrote you and the answer was very rapidly, I knew that Dr. Kevin Flanigan with Audentes Therapeutics is working in a AT’702 to skip the exon2 duplication, it is any update about the clinical trial beginning date?
Dear Julio,
Audentes and Kevin Flanigan are still working on exon 2 skipping for exon 2 duplications. To my knowledge no announcements have been made about when the clinical trials will start.
Im a 23 year old boy with DMD exon 45 deletion from Tirana,Albania
recently a group of scientists from Centogene took muscle samples from me and my parents.
The results of the samples advise me exon skipping therapy, is there any bio pharm company or hospital who does the skipping for my exon?
Every advise from you would be very helpful.
Keeping in mind my age , i think something must be done before its too late.
Best regards ,Xhorxho Vesha
The genetic code for your deletion can be restored by exon 44 skipping. However, currently, exon 44 skipping is not tested in clinical trials.
BioMarin/Prosensa did a test for exon 44 skipping a couple of years back, but that development stopped when they stopped with the drisapersen (exon 51 skipping) development, because the compounds used then were suboptimal (minor therapeutic effects in some patients and side effects in almost all patients).
My son has the dmd c.10567 g>c variant (p.Glu3523Gln)
He has been diagnosed with fatigue and pain in lower extremities. He has show on a muscle biopsy small type 2 muscle fibers, CK has been fine they haven’t checked in since 2017. They said since he was the only one back in 2017 with the variant there wasn’t enough info and it would never affect him. They believe his leg pain, fatigue, motor delays are from something else.
Anyways, I believe it is possibly the gene missense. But, since there is not enough information they say he’s fine go just keep doing occupational therapy and physical therapy. I’m not sure I’m at my wit ends.
It is possible that the fatigue and pain are not caused by this missense mutation but are due to a mutation elsewhere in another gene.
Another option is that the mutation leads to altered splicing and that he skips exon 75 (which contains the missense mutation). If that would happen, this would abolish dystrophin production. However, since the mutation is almost at the end of the gene, it is possible that the resulting protein is partially functional.
If a muscle biopsy was obtained they should be able to analyze whether exon 75 is skipped due to the mutation on ‘RNA level’ and whether dystrophin protein is produced or not.
If there is dystrophin and if exon 75 is not skipped, the symptoms are due to another mutation in another gene.
If there is a skip and/or if the protein is smaller or present in reduced amounts, this missense mutation does cause the symptoms most likely
I am mother of 30 years old daughter, who has congenital muscular dystrophy. We have tested Whole Exome Sequencing and Mitochondrial Genome Sequencing in Centogene Ag Am Strande 7, Germany.
An the result is Lama2, Chr6(GRCH37):g. 129781432c>T, NM_000426. 3:c.6955c>T p.(Arg2319) Exon 49 HET and Lama2 Chr6(GRCh37):g.129475791G>A NM_000426.3:c.1169G>A p.(Cys390Tyr) Exon8 HET.
We search for possible treatment for this diagnosis and We need to find scientist or doctor who works and is interested on this variant of illness.
Please contact us.
Thank you in advance,
Best Regards
Maka Kobakhidze
Dear Maka,
I am sorry to hear about your daughter. I am not an expert on congenital muscular dystrophy so I am afraid I cannot help you with the diagnosis.
Hello doctor
My son has been diagnosed with DMD , he is missing exon 46 and 47 . We live in Dallas TX I was wondering if there is any trials we could put him in.
Thank you so much
The genetic code for your son would be restored by exon 45 skipping. There is a clinical trial ongoing for an exon 45 skipping compound (casimersen, developed by Sarepta therapeutics).
There are also many compounds tested that are mutation independent. For an overview please see: https://treat-nmd.org/research-overview/dmd-research-overview/
There are no mutation specific trials for a duplication of exon 22.
However, there are many compounds in trials that apply to all patients, regardless of the mutation. You can find an overview here: https://treat-nmd.org/research-overview/dmd-research-overview/
This mutation disrupts the genetic code. Exon 53 skipping would restore the genetic code. Exon 53 skipping is currently tested in clinical trials. Thus far we know that this leads to very minor increases in dystrophin in treated patients. Whether this is enough to slow down the disease progression is not yet known.
Note that unfortunately currently all therapies in development aim to slow down the disease progression for Duchenne patients. There is no cure – unfortunately the damage accumulated can not be undone and the functions lost cannot be regained. We hope to be able to do this in the future – for now we work on slowing down the progression – this is the only thing we can do with the tools available to us.
I’m father of DMD child from Taiwan,he been diagnosed as deletion of exon 46 to 50.
We are so helpless and feel desperation day after day.
If we’re interesting to join any clinical trial or treatment in the future, what can we do now?
This would required the combined skipping of exon 45 and exon 51. The problem is that double exon skipping is much more challenging than single exon skipping. This is because currently the delivery of exon skipping compounds to skeletal muscle fibers is not very efficient. So only a few fibers will take up an exon skipping compound. When double exon skipping is required, fibers need to take up both compounds – the chance of this is very small.
Hello,
My cousin (a boy, 12 years old) was diagnosed with Duchenne and Becker MD. The mutation is EX45_54 DEL (Hemi) on DMD gene. He was very active and played a lot until 5 years old. then, he used to walk on toe. no one found the problem. now, he can not walk and he uses a wheelchair.
Just to ask if there is any treatment currently or any medication to slow down the progression.
Thank you
This mutation disrupts the genetic code. Exon 55 skipping would restore the genetic code. However, currently there are no trials planned for this.
There are a lot of other therapeutic approaches in clinical development that apply to all mutations. See for an overview: https://treat-nmd.org/research-overview/dmd-research-overview/
These all aim at slowing down disease progression.
Hii professor
My 4 year old son is diagnosed with DMD his genetic test results have just come today
Their is a deletion of Exons 46 and 47 in the DMD gene as tested by MLPA
He has not started any medication as of now right now we r showing him in NIMHANS In Bangalore..
I’m from India and we are ready to travel anywhere in the world to help him
Please help us and suggest what step to take next..
I can suggest you contact DART, a patient organization in Bangalore, that also coordinates research.
There are currently many therapeutic approaches evaluated in clinical trials for Duchenne patients. See for an overview: https://treat-nmd.org/research-overview/dmd-research-overview/
There are also mutation specific approaches, which do not apply to all patients. However, your son’s mutation would require exon 45 skipping and there are trials to evaluate the safety and efficacy of this coordinated by Sarepta. The test compound is called casimersen.
Hello Prof. Dr. Annemieke Aartsma-Rus,
I am a father of child with exon 55 deletion reported in DNA Blood test.
1. I want to know is MLPA report trustworthy or i need to go for another test/method/technique to reconfirm
2. My kid is 5.6 yrs and is able to walk and play. only difficulty with him is stair climbing now.
3. He is on put on Steroid 20mg, after a month having this medicines his face changed to moon one.
4. What are the possible therapeutic treatments we can have in any part of world and would like to suggest Best Dr. in India to effectively treat my child as lot of them have already raised their hands i beilieve due to lack of knowledge on DMD
Pl. pl. support my child to live a normal life with and strength to overcome this.
I am sorry to hear about your son’s condition.
With regards to your questions: Steroids unfortunately have side effects (such as the moon face) – however, they are slowing down the disease a lot. They allow patients to walk longer and have a better respiratory function and better survival among others.
MLPA: when a deletion of one exon is found with MLPA, a second test is needed. MLPA uses probes to test whether the exon is there or not. Most likely your son has a deletion of exon 55 (i.e. exon 55 is not present). However, it is also possible that there is a small mutation within exon 55, which would mean that the probe cannot bind to exon 55. So a PCR test is needed to check whether exon 55 is deleted or not – generally this is done automatically, but please check with the team that did the diagnosis that this was done.
Several mutation specific therapies are available, such as eteplirsen (exon 51 skipping, would not work for an exon 55 deletion) and translarna (only for nonsense codons, not for deletions).
In India I know Dr Vishwanathan in Chennai – he has a lot of expertise with trreating DMD patients.
First of all, I want to thank you for your hard work. My son is 2 years old. We had a CK Blood Test done on him due to the fact that he was a late walker. The CK Levels came back at 15,800. We are now waiting for our Genetics Testing to be done. With the CK Levels being at that mark, is there any possibility of Becker’s MD? Or is that level of CK certainly Duchenne? Thank you so much.
Apologies for the late response, I missed this comment.
Elevated CK indicates there is muscle damage. This can mean Duchenne or Becker or other muscle diseases. The genetic tests and the clinical evaluation are needed to assess whether your son has Duchenne or Becker.
Exon skipping for duplications is challenging. What would be required in case of your sons is skipping of either the first exon 44 OR the second exon 44. Either way would restore the normal dystrophin code. HOWEVER, the compounds used for exon skipping (antisense oligonucleotides, AONs) recognize both exons 44 – so there is a possibility that both exons will be skipped. This would disrupt the genetic code (just like the exon 44 duplication does).
If we test AONs for exon 44 skipping in cultured cells of a patient with an exon 44 duplication, what we see is that both exons are skipped. So this is not helpful. It is possible however that when patient would be treated this would not be the case. For both exons to be skipped you need 2 AONs in the same cell (one to bind the first exon 44 and one to the second exon 44). In cultured cells this is easy to achieve (the cells receive an overdose of AONs so to say). However, in a human being the amount of AONs is much lower and as such it is anticipated that most cells will have no AON at all, and some will have 1 AON and hardly any with have 2 AONs. Therefore it is expected that in a patient, this would work better than in cells and that there might be some dystrophin restoration expected. However, exon skipping has so far never been tested in patients, so there is no hard evidence yet.
At the moment there are no exon 44 skipping compounds in clinical development, so for now this is unfortunately only theoretical.
In theory exon 45 skipping would restore the genetic code for your sons. This is currently evaluated in a clinical trial by Sarepta – the compound is called casimersen. It is not yet clear whether this treatment is safe or whether it leads to benefits.
I would expect this to lead to a mild Becker disease. However, notably, there is a lot of variation observed between individuals – even with the same deletion – and there are also always exceptions to the rules. So possibly the prognosis is different
Hello my son who is 5 yr old has been diagnosed with problem of exon 57 of the DMD gene, is there any cure or medicine in the pipiline to correct this dysfunction of exons? C.8479G>T
I think this is a so called nonsense mutation. If this is indeed the case, ataluren would be an approved therapy in Europe (not available in all countries though).
The company developing this compound is called PTC Therapeutics.
Can you kindly guide how can we determine whether a point mutation in DMD gene is in frame or out of frame mutation? and if a particular nonsense mutation can be corrected by ataluren.
I would be grateful if you can provide me literature on the recent mutation spectrum of Duchenne worldwide and the diagnostic methods and therapies available so far.
All nonsense mutations should be correctable by ataluren. Whether a point mutation is in-frame or out of frame depends on how many basepairs are involved (a basepair is a DNA building block). If there is a deletion or insertion of basepairs: if the number is divisible by 3 (e.g. deletion of 6 basepairs or insertion of 3 basepairs) the mutation is in-frame. If it is not divisible by 3 (e.g. deletion of 5 basepairs or insertion of 1 basepair), it is out-of-frame. A nonsense mutation does NOT disrupt the reading frame – however, because the code for an amino acid is changed into a STOP code, it leads to truncation of translation of the code from gene to protein and therefore a non functional protein. So the effect is the same (out-of-frame mutations also lead to a premature truncation of translation, but for a different reason – the code becomes unreadable).
For a paper on diagnostics for Duchenne I refer you to this paper: https://jmg.bmj.com/content/53/3/145.long
An overview of therapeutic approaches can be found here: http://www.treat-nmd.eu/dmd/research-overview/introduction/
More information on mutations and their effects can also be found with the Dove tool: http://www.dmd.nl/DOVE
Hi, my 4 year old son have DMD/BMD diagnosis and his result of DNA test is Exon deletions 45-53 , “in frame” mutation.I am not a carrier, so his doctor don’t know is this Becker or Duchenne.Can you help me about his diagnose?
Dear Jelena,
This is an in-frame mutation so I would expect a Becker disease. However, there are always exceptions to the reading frame rules possible. What is leading is how your son clinically develops. If he has a severe progression and symptoms at a very young age, that resembles Duchenne. However, if he has not a lot of symptoms at 4 years, that resembles Becker.
Thank you very much for your prompt response, I think I have the child well on track because he is enrolled precisely with Kevin Flanigan at the Ohio hospital, where he is working on the subject, what worries me is that he is alone with his team watching this issue of exon 2 duplication.
Anyway, I thank you for your attention and I am happy to know that there are still good people in this world who try by all means to make happy the families that suffer for their children.
A duplication of exon 52 and exon 53 would be expected to maintain the reading frame. So in theory one would expect this mutation to be associated with Becker muscular dystrophy. However, duplication mutations often have unpredictable impacts on how the gene transcripts are processed and a significant number of duplication mutations that do not disrupt the readin frame result in Duchenne, and vice versa duplication mutations that disrupt the reading frame can also result in Becker muscular dystrophy.
So the ‘prediciton’ is a lot less reliable than with deletion mutations.
At the moment there is no cure for Duchenne. There are therapies in development that aim to slow down disease progression. This is done by one in 2 ways: 1) trying to restore the missing protein 2) trying to improve the muscle quality.
Restoring dystrophin is often done in a mutation specific way. For an exon 2 duplication, exon 2 skipping would restore the genetic code of the dystrophin gene. At the moment this is not tested in clinical trials, but Kevin Flannigan is doing preclinical tests to assess exon 2 skipping in cell and mouse models.
Respected Doctor,
Hello my son who is 3 yr old has been diagnosed with duplication of exon from 8 to 11 of the DMD gene, is there any cure or medicine in the pipiline to correct this dysfunction of exons?
Research is ongoing on genome editing for duplication mutations in Toronto (lab of Ronald Coen) -however, this is in a very early stage (cultured cells). There is a lot of research happening on approaches that improve muscle quality – some of which are in clinical trials and all of which are not mutation specific (i.e. they apply to all patients). Furthermore, there are trials ongoing on bringing back a short version of dystrophin (micro-dystrophin) with viral vectors. You can see an overview of all the research that is in trials or close to trials here: http://www.treat-nmd.eu/dmd/research-overview/introduction/
Hi
My son have Exons 45,46 and 47 are deleted. He is 32 months old now,we don’t see any notable symptoms so far. He is ahead to reach his motor skills like crowling and walking.
When he tested for jaundice last year due to some other illness his liver enzymes were elevated and they see liver was normal so they started testing ck and genetic testing.
His ck levels drawn 3 times(Oct 2017- 15k, March 2018- 13k and April 2018- 29k)
His doctor is saying RNA analysis is needed to confirm whether this is mild and severe type though it’s a inframe mutation.
We are so scared what will be the outcome of RNA tests.
Can you please help to confirm is this kind of mutation happened to anyone already ( Exons 45,46 and 47 deleted) and what will be the type of their disease whether it’s mild or severe.please help.
Sorry to hear your son has a mutation in his dystrophin gene, but glad to hear he has no notable symptoms so far.
For mutations that are in-frame, one would expect the milder disease (Becker) rather than the severe disease (Duchenne). Note that RNA analysis requires a muscle biopsy – which is a painful and invasive procedure. As such, this is only recommended when the symptoms do not match the genetics (e.g. in-frame with severe symptoms or out-of-frame with mild symptoms). This does happen sometimes (in about 10% of cases) and the mutation you describe has been found in Becker patients but also in some Duchenne patients.
So I recommend that you ask the doctor why (s)he thinks RNA is needed. Is the disease more severe than expected for a Becker patient? If so, then the analysis makes sense. However, if your son does not have the typical Duchenne symptoms, I do not think the RNA analysis is needed.
Thank you so much for your response
Doctor mentioned it’s a blood test for RNA analysis not the muscle biopsy.
They say in particular in frame deletions (like my son’s) needs RNA analysis to confirm whether it’s a Becker or Duchene.
Does CK elevation (as it was around 30k ) matters to confirm Becker Vs Duchenne.
CK elevation means there is something wrong with the muscle – in case of muscular dystrophy the muscular dystrophy is ‘what is wrong’ and why the enzyme leaks from the muscle into the blood. The elevation points to a problem with muscles, but it does not tell you which problem there is (i.e. which protein is missing or not only partially functional) – this is why the genetic tests are needed. One cannot say which muscular dystrophy a person has based on how high the CK levels are because CK levels also vary due to e.g. time of day, how active you have been and how muscular you are etc.
RNA analysis in the blood will not be informative at all. Dystrophin is not expressed in the blood, which will make the analysis very challenging and has the risk of misinterpretation. The guidelines (internationally recognized, published in The Lancet) say that DNA analysis by MLPA is sufficient for deletions involving multiple exons. There is never a need for RNA analysis in the blood (because this is not informative) – if the symptoms do not match the genetics, RNA anlaysis can be done on muscle.
Feel free to direct the doctor to me for his/her questions about this (a.m.rus@lumc.nl)
Thank you!
I had a discussion with doctor and currently hold on RNA analysis. We have in person appointment scheduled for next week to talk more on this.
Earlier you mentioned exon 45-47 deletion shows in both Becker and Duchenne.
Without RNA analysis what decides the disease is mild (Becker) or severe (Duchenne), is it symptoms? or based on the age symptoms occurs?
can you please give more details like in Duchenne at which age age typically symptoms start and is developmental growth (motor skills) is always delayed with this case.
And with Becker what will be the symptoms and usually at which age symptoms start.
Thank you!
7 May, 2018 at 6:56 am
Author
Exonskip
The severity of the disease is determined by the symptoms and when they occur. Duchenne is the more severe form, and symptoms occur already early in life, at around the age of 1-3 years old. Patients e.g. will have difficulty with walking, hopping/jumping, climbing stairs and will fall frequently already before the age of 4 years.
For Becker there is a lot more variation in when the disease starts – in some patients this is in childhood, in some patients this is in adolescence or even adulthood. So here it is not possible to give a specific age – it varies – even when several patients are affected in the same family, when the symptoms start and how severe they are can differ between the patients.
Note that I am NOT a medical doctor – what I write about the symptoms is what I know from the literature and what I have heard from clinicians treating Duchenne and Becker patients.
7 May, 2018 at 8:27 am
Jaydeep Bhatt
My son is 5 years old and gene 49, 50, 51 and 52 are delete, I would like to know more about possible treatment and institutes where I can contact for cure of his DMD illness, I really need guidance please help.
Unfortunately there is no cure yet for DMD – not anywhere in the world.
There is good care which can help slow down the progression of the disease – you can find out more about this here: http://www.treat-nmd.eu/care/dmd/diagnosis-management-DMD/ It is important to find a hospital with experience in caring for Duchenne patients so that your son can receive the care he needs.
Also there are therapies in development and two therapies have been approved now. However, these are mutation specific and your son is not eligible for those. He would be eligible for “exon 53 skipping”, which is tested in clinical trials. This means that as yet we do not know whether this appraoch is safe and/or effective. Also know that the therapies currently in development are unfortunately not cures – they aim to slow down the progression of the disease.
More information on this can be found here: http://www.treat-nmd.eu/dmd/research-overview/introduction/
I am sorry I cannot give you more positive news. Know that there are many people world wide who work hard to find a better therapy for Duchenne, but that this is challenging.
The dystrophin that is produced after exon skipping needs to have all its functional domains.
The dystrophin has one dystroglycan binding domain encoded by exon 64-70. This is absolutely crucial. So if a mutation is located/includes exon 64-70, exon skipping will not result in functional dystrophins. This goes for all types of mutations (deletions, small mutations and duplications). With deletions parts are missing, while with duplications parts are double. However, the extra parts of dystrophin can affect the folding of the protein, so that while they are present, they are not functionally active.
The dystrophin has 3 actin binding domains, two encoded by exons 2-10 and one encoded by exon 32-45. To be functional dystrophin needs at least one actin-binding domain. So mutations that remove all three are not eligible for exon skipping, since the resulting dystrophin will not be functional. Note that the first two actin binding domains are “better binders” than the third one. So a dystrophin that lacks the first two domains is less functional (associated generally with more severe Becker) than a dystrophin lacking the third actin binding domain (associated with typical Becker). For small mutations (point mutations) it is not possible to affect all three domains – only for large deletions and duplications this can be an issue. With deletions parts are missing, while with duplications parts are double. However, the extra parts of dystrophin can affect the folding of the protein, so that while they are present, they are not functionally active.
The dystrophin has a connecting domain that is encoded by exons 11-63. This domain is largely dispensable. However, when deletions are longer than 36 exons, the domain probably becomes too short. For duplications it is not known how large they can be and still result in a functional protein. For small mutations of course the exons deleted after exon skipping will never involve more than 36 exons.
My 6 months grandson was found to be missing exon 46-47. We were told it is Duchenne. Is there any chance this could change as he gets older? What about skipping therapy?
Dear Janice,
I am sorry to hear about your grandson. For a deletion of exon 46-47 indeed Duchenne muscular dystrophy is expected, because this mutation disrupts the genetic code. There are sometimes exceptions (i.e. patients who have a milder progression than anticipated), but unfortunately these are few.
Dear Doctor Aartsma-Rus,
I heard about crispr cas 9 can correct mutations between exon18 and 58,
My question is that means both deletions and duplications or only deletions, noting that my 7 years old son has a duplication of exon 53 to 57 and I am searching for ongoing trials meeting his mutation (duplication)
Thanks in advance
Genome editing (using CRISPR/Cas9) can in theory correct both deletions and duplications. For deletions, the aim is to restore the genetic code, while for duplications, the aim is to restore the normal code. This can be achieved by cutting out the duplicated parts. However, this work is as yet in a very early stage and only tested in patient-derived cell cultures. So there are no clinical trials ongoing specifically for duplications at the moment.
Hello, the 5 year old son of our very good friends has just been diagnosed with DMD with duplications of Exon 6 and 7. We live in Turkey and I wondered if you could give us any information on clinical trials or treatment options available in this country?
Also, if they were able to travel would there be any other trials you could recommend?
Dear Ziggy,
I am sorry to hear about your friends’ son. Note that Turkey has a very good Duchenne specialist, Dr. Haluk Topaloglu and that he is involved in multiple clinical trials. I do not know by heart which ones are currently happening and whether your friends’ son would be eligible to participate, but I am sure his team will be able to inform you about that.
Note that participation in clinical trials is a burden. Clinical trials are experiments in humans. There is no guarantee that the test drug will work and they may be unsafe. Also trials generally mean many hospital visits – so this in and of itself is a burden as well. It is best to participate in a trial that is local – this reduces the travel burden for the patient and the family (e.g. weekly hospital visits are more rule than exception) and trials may be daunting to the patient, especially when he is young and when the trial is in another country where they speak a different language. So when possible I would recommend a local trial.
My son has a single base deletion in exon 56 (c.8375delA). Is exon skipping working with such small deletions. Which exon needs to be skipped to restore a truncated dystrophin for him?
Dear Alexander,
Exon skipping is in theory possible also for small mutations. Then the point is not so much to restore the reading frame (or genetic code) but to bypass the mutation. The challenges here are twofold:
1. For the majority of exons if you skip them this will disrupt the reading frame. Exon 56 is such an exon, so skipping this exon will bypass the mutation but this will disrupt the reading frame. As such TWO exons would need to be skipped (either exon 55 and exon 56 OR exon 56 and exon 57). This way the mutation is bypased while the reading frame is not changed. Skipping two exons is a lot more challenging than skipping one exon
2. While the larger deletions that remove one or more exons are clustering in the area of exon 45-55, small mutations (like the one of your son) occur in all exons. This means that exon skipping for small mutations applies to very small groups of patients (less than 0.1% of all patients generally).
So exon skipping as it is currently in development for DMD will not be applicable to your son, unfortunately. However, all the mutation independent approaches in development (anti-fibrosis, anti-inflammation, pro-regeneration, mini-dystrophin, utrophin upregulation etc) do apply.
I’ve sent you an email about the twin boys of a friend of mine. Is there a clinic you work in The Netherlands? By any chance can we contact you for an appointment? Please, my friend is desperate specially becouse in the city he lives in Brazil doctors know very little about it.
Dear Doctor,
Hi
The results of the Gene / DNA has showed the below :
The MLPA results suggest there is deletion of exon 48 to 52 of the DMD gene at hemozygous state. However this test will not detect any alteration that lie outside the target probe sequence.The deletion within the DMD gene results in frame-shift and therefore premature dystrophin , which agrees with the DMD diseases. diagnosis.
Can you please let me know if the exon 51 skipping is valid in this case
The MLPA will test for each part of the genetic code of the dystrophin genes (the so called exons) whether they are present or not. In case of your son, exons 48, 49, 50, 51 and 52 are missing. This disrupts the genetic code, so starting at exon 53 this becomes unreadable for the machinery that translates gene to protein. He therefore cannot produce functional dystrophin.
Exon skipping aims to restore the genetic code by making the deletion one exon larger. In case of your son’s mutation, exon 53 skipping would restore the genetic code. Exon 51 skipping will not work because your son does not have exon 51, so it cannot be skipped.
Dear Shady,
I am not a clinician but a researcher so I cannot provide you advise on the care of your son. I can point you to the standards of care for DMD which have been published also in a family friendly version: http://www.treat-nmd.eu/care/dmd/family-guide/
There are no clinical trials ongoing specifically targeting your son’s mutation. However, there are multiple trials ongoing for which mutation type is not an issue. See for an overview: http://www.treat-nmd.eu/dmd/research-overview/introduction/. The mutation specific approaches currently under evaluation (exon skipping and nonsense codon readthrough) will not apply to your son’s mutation. However, approaches aiming to reduce fibrosis, improve regeneration, decrease inflammation will apply to all DMD patients.
Dear Annemieke
Thanks for your valuable information ,
Could you please tell me what is the difference between non sense (stop codon) mutation and large duplication that alter the reading frame like my son’s case,as i know that both disrupt the reading frame but do both have the same severity phenotype? And different propability of the total absence of the dystrophin protein?
Thanks
Sh.y
A nonsense mutation does not disrupt the reading frame. It changes the genetic code at one position so that the code reads “stop” rather than genetic information. These stop codes are normally only present at the end of the genetic code, so the translation machinery knows the protein is complete. When a mutation changes the genetic code into a stop earlier in the gene, the translation stops too early and the protein is not functional. So the consequence is the same as with frame-shifting mutations (translation stops too early and protein is not functional). As such, these nonsense mutations cause DMD, like the frame shifting mutations.
Hello Dr.
Mlpa was done for my 7 years old son, showed a duplication from Exon 53-57 that disrupt the reading frame ,
The question is the said mutation disrupted the whole function of the gene or only the site beyond or below the mutation site(exons)in other words the gene is functioning till Exon 52 only that can translate the proteins before the duplicated exons or not functioning at all?
Another question if the site (region) of mutation in specific area of the gene differs in severity than other parts of the gene even if disrupt the reading frame for example if I have 2 patients,1 with duplication of Exon 18-22 (out of frame) and the other patient has duplication of Exon 53-57 ( out of frame also) do both of them have the same severity or not?
Thanks in advance
Dear Shady,
I am sorry to hear your son has Duchenne. I will try to explain some of the genetics to you – hopefully this will answer your questions.
Duchenne is caused by a failure of patients to produce a functional dystrophin protein. The dystrophin protein fulfills a linker function in the muscle. One side of it connects to the skeleton/internal structure of the muscle fiber, the other size connects to the connective tissue surrounding the muscle fiber. In between there is a spring like system consisting of 24 similar domains. The connection stabilizes muscle fibers upon contraction.
Duchenne patients have a mutation that disrupts the genetic code of the dystrophin gene (out-of-frame mutations). Consequently, the code becomes unreadable after the mutation. Because the important domains of dystrophin are located at the start and the end of the protein, the resulting dystrophin will not be functional. It will lack the domain that connects to the connective tissue. As such it does not matter whether the mutation is at the start or in the middle are even close to the end – the crucial domain at the end will be missing and therefore the dystrophin is not functional.
In fact, the part in the middle of dystrophin is redundant. We know this because in-frame mutations affecting the middle of the protein keep the genetic code readable. As such dystrophins can be produced that have the important domains at the start and the end, but are shorter in the middle. These proteins are found in the less severe Becker muscular dystrophy.
In summary, for out of frame mutations it does not matter where the mutation is located – if the domain at the end of the protein (encoded by exons 64-70) cannot be produced, the protein will not be functional. As such they will both cause Duchenne.
Please do not hesitate to ask for clarification if this is not clear to you or ask follow up questions.
Thanks for your kind reply,I just need to ask some questions
First:is there any trials currently recruting regarding the mentioned mutation for my son(duplication 53-57)?
Second:what is the best treatment should I start with my son ,noting that my son is 7 years old,he is active and still ambulant in good condition except for climbing stairs with support by himself and Gower’s sign
Third: which is better “Prednisone or deflazacort” noting that our neourlogist has recommended Prednisone 15 mg/d in addition to multivitamins,but we didn’t start steroids yet?
Fourth:she recommended swimming 1hr a week but didn’t recommended physiotherapy right now?
Last question:shall we start using night splint and hand braces for him now or later?,also shall we delay steroids or start now?
Thanks for your time
My grandson is 7 years old and was diagnosed as having DMD ( most probably )due to duplication of exons 53 to 57 .He is ambulatory and does physiotherapy is specialized center . we give him Tamoxifen 10 mg daily for 1.5 months now . He is doing better since then . What is your comment on the duplication regarding prognosis and treatment . Also ,if you have any comments on Tamoxifen ( I know that it is in clinical trial but I took the risk because I cannot wait till I see him helpless and not moving so early ) .
I am sorry to hear about your grandson. Good care is really the best thing that can be doen for him – this means physiotherapy but also has other aspects (see http://www.treat-nmd.eu/care/dmd/family-guide/). I cannot comment on tamoxifen other than that it is a therapy that has yet to be tested in Duchenne patients. It has yet to be shown that this drug is effective and that it is safe in Duchenne patients. The fact that it works in mice is no guarantee that it will work in patients. The fact that it appears to be safe in mice is no guarantee that it will be safe in Duchenne patients.
Regarding the duplication: it is expected to disrupt the genetic code of the dystrophin gene and as such is a “Duchenne type” of mutation. The milder disease course of Becker is expected for mutations that do NOT disrupt the genetic code. However, how your grandson will progress exactly is difficult to predict since every patient is unique. This will depend on how well his muscle regenerates, how well his immune system works, how muscular he is to begin with etc.
Coming back to the start: the best thing to do is to make sure he has good care – this is the best way to slow down the breakdown of muscle as much as possible.
Mijn zoontje is 19 maanden en heeft Duchenne, hij heeft deletie 51. Kan hij met deze deletie in aanmerking komen voor exon skipping of is dit niet voor deletie 51 van toepassing?
Beste Valerie,
Exon skipping is een mutatie specifieke aanpak waarbij gepoogd wordt om Duchenne patienten een deels functioneel dystrofine eiwit te laten maken in plaats van een niet functioneel eiwit. Hiervoor moet tijdens het verwerkingsproces van gen naar eiwit dus een exon geskipt worden. WELK exon hangt af van de locatie van de mutatie. Een exon 51 deletie komt in theorie in aanmerking voor deze aanpak. Om de leesbaarheid van het gen te herstellen moet exon 52 OF exon 50 worden geskipt. Momenteel wordt er geen klinisch onderzoek gedaan met middelen om deze exonen te skippen. De focus ligt vooral op het skippen van exon 51, 45 en 53 momenteel omdat dit toepasbaar is op de grootste groep patienten.
My Son is 7-years, Muscle Biopsy says consistent with DMD but MLPA ( Genetic Test ) reveals point mutation at 46 chromosome.
He is on protein diet and also physiotherapy, swimming etc. going regularly
Please guide me regarding any treatment pertaining to point mutations ( exon skipping, ataluren ( translarna)
I am sorry to hear your son has DMD. The mutation you describe however, does not make sense to me. Do you mean a deletion or duplication of exon 46? A small mutation in exon 46? Feel free to email me privately if you prefer (you can find my email address on publications). I will need this information to provide information about mutation specific appraoches.
Very good to hear your son is doing physiotherapy – good care is the most important thing you can do for him!
My son is 4 years old and has exon deletion from 48 – 52 . How feasible is an exon 53 skipping and i have read that trial results are due only in 2019 . What other treatments can be done in the mean time ?
Exon 53 skipping is indeed tested in clinical trials at the moment. As yet we do not know whether it is effective or safe (of course we all hope it is both effective and safe, but the trial is done to evaluate this).
What can be done already is provide good care to your son to keep him in as good a condition as possible for when hopefully a therapy is available. More information on care guidelines for Duchenne can be found here: http://www.dmd-guide.org/. This is based on two scientific papers published on this topic, but ‘translated’ into more accessible language non medically trained individuals.
A deletion of exon 48-52 unfortunately disrupts the genetic code of the dystrophin gene. That means your son cannot produce functional dystrophin and he would be expected to have Duchenne muscular dystrophy – the more progressive form of the disease.
Hi,
I have come across a child who is 7 yrs old and has exon 48-52 deletion. Can you let me know when the trial is going to come up. The patient is in India..I am wondering how can he be a part of the trial
You can see an overview of therapies in clinical development at many places, e.g. the TREAT-NMD website: http://www.treat-nmd.eu/dmd/research-overview/introduction/
Here you will see that there are approaches in development that apply to all Duchenne patients regardless of their mutation. In addition there are mutation specific therapies in development. The latter have been developed furthest and two compounds have been approved: Translarna (in Europe) and Eteplirsen (in the USA). Translarna only applies to nonsense mutations – so the child you mention would not be eligible since he has a frame-shift. Eteplirsen is an exon 51 skipping compound, aiming to restore the reading frame. However, this would also not work for the child you mention since exon 51 is deleted already. Exon 53 skipping would restore the reading frame for this patient. Exon 53 skipping compounds developed by Sarepta therapeutics are in clinical development in the USA and Europe. To my knowledge no trial is currently going on in India, but I know DART (Duchenne Annihilation Research Trust, located in Bangalore) is preparing clinical trials in India.
Thank you for your reply what are the future treatment which will be available for gene duplication please let me know if any so that I can follow theme
Dear Mangesh,
I am sorry to hear about your nephew. The dystrophin gene has 79 exons. A deletion means that part of the gene is missing (e.g. exon 57-60). A duplication means that part of the gene is ‘doubled’, in case of your nephew he has exon 1-60, but then instead of exon 61, he has an extra copy of exon 57, 58, 59, and 60, and only then exon 61-79. The consequence of deletions and duplications can be two-fold: 1. They can disrupt the genetic code. This means that dystrophin protein cannot be produced and patients have Duchenne. 2. They can maintain the genetic code, allowing the production of a dystrophin that is slightly shorter but has its functional domains. These proteins are partially functional and are found in Becker patients (less severe disease).
A duplication of exon 57-60 is unfortunately of the type that disrupts the genetic code. So you would expect him to have the severe type of the disease. There are exceptions to this rule however, so it is not possible to say this with 100% certainty.
Hello,
I have son with DMD and we recive genetic test which shows c.3151C>T in exon 23coresponding to the mutation p.Arg.1051.
What these mean? Can he take some terapy?
Dear Amir,
I am sorry to hear about your son.
The mutation you describe is a so called nonsense mutation (also called stop mutation). Genes contain the genetic code for proteins. Each gene has a start and a stop signal so the translation machine knows where to start translating the gene into protein and when the protein is finished. For most Duchenne patients part of the genetic code is lost (deleted) and therefore the code becomes unreadable, so it is not translated. However, for some patients, like your son, there is a very small change that changes the code for a part of the protein into a stop signal. This means that translations is stopped prematurely and no functional protein is produced.
There is a therapy that addresses this type of mutations. It is called stop codon readthrough and the drug that achieves this is called Ataluren (tradename Translarna). Ataluren is approved for treatment of ambulant Duchenne patients 5 years and older in Europe by the European Medicines Agency. It is on the market in several countries in Europe. In addition there are access programmes for patients outside Europe. It is a treatment, not a cure. It does not stop the disease, but slows down its progression.
For more information I refer you to: http://www.treat-nmd.eu/dmd/research-overview/mutation-specific-approaches/exon-skipping/ and to the website of the company producing Ataluren (PTC): http://www.ptcbio.com/en/
Thank You very much for Your qucik replay. Can You tell me which clinic in Europa I can contact and go with my son. Ina our country, Bosnia, we do not have good doctors. Nobody tell as about this tretman. They do not know abou it. If You have some contacts please send me. Thank You very much.
I ‘ m father of a child With dmd due to a deletion Of exons 45 to 53 .My son is 7 Years old What you Can’ do today for this
Type of mutation?
Thank you
Dear Mohammad,
Sorry to hear about your son. At the moment there is no therapy available for Duchenne. There are care guidelines available, see here for a family friendly version: http://www.treat-nmd.eu/care/dmd/family-guide/
Good care is very important to keep Duchenne patients as functional as possible for as long as possible.
The exon skipping approach probably will not apply to your son. The approach aims to restore the genetic code. However, a deletion of exon 45-53 does not disrupt the genetic code (so therefore it cannot be restored). For this mutation we would expect a milder progression (Becker) – However, there are exceptions, e.g. it is possible that while on DNA level the genetic code seems not to be disrupted, it IS disrupted in the temporary RNA copy because parts of the gene that are important for gene processing are missing. Since the protein is translated from this RNA copy (and not directly from DNA), the way the RNA copy looks like, is what determines whether protein can be produced. However, RNA and protein analysis can only be done on muscle tissue. How was the mutation found? Only by DNA analysis? Or was protein analyzed as well?
is het nu niet mogelijk dat het medicijn wat nu er is niet te gebruiken voor de patenten die in de proef bij jullie waren
want op de congres zag ik de bij nr 53 goede voorgang zat // groen was kleine doorlatingen van eiwitten // zie foto
ik zag dat ook nu bij mijn klein zoon / nu zie je dat deze toch wat achteruit gaat
daarom vind ik dat als je ziet dat er een kleine tijd verlenging tot stand komt het toch werkt
Het is niet mogelijk om dit middel te gebruiken – het is namelijk niet een medicijn want nog niet goedgekeurd. De ontwikkeling van de “Biomarin/Prosensa” exon skip middelen is gestopt omdat de bijwerkingen niet opwogen tegen de zeer beperkte effecten in een klein groepje patienten.
In Amerika is afgelopen week een ander exon skip middel goedgekeurd (Eteplirsen, van het bedrijf Sarepta). In Europa wil Sarepta ook exon 53 middelen testen.
Hi, we’re desperately trying to find out how to get exon skipping for TJ. He’s a three year old boy who has just been diagnosed. We’ve just started raising funds to help us in our endeavour. However we have no idea where to start in terms of having access to the treatment or how much money we need or even when he might be eligible for the treatment. Please, please help us? Any information on who to contact or how to start on this journey would mean the world to us! Thank you so much for taking the time to read this. I hope to hear from you soon. Warm regards Mrs Jennifer Batterbee.
Message for Dr Aartsema.
Dear Annemieke , today i heard the last part of an interview with you on Radio1 about the influence of mobile phones on the well-being of youngsters. What survey or news item did this refer to? Would you also think that such devices have an impact on persons at their workplace? As i am interested in how advanced automation and robotisation will impact the life of people on the workplace.
My interest is therefore both professional and private.
Thank you in advance for your response.
The problem with mobile phones and tablets is that they produce a lot of light – especially in the blue spectrum. This is not harmful in itself. The problem is that blue light interferes with the production of melatonin. Melatonin is a substance your body makes that helps you sleep. It needs to accumulate for about 3 hours before there is enough to get you to sleep easily. So if you use tablets or mobiles in the evening, melatonin can not accumulate due to the blue light exposure. This can lead to difficulties falling asleep.
So it is not the mobile phones that are harmful, but the lack of sleep if you use them until very late.
Exon skipping is an approach that aims to slow down disease progression. Muscle function that is lost will not return.
It is also a mutation specific appraoch. Not all mutations are suitable unfortunately.
Ho
I ‘ m father of a child With dmd due to a duplication Of exons 8 9 .My son is 5 Years old What you Can’ do today for this
Type of mutation?
Tank you
Leave a comment
309 comments
Radhu
Hello Mam,
My 5 year old child is having exon 45 deletion. Last year his cpk total was 18160 again we checked for the second time this week now it came to 244. What does this mean??
Currently he is on steroids defcort 12 mg.
5 December, 2022 at 7:50 am
Exonskip
Exon 45 skipping would restore the genetic code for this deletion. However, I do not know whether exon 45 skipping is available where you live. It is approved in the USA and tested in clinical trials at several locations in Europe and North-America.
Note that exon 45 skipping results in only low levels of dystrophin and that it is not known whether this results in functional effects yet. The currently ongoing clinical trials aim to test this.
14 November, 2022 at 9:43 pm
Sven
Dear Prof. dr. Annemieke Aartsma-Rus,
In one of your comments below you’ve mentioned “it is possible that your body already spontaneously skips exon 45 at a low level”. That’s quite interesting and I would really appreciate if you would be able to share a bit more information or resources. Do you think that there is a way somehow to force the body to do that?
Thank you in advance!
8 November, 2022 at 8:33 am
Exonskip
There is a way to specifically increase exon 45 skipping with antisense oligonucleotides.
There may also be other compounds (chemicals) that do this not specifically. This means they would increase exon 45 skipping, but likely also induce the skipping of other exons, which may have detrimental effects.
12 November, 2022 at 11:57 am
Neha
Exon 40 small deletion was observed gene sequencing
Our doctor suggested that 39 and 41 will automatically join up and BMD like symptoms will show up probably. As of there are no clear symptoms are age of 5. So he has told to wait and watch ? We are in dilemma should we go for exon skipping or not? Please rep soon
21 October, 2022 at 7:31 pm
Exonskip
apologies for the delayed reply. The alert messages do not arrive in my inbox for some reason.
If exon 40 is deleted, indeed this is ‘in-frame’ so the code remains readable. So indeed we expect him to have Becker. The problem is that Becker is very variable, some patients have first symptoms at age 7 while others have first symptoms at a much later age (sometimes in the 40s or even 60s).
You should not go for exon skipping, because exon skipping is not going to help. The aim of exon skipping is to make the code readable. If the code is already readable, you cannot make it more readable.
12 November, 2022 at 12:01 pm
mj
is amondys 45 recommended for deletion of 46-63 genes?
11 October, 2022 at 3:21 am
Exonskip
No it is not. Exon 45 skipping will not restore the reading frame for this deletion (exon 44 does not fit to exon 64).
14 November, 2022 at 9:39 pm
julio cesar ruiz gallardo
it´s anything new about exon 2 skipping?
6 October, 2022 at 4:55 pm
Exonskip
None that I have heard since Kevin Flannigan’s presentation at PPMD meeting on the baby he treated with the exon 2 skipping gene therapy who had very good dystrophin restoration.
14 November, 2022 at 9:41 pm
Mingi
Hello.
I am writing to you because I have been following you on Twitter for a long time.
I’m impressed with your work on Duchenne’s disease.
Not to be too long, my 2 boys aged 10 and 6 have Duchenne muscular dystrophy, deletion of exon 7 (the mother does not have the gene).
Do you have any information on this type of deletion?
I use Google Translate, forgive me, we are from France.
Cordially
18 August, 2022 at 1:10 pm
Exonskip
Apologies for the delayed reply. The email alert system did not work so I was not aware of your question.
What we know about exon 7 deletions is not a lot. Generally speaking Duchenne patients with deletions before exon 8 have a slower disease course than other Duchenne patients (but they still have Duchenne AND this is on average, so there is still variability).
For dystrophin restoration approaches this is not a good mutation, as microdystrophin is currently not possible due to the risk of an auto-immune response to the microdystrophin for patients with deletions in the beginning of the gene. Also for exon skipping this is not a good mutation as two exons need to be skipped (exon 6 and exon 8) and that is very challenging.
however, options to improve muscle quality apply to all mutations, so your sons would be eligible for those. Currently none are approved, but this may change in the future. For an overview of approaches in development: https://treat-nmd.org/resources-support/research-overview/dmd-research-overview/drug-therapy/
14 November, 2022 at 9:48 pm
Krausz Nóra
Greeting!
My son’s Duchenne muscular dystrophy is defective in exon 44. I would be interested in the skipping 45 therapy, where it is done, how to get into the program and try it out. Please write if you have any information. Thanks Nora
15 August, 2022 at 7:35 am
Exonskip
Sorry for the late reply. Exon 45 skipping is tested in clinical trials at several locations. See: https://clinicaltrials.gov/ct2/show/NCT02500381?term=casimersen&cond=Duchenne+Muscular+Dystrophy&draw=2&rank=3
It is approved for treatment of Duchenne patients with eligible mutations (like exon 44 deletions) in the USA.
14 November, 2022 at 9:50 pm
Brianna
I just found out I have a deletion in Exons 49-50. I am also currently pregnant with a boy. What does this mean?
30 July, 2022 at 2:23 am
Exonskip
I am very sorry for the late reply.
A deletion of exon 49-50 is out of frame, i.e. it disrupts the genetic code of the dystrophin gene. Since the dystrophin gene is located on the X-chromosome, and you have 2 of those, you are not sick. However, your boy has 50% chance of having this deletion. Then he would not be able to make dystrophin protein and he would have Duchenne.
Please note that as a carrier of this mutation, you CAN have symptoms (muscle cramps and weakness) and you are also at risk to develop heart problems. The heart problems can be treated if they do develop. however, it is important that they check you regularly (every 3 years and more frequent if problems do develop). There are guidelines available for this. For more information, see e.g. https://www.duchenneuk.org/study-paves-the-way-for-improved-detection-of-heart-disease-in-female-carriers-of-dmd/
14 November, 2022 at 9:54 pm
Reet
Hi my son 5 years has hemizygous deletion of exon 52 out of frame .exon 51 and 53 are present in entirety. .ck is 18000.does it indicate dmd.how severe will it be and is exon skipping option available .thank you
28 July, 2022 at 4:26 pm
Exonskip
This is indeed Duchenne. How severe it will be is difficult to predict as there is variation between Duchenne patients. however, Duchenne is sadly a severe disease.
Exon skipping is an option: both exon 51 skipping (eteplirsen) and exon 53 skipping (golodirsen and viltolarsen) are options. Since exon 53 skipping is more efficient so far than exon 51 skipping, if you have the option, I would recommend exon 53 skipping.
14 November, 2022 at 9:56 pm
Dan
Hello,
We found out that my nephew, 7 years old, has deletion on exons 45-50. He is showing some weakness symptoms. Does this deletion lead to the serious DMD or to the milder one, BMD?
Thank you very much!
8 June, 2022 at 11:49 am
Exonskip
sadly a deletion of exon 45-50 leads to the serious DMD.
Depending on where you live a treatment may be available. Exon 51 skipping restores the genetic code for this mutation. In the USA exon 51 skipping drugs are approved (eteplirsen). They have only been shown to restore the missing protein (dystrophin) at low levels. It is not known if that is enough to slow down disease progression. The drug is approved in the USA, but trials to assess what the functional effects are, are ongoing at different locations. Also, other exon skipping drugs (that lead to hopefully more dystrophin restoration) are being evaluated in clinical trials. For more information see https://treat-nmd.org/resources-support/research-overview/dmd-research-overview/mutation-specific-approaches/#1555493313072-b6404a52-9df4
14 November, 2022 at 9:59 pm
Shivaling
Hi
Recently my son is detected with DMD and would and genetic test shows 45-50 exons are missing. Is there any cure for this.
Please suggest if there is therapy to fix this missing exons
4 June, 2022 at 4:09 pm
Exonskip
Unfortunately there is not cure for Duchenne.
Exon 51 skipping would restore the genetic code. However, this is only approved in the USA and is very inefficient. It is not yet known whether it slows down disease progression.
There is no way yet to restore the exons that are missing.
And overview of therapeutic approaches in development can be found here: https://treat-nmd.org/resources-support/research-overview/dmd-research-overview/
14 November, 2022 at 10:19 pm
Mukesh
Hello Doctor Rus,
My Nephew is 9 year old and was detected DMD for 46-48 exon deletion.At present he is walking on his toe. we are very tensed about his health. kindly suggest the available treatment for him.is Exon 45 skipping is possible in his case? Kindly suggest us the possible way out for his treatment.
regards
25 May, 2022 at 12:06 pm
Exonskip
Indeed exon 45 skipping would restore the genetic code for this mutation and would restore dystrophin production.
Note that exon 45 skipping is approved in the USA (Casimersen) based on low levels of dystrophin restoration. It is not yet known whether this will slow down disease progression. Clinical trials to study this in more detail are ongoing.
14 November, 2022 at 10:01 pm
RD USMANI
Hi.
My nephew has deletion detected exon 46-52
Please guide me …
Help me for his treatment, he is 4yr young boy..Date of birth – 26 january 2018.
28 April, 2022 at 10:54 am
Exonskip
I am sorry to hear about your nephew.
There is no treatment available for this mutation yet. IT requires the skipping of exon 45 AND of exon 53 both. While exon 45 and exon 53 skipping drugs have been approved in the USA, they have never been test in combination in humans. What we know from mice is that the skipping of two exons is very inefficient for the type of exon skipping drug that has been approved.
An overview of other therapies in development can be found here https://treat-nmd.org/resources-support/research-overview/dmd-research-overview/
14 November, 2022 at 10:03 pm
Umut
Dear Annemieke,
My nephew’s genetic test results indicate deletion in exons 45-47, and he was diagnosed with BMD. He doesn’t show any symptoms, apart from occasional mild pain in one of his legs after strenuous activity. I was wondering if you are aware of any treatment options/clinical trials for this specific mutation (anywhere in the world but especially in Europe).
Thank you and best wishes,
Umut
10 April, 2022 at 9:00 pm
Exonskip
It is indeed expected that this mutation results in Becker as it allows production of a partly functional dystrophin.
There are limited clinical trials ongoing for Becker patients. Edgewise and Italpharmaco are evaluating their treatments in both Duchenne and Becker patients. There may be others but I am not aware of them. Treatment developments for Becker are being discussed during annual meetings of the Italian Duchenne Parent Project and of the Parent Project Muscular Dystrophy.
14 November, 2022 at 10:05 pm
Forrest
My cousin who is 12 years old has duplicated exon 44, is there any treatment or clinical trials? Thank you!
4 April, 2022 at 10:22 pm
Exonskip
There is currently no specific treatment for exon 44 duplications.
Trials for exon 44 skipping are in preparation. I do not know whether the inclusion criteria will allow patients with duplications to be included as well. The companies preparing exon 44 skipping trials are Entrada and Avidity.
14 November, 2022 at 10:10 pm
Vishnu
My son is 7.11 yrs old detected with DMD with deletion of exons 46,47,48.
Could you please suggest us which treatment will be helpful or any clinical trials are there for above mentioned deleted exons.
Is stem cell therapy treatment will help in this case.
2 April, 2022 at 1:59 pm
Exonskip
Stem cell treatment to restore dystrophin will not help in this case or in any case. Thus far it has not been possible to achieve significant restoration of dystrophin with stem cell treatment.
Exon 45 skipping would restore the genetic code and restore dystrophin production – albeit at low levels so far. Exon 45 skipping is approved in the USA (casimersen) and tested in clinical trials in other countries.
14 November, 2022 at 10:12 pm
Mustafa ciftci
Hallo,
Met Mustafa heb zelf dmd en ben 31 jaar oud. Wilde meer informatie over stem cell therapie wat is het precies en kom ik daarvoor in aanmerking. Heb je ook trails waar ik aan mee kan doen. Ik hoor graag van u.
16 March, 2022 at 2:14 pm
Exonskip
Hoi,
Bij stamcel therapie voor Duchenne is het doel om spierstamcellen in het lichaam te brengen die gaan fuseren met de zieke spieren van Duchenne patienten. Dan zorgen die stamcellen ervoor dat de spieren herstellen en dat er dystrofine gemaakt kan worden
Klinkt heel mooi in theorie, maar helaas werkt het niet in de praktijk. Namelijk als je de stamcellen in de bloedbaan inbrengt gaan ze NIET naar de spier maar blijven ze in het bloed en gaan ze dood. Als je ze in spieren injecteert blijven ze rondom de injectieplek zitten en zou je dus miljarden injecties moeten doen en heel veel stamcellen nodig hebben (dan heb je meerdere mensen nodig die hun armen en benen afstaan hiervoor – dat gaat dus ook niet werken).
Ik ben wetenschapper en geen arts en heb dus zelf geen trials. Er zijn wel klinische studies gaande in Nederland (zie Duchenne Centrum Nederland). Echter, ik weet niet of patienten van 31 in aanmerking komen hiervoor.
14 November, 2022 at 10:17 pm
Iko
37 Yrs old just found have deletion in Exons 45-53 guessing some from of BMD no family history of DMD mutation. What does it mean since I am not really showing any symptoms other than some minor calf hypertrophy and slight weakness in proximal muscles. Is there any options for treatment.
25 February, 2022 at 3:04 am
Exonskip
Please bear in mind that I am not a medical doctor so my information should not be interpreted as medical advice.
This is an in-frame deletion so it would indeed be expected to result in Becker muscular dystrophy. This disease is very variable with some patients not showing pathology until their 40s or even 60s, while others have pain and weakness from childhood. From what you describe you seem to be one of the milder cases.
Given the mildness of the symptoms it is possible that other family members are affected as well but never realized because the symptoms were not very severe.
Currently there is no treatment for Becker muscular dystrophy. Patients are usually followed by neuromuscular specialists who also assess heart function, as a subset of Becker patients develops cardiomyopathy.
There are clinical trials ongoing to study whether compounds that preserve muscle or improve muscle metabolism benefit Becker patients. However, as yet it is not clear if these are safe and effective.
Best regards
Annemieke
11 March, 2022 at 1:01 pm
ines velcheva
Hi Dear Doctor Rus,
During a routine test of my amniotic fluid I see that an in frame deletion of 48-51 was noticed.
I am absolutely terrified and scared. I am pregnant with twin boys and we are in week 24 already.
Can you please let me know if there is a chance to not have a disease with this sequence?
What does it mean?Can it result in a mild form of a disease?
Please let me know.
Best Regards,
Ines
19 February, 2022 at 5:20 pm
Exonskip
Apologies for the delayed reply Ines.
This deletion is in frame and expected to lead to Becker muscular dystrophy. This is the milder form of the disease (if you compare it to Duchenne). Becker is variable with some patients having muscle problems in late childhood while others do not have any symptoms until later in life.
I am sorry I cannot give more detailed information.
Annemieke
11 March, 2022 at 1:03 pm
Elisa
Good evening,
my son has a deletion of exons 51 and 52. He is only 6 months old and not showing any symptoms yet. I was just wondering if you could tell me more about this particular deletion. I have just recently found out I am a carrier but no one in family has this desease (at least that we know). I know it is likely to be associated with Becker since it is an in frame deletion. But I was wondering how many documented cases of this deletion there are and how it has affected those individuals with it. I am in many Facebook and internet groups about MD but I have NOT found one single person with this deletion. Also, I was reading an article that it said it was pretty rare and one individual with this deletion is actually asymptomatic and with normal CK levels. Maybe I am just trying to be optimistic…or is there a chance this deletion is actually pretty rare and very very mild?
Sincerely, Elisa.
11 February, 2022 at 3:04 am
Exonskip
Dear Elisa,
This deletion is indeed expected to result in Becker muscular dystrophy. I checked the LOVD Duchenne/Becker database and discovered ~20 other individuals with this deletion. However, it was not indicated whether they have Duchenne or Becker so that is not very helpful. I have heard of an individual with very mild symptoms with this mutation in Israel on top of the publications. We also know that in a mouse with a deletion of exon 52, skipping exon 51 results in production of a functional dystrophin, further underlining that the exon 51-52 deleted dystrophin is partially to largely functional.
The challenge with Becker is that it is very variable and patients with the same deletions can have different severity. So there is never a guarantee that it will be very mild unfortunately.
Given that the mutation is very mild in some individuals, it is possible that your male relatives (e.g. your father, brother, or uncles) also carry it but are not aware because it is very mild. If it is severe it must be inherited via the mother if no one in the family has the disease. However, if it is mild it is possible that it was inherited via your father as well. If that is the case, that will of course tell you that it likely will be very mild in your son. However, it is also possible that the mutation started with you or was inherited via your mother.
I am sorry I cannot give a clear cut answer
Best regards
Annemieke
11 February, 2022 at 8:47 am
Tomas
Is het mogelijk om exon 24-29 duplicate te skippen? Als het goed is is de rest dan intact.
29 January, 2022 at 7:13 pm
Exonskip
Beste Tomas,
Het skippen van duplicaties van meerdere exonen is heel erg lastig. Dit komt omdat bij een duplicatie sommige exonen dubbel aanwezig zijn. Er kunnen dan meerdere dingen gebeuren voor elk exon in de duplicatie: het originele exon wordt geskipt, het extra exon wordt geskipt, beide exonen worden geskipt of geen van beide exonen worden geskipt. En dat dan voor elk exon afzonderlijk. Het gevolg is dat je heel veel verschillende combinaties krijgt waarvan er maar een paar zijn wat je daadwerkelijk wilt (exon 24-29 skippen voor ofwel het origineel ofwel de duplicatie). Je krijgt dus een ernstige verdunning van het effect.
Dus hoewel het in theorie heel mooi lijkt (inderdaad je gaat terug naar een ‘intact/normaal’ dystrofine transcript), is de praktijk dat het al heel erg lastig is bij een duplicatie van 2 exonen, laat staan een duplicatie van 6 exonen).
Groeten Annemieke
31 January, 2022 at 9:47 am
Pete
Dear Prof. Aartsma,
We live in the UK. Our 2yr old son has just been diagnosed as having muscular dystrophy- Hemizygous duplication of Exon 46.
We are struggling to find any information on this particular variant.
Are you or your group familiar with single Exon 46 duplication? Am I correct in thinking that it is out of frame, as not divisible by 3?
Any information on phenotype or implications for therapies available or undergoing research would be greatly appreciated. I’ve read the website section on exon skipping for single duplications and note some success with 45 but 44 was more complex. Has any work been done on skipping 46 duplication?
The genetic report notes that the variant is associated with both Duchenne and Becker. Our son has a raised CK -9000, and proximal leg muscle weakness with a positive modified Gower sign. We’re assuming the phenotype will be more likely Duchenne while noting that genotypes do not always perfectly correlate with phenotype.
Many thanks
Pete
27 January, 2022 at 8:36 pm
Exonskip
Dear Pete,
I am very sorry to hear you son has been diagnosed with muscular dystrophy. A duplication of exon 46 is quite rare. You are correct in your thinking: this duplication would be expected to lead to Duchenne as the length of exon 46 is not divisible by 3. Duplications are known for sometimes ‘misbehaving’, so in-frame duplications leading to Duchenne, and out-of-frame ones leading to Becker. However, sadly I agree with you that the symptoms your son presents at such an early age suggests that he has Duchenne indeed.
Exon skipping for single exon duplications is difficult when done in cultured cells. However, exon skipping in cultured cells is very easy – you “overdose” the cells with the exon skipping compound (ASO). This means there is so much ASO in each cell that instead of one ASO binding to an exon 46, two bind to both exons 46. You then end up with a deletion of exon 46 – which is also out-of-frame.
In a body this will not happen. Here actually it is very difficult to get the ASOs to go to the muscle fibers. So it is difficult to get even a single ASO into a cell – thus the chance of skipping both exons 46 is very low. As such we expect that exon skipping for single exon duplications will be feasible.
Sarepta is currently doing a clinical trial to test this for exon 45, 51 and 53 single exon duplications. This is because they have ASOs approved targeting those exons.
To my knowledge no one is working on developing an exon 46 skipping ASO at the moment.
I am sorry I do not have better news for you. If you have any questions please do not hesitate to contact me again.
While there is no treatment yet for your son, there is multidisciplinary care, which can achieve a lot.
Furthermore, there are patient organisations that can help you with emotional and logistic support if you need it.
Take care
Annemieke
28 January, 2022 at 8:44 am
Parv
Hi Dr. Annieke ,
My son 7 year old , recently diagnose with MD symptoms. He was tested for CKP 7800 and MLPA report says “a deletion in dystrophin gene involving multiple exon (8-16) was observed (exons 7 and 17 were present)”.
Please let me know its meaning if it is a case of DMD or BMD and how severe?
We really need your directions and treatment option available for him.
Thanks,
26 January, 2022 at 8:31 am
Exonskip
Dear Parv,
I am sorry to hear about your son having muscular dystrophy. For a deletion of exon 8-16 we would expect Duchenne, as the deletion disrupts the genetic code. However, whether someone has Duchenne or Becker mainly is determined by the symptoms. When did they start (for Duchenne signs are there at 2-4 years of age, difficulty climbing stairs and frequent falls and a waddling gate).
How your son will develop is difficult to predict. What I do know however, is that with optimal care the disease can be slowed down. You can find information on care for Duchenne here: https://treat-nmd.org/resources-support/care-overview/the-diagnosis-management-of-dmd/guide-for-families/
This must be a very difficult time for you. Note that patient groups are in place in many countries to help you with information and also to give emotional support.
If you have additional questions, please do not hesitate to ask here or on via email (a dot m dot rus ad lumc dot nl)
Annemieke
26 January, 2022 at 9:50 am
julio cesar
Dear Annieke
It´s anything new about exon 2 skipping?
24 January, 2022 at 11:21 pm
Dinesh Kumar
Respected Sir,
I have an eighteen years old son who is suffering from DMD ( Deletion of 45 exon ). Costly medicine Amondys can be given. Dr. in India does not want to prescribe it. What can I do to save the life of my son ?
Dinesh Kumar ( Punjab, India)
10 December, 2021 at 12:36 pm
Exonskip
Dear Dinesh,
I am sorry to hear about your son having DMD. Amondys (casimersen) is a compound that is only approved in the USA. It aims to make the genetic code readable by patient with specific mutations through skipping exon 45. This would NOT apply to your son unfortunately. A deletion of exon 45 means the genetic code is disrupted because exon 45 is absent. To make the genetic code readable again exon 44 or exon 46 would have to be skipped. There is currently no exon 44 or exon 46 compound in clinical development.
I’m sorry I do not have better news for you
Annemieke
10 December, 2021 at 2:12 pm
Abhishek
Hello dr my son is 5 year old and after test found exxon deletion 47-50 , exxon 46&51 were present, i am from india east coast, request treatment and any medication also if required would travel to us for treatment, please guide me am helpless at present due to my son illness
27 November, 2021 at 8:45 pm
Exonskip
I’m very sorry to hear about your son having Duchenne. The mutation would be eligible for exon 51 skipping. There is an exon 51 skipping compound approved in the USA (eteplirsen). However, that is based only on small increases in dystrophin expression (less than 1% after weekly intravenous infusions for over 3 years). The question is whether this will slow down disease progression. This is still being studied.
Eteplirsen treatment is not available outside of the USA as far as I am aware.
I am sorry I cannot be of more help.
Annemieke
29 November, 2021 at 10:43 am
John
Hello – what is the expected phenotype for a deletion of exons 46-48
Thanks for your help
22 November, 2021 at 12:57 am
Exonskip
Dear John,
A deletion of exon 46-48 is expected to result in Duchenne, because the reading frame (genetic code) is disrupted. Note however, that whether someone has Duchenne or Becker is decided by the symptoms and when they appear.
Best regards
Annemieke
22 November, 2021 at 9:05 am
Sundar
Hi Annemieke, my son is 3 years old this nov-21 in Singapore , and he has been diagnosed with DMD with Exon 46 & 47 deletions on the same day. We can’t explain emotions. We really need your directions and option available. What is the process to enroll for trials or how to get the medication which is available in any other country like USA. Any links would help.
14 November, 2021 at 7:40 am
Exonskip
Dear Sundar,
I am very sorry to hear about your son having Duchenne.
The most important thing to do now is to make sure you have access to good care. Care guidelines are available in family friendly form in many languages. https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/ We know that good care can slow down disease progression significantly.
The therapies that are approved in Europe and the USA are mutation specific. The only applying to your son’s mutation is casimersen (exon 45 skipping). Please note that this therapy is approved based on the restoration of very low levels of dystrophin (~1%). It is not yet known whether those small increases will be enough to slow down disease progression. That is something that is currently being evaluated in clinical trials (see https://clinicaltrials.gov/ct2/show/NCT02500381?term=casimersen&draw=2&rank=4). I do not know whether that trial also occurs close to Singapore. That is something you could ask the company developing casimersen (Sarepta). I would contact them on their website to ask about this: https://www.sarepta.com/
I am sorry I cannot be of more help to you. I will be praying for you and your family.
Annemieke
15 November, 2021 at 9:27 am
Carol Smit
I would love to make contact with Prof Dr Annemieke Aartsma-Rus. I have a 3 year old grandson with DMD . I live in South Africa where the only treatment is corticosteroids.
Thank you kindly.
Kind Regards
Carol Smit
4 November, 2021 at 10:01 am
Exonskip
Dear Carol,
I am sorry to hear your grandson has Duchenne. Please note that steroid treatment is what is available to most patients around the world. This slows down disease progression significantly but of course it is not without side effects.
There are drugs approved for Duchenne patients who carry specific mutations. In Europe and Russia: Translarna (ataluren) specifically for nonsense mutations.
In the USA and Japan: viltolarsen specifically for patients where the genetic code can become readable after skipping exon 53.
In the USA: eteplirsen, golodirsen and casimersen specifically for patients where the genetic code can become readable after skipping exon 51, 53 and 45, respectively.
Note that these drugs are not cures. They restore dystrophin production at a very low level and how much this will slow down disease progression is not yet clear.
To my knowledge these compounds are not approved or available in South Africa. Furthermore, whether your grandson would be eligible for these therapies depends on his mutation.
I am sorry I do not have better news for you.
Best regards
Annemieke
8 November, 2021 at 12:10 pm
Sridhar
My son age is 7, exon 54 out of frame deletion, is there any medicine for him?
2 November, 2021 at 8:01 am
Exonskip
I am sorry to hear your son has Duchenne.
Currently for his mutation there are no approved medicines.
What is available is multidisciplinary care aiming to slow down disease progression. You can find more about that here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/guide-for-families-in-different-languages/
Also there are many therapeutic approaches in development. You can find an overview of those here: https://treat-nmd.org/research-overview/dmd-research-overview/
8 November, 2021 at 12:05 pm
julio cesar
Dear Annieke
I have not all the informations of september 2021 WMS presentations, was any presentation about exon 2 skipping?
26 October, 2021 at 8:51 pm
Exonskip
I have not seen additional information on the exon 2 skipping trials either.
8 November, 2021 at 12:06 pm
Igor Sabic
Dear Prof. dr. Annemieke Aartsma-Rus,
Thank you for answers and guidelines. I do have more questions than answers.
1. Regarding to steroid therapy. Obviously next step is to apply deflazacort (Calcort). My question is; what is better steroid prednisone or deflazacort? What is yours experience. What are side effects to each one.
2. Exon 44 skipping – is in progress NCT04129294 (Nippon Shinyaku Co., Ltd.). My question is: do you have any other information regarding to/from development from other Pharmaceutical company. Do we have any in EU or worldwide.
Thank you for you time and answers.
Best regards
Igor
4 October, 2021 at 11:01 am
Exonskip
Dear Igor,
I am not an MD so do not have personal experience with different steroids (deflazacort vs prednisone). I know there are MDs who prefer one over the other (both for prednisone and deflazacort). There is a clinical trial ongoing (FOR-DMD) that compares the efficacy and side effect profile – the trial has completed and data is currently being analyzed. Hopefully that will shed more light on this question. For now the answer is that we do not know whether one is better than the other with regards to efficacy and side effects. What we DO know is that using either of them slows down disease progression significantly compared to no steroids.
I was not aware of the exon 44 skipping trial by Nippon Shinyaku. As far as I am aware this is the only trial with exon 44 skipping ongoing at the moment. I know Sarepta mentioned preclinical work on exon 44 skipping at patient conferences. Some of the newer companies are mentioning exon 44 skipping as well (e.g. Entrada). However, I have not heard of any plans for clinical trials yet.
Best regards
Annemieke
4 October, 2021 at 11:07 am
Ras
Hello dear dr.Annemieke
My 7-years -old son affected with Duchenne mascular dystrophy (deletion from exon 46 to 55, hemyzigote). Do you have any information about this mutation and avaliable treatments?
28 September, 2021 at 10:01 pm
Exonskip
Dear Ras,
I am sorry to hear about your son having Duchenne.
Your son cannot make dystrophin because the gene code is unreadable. An approach called ‘exon skipping’ aims to make the code readable again. This allows patients to produce shorter dystrophins that are partially functional. This is not a cure but hopefully something to slow down disease progression. Exon skipping is ‘mutation specific’ Depending on which exons are missing, different exons have to be skipped. Your son would need ‘exon 45 skipping’. There is a drug approved in the USA that induces exon 45 skipping (casimersen). Note that this drug is approved based on very small increased in dystrophin in treated patients (~1% dystrophin after 1 year of treatment). What is not yet known is whether these low amounts are enough to slow down disease progression.
In other parts of the world casimersen is not approved.
There are many therapies in development as well. You can see an overview here: https://treat-nmd.org/research-overview/dmd-research-overview/
Finally, good care is critically important for Duchenne patients. You can find more information about that here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/guide-for-families-in-different-languages/
Best regards
Annemieke
29 September, 2021 at 9:04 am
Igor Sabic
Dear Prof. dr. Annemieke Aartsma-Rus,
We are from Slovenia (EU).
My son all so affected from Duchenne Muscular Dystrophy (DMD) Exon 45 deletion.
He is 7 years old. Do you have any information regarding to the treatment coming.
Best regards
28 September, 2021 at 12:54 pm
Exonskip
Dear Igor,
I have recently updated the research overview (https://treat-nmd.org/research-overview/dmd-research-overview/). This explains how different therapeutic approaches work that are in or close to clinical trials and what the current stage of development is.
Currently there is no approved therapy available for your son in Europe. There are a number of clinical trials ongoing with compounds that aim to slow down disease progression. Givinostat and tamoxifen trials should have results shortly. We all hope that these results will be positive (the drugs are save and effective). However, clinical trials are conducted to evaluate this and unfortunately we have also seen clinical trials show that drugs were not effective or not safe.
With regards to mutation specific approaches: exon 44 skipping would restore the genetic code for your son. However, this is currently only in preclinical development.
Finally, good care is something with a proven track record for Duchenne. It can significantly slow down disease progression (later loss of ambulation, better respiratory function, better heart function). You can read more about optimal care here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/guide-for-families-in-different-languages/
Best regards
Annemieke
28 September, 2021 at 1:02 pm
Gaurav goyal
Hello,
My son affected from Duchene Muscular Dystrophy (DMD) Exons 46-47 deletion Now my son age is 7.5 years old. When will be the treatment coming.
18 September, 2021 at 6:38 pm
Exonskip
I am sorry to hear about your son having Duchenne.
What is currently available is multidisciplinary care. This applies to all patients and slows down disease progression.
What is approved in the USA: exon skipping. This applies only to specific mutations and so far we do not know if and how much this slows down the disease. Your son’s mutation would required ‘exon 45 skipping’. Casimersen is a drug that induces exon 45 skipping. However, it has only been approved in the USA at the moment. In other countries it is not yet approved or available (except in clinical trials). Note that while caismersen is approved, this is only based on the fact that it can restore very tiny amounts of dystrophin (the protein missing in Duchenne). Whether these tiny amounts will slow down disease progression is not yet know.
I am sorry I cannot give you better news.
Annemieke
20 September, 2021 at 9:21 am
Giorgio
thank you for mirroring the reality to us patients and keeping us away from marketing dissinformation.
Good luck on your work.
16 September, 2021 at 1:31 pm
Giorgio
greetings dr. im 25 affected by duchenne exon45 deletion at my age how effective is exon skipping ? and is there any skipping available for my mutation? i know there are comercial aons for 45 53 and 51. is it do Abble for 44 or 46?
16 September, 2021 at 12:00 pm
Exonskip
Exon skipping restores very low levels of dystrophin. As yet it is not known whether these levels will slow down disease progression – that is currently being studied for exon 45, 53 and 51 exon skipping compounds. What is known is that muscle function that is lost will not return. There are currently no exon 44 skipping compounds available or tested in clinical trials
Sorry I do not have better news for you.
16 September, 2021 at 12:27 pm
Shipra
Good morning
Please share some information about zolgensma.
Could it be helpful for kids with Becker’s muscular dystrophy ???
15 September, 2021 at 7:45 pm
Exonskip
Zolgensma is only applicable for patients with Spinal Muscular Atrophy. It provides motorneurons with a gene for the protein that is missing in SMA patients. This will not be helpful for Duchenne or Becker muscular dystrophy patients.
16 September, 2021 at 12:25 pm
Elisa
Dear Dr.,
I am a carrier of muscolar dystrophy with a 51-52 deletion. My newborn son genetic screening was positive. What type of MD we can expect him to have and how severe?
Please I need answers as I am devastated and desperate…
25 August, 2021 at 7:21 am
Exonskip
Dear Elisa,
A deletion of exon 51-52 does not disrupt the genetic code of the dystrophin gene. As such, it is expected to allow the production of a shorter, but partially functional dystrophy and be associated with Becker muscular dystrophy rather than the more severe Duchenne muscular dystrophy (which is caused by mutations that DO disrupt the genetic code). How severe the disease is is difficult to predict unfortunately – there is a lot of individual variation between patients with mutations that do not disrupt the genetic code from patients who experience the first symptoms in childhood or adolescence to those that experience first symptoms when they are in their forties or fifties.
I understand you would like to have more clear answers, but unfortunately I cannot give them to you. I’ll pray for strength for you and your family.
Annemieke
29 August, 2021 at 4:19 pm
julio cesar
it´s any new result of exon2 skipping,clinical trial?, I´m trying to receive any updates, even if you think that is a same questions, it´s not because the DMD life depends of time, that´s why every month i make you the same question, sorry.
24 August, 2021 at 2:07 pm
Exonskip
I am not aware of any updates on this trial. Hopefully there will be an update during the World Muscle Society meeting in September.
Don’t worry about asking this question again and again. I know time is of the essence for Duchenne.
29 August, 2021 at 4:13 pm
Shipra
Do you feel Givinostat is going to help patients with Becker muscular dystrophy in future?
10 August, 2021 at 4:33 pm
Exonskip
Dear Shipra,
We do not know this yet. Current givinostat is evaluated in clinical trials for Duchenne and Becker. These clinical trials will reveal whether givinostat has therapeutic effects in Duchenne and Becker patients. I hope it works, but we need to results of the trial to draw any conclusions.
Annemieke
11 August, 2021 at 7:44 am
Shipra
Hello Dr.Aartsma-Rus,
My 10 year old is hemizygous for a-243.88kb deletion within the DMD (NM-004006.2)gene.Deletion includes exons 45 to 48 with breakpoints in introns44 and 48.
Please tell me If it is mild or severeand what can I do for him ?
4 August, 2021 at 10:42 pm
Exonskip
Dear Shipra,
A deletion of exon 45-48 does not disrupt the genetic code of the dystrophin gene. As such one would expect this to be Becker muscular dystrophy (The milder form of the disease). However, there are exceptions. About 10% of patients with this type of mutations still develops Duchenne, the severe type of the disease.
Whether he has the mild or severe form depends on how his muscle function is. If he is 10 with Duchenne he would have great difficulty walking or be in a wheelchair.
Regardless of whether he has Duchenne or Becker, the best thing to do is to go to an expert clinic so he can receive the optimal care for Duchenne or Becker.
Best regards
Annemieke
5 August, 2021 at 7:26 am
Khan
Hello
How many nucleotides in each exon? Is there any table you can share ?
My son has deletion of exon 45 , 46 ,47 and 48.
45 and 46 has 176 nucleotides each.
How many in 47 and 48?
Thanks
4 August, 2021 at 7:49 am
Exonskip
You can find the number of nucleotides in each exons on the following website: https://www.ensembl.org/Homo_sapiens/Transcript/Exons?db=core;g=ENSG00000198947;r=X:31097677-33339609;t=ENST00000357033
You have to scroll down to see each exon – the table will say how long the exons are (and also the introns).
Exon 45 has 176 nucleotides
Exon 46 has 148 nucleotides
Exon 47 has 150 nucleotides
Exon 48 has 186 nucleotides
Best regards
Annemieke
4 August, 2021 at 8:39 am
A khan
Hello
First of all I sincerely re appreciate your responses and time given for answering to people who has indeed lots of questions.
My son 10 years old. He has hemizygous exon 45 to 48 deletion. This is “in frame deletion”. The result has made us so much worried.
He is doing well right now with some muscle pain and weakness. He scored 29 out of 34 on north star assessment and 38 out of 40 on hammersmith scale.
Is it DMD or BMD ? Dr has said that he has intermediate DMD.
What is the criteria in mutation for declaring someone with DMD or BMD?
Will he get benefit from exon skipping ? What exon need to be skipped for this?i thought he has in frame deletion so some protein is being generated.
What is western bolt technique ? to measure dystrophin in the muscles.
What about stem cell therapy, has this been tried on dystrophy patients anywhere?
Kjnd regards
A Khan
4 August, 2021 at 1:16 am
Exonskip
Indeed a deletion of exon 45-48 is in-frame. This means that in theory your son should be able to make a shorter dystrophin and as such one would expect him to have Becker muscular dystrophy. However, there are unfortunately exceptions to the in-frame means Becker rule. Whether your son has Duchenne or Becker or is intermediate depends on how he develops clinically. If he presents as a Duchenne, he has Duchenne, even with an in-frame mutation. I am not a clinician, so I cannot say if he has Duchenne or Becker – the treating clinician can do this. But it is based on his function and progression – not on his mutation.
The question is of course why your son has a more severe disease than would be expected. Western blotting is a technique that can measure if your son produces dystrophin and if so how much. For this a muscle biopsy is needed. This is painful and invasive – while knowing whether he makes dystrophin will not alter how he does clinically.
Since your son has an in-frame mutation, exon skipping is not an option. Exon skipping aims to make out-of-frame mutations in-frame on gene transcript level.
Stem cell treatment has been tried for many Duchenne patients but unfortunately so far without success. The problem is that muscle stem cells do not go to muscle when you inject them in the bloodstream and do not migrate far if you inject them into a muscle. If you use other stem cells, these can go to muscle from the bloodstream, but this is incredibly inefficient so you would get maybe a few stem cells in the diseases muscles – that is not enough to change the disease in those muscles.
Note that there are companies that claim that stem cells work for many diseases including Duchenne. There is no evidence whatsoever to support these claims so I would strongly advise against going for stem cell ‘therapy’.
Best regards
Annemieke
4 August, 2021 at 8:35 am
julio cesar
it´s any new result of exon2 skipping,clinical trial?
22 July, 2021 at 10:17 pm
Ahmad
Hello Professor My name is Ahmad I am 24 years old I was diagnosed with DMD at age 6. I have a deletion of 46-47. I just wanted to see what you thought I am using a wheelchair full time but I have very mild symptoms and still have strength to transfer and do most things my self and haven’t really progressed. Do you think it could be considered Severe Becker’s instead of Duchenne because we are still unsure. Also would Amondys 45 be beneficial in my case.
16 July, 2021 at 11:22 pm
Exonskip
Dear Ahmad,
A deletion of exon 46-47 is quite rare. This deletion disrupts the genetic code. Indeed exon 45 skipping would restore the genetic code, so Amondys45 (casimersen) should restore dystrophin production. Note that this drug was approved based only on dystrophin restoration. It is as yet unknown whether it will also slow down disease progression / have an impact on muscle function. That is currently evaluated in ongoing clinical trials.
Since you have a relatively mild progression, it is possible that your body already spontaneously skips exon 45 at a low level. However, that does not make you ineligible for Amondys45. Amondys is currently only approved by the FDA, so only available in the USA outside of clinical trials.
Best regards
Annemieke
19 July, 2021 at 9:10 am
Walaa samir
Hi my son has dmd with deletion 46-52 he is 13years old and use wheelchair are there any exon skipping drug for him
8 July, 2021 at 5:35 pm
Exonskip
A deletion of exon 46-53 would require the skipping of exon 45 AND exon 53. Only when both are skipped would the genetic code be restored. Exon 45 and exon 53 skipping drugs are approved in the USA (casimersen (exon 45) and golodirsen or viltolarsen (exon 53). However, double exon skipping is much more difficult than skipping a single exon. This is because only when both drugs make it to the same muscle fiber and even to the same dystrophin gene transcript will this be therapeutic.
The expected efficiecy of this would be very low – best case scenario it would be increasing dystrophin levels by 0.05% (1% (casimersen) of 5% (viltolarsen). Furthermore, the combination of both has never been tested so it is also not sure whether combining these drugs would be safe.
I am sorry I do not have a better answer for you. Hopefully one of the other therapeutic approaches in development (those that are not mutation specific) will be effective in slowing down disease progression.
Best regards
Annemieke
9 July, 2021 at 8:09 am
Alexandra
Dear Prof. Annemieke
My boyfriend was diagnosed with BMD- in his case exon deletion 45,46,47 (in frame)
We live in Europe
He is 28 years old now, has to be cautious while walking upstairs
1.Are there any possible clinical trials which would be helpful here in Europe
2.Neurologist told him that he will remain walking with mild problems – Is there any real evidence for this opinion (probably he was talking about it because his symptoms around his age were mild?…)
3.What we know about his deletion in general?
Regards
Alexandra
29 June, 2021 at 9:15 am
Exonskip
Dear Alessandra,
Becker muscular dystrophy (BMD) presents with variable severity – even for the same mutation. I know Luca Bello has studied a lot of Becker patients and he found that some deletions are presenting milder than others. I would email him to ask if indeed a deletion of exon 45-47 is one of the mild deletions.
1. There is a clinical trial with givinostat for Becker patients.
2. I am not a clinician so I am unable to answer this question, I would ask Dr. Luca Bello what he thinks.
3. We know this is one of the more common Becker mutations and that it is not associated with severe Becker muscular dystrophy. For more details I would againd defer you to Dr. Luca Bello.
Finally not that every patient is a unique individual. So when we say milder or more severe this is based on averages.
Best regards
Annemieke
29 June, 2021 at 10:11 am
Fatima
Hello,
Thank you for such feature helping us to understand further about DMD. I would like to know the feasibility of treating a DMD patient with Exon 1-2 deletion.
Regards,
22 June, 2021 at 6:12 am
Exonskip
Dear Fatima,
Currently approved therapies are mutation specifici. For a deletion of exon 1 or 2 the mutation specific approaches unfortunately would not work. Stop codon readthrough does not work for deletions. Exon skipping is not possible because exon 1 is deleted.
However, there are many approaches in clinical development that apply to all patients, e.g. micro-dystrophin gene therapy, improving muscle quality (with e.g. givinostat or tamoxifen). Should the clinical trials reveal these compounds are safe and effective, then they would apply to all patients.
Furthermore, there is multidisciplinary care. THis is something you can do now already and something for which it is proven that it slows down disease progression significantly. You can find more information about care here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/
Annemieke
22 June, 2021 at 9:34 am
Semra Turkum
Hello,
My brother is Dmd exon 53. I really want to help my brother. He is 21 years old.
Is there any medicine for exon 53?
18 June, 2021 at 8:52 pm
Exonskip
Dear Semra,
Unfortunately there is currently no cure for DMD. There are treatments that can slow down progression, such as corticosteroids.
There are also mutation specific treatments in development for Duchenne that aim to restore dystrophin protein – however, for now these it is not yet fully clear whether they slow down disease progression.
With regards to the mutation:
I assume you mean a deletion of exon 53? Or does he have a mutation inside exon 53?
I am very sorry I cannot offer more to your brother.
Best regards
Annemieke
19 June, 2021 at 10:34 am
Arid
Hello,
My son was diagnosed with DMD at the age 18 months and now he just turned 4 years. Exon deletion 45 46 47, is there any therapy for this deletion? Is this DMD or BMD
Thanks
11 June, 2021 at 9:28 pm
Exonskip
Dear Arid,
I’m sorry to hear about your son. For a deletion of exon 45-46-47 the genetic code of the dystrophin gene is readable, so we would expect this to result in Becker. However, there are exceptions. What is leading in deciding whether someone has Duchenne or Becker is the clinical presentation. If a patient presents with symptoms at an early age (2-3 years), he has Duchenne, regardless of whether the code is readable or not. So the question is whether you son has symptoms or whether this was a chance finding?
Best regards
Annemieke
14 June, 2021 at 8:59 am
Maria
Hello , my child has exons 44-45 deletion. We found it by genetically testing myself for something else and then also tested the child .Started walking at 10 months and now at 30 months old has no symptoms and the cpk levels are normal . Any predictions for the future ; I can not find others with this deletion .
1 June, 2021 at 8:29 am
Exonskip
Dear Maria,
First a disclaimer. I am not an MD, I am a researcher. I have a lot of experience with dystrophin and dystrophin mutations, but cannot give medical advice, only speculate based on what I know.
Is the child a boy or a girl? If it is a girl, I would not expect problems, since the dystrophin gene is located on the X-chromosome. That means she would have a backup copy (like you have). If it is a boy, this is the only copy he has, and there is a deletion in his only dystrophin gene. However, this deletion is expected to maintain the genetic code of the dystrophin gene. This means he would be able to produce a dystrophin protein that is partially functional. As such, one would expect Becker muscular dystrophy. This is a disease of varying severity, with some individuals having symptoms in childhood and others in midlife or even later. It is difficult to predict which type of Becker he would have, as sometimes there is variation even within a family.
In theory it is still possible to have Duchenne with a mutation that maintains the code – there are exceptions. However, if the CK is normal at 30 months, I think that can be ruled out.
I am sorry I cannot give more clear answers – hope you and your child stay well.
Annemieke
1 June, 2021 at 9:02 am
klein
Hallo Pr. Dr. Aartsma- Rus,
vielen, vielen Dank für Ihre Antwort, das ist schon große Hilfe .
Herzlichen Grüßen 🙂🙋🏻♀️
26 May, 2021 at 12:03 pm
Exonskip
Good to hear! And all the best!
Annemieke
26 May, 2021 at 12:18 pm
klein
Hallo noch mal , bei letzte Email habe ich Medikamente geschrieben und bei schicken das Wörter hat sich selba gewechselt auf Folgen 🙂.
Ich habe noch Fragen, welche Vitamine kann man einnehmen für Unterstützung:
-BISPHOSPHONATE, CARNITIN, ARGININ, CALCIUM, CITRULLIN oder was anderes ? Was meinen Sie ?
-VITAMIN-COCTAIL für Mitochondrien:
aus Q10, Thiamin, Riboflavin, Biotin ? Was meinen Sie ?
Mein Sohn gebe ich Q10, Vitamin B und D .
Danke voraus. Liebe Grüße🙂
25 May, 2021 at 9:10 pm
Exonskip
Please note that I am not a medical doctor but a researcher. This means I cannot give medical advise.
What I know from presentations on clinical care:
Bisphosphonate is used in patients who show osteoporosis or problems with bones.
Carnitin, arginin, calcium, citrullin: this has been evaluated in animal models and some also in patients but this has not shown large effects as yet
Vitamin cocktails and supplements etc: note that supplements seem harmless. However, because they have to fullfil less strict criteria than medicines, the concentrations of the vitamins etc can very. Also overdosing of these compounds can result in health problems and sometimes there are also toxic impurities inside. So be careful with these.
Annamaria de Luca and the world duchenne organisation published a scientific paper about the use of supplements. You can read this for free: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261230/
Best regards
Annemieke
26 May, 2021 at 8:52 am
klein
Hallo noch mal Pr. Dr. Aartsma- Rus,
ich wollte noch was Fragen , welche Medikamenten passt für Unterstützung unsere Krankheit:
-METFORMIN und L- ARGININ- verbessert Muskelkraft, EnergieStoffwechsel ?
-METFORMIN und L-CITRULLIN- Baustein von Eiweiß ?
-UTROPHIN- kompensiert Dystrophin und unterdrückt Myostatin ?
-ELAMIPRETID-schütz die Membran der Mitochondrien ?
-TAMOXIFEN-verbessert Muskelkraft und erhöht MembranStabilität der Muskelfibrille ?
-GIVINOSTAT- reduziert Fibrose ?
-TADALAFIL ?
-ETEPLIRSEN oder GOLODIRSEN ?
-CASIMERSEN – Sie haben geschrieben , das passt für uns , aber wo kann man das kaufen ,wenn in Europa noch nicht zugelassen ? Und das ist Medikament oder Spritze ?
-Micro-dystrophin Therapie ?
Danke voraus. Liebe Grüße.
25 May, 2021 at 8:54 pm
Exonskip
Metmorfin and combinations are evaluated in clinical trials at the moment – we do not know whether they will have a therapeutic effect
Utrophin upregulation was tested in clinical trials but these were stopped because no therapeutic effects were found.
Elamipretid: I do not know but things that improve mitochondria for Duchenne have therapeutic potential. Other compounds that do this are in clinical trials so we do not know yet if they are safe and effective.
Tamoxifen: tested in clinical trials – we do not yet know if it is safe or effective
Givinotat: currently tested in clinical trials – hopefully later this year we will learn whether this was safe and effective.
Tadalafil: was tested and did not show therapeutic effects.
Eteplirsen and golodirsen: approved in the USA by the FDA – however these skip exon 51 and exon 53 – your son needs exon 45 skipping
Casimersen: skips exon 45 and is approved in the USA but not yet in Europe. This means you cannot buy it – it is not marketed in Europe. This is because it is not yet known whether the treatment will slow down disease progression – it is only known that treatment increases dystrophin levels in tiny amounts. It is tested in clinical trials that are ongoing in Europe to hopefully show functional effects – however it is possible that the tiny amounts produced do not result in functional effects.
Microdystrophin therapy: this is not a therapy yet – it is tetsed in clinical trials. Sarepta and Solid have trials only in the USA, however, Pfizer is also doing trials in Europe and Roche will also initiate this in Europe (with the Sarepta gene therapy product).
I hope this helps
Annemieke
26 May, 2021 at 8:45 am
klein
Hallo Liebe Dr. Pr. Aarstma- Rus,
vielen Dank für die Antwort, aber ich noch Frage . Welche Therapie passt für uns:
-PTC ?
-AONS ?
-AAV- Genabgabe von U7-Ribonukleoprotein(snRNPs) ?
-GEN- Therapie ?
-ASO- Leserahmewiederhergestellt ?
– READ-THROUGH-Therapie ?
-CRISPR-CAS9 – (Base-Editing oder Meilenstein) ?
-mRNA- molekulare Therapie ?
-Micro- Dystrophin ?
Danke voraus . Liebe Grüße .
25 May, 2021 at 8:20 pm
Exonskip
For a deletion of exon 46-47
PTC/Ataluren does NOT work
AONs: exon 45 skipping would restore the genetic code and protein production (so this would apply)
AAV U7 would in theory work, but you would need AAV U7 genes that target exon 45 (these are currently not in clinical development)
Gene therapy (microdystrophin) applies to all patients independent of mutations, so that would also work
Readh-through is the same as PTC ataluren: would not work
CRISPR/Cas9: base editing would work in theory. One would have to edit the splice site of exon 45. However I do not know if this is possible (depends on genetic context).
mRNA: in theory would work – however producing dystrophin mRNA is very challenging because it is so long and delivering it to all muscles is also difficult
micro-dystrophin is the same as gene-therapy: would work.
NOTE that of the options you mention only ataluren and exon 45 skipping with AONs has received regulatory approval.
Gene therapy is tested in clinical trials so it is not yet know if it is safe and effective.
Crisper and mRNA are in the preclinical phase. So here it is not know if it will ever make the clinical stage.
Best regards
Annemieke
26 May, 2021 at 8:39 am
Abhilash V Rao
Dear Dr.Annemieke,
many thanks for your revert.
While going through some readings found that their is something known as Gene therapy which is one time solution for DMD, how do we get to know more about it & how soon this would be available for patients.
many thanks for your time.
Regards,
Abhilash
24 May, 2021 at 3:00 pm
Exonskip
Dear Abhilash,
Unfortunately gene therapy for Duchenne will not be a one time solution.
First gene therapy for Duchenne delivers a microdystrophin – this is a partially functional version of normal dystrophin. The gene is delivered to muscle fibers – it does not integrate into the DNA but floats around in the fibers and allows production of microdystrophin. What we do not know yet is how functional this will be in humans. We do know however that it is not fully functional. At best it will slow down disease progression.
Secondly, because the microdystrophin is not fully functional, with time muscle fibers will be lost and replaced by muscle stem cells. The viral vector used to deliver microdystrophin does not target the muscle stem cells. This means that with muscle turnover you will get less and less microdystrophin genes and less and less microdystrophin protein. What we do not know is how long this process will take.
Sorry to have to tell you this negative news.
Microdystrophin is currently tested in clinical trials for Duchenne by several companies (Pfizer, Sarepta and Solid). It is not known if and when it will be available. This depends on the results of the clinical trials.
Best regards
Annemieke
26 May, 2021 at 8:34 am
Hüseyin çul
What can you say about the positive results of the srp 9001 study announced by Sarepta in May? Also, I learned that there is a study in Japan for exon 44 skipping?
23 May, 2021 at 9:17 pm
Exonskip
There is a clinical trial for exon 45 skipping ongoing in Japan. This is coordinated by Daiichi Sankyo. The early results showed exon skipping but no dystrophin restoration yet. However, these were obtained in biopsies after 12 weeks of treatment. Results after longer term treatments are not yet in.
The Gene Therapy studies from Sarepta in May show that with their viral vector it is possible to safely and effectively deliver a microdystrophin in young Duchenne patients (4-7 years old). The levels of microdystrophin are very good (both total levels and percent of positive fibers). However, what we do not know yet is how functional microdystrophin will be in humans – we are waiting to see if the expression of microdystrophin slows down disease progression (hopefully it does). Furthermore, we know that the microdystrophin will disappear with time due to muscle fiber turnover (it is a partially functional protein after all – cannot fully protect fibers against damage). What we do not know is how long this will take. Hopefully decades but we just do not know yet.
26 May, 2021 at 8:29 am
klein
Hallo Dr. Annemieke
Frage : es gibt schon eine Therapie für Muskeldystrophie (Exon 46-47 out of frame deletation) neu Mutation ?
Und noch Frage : Medikament Idebenone hilft bei Muskeldystrophie oder ? kann man das einnehmen ? oder es gibt was anderes ?
Danke voraus.
Beste Grüsse .
19 May, 2021 at 7:08 pm
Exonskip
Good morning,
I hope you do not mind me replying in English – I understand German but do not speak/write it well. For a deletion of exon 46-47 in theory the skipping of exon 45 would restore the genetic code and allow production of Becker-type dystrophin. Exon 45 skipping is approved in the USA (casimersen developed by Sarepta). This is based on very minor increases in dystrophin levels in treated patients – it is not yet known whether this will slow down disease progression. Casimersen is not approved in Europe.
Idebenone has been tested in placebo controlled clinical trial. Although early phase results seemed promising, larger clinical trials showed no therapeutic effect of idebenone treatment in Duchenne patients. This development has therefore been stopped by the company developing idebenone for Duchenne (Santhera).
What is more important for Duchenne patients is to provide multidisciplinary care. There are guidelines for this – also translated into German. For more information see: https://treat-nmd.org/family-care-guide/2018-dmd-family-guide-in-german/
There are many therapies in development – an overview can be found here: https://treat-nmd.org/research-overview/dmd-research-overview/
Unfortunately this is outdated. I hope to update this soon. For more up to date information you can also have a look at the website of parent project muscular dystrophy. https://www.parentprojectmd.org/
I hope this information is helpful to you.
Annemieke
20 May, 2021 at 9:01 am
Abhilash V Rao
Dear Dr. Annemieke,
Hope you & your family is safe!!
My Son is 5 years old & is detected with Hemizygous deletion of exons 45 – 50 & is mentioned as Out-Of-Frame deletion in the report.
1)How severe it is.
2) Do we have any treatment for it, Does Exon skipping can reduce the issue or do we have any medication for this.
3) How can the progress of this be reduced.
We are very anxious & worries as a parents, looking for your response.
Best Regards,
Abhilash
6 May, 2021 at 3:08 pm
Exonskip
Dear Abhilash,
I am very sorry to hear about your son having a deletion. This deletion disrupts the genetic code, so it would be expected to lead to Duchenne (the severe form of the disease).
Exon 51 skipping would restore the genetic code and allow production of a partially functional protein, like those found in Becker patients. An exon 51 skipping drug has been approved in the USA (eteplirsen developed by Sarepta). Note that this drug has been approved based only on restoring dystrophin in patients and that it restored very low levels of dystrophin (<1%). Whether this is sufficient to slow down the disease progression is something that is currently being evaluated in additional clinical trials.
The progress of the disease can be reduced by providing multidisciplinary care - this can slow down the disease a lot. More information about this can be found here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/
Note that this would be in addition to potential treatment with eteplirsen.
Best regards
Annemieke
6 May, 2021 at 4:03 pm
Hawkar
Thanks very much fir helping me
But i just have one other question
Can i use (Deflazacort) and (Prednisone) is that do any improvements to my muscles strength ?
Its my second comment for knowing
Thanks again
30 April, 2021 at 2:10 am
Hawkar
Hi
I have exon skipping 3-4 – deletion
Iam 29 years old
What can we do? what type of treatment or drugs available to using?
29 April, 2021 at 8:00 am
Exonskip
Helloj,
A deletion of exon 3-4 is in-frame and therefore one would expect this to result in Becker muscular dystrophy. There is currently no cure for Becker. Recently treatment guidelines were developed in Italy and these are currently being translated. You would have to inquire with the Italian Parent Project about these (http://parentproject.it/). There are also several clinical trials ongoing in Becker patients, e.g. givinostat (Italfarmaco) and a compound to improve mitochondria (the energy producers of the cells) by Empirio. There were presentations about these trials at the Italian Parent Project meeting in February – the meeting was virtual and the presentations should still be viewable ( http://conferenza.parentproject.it/).
I am sorry I cannot be of more help
Best regards
Annemieke
29 April, 2021 at 9:09 am
Radhu
Hello Maam
My Son, 4 year old has been diagnosed with Hemizygous deletion of Exon 45 Out of frame, How severe is that, what should I do right now ? Will Amondys 45 (casirmersen) be an option?
Thanku in Advance.
14 April, 2021 at 2:45 pm
Exonskip
I am sorry about your son having a deletion in the dystrophn gene. A deletion of exon 45 will disrupt the genetic code of the dystrophin gene. Therefore this is expected to lead to Duchenne. Amondys45 will not be therapeutic – this is a drug that induces exon 45 skipping to restore the genetic code. In your son’s case, this exon is not present (deleted), so it cannot be skipped. Restoring the genetic code would require exon 44 skipping. Compounds for exon 44 skipping are in preclinical development but not yet tested in clinical trials.
Amongst all this bad news, also some good news: patients who need exon 44 skipping on average has a slower disease progression than ‘other Duchenne patients’, because of spontaneous exon 44 skipping at very low levels.
What you should do right now is make sure your son receives good care at an expert Duchenne center. You can find more information on care here: http://www.dmd-guide.org/
Please do not hesitate to ask if you have more questions.
Warm regards
Annemieke
15 April, 2021 at 9:37 am
Peter
Hello,
My son, 10 years old, has been diagnosed with exon 2 duplication. How severe is that? What are the possible prognosis for his disease? What can be done to slow down the illnes? Any chances of an effective treatment? He is an active boy but signs of the illness are already starting to appear. He’s able to walk for a long time. He’s playful but has studying problems. He’s not able to concentrate for long periods and he’s been having problems such as not being able to memorize the multiplication table or learning his lessons. He has occasional anger issues for no apparent reasons. Besides that he’s bright minded and has lots of other interests where he’s learning quite well. I’ve been searching the internet for all possible information but would like to hear your opinion and advice. We live in Bulgaria and healthcare is not the best but we’re willing to do whatever it takes so that our boy has a normal life. Thank you in advance!
Regards, Peter
1 April, 2021 at 8:45 am
Exonskip
Dear Peter,
I am sorry to hear your son has a duplication of exon 2. Every patient with mutations in the dystrophin gene is unique and there is variation even between patients with the same mutations so it is difficult to give predictions or prognosis.
What you can do is make sure your son receives optimal care. There are care guidelines for Duchenne muscular dystrophy – you can find them here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/guide-for-families-in-different-languages/ This is a version that is accessible also to lay people and translations in many languages are available now.
There are currently a few treatments approved for DMD in Europe and the USA and Japan. However, they are all mutation specific and would not apply to an exon 2 duplication unfortunately. In the USA a clinical trial is ongoing specifically for exon 2 duplications – this one uses gene therapy to try and restore the readability of the dystrophin gene. I do not know whether this is open only for patients in the USA and what the inclusion criteria are. You can find more information about this here: https://clinicaltrials.gov/ct2/show/NCT04240314?term=exon+2&cond=Duchenne+Muscular+Dystrophy&draw=2&rank=1
Learning difficulties are common in Duchenne patients. Dystrophin is also present in the brain and lack of this causes amongst others the problems you describe (automization and focusing). So this is part of the disease. There are studies done into how to best deal with these learning difficulties. Jos Hendriksen is a Dutch neuropsychiatrist who has done work on this.
I am not a clinician so I cannot advise on medical treatments. However, what I’ve learned from Duchenne patients is that they appreciate it if their parents treat them like normal boys/men even if there may be impediments (e.g. also helping with chores, but then those that they could do).
If you look for inforation, I suggest also starting with the World Duchenne Organization. This is a collaborative effort of the Duchenne Parent orginisations around the world https://www.worldduchenne.org/. You will be able to find a lot of information there.
Take care and do not hesitate to ask other questions either here or via email (a dot m dot rus at lumc dot nl).
Annemieke
1 April, 2021 at 10:15 am
Agnetta
Hello Maam ,
I’ve heard of Gene therapy treatment for DMD. Which will be coming soon . I just want to know the status of it ? How long will it take for a common man to access it ? Is it a one time treatment ? My son is 4 yrs old . What should i do right now , go for a steroid as of now ? Go for exon skipping as well ?? Or wait till he gene therapy is been approved? Thank you Maam
31 March, 2021 at 5:29 pm
Agnetta
Hello Madam ,
My son is 4 yrs old . He has been diagnosed with DMD. We have visit few doctors and they have suggested for the exodys 51 therapy as his deletion is 45-50. I just want to know how effective is this ? Are there many side effects ? When can i start my sons therapy as in, right now or when we see some symptoms in future ? How successful is this treatment in the world? Pls give me your opinions Doctor. Thank you
27 March, 2021 at 2:29 am
Exonskip
Dear Agnetta,
I am sorry to hear about your son being diagnosed with DMD.
Indeed for a deletion of exon 45-50, exon 51 skipping can restore the genetic code and dystrophin production. Exondys51 is a drug that induces exon 51 skipping. It is approved in the USA for all patients with eligible mutations (so no age specified), but not yet anywhere else. For now it is approved based only on the fact that the protein that is missing in Duchenne (dystrophin) is restored at very low levels. What is not yet known is whether these low levels are sufficient to slow down the disease progression. This is something that is still being evaluated in clinical trials around the world. As far as I am aware, exondys51 does not induce a lot of side effects. It needs to be delivered via intravenous infusion once weekly.
I am sorry I cannot give you more information than this. In summary: exondys51 is only approved in the USA, we know it restores dystrophin a minute amounts but we do not yet know whether this will have an effect on disease progression.
Best regards
Annemieke
29 March, 2021 at 10:26 am
julio cesar
it´s any recently news about DMD exon 2 skipping research?
22 March, 2021 at 10:33 pm
Exonskip
I am not aware of any updates.
23 March, 2021 at 10:42 am
Mistu ghosh
My son has exon 44 deletion out of frame, what is the treatment for him, though he is having defcort at present and he is 8 years old now, will exon 45 skipping be an option? if so how it will work? please give your valuable reply
16 March, 2021 at 3:26 pm
Exonskip
Dear Mistu
First of all it is important to give your son optimal care – like you are doing, with corticosteroid treatment.
Duchenne is caused by the dystrophin gene being unreadable for the protein translation machinery. The exon skipping approach aims to make the code readable so a partially functional dystrophin can be produced rather than no dystrophin at all. For a deletion of exon 44, exon 45 skipping would restore the genetic code. Exon 45 skipping can be achieved by casimersen. This compound is approved by the FDA since last month. However, the approval was based only on dystrophin restoration. What is not yet clear is whether the low amounts of dystrophin restored by casimersen will slow down disease progression. Clinical trials are ongoing to evaluate this at the moment. If you live in the USA you could request casimersen treatment (with the caveat that it may not slow down disesae progression while it is a weekly intravenous infusion). Outside of the USA you could consider taking part in a clinical trial with the caveats that 1) it may not slow down disease progression 2) there are additional burdensome evaluations involved in clinical trial participation.
You can find more on the casimersen clinical trial here: https://clinicaltrials.gov/ct2/show/NCT04179409?term=casimersen&cond=Duchenne+Muscular+Dystrophy&draw=2&rank=2
Best regards
Annemieke
16 March, 2021 at 3:51 pm
Milka M
Hello.
My son has DMD gene duplication 18-44. He is 7 yrs now. We are still not taking steroide because of possible side effects, but we decided to start with DEFLAZACORT. Once Vomorolone is available in Slovenia, we could continue with that.
What is the prognosis for my son’s mutation I would like to ask You about gene therapies currently in clinical trials and whether any of this would be an option for him. Would CRISPR Cas9 be the option for him? Or exon skipping 45 Casimersen? I would also like to ask about dosing steroide, do you recommend more daily or weekend dose.
Thank You very much for your answers.
Best regards
14 March, 2021 at 10:24 pm
Exonskip
Dear Milka
I am sorry to hear about your son having DMD. Hopefully vamorolone will turn out to be a safe and effective alternative to corticosteroids (it is currently tested in clinical trials).
It is difficult to say anything about the prognosis. Especially large duplications, such as the one your son has, are known to not follow the rules, meaning that it is possible he will have a slower progression but also that he will have typical DMD progression. The only way to find out is to see what happens when he grows older. I’m sorry I cannot say more about this.
For your questions:
I am not an MD so cannot give you a recommendation about the dosis regimen of corticosteroids. You have to discuss the pros and cons with your treating physician and then make your own decision I’m afraid.
Micro-dystrophin gene therapy would in principle apply to your son (it is not mutation specficic). Currently this is only tested in clinical trials.
Casimersen would in theory also work – however, because large duplications often do the unexpected in the process from gene to transcript to protein, and the exon skipping approach (casimersen) influences the process of transcript formation, it is not a guarantee that after exon skipping, your son would make dystrophin. Likely this is something that first would have to be tested. Note that casimersen is only approved in the USA and not in Europe. Clinical trials are ongoing worldwide though.
Finally the CRISPR Cas9 option: first note that CRISPR Cas9 is currently in preclinical studies as a whole. So there is no disease for which this technique has been approved. There are many unknowns for now about safety (because it causes irreversible changes in the DNA). In theory editing out the duplication would restore the normal dystrophin transcript and protein. However, because the duplication is so large, this would likely not be very efficient. Much more preclinical research is required for this.
I am sorry I cannot give you more positive answers.
Annemieke
15 March, 2021 at 8:15 am
SANJA
Dear Annemieke ,my son is 6.5y old. He is in Vamorolone study and he is doing great. We have not seen any side effect so far. He has a frequently mutation, DELETION OF EXON 44.
I am wondering if you know what is prognosis of this mutation (deletion of exon 44) in Dystrophin gene? I am also interesting on Casimersen for my son, what is your opinion on this treatment?
Thank you very much for your ansvers.
Kind regards, Sanja
11 March, 2021 at 10:32 am
Exonskip
Dear Sanja,
Happy to hear your son is doing so well! For a deletion of exon 44 I would expect typical DMD. However, you are probably aware that there is no such thing as typical DMD, but that there are patients who progress faster than others. Likely this is due to a combination of genetic factors – the majority of which we have no idea about. Sorry I am so vague, but this is the best answer I can give you.
Casimersen has been approved by the FDA for use in DMD patients with eligible mutations (such as indeed a deletion of exon 44). The approval is based only on dystrophin restoration (of ~1% after a year of treatment). What is not yet know is whether this low amount of dystrophin restoration is enough to slow down the progression of the disease. Currently ongoing clinical trials are done to test this. So we know the therapy works in that it restores dystrophin, but we do not know yet whether this will have a therapeutic effect (slower disease progression). Note that the treatment involves weekly intravenous infusions so this is more burdensome than vamorolone (tablet).
Best regards
Annemieke
12 March, 2021 at 12:43 pm
Hits
Exon 45 to 51 deletion treament are available……
8 March, 2021 at 7:58 pm
Exonskip
A deletion of exon 45-51 does not disrupt the genetic code. So this deletion is expected to result in Becker muscular dystropy. There are currently no approved drugs for Becker but several are in development. The Duchenne Parent Project Onlus from Italy recently had a session on Becker therapy development during their virtual meeting (see http://conferenza.parentproject.it/).
If the mutation is found in a patient with Duchenne (so severe symptoms already at 3-4 years old), something strange is happening to prevent this individual from making dystrophin. For mutation specific approaches, this first has to be elucidated. However, there are also approaches in clinical trials that are not mutation specific (e.g. AAV micro-dystrophin gene therapy, givinostat, vamorolone etc). You can find an overview of these approaches here: https://treat-nmd.org/research-overview/dmd-research-overview/ (I hope to soon be able to update this). Updates can also be seen using the link to the Italian parent project conference.
Annemieke
9 March, 2021 at 10:40 am
Sheila newby
Hi my son has duchenne muscular dystrophy he is nearly 5 he has deletions 46/47 is there any treatment for him at the moment ?
4 March, 2021 at 1:59 pm
Exonskip
Dear Sheila,
A deletion of exon 46-47 disrupts the genetic code. The code can be made readable by exon 45 skipping. In the USA a drug for exon 45 skipping was approved on Feb 25 2021 (casimersen). Outside of the USA, Sarepta (the company developing casimersen) is conducting clinical trials with casimersen.
Note that the approval was only based on the ability of casimersen to restore very low amounts of dystrophin (1%). Currently ongoing trials are needed to see if this also results in a slower disease progression.
Please do not hesitate to ask me additional questions should you have them
Annemieke
4 March, 2021 at 2:44 pm
Sara
My son is 13 he has deletion exon 43, would exon skipping 44 be suitable for him ,diagnosed age 9
1 March, 2021 at 2:33 pm
Exonskip
Dear Sara,
Exon 44 skipping would restore the genetic code for an exon 43 deletion. Please note however that exon 44 skipping is currently in a preclinical development stage.
Best regards
Annemieke
1 March, 2021 at 2:45 pm
Shilpa Sethi
Dear Dr. Aartsma-Rus,
My son 15 year old is DMD. His exon 45 is deleted. I came to know that he is amenable to exon 44 skipping. I need to know about the progress of any research going on for 44 exon skipping
Regards Shilpa
1 March, 2021 at 11:39 am
Exonskip
Dear Shilpa,
Indeed exon 44 skipping would restore the genetic code for an exon 45 deletion. However, exon 44 skipping is currently not evaluated in clinical trials. During the most recent presentation by Sarepta at the Italian Duchenne Parent Project however, they mentioned that exon 44 skipping is in preclinical development: http://conferenza.parentproject.it/schedule/ The video should be available on youtube.
If and when exon 44 skipping compounds will be tested in clinical trials is not known yet.
Best regards
Annemieke
1 March, 2021 at 12:58 pm
Maria Lujan
Hello, my son is 9 yrs old and has DMD nonsense mutation on exon 44. Is exon skipping an option at this time?
26 February, 2021 at 4:14 am
Exonskip
Dear Maria,
No exon skipping is not an option. If we skip the exon with the nonsense mutation (exon 44), this will cause a frame-shift. In other words, skipping this exon will make the code unreadable. So that will not improve matters, because still no dystrophin can be produced.
However, ataluren/translarna is a drug that is approved to treat ambulant Duchenne patients with nonsense mutations in Europe and several other countries as well. Depending on where you live, this may be an option.
Best regards
Annemieke
1 March, 2021 at 12:56 pm
Camelia
Hi Dear Dr.Aartsma-Rus
My son has a point deletion on exon 45 out of frame.
I would like to know if at the moment are any ongoing trials for his mutation and if there is any chance for him to be accepted, considering that he is not walking anymore and his arms become weaker every day.
Thank you!
Kind Regards
Camelia Marian, Ianis’s mum
25 February, 2021 at 9:47 pm
Exonskip
Dear Camelia,
I am sorry to hear about your son having Duchenne. If he has a small mutation within exon 45 that disrupt the reading frame, he is unfortunately not eligible for mutation specific therapies that are currently in development. Translarna/ataluren only works for nonsense mutations (small mutations that maintain the reading frame). Exon skipping will not work either because if we skip the exon with the mutation (exon 45) that will not help, as skipping this exon will also be out of frame.
There are also approaches in development that are not mutation specific however. For some of them companies are planning trials also in non-ambulant patients. The most recent update on this was presented at the meeting of the Italian Parent Project. You can watch the presentations on youtube: http://conferenza.parentproject.it/schedule/
I am sorry I do not have a better answer for you
Annemieke
1 March, 2021 at 12:54 pm
Mr Singh
Hello Dear Dr. Aartsma-Rus
My Three year Son has been told he has (( hemizygous duplication of exon 3-4))
What does this mean ?
kind regards
24 February, 2021 at 7:56 pm
Exonskip
Dear Mr Singh,
I am sorry to hear your son has a mutation in his DMD gene. A duplication of exon 3-4 means these exons are present twice. The question is whether this mutation was found because your son has symptoms of Duchenne, or whether it was found by chance. The reason I ask is that duplications can cause Duchenne, but also Becker or no disease at all. If you want to provide me more information, you can also email me direction at a dot m dot rus at lumc dot nl.
Finally, I’ll explain what hemizygous means. Our genes are located on chromosomes. We have two copies of each chromosomes – one from our father and one from our mother. This means that we have two copies of each genes as well. When both genes are the same, we say this is ‘homozygous’, when they are different we say ‘heterozygous’. There is one exception: the sex chromosomes. Females have two X-chromosomes, while men have an X and a Y chromosome. This means that men have only one copy of each gene on the X-chromosome. The dystrophin gene is located on the X-chromosome. When there is a mutation or variation in the X-chromosome in a man, this is called hemizygous.
25 February, 2021 at 10:51 am
julio cesar
thanks by your fast answer, best regard.
19 February, 2021 at 3:53 pm
Jia
Dear Dr. Aartsma-Rus,
My family member (male, 9.5 years) has been diagnosed with DMD very recently. His deletions are exons 10-43.
1) Do these deletions mean that he is amenable to exon 44 skipping only?
2) Are there any current treatment options (besides steroids) or trials in the foreseeable future that he may qualify for?
3) We have come across some research that indicates that patients that are amenable to exon 44 skipping may have delayed loss of ambulation as compared to patients that are amenable to certain other types of exon skipping. What are your thoughts on that?
As you can imagine, we are very eager to better understand this disease and explore all treatment options.
Thanks very much in advance!
18 February, 2021 at 7:34 pm
Exonskip
Dear Jia,
1. When considering exon skipping, indeed only exon 44 skipping would restore the genetic code.
2. There are many different therapeutic approaches in clinical development that do not depend on the mutation. e.g. AAV-microdystrophin gene therapy and compounds to improve muscle quality. See this overview that I hope to update soon – still it will give you an idea of the different approaches currently in clinical trials. https://treat-nmd.org/treat-nmd-diseases/duchenne-muscular-dystrophy/#research-overview-link
3. The finding that exon 44 skippable patients have on average a slower disease progression has been found in different independent cohorts in different countries. So I am convinced this is a true thing. However, these analyses look at averages. On average exon 44 skippable patients have a slower disease progression than those that have other mutations. That means it is still possible that a poor performing exon 44 skippable patient does worse than a good performing ‘other’ patient. Hopefully your family member is a good performing exon 44 skippable patient though.
Best regards
Annemieke
19 February, 2021 at 11:22 am
julio cesar
it´s any new research results of a exon 2 skipping?, I was looking for in any DMD research page but i´m not find anything new about it
18 February, 2021 at 4:27 pm
Exonskip
Dear Julio,
Apologies for not updating the DMD research page. It is on the to do list. What has been presented at meetings is that 2 DMD patients have been treated with the AAV U7snRNP (the exon 2 skipping antisense ‘gene’). Biopsies were taken and dystrophin was seen at low levels (~2% in one and ~8% in the other patient). This was presented last October at the WMS meeting and I have not heard of an update since.
Annemieke
19 February, 2021 at 11:17 am
Eyad
Hi,
My friend’s son 8 years boy has deletion of exons 45 – 47, would you kindly advise available treatment options? Thanks
15 February, 2021 at 3:09 am
Exonskip
Dear Eyad,
This is an in-frame deletion, meaning that it does not disrupt the code. As such, Becker muscular dystrophy would be the expected disease. However, exceptions do occur, so if the disease looks like Duchenne (difficulty with walking and stair climbing from 2-3 years of age), he would have Duchenne. Depending on the disease, care would very. For Duchenne guidelines for care are in place. For Becker this is not the case to my knowledge. In either case, he should be seen by a neuromuscular specialist.
Therapies for Duchenne that are approved are all mutation specific. Unfortunately, there is no specific treatment for this mutation.
Annemieke
15 February, 2021 at 8:35 am
Susanna
Dear Professor!
My 7 month old grandchild was diagnosed with DMD( 45 exon deletio).
I know we have a few good years, but we need a safty trial for a future.
I heard about Viltolarsen to exon 53 skipping.
Wich exon skipping is working for 45 exon deletio?
Thank you for your answer
Best regards
Susanna
24 January, 2021 at 10:34 pm
Exonskip
Dear Susanna,
I am sorry to hear your grandchild was diagnosed with DMD. With optimal care, there will be many good years. However, I understand you are also looking into treatment options.
The exon skipping approach aims to make the genetic code for the dystrophin protein readable. In DMD, this code is mutated making it unreadable. By making it readable the muscle can produce a shorter but partially functional dystrophin protein, which is better than no dystrophin protein at all.
This approach is however mutation specific. So depending on where the code is mutated, different exons have to be skipped to make the code readable.
Viltolarsen (exon 53 skipping) will not work for an exon 45 deletion. Rather, exon 53 skipping for a patient with an exon 45 deletion, will make the code even more unreadable.
There are two other exon skipping drugs approved in the US: golodirsen (also exon 53 skipping so same story) and eteplirsen (exon 51 skipping, which unfortunately also does not work for an exon 45 deletion).
Casimersen is in development for exon 45 skipping. FDA will discuss the approval (or not) of this compound in February this year. Exon 45 skipping will unfortunately also not help for your grandchild’s mutation. He does not have exon 45, so it is not possible to skip it.
To make the code readable for an exon 45 deletion, exon 44 OR exon 46 should be skipped. I know Sarepta is working on preclinical studies for exon 44 skipping but I have not heard them present plans to move this into clinical trials. Other exon skipping companies may also work on exon 44 skipping.
I am sorry I cannot give you more positive news. Please note that there are also many therapeutic approaches evaluated in trials that do are not mutation specific. These target all Duchenne patients.
Warm regards and do not hesitate to contact me if you have any further questions
Annemieke
25 January, 2021 at 10:45 am
Amro Mejri
Hello!!
I’m from Tunisia, I was diagnosed when I was 10 years old as having DMD (and now I’m 21) , and they said that I don’t have any deleted or duplicated exons, I just have a mutation in some of them (one or more)
but they don’t know exactly which one, because they couldn’t continue their analysis back then.
So, now after I heard about the recently approved method (which is “exon skipping”) I wanted to ask you if you can guide me so I can reach an hospital in any country to take this method (the government of my country will take care of the price if it very high, so you just have to guide me, if you want)
Thanks in advance.
16 January, 2021 at 1:51 pm
Exonskip
Dear Amro,
Exon skipping is a mutation specific approach. Duchenne is caused by mutations that make the genetic code of dystrophin unreadable. Exon skipping aims to make the code readable again. Which exon needs to be skippend and whether exon skipping will work at all depends on where the mutation is. For now exon skipping is used only for patients with deletions and duplications. So for your mutation this will unfortonately not work.
There is another approach, nonsense codon read through, that works for a subset of small mutations (i.e. those that are nonsense mutations). However, to know whether you would be eligible it is crucial that you know your excact mutation is. So my first advise would be to have them identify this. Note that 10 years ago finding small mutations was challenging, while now it is easier. Also for laboratories that cannot do this analyisis themselves, there are opportunities to send the DNA to other labs that can do this type of analysis.
I hope this helps.
Annemieke
18 January, 2021 at 8:59 am
Suniel Singh Makh
My friends son has been diagnosed with Duchenne. Missing exon 51
Is there treatment you can offer to help?
14 January, 2021 at 8:12 pm
Exonskip
Dear Suniel,
I am sorry to hear about your son’s friend being diagnosed with Duchenne. This disesae is caused by mutations in the dystrophin gene that make the code unreadable. Therefore no dystrophin protein can be produced. Since dystrophin has a stabilizing function in muscle during contraction, muscle lacking dystrophin are very sensitive to damage and this results in Duchenne patients gradually losing their muscle tissue and function.
At the moment there is no cure for this disease. However, the disease can be slowed down by using good care. There are care guidelines that you can find here.https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/guide-for-families-in-different-languages/
In addition, therapies are in development for Duchenne and some are already approved. You can find an overview here: https://treat-nmd.org/research-overview/dmd-research-overview/(I hope te be able to update this soon). The currently approved therapies are all mutation specific. This means they only work for some mutaitons. Unfortuantely, none of these approved therapies work for a deletion of exon 51.
Eteplirsen is a compound that induces exon 51 skipping and that way makes the dystrophin gene code readable again. However, because your friends’ son does not have exon 51, this exon cannot be skipped (it is already missing). Golodirsen and viltolarsen induce exon 53 skipping. However, exon 53 skipping does not make the code readable for a deletion of exon 51. Finally, ataluren makes the cell ignore premature stop signals. This works only for a specific type of mutation (premature nonsense mutations), and not for exon deletions.
I am sorry I cannot be of more help.
Annemieke
15 January, 2021 at 8:38 am
Andreea
Hi, my son has been diagnosed with DMD. He is 11 month old. He’s exon missing is exon 51. Is there any treatment for this ? On the letter is saying loss, encompassing 51. What dose this exactly means? Is an exon missing and is there anything I can do?
Please help
14 January, 2021 at 6:47 pm
Exonskip
Dear Andreea,
I am sorry to hear about your son being diagnosed with Duchenne. This disesae is caused by mutations in the dystrophin gene that make the code unreadable. Therefore no dystrophin protein can be produced. In your son’s case, the code becomes unreadable because one of the coding pieces (exons) is missing. The exons fit together like puzzle pieces normally. Due to exon 51 missing, they do not ‘fit’ and the code becomes unreadable and the muscles cannot translate the code into dystrophin protein.
At the moment there is no cure for this disease. However, the disease can be slowed down by using good care. There are care guidelines that you can find here.https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/guide-for-families-in-different-languages/
In addition, therapies are in development for Duchenne and some are already approved. You can find an overview here: https://treat-nmd.org/research-overview/dmd-research-overview/(I hope te be able to update this soon). The currently approved therapies are all mutation specific. This means they only work for some mutations. Unfortuantely, none of these approved therapies work for a deletion of exon 51.
Eteplirsen is a compound that induces exon 51 skipping and that way makes the dystrophin gene code readable again. However, because your son does not have exon 51, this exon cannot be skipped (it is already missing). Golodirsen and viltolarsen induce exon 53 skipping. However, exon 53 skipping does not make the code readable for a deletion of exon 51. Finally, ataluren makes the cell ignore premature stop signals. This works only for a specific type of mutation (premature nonsense mutations), and not for exon deletions.
I am sorry I cannot be of more help. If you have additional questions, please do not hesitate to ask.
Annemieke
15 January, 2021 at 8:41 am
julio cesar
sorry, my question last December 22 was if anybody knows something a results of a two child’s already inoculate with the solution of an exon 2 duplication.
In October 2020, Megan Waldrop said the encourage results but since them, nothing else was said by the nationwide children´s.
Best regard, Julio.
6 January, 2021 at 10:00 pm
Exonskip
I have only heard the results that were presented at the World Muscle Society meeting, where they found dystrophin restoration in two patients treated with the ‘exon 2 skip antisense gene therapy’. Low dystrophin levels were found in both patients (1-2% in one and 6% in the other patient).
Best regards
Annemieke
7 January, 2021 at 10:21 am
Mel
My 3 year old son was diagnosed with DMD we were advised he has a hemicigote genotype for a pathogenic variant of point-transition type and that eliminates to the Intron 5 splicing accepting canon site of the DMD gene. Do you have any info on this particular deletion?
Best regards
Mel
28 December, 2020 at 7:33 pm
Exonskip
Dear Mel,
I am sorry to hear about your son being diagnosed with DMD.
DMD is caused by changes in the DNA that cause the dystrophin gene code to become unreadable. Therefore, the dystrophin protein cannot be translated from the DMD gene.
The pieces of the gene that contain the genetic information for the dystrophin protein are called exons. These exons are recognized by the cells via specific ‘signals’, which are called splice donor and splice acceptor site. In case of you son’s mutation, one of these signals is not functionig, i.e. the spilce acceptor site in intron 5. This intron is located between exon 5 and exon 6. The splice acceptor site of intron 5 in involved in the recognition of exon 6. When the acceptor site does not function properly, the exon involved is not recognized by the cell. Therefore, when the exons are joined together by the cell, in case of your son, exon 6 is not included. This causes the protein code to become unreadable and therefore no dystrophin is produced by your son’s muscle cells.
There are many therapies in development for DMD. Some are approved already – however, these are ‘mutation specific’ therapies, meaning they only work for specific variants. There is no specific therapy for your son’s particular variant. However, there are therapies in development that apply to all variants. You can find an overview here: https://treat-nmd.org/research-overview/dmd-research-overview/
Furthermore, it is of the utmost importance that your son has access to the proper care – good care can delay the disease a lot. More information on the care guidelines in different languages can be found here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/guide-for-families-in-different-languages/
Best regards
Annemieke
4 January, 2021 at 11:50 am
julio cesar
por favor alguien puede decirme los resultados de la investigación que se está haciendo en dos niños en el nationwide children´s de ohio para la eliminación de la duplicación del exon 2 del gen de la distrofina
22 December, 2020 at 11:13 pm
Exonskip
I am sorry but I only speak english and dutch
Annemieke
4 January, 2021 at 11:50 am
Lyndsey Robinson
Hello,
Our son was diagnosed with BMD last year at almost 9 years old. We were advised he has a deletion of exon 3-4 in the DMD gene.
I have read conflicting information on the progression of this deletion, and if there are any treatments on the horizon to ease symptoms. Do you have any info on this particular deletion?
Regards,
Lyndsey
2 December, 2020 at 5:01 pm
Exonskip
Dear Lyndsey,
I am sorry to hear about your son’s diagnosis. Based on the genetic properties of exon 3 and 4, indeed Becker would be expected. This deletion does not disrupt the genetic code, so the transcript remains readable for the protein translation system and this will produce a dystrophin that is slightly shorter than normal, but has its crucial domains.
I have looked in our online database (www.dmd.nl) and found only two reports of this deletion – and they were very old. No information on the disease progression was given unfortunately.
From a dystrophin protein perspective I would expect this mutation to be associated with a more severe type of Becker (i.e. milder than Duchenne, but more severe than ‘typical’ Becker). The dystrophin protein connects two proteins in the muscle fiber, actin and dystroglycan. In this way the ‘skeleton’ of the fiber is connected to the protective layer surrounding each muscle fiber. For dystrophin to be functional it needs to be able to bind to these two proteins. Dystroglycan binding happens at the end of the protein (encoded by exons 64-70). Actin binding happens via 3 parts, encoded by exon 2-8 (part 1 and 2) and exon 32-45 (part 3). As long as you have 1 actin binding part the dystrophin is functional. However, the first 2 actin binding parts are most important (they bind best so to say). Your son’s mutation disrupts at least one of these actin binding parts – and it is possible that due to this the second part will also not work optimally (part 1 and 2 work together). This is why patients who have mutations affecting the first 2 actin binding parts generally have a more severe Becker disease and this is why I would expect this for a deletion of exon 3-4.
Having said all this: every patient is unique and everything is relative. There are examples of patients with mutations in the first 2 actin binding parts who have very mild Becker and there are patients who have mutations that leave all three actin binding parts in tact who still have severe Becker. We know what happens ‘on average’, but as I said each patient is unique and not ‘an average patient’. So it is always difficult to predict what will happen.
I’m sorry I am unable to provide you with more clear information about the disease progression.
With regards to therapies: Givinostat is a compound that is tested in both Duchenne and Becker patients in clinical trials. You can find more information on the trial in Becker patients here: https://clinicaltrials.gov/ct2/show/NCT03238235?term=givinostat&cond=Becker+muscular+dystrophy&draw=2&rank=1
Best regards
Annemieke
3 December, 2020 at 9:46 am
Aleksandra
Dear Prof. Aartsma-Rus,
I am a mother of a 10-month-old boy, while I was still pregnant, it turned out that my son has duplications of exons 45-48. I am a carrier. I searched the databases and found nothing. My son had CK levels and liver parameters checked and everything was normal so far. Can I ask you for help in understanding a few things: what can we expect? How could the location and type of our mutation theoretically affect the production of dystrophin? Are there any attempts to treat such mutations? Thank you for your answer and best regards from Poland
15 November, 2020 at 10:32 pm
Exonskip
Dear Aleksandra,
Unfortunately I am unable to tell you what to expect. There are several possibilities.
1. The duplication is located within the dystrophin gene. In this case this will disrupt the production of dystrophin. There are two ways in which mutations (genetic mistakes) can do this. First they can make the code unreadable. Then no dystrophin can be formed and individuals will develop Duchenne. Secondly, the code can remain readable. Then individuals can still form a dystrophin, only it is altered from what is normal. These altered dystrophins are partially functional and found in individuals with Becker.
A duplication of exon 45-48 is expected to keep the code readable. So Becker would be expected. There are however, exceptions to the rule (patients where the code is unreadable who still develop Becker and vice versa). However, based on what you describe, Duchenne is not likely. Duchenne patients have elevated CK levels from birth onwards. Note that the liver parameters you mention are not actually liver parameters. Rather these enzymes exist in liver but also in muscle. Normally they are a sign of liver damage (which is more common than muscle damage). however, in case of muscle damage they are also leaking into the blood. So when they are elevated and CK is elevated in the blood this is a sign of muscle damage. Regardless, so far there seem to be no signs of muscle damage in your son – which is of course good.
Becker is a very variable disease. Some individuals develop the first symptoms in midlife, while other develop them in adolesence. Sometimes there is even variation within the same family with the same mutation.
2. For duplications only: it is possible that the duplicated region is not located in the dystrophin gene, but somewhere else in the genome. With generally used techniques (e.g. MLPA) this cannot be detected (whether it is in dystrophin or not). Most commonly the duplication will be within the dystrophin gene but there are examples where the duplicated part is somewhere else completely. In that case, dystrophin production is not affected at all.
I am sorry I cannot give a more definitive answer. I hope you and your son stay well
Annemieke
16 November, 2020 at 8:26 am
Hüseyin çul
Hello
my 8 year old boy was diagnosed with deletion of exon 45 2 months ago. Is there a cure for us?
10 November, 2020 at 1:27 pm
Exonskip
Unfortunately there is currently no cure for Duchenne.
However, the disease progression can be slowed down with good care. Guidelines for this are available and you can find them here in many languages: https://treat-nmd.org/treat-nmd-diseases/duchenne-muscular-dystrophy/#family-guides-link
In addition, many therapies are in development and some are even approved in some countries. An overview can be found here: https://treat-nmd.org/research-overview/dmd-research-overview/
Shortly, the approved drugs are mutation specific and unfortunately do not apply to your son’s mutation.
Finally, it has been found that patients with a deletion of exon 45 on average have a slower disease progression than most other patients. They still have Duchenne but compared to other patients, major disease milestones like loss of ambulation occur later.
I am sorry I can not be more helpful than this.
Annemieke
11 November, 2020 at 12:58 pm
Milena
Hello Prof.dr.Annemieke Aartsma-Rus,
I’ d like to request if an exon skipping therapy for Exon 18 and 19 in the Dystrophin gene is available, since our 6y and 8 months old son was diagnosed with DMD 5 months ago. We are originally from Bulgaria but we are considering participating in every treatment that will hopefully improve our son’s quality of life. We started Deflazacort therapy 2 ago months and we are observing improvement in his motor functions.
3 November, 2020 at 1:41 pm
Exonskip
Dear Milena,
Do I understand correctly that your son has a deletion of exon 18 and 19? Unfortunately this is a deletion that is very difficult to restore the genetic code for. It would require skipping of at least 10 exons – this is not feasible with current techniques. I am sorry to be the bearer of bad news. Note that there are many therapies in development that do not rely on the mutation.
Annemieke
4 November, 2020 at 2:05 pm
Daniel
My son has deletion of exon 45. Are there any ongoing trials or medicine in progress for exon skipping 44? As i understood the group who are missing exon 45 are large. Why cant i find any ongoing projects skipping 44?
18 October, 2020 at 8:33 pm
Exonskip
Dear Daniel,
Currently there are no exon 44 skipping trials ongoing. They have occurred in the past (Prosensa/BioMarin). This was with an exon skipping compound that had the same chemistry as drisapersen (exon 51 skipper). FDA did not approve drisapersen because they were unconvinced about the therapeutic effects and there were safety concerns. BioMarin then decided to stop the development of all exon skipping compounds with the same chemistry that were in clinical trials at that point (exon 44, exon 45 and exon 53) in addition to drisapersen (exon 51).
Exon 51, exon 45 and exon 53 are the three most applicable exons (respectively 14%, 8% and 8% of patients) – exon 44 is next in line (6% of patients). I know that companies that work on exon skipping are doing preclinical work for exon 44 skipping (e.g. Sarepta Therapeutics), but I do not know if and when this will move into clinical development.
Best regards
Annemieke
19 October, 2020 at 7:37 am
julio cesar ruiz
sorry I´m a 9years old boy who have a DMD because of a exon 2 duplication and I would like to know the progress of a exon 2 skipping treatment.
Best regard to you and to your family, best wishes to your brave son who is under this revolutionary treatments.
22 September, 2020 at 9:24 pm
OLIVER MONTAS
I am writing you in the name of a family ( I am Godfather of the kid ) that has a young boy with duchenne Exon deletion 44. The boy´s name is Angel Mercado, whose mother name is Euridisis Jimenez. ( Copied on this email )
We are really interested to get him into this hopeful trial, thinking about his future.
Let us know if he has the chance, and if we could contact you to talk about it.
Thanks in advance for any information you could provide us.
17 September, 2020 at 7:27 pm
Exonskip
Dear Oliver and Euridisis,
There are currently many clinical trials ongoing for Duchenne patients. You can find an overview e.g. here: https://treat-nmd.org/research-overview/
Some of these approaches are mutation specific, stop codon readthrough (ataluren) and exon skipping. Ataluren would not be applicable for a deletion. Exon skipping would be an option – a deletion of exon 44 requires the skipping of exon 45 to make the code readable again. Exon 45 skipping is currently tested in clinical trials in the US, Europe and Japan. You can find more information about that also in the research overview.
18 September, 2020 at 12:31 pm
julio cesar ruiz
I´m a father of a 7 years old boy, he have DMD because of exon2 duplication’, is any solution available today to solve this kind of mutation, in July 2018 I wrote you and the answer was very rapidly, I knew that Dr. Kevin Flanigan with Audentes Therapeutics is working in a AT’702 to skip the exon2 duplication, it is any update about the results of a two boys inoculated in January 2020?
28 August, 2020 at 8:51 pm
Exonskip
Audentes gave an update on their programme during the virtual Parent Project Muscular Dystrophy meeting. You can find that here: https://www.parentprojectmd.org/aiovg_videos/in-the-pipeline-gene-therapy-audentes-therapeutics/
No results were presented on the to inoculated patients other than that they are doing OK.
1 September, 2020 at 8:32 am
Ewelina
Hallo.
Thank You very much for answer. I have one more question. What is currently available in the Netherlands for a 5-year-old boy? He has deletion 46,47. How we can help him now? What we can do that he will be longer efficient?
Greetings.
27 May, 2020 at 7:13 pm
Ewelina
Hallo.
I have a questions about terapie exon skipping 45, because my son has deletion 46,47. We leave now in Nederland, will be this therapy also available in the Netherlands in the near future? Please Let me know.
Greetings
16 April, 2020 at 8:58 am
Exonskip
Dear Ewelina,
Exon 45 skipping is currently tested in clinical trials. These are done to assess whether the compound to induce exon 45 skipping (casimersen) is effective and safe. Whether this therapy will be available in the Netherlands depends first on the outcome of the clinical trial. If it is unsafe or not effective it will of course not be approved. If it is deemed sufficiently effective and safe by the regulators (European Medicines Agency for Europe), it will be approved. Then, the drug will have to be marketed in each European country individually. So even if it is approved, there is no guarantee that it will be available in the Netherlands, because this depends on whether the company wants to market it in the Netherlands and how the Dutch Zorg Instituut Nederlands evaluates the drug. Regardless, all these processes (clinical trial, analysis of trial data, regulatory application, marketing in different countries) take time. So unfortunately, it will not be available in the near future.
16 April, 2020 at 11:56 am
Anonymous
Hi,
My son was recently diagnosed with mild form of Becker. He’s results show 48-49. He is 13 years old very active and no signs. This was accidental finding as he’s active playing competitive soccer and we noticed hamstring tightness no more than 3 times a year (plays about 125/games practice a year) after sports doctor recommended ck. Three ck tests highest one was over 2000. His heart test came perfect. Mother is the carrier, no noticeable signs. We do know which grandparents came from yet, but both are alive around 60s. Fully functional and no signs of muscle or health issues.
What is the function of 48-49. Can other Exons fill in to continue providing muscle support needed.
Is there a medicine/treatment?
What kind of activities make it worse?
What kind of activities make it better?
We just found out about this before corona virus, which has stopped us from continuing doctors visits for additional info until further notice.
Thank you!
5 April, 2020 at 4:44 pm
Exonskip
I am sorry to hear your son was diagnoses with Becker but of course I’m happy that the signs are very minimal.
I am not a medical doctor or a rehabilitation specialist. As such I cannot recommend treatments or activities for your son. Is it possible to have a digital meeting with the specialists who diagnosed your son? They are probably better qualified to address your questions.
Annemieke
6 April, 2020 at 8:22 am
Parimita
Hi,this is Parimita Rath, my son has been diagnosed of DMD recently. Is there any treatment Or clinical trials available for exon2 duplication in dmd.
24 March, 2020 at 1:43 pm
Exonskip
Dear Parimita,
There is currently no therapy and there are currently no specific trials for an exon 2 duplication.
However, Audentes and Prof Kevin Flanigan/Dr Nicolas Wein are preparing for a therapy for exon 2 duplications.
You can find an overview of therapies in development here – these also include therapies that are not mutation specific and apply to all patients: https://treat-nmd.org/research-overview/dmd-research-overview/
25 March, 2020 at 8:11 am
Irine Levchenko
Dear Annemieke,
My son is 7 years old, a genetic test confirmed the diagnosis of Duchenne myodystrophy – a deletion of 45 exon. At the moment, from the symptoms of the disease: it is difficult to climb the stairs, but he copes with it on his own, he runs in a peculiar, slow, jumping way, but also with difficulty. In general, a very active child, goes to school. Could there be a milder form of Duchenne or Becker with our deletion, despite the rule of violating the reading frame? I read some sources that spoke about exceptions to the reading frame rule, which included patients with a deletion of one45 exon in particular. It was an endogenous exon skipping, and this is somehow related to 44.
And what do you think about the fate of research related to microdystrophin – will we live to see the medicine? We are from Russia, and, unfortunately, we do not have knowledgeable doctors, rehabilitation centers, or financial support for families. We are ready to go for treatment, or participation in trials to any part of the world.
17 February, 2020 at 6:23 pm
Exonskip
Dear Irene,
I’m sorry to hear about your son. Indeed, a deletion of exon 45 can be milder than ‘typical’ Duchenne. This is because exon 44 is spontaneously skipped in all of us at a very low level. For healthy individuals this means that they make slightly less dystrophin. However, for a deletion of exon 45, skipping exon 44 makes the genetic code readable again, so this would mean your son can make a little bit of dystrophin. Not enough to prevent the disease and generally also not enough to have Becker, but slightly more than other Duchenne patients – and enough to have a slightly slower disease progression.
For therapeutic approaches, I refer you to an overview available on the TREAT-NMD website: https://treat-nmd.org/research-overview/dmd-research-overview/
For microdystrophin specifically: this is still tested in clinical trials. We do not know if it works and whether it is safe. What we know is that some patients develop a severe immune response after treatment with the virusses that carry microdystrophin. We also know that treated patients will produce the microdystrophin. What we do not know is whether the microdystrophin is functional – it is very small – much smaller than the dystrophin Becker patients produce. We know it is functional in mice – but unfortunately that is no guarantee it will be functional in humans. We do know it is not a cure – it is a very small dystrophin – it will be less functional than the ‘regular’ dystrophin.
Finally, it is important that your son receives the best care possible. There are care standards – a family guide is available in many languages including Russian. You can find more information here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/
20 February, 2020 at 2:23 pm
Sebastian
Dear Annemieke,
Thank you for the update, will exon skipping help in this case. Translarna is currently in trial phase here in India.
Regards
Sebastian
27 January, 2020 at 5:58 pm
Exonskip
We do not know whether exon skipping will help. For now we know that exon 51 skipping and exon 53 skipping can restore minute amounts of dystrophin. Whether this has functional effects we do not know yet – this is something Sarepta Therapeutics is currently establishing in phase 3 clinical trials. For exon 48 skipping we have no clinical evidence yet that it will restore dystrophin (or slow down disease progression).
For translarna we know that it slows down disease progression in ambulant DMD patients – however, here the functional data was not yet sufficient for full approval. So in Europe translarna is conditionally approved and PTC Therapeutics is currently conducting a confirmatory phase 3 clinial trial.
In summary, there is unfortunately no certainty yet.
28 January, 2020 at 9:06 am
Sebastian
Dear Annemieke,
My sons is tested positive for DMD, and his report results are mentioned below, can you kindly help me understand whether this is a non-sense mutation,
What could be the possible treatment ahead?
“A hemizygous nonsense variation in exon 48 of the DMD gene (chrX:g.31893448G>A; Depth: 218x)
that results in a stop codon and premature truncation of the protein at codon 2319 (p.Gln2319Ter; ENST00000357033.4) was detected (Table). The observed variation has reported as pathogenic in the ClinVar database [18]. The p.Gln2319Ter variant has not been reported in the 1000 genomes, ExAC and our internal databases. ”
Regards
Sebastian
26 January, 2020 at 12:39 pm
Exonskip
Dear Sebastian,
This is indeed a nonsense mutation. A nonsense mutation changes the code for an animo acit into a stop code (this is what the p.Gln2319Ter means – on position 2319 of the protein there is normally a glutamine, but due to the mutation there is a stop – Ter(mination).
In Europe there is an approved treatment for ambulant patients aged 2 and up with nonsense mutations. It is called Translarna (or ataluren – same thing). Translarna is available in several European countries, as well as some other countries. It is conditionally approved based on trials that suggest it slows down disease progression in Duchenne patients to some extent.
Regards
Annemieke
27 January, 2020 at 9:13 am
navin jain
my 09 year old son has exon 46&47 diletoin .any treatment for this.
6 December, 2019 at 5:07 pm
Exonskip
Dear Navin,
There is currently no mutation specific therapy approved for this mutation. Exon 45 skipping would restore the genetic code. This is currently tested in clinical trials.
Note that multiple additional therapies are in clinical development (not mutation specific) and also that good care is important to keep patients is as optimal a condition as possible.
You can find information on care guidelines for Duchenne here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/
You can find information on therapies in development for Duchenne here: https://treat-nmd.org/treat-nmd-diseases/duchenne-muscular-dystrophy/#research-overview-link
10 December, 2019 at 5:18 pm
Kelly Colon
Hello,
I have a 12 week old son who has deletions 51-52. I was found to be a carrier with the same deletions during the third month of my pregnancy. Our doctors have been unable to find record of deletions 51-52 in 2 US databases and 1 in France. There is no known family history. We do know it is an in frame deletion and they suspect it is Becker. We continue to research but have been unsuccessful in finding really anything.
If you have any information to share about deletions 51-52, please let me know. Thank you.
13 November, 2019 at 10:34 pm
Exonskip
Dear Kelly,
I am sorry to hear about this story – must be very stressful for you.
I have checked the DMD Leiden Open Variation Database and also there, there is no record of a deletion of exon 51-52. So based on humans we cannot make a comparison, only a prediction that likely this will be Becker.
What I do know is that in a mouse model with a deletion of exon 52, skipping exon 51 restores production of dystrophin. This dystrophin lacks the parts encoded by exon 51 and exon 52 – like your son. This treatment is beneficial for this mouse, suggesting that at least in mouse a dystrophin lacking the parts encoded by exon 51 and exon 52 is partially functional.
Humans and mice differ, so this is not a definitive answer. However, it makes it more likely that your son has of Becker muscular dystrophy.
Best regards and take care,
Annemieke
14 November, 2019 at 9:47 am
julio C Ruiz Gallardo
I´m a father of a 7 years old boy, he have DMD because of exon2 duplication’, is any solution available today to solve this kind of mutation, in July 2018 I wrote you and the answer was very rapidly, I knew that Dr. Kevin Flanigan with Audentes Therapeutics is working in a AT’702 to skip the exon2 duplication, it is any update about the clinical trial beginning date?
5 November, 2019 at 7:18 pm
Exonskip
Dear Julio,
Audentes and Kevin Flanigan are still working on exon 2 skipping for exon 2 duplications. To my knowledge no announcements have been made about when the clinical trials will start.
Annemieke
14 November, 2019 at 9:48 am
Xhorxho Vesha
Dear Doctor,
Im a 23 year old boy with DMD exon 45 deletion from Tirana,Albania
recently a group of scientists from Centogene took muscle samples from me and my parents.
The results of the samples advise me exon skipping therapy, is there any bio pharm company or hospital who does the skipping for my exon?
Every advise from you would be very helpful.
Keeping in mind my age , i think something must be done before its too late.
Best regards ,Xhorxho Vesha
25 October, 2019 at 7:47 pm
Exonskip
Dear Xhorxho,
The genetic code for your deletion can be restored by exon 44 skipping. However, currently, exon 44 skipping is not tested in clinical trials.
BioMarin/Prosensa did a test for exon 44 skipping a couple of years back, but that development stopped when they stopped with the drisapersen (exon 51 skipping) development, because the compounds used then were suboptimal (minor therapeutic effects in some patients and side effects in almost all patients).
I am sorry I do not have better news for you.
Best regards
Annemieke
28 October, 2019 at 9:14 am
Adrieanna Zimmerman
Hello,
My son has the dmd c.10567 g>c variant (p.Glu3523Gln)
He has been diagnosed with fatigue and pain in lower extremities. He has show on a muscle biopsy small type 2 muscle fibers, CK has been fine they haven’t checked in since 2017. They said since he was the only one back in 2017 with the variant there wasn’t enough info and it would never affect him. They believe his leg pain, fatigue, motor delays are from something else.
Anyways, I believe it is possibly the gene missense. But, since there is not enough information they say he’s fine go just keep doing occupational therapy and physical therapy. I’m not sure I’m at my wit ends.
Thank you for you time.
23 September, 2019 at 4:55 am
Exonskip
Dear Adrieanna
It is possible that the fatigue and pain are not caused by this missense mutation but are due to a mutation elsewhere in another gene.
Another option is that the mutation leads to altered splicing and that he skips exon 75 (which contains the missense mutation). If that would happen, this would abolish dystrophin production. However, since the mutation is almost at the end of the gene, it is possible that the resulting protein is partially functional.
If a muscle biopsy was obtained they should be able to analyze whether exon 75 is skipped due to the mutation on ‘RNA level’ and whether dystrophin protein is produced or not.
If there is dystrophin and if exon 75 is not skipped, the symptoms are due to another mutation in another gene.
If there is a skip and/or if the protein is smaller or present in reduced amounts, this missense mutation does cause the symptoms most likely
30 September, 2019 at 2:47 pm
Maka
Dear Prof. Dr. Annemieke Aartsma-Rus,
I am mother of 30 years old daughter, who has congenital muscular dystrophy. We have tested Whole Exome Sequencing and Mitochondrial Genome Sequencing in Centogene Ag Am Strande 7, Germany.
An the result is Lama2, Chr6(GRCH37):g. 129781432c>T, NM_000426. 3:c.6955c>T p.(Arg2319) Exon 49 HET and Lama2 Chr6(GRCh37):g.129475791G>A NM_000426.3:c.1169G>A p.(Cys390Tyr) Exon8 HET.
We search for possible treatment for this diagnosis and We need to find scientist or doctor who works and is interested on this variant of illness.
Please contact us.
Thank you in advance,
Best Regards
Maka Kobakhidze
7 August, 2019 at 8:39 pm
Exonskip
Dear Maka,
I am sorry to hear about your daughter. I am not an expert on congenital muscular dystrophy so I am afraid I cannot help you with the diagnosis.
Annemieke
30 September, 2019 at 2:48 pm
Rewan Tovi
Hello doctor
My son has been diagnosed with DMD , he is missing exon 46 and 47 . We live in Dallas TX I was wondering if there is any trials we could put him in.
Thank you so much
26 July, 2019 at 3:40 pm
Exonskip
The genetic code for your son would be restored by exon 45 skipping. There is a clinical trial ongoing for an exon 45 skipping compound (casimersen, developed by Sarepta therapeutics).
There are also many compounds tested that are mutation independent. For an overview please see: https://treat-nmd.org/research-overview/dmd-research-overview/
30 September, 2019 at 2:49 pm
Rebekah
Hi, my twins have just been diagnosed with having a duplication on exon 22.
Is there any trials that they would be eligible for?
Thank you
26 July, 2019 at 1:25 pm
Exonskip
There are no mutation specific trials for a duplication of exon 22.
However, there are many compounds in trials that apply to all patients, regardless of the mutation. You can find an overview here: https://treat-nmd.org/research-overview/dmd-research-overview/
30 September, 2019 at 2:50 pm
Pratik chhatriwala
My son is 1.5 yr has dmd and exon 46 47 duplication……..is there skipping therapi useful in that case…..
13 July, 2019 at 10:13 am
Exonskip
The genetic code would be restored by exon 45 skipping. This approach is currently tested in clinical trial. This means we do not yet know whether we can achieve exon 45 skipping at sufficient levels to have a therapeutic effect and whether this can be done safely. For more information see: https://treat-nmd.org/research-overview/dmd-research-overview/mutation-specific-approaches/#1555493313072-b6404a52-9df4
30 September, 2019 at 2:52 pm
Yunni
Hi, my 8th years old son has deletion of exons 49 to 52 in dystrophin gene. Is there any cure for him?
20 June, 2019 at 3:47 pm
Exonskip
This mutation disrupts the genetic code. Exon 53 skipping would restore the genetic code. Exon 53 skipping is currently tested in clinical trials. Thus far we know that this leads to very minor increases in dystrophin in treated patients. Whether this is enough to slow down the disease progression is not yet known.
Note that unfortunately currently all therapies in development aim to slow down the disease progression for Duchenne patients. There is no cure – unfortunately the damage accumulated can not be undone and the functions lost cannot be regained. We hope to be able to do this in the future – for now we work on slowing down the progression – this is the only thing we can do with the tools available to us.
30 September, 2019 at 2:54 pm
KC.YANG
Dear Annemieke
I’m father of DMD child from Taiwan,he been diagnosed as deletion of exon 46 to 50.
We are so helpless and feel desperation day after day.
If we’re interesting to join any clinical trial or treatment in the future, what can we do now?
14 June, 2019 at 10:29 am
Exonskip
This would required the combined skipping of exon 45 and exon 51. The problem is that double exon skipping is much more challenging than single exon skipping. This is because currently the delivery of exon skipping compounds to skeletal muscle fibers is not very efficient. So only a few fibers will take up an exon skipping compound. When double exon skipping is required, fibers need to take up both compounds – the chance of this is very small.
however, there are also compounds in development that apply to all mutations. See for an overview: https://treat-nmd.org/research-overview/dmd-research-overview/
30 September, 2019 at 2:57 pm
mahnaz
Hello,
My cousin (a boy, 12 years old) was diagnosed with Duchenne and Becker MD. The mutation is EX45_54 DEL (Hemi) on DMD gene. He was very active and played a lot until 5 years old. then, he used to walk on toe. no one found the problem. now, he can not walk and he uses a wheelchair.
Just to ask if there is any treatment currently or any medication to slow down the progression.
Thank you
22 April, 2019 at 7:06 pm
Exonskip
This mutation disrupts the genetic code. Exon 55 skipping would restore the genetic code. However, currently there are no trials planned for this.
There are a lot of other therapeutic approaches in clinical development that apply to all mutations. See for an overview: https://treat-nmd.org/research-overview/dmd-research-overview/
These all aim at slowing down disease progression.
Furthermore, it is important to adhere to the care guidelines – good care will also slow down the disease a lot. Family friendly care guidelines can be found here: https://treat-nmd.org/care-overview/the-diagnosis-management-of-dmd/guide-for-families/
30 September, 2019 at 2:59 pm
Deepthi vemula
Hii professor
My 4 year old son is diagnosed with DMD his genetic test results have just come today
Their is a deletion of Exons 46 and 47 in the DMD gene as tested by MLPA
He has not started any medication as of now right now we r showing him in NIMHANS In Bangalore..
I’m from India and we are ready to travel anywhere in the world to help him
Please help us and suggest what step to take next..
12 April, 2019 at 2:33 pm
Exonskip
I can suggest you contact DART, a patient organization in Bangalore, that also coordinates research.
There are currently many therapeutic approaches evaluated in clinical trials for Duchenne patients. See for an overview: https://treat-nmd.org/research-overview/dmd-research-overview/
There are also mutation specific approaches, which do not apply to all patients. However, your son’s mutation would require exon 45 skipping and there are trials to evaluate the safety and efficacy of this coordinated by Sarepta. The test compound is called casimersen.
30 September, 2019 at 3:02 pm
Rahul
Hello Prof. Dr. Annemieke Aartsma-Rus,
I am a father of child with exon 55 deletion reported in DNA Blood test.
1. I want to know is MLPA report trustworthy or i need to go for another test/method/technique to reconfirm
2. My kid is 5.6 yrs and is able to walk and play. only difficulty with him is stair climbing now.
3. He is on put on Steroid 20mg, after a month having this medicines his face changed to moon one.
4. What are the possible therapeutic treatments we can have in any part of world and would like to suggest Best Dr. in India to effectively treat my child as lot of them have already raised their hands i beilieve due to lack of knowledge on DMD
Pl. pl. support my child to live a normal life with and strength to overcome this.
Thanks & regards,
Rahul
9 January, 2019 at 11:36 am
Exonskip
Dear Rahul,
I am sorry to hear about your son’s condition.
With regards to your questions: Steroids unfortunately have side effects (such as the moon face) – however, they are slowing down the disease a lot. They allow patients to walk longer and have a better respiratory function and better survival among others.
MLPA: when a deletion of one exon is found with MLPA, a second test is needed. MLPA uses probes to test whether the exon is there or not. Most likely your son has a deletion of exon 55 (i.e. exon 55 is not present). However, it is also possible that there is a small mutation within exon 55, which would mean that the probe cannot bind to exon 55. So a PCR test is needed to check whether exon 55 is deleted or not – generally this is done automatically, but please check with the team that did the diagnosis that this was done.
At the moment there is no treatment available for Duchenne patients beyond the corticosteroid treatment and care (multidisciplinary care – see also the guidelines: http://www.treat-nmd.eu/care/dmd/diagnosis-management-DMD/
Several mutation specific therapies are available, such as eteplirsen (exon 51 skipping, would not work for an exon 55 deletion) and translarna (only for nonsense codons, not for deletions).
In India I know Dr Vishwanathan in Chennai – he has a lot of expertise with trreating DMD patients.
Annemieke
14 January, 2019 at 10:22 am
Kyle
First of all, I want to thank you for your hard work. My son is 2 years old. We had a CK Blood Test done on him due to the fact that he was a late walker. The CK Levels came back at 15,800. We are now waiting for our Genetics Testing to be done. With the CK Levels being at that mark, is there any possibility of Becker’s MD? Or is that level of CK certainly Duchenne? Thank you so much.
3 December, 2018 at 9:40 pm
Exonskip
Apologies for the late response, I missed this comment.
Elevated CK indicates there is muscle damage. This can mean Duchenne or Becker or other muscle diseases. The genetic tests and the clinical evaluation are needed to assess whether your son has Duchenne or Becker.
30 September, 2019 at 3:03 pm
Bithika Ghosh
Hello Anamica
Both my sons have single deletion of 44. Can exon skipping help them
12 November, 2018 at 6:32 am
Exonskip
Dear Bithika,
Exon skipping for duplications is challenging. What would be required in case of your sons is skipping of either the first exon 44 OR the second exon 44. Either way would restore the normal dystrophin code. HOWEVER, the compounds used for exon skipping (antisense oligonucleotides, AONs) recognize both exons 44 – so there is a possibility that both exons will be skipped. This would disrupt the genetic code (just like the exon 44 duplication does).
If we test AONs for exon 44 skipping in cultured cells of a patient with an exon 44 duplication, what we see is that both exons are skipped. So this is not helpful. It is possible however that when patient would be treated this would not be the case. For both exons to be skipped you need 2 AONs in the same cell (one to bind the first exon 44 and one to the second exon 44). In cultured cells this is easy to achieve (the cells receive an overdose of AONs so to say). However, in a human being the amount of AONs is much lower and as such it is anticipated that most cells will have no AON at all, and some will have 1 AON and hardly any with have 2 AONs. Therefore it is expected that in a patient, this would work better than in cells and that there might be some dystrophin restoration expected. However, exon skipping has so far never been tested in patients, so there is no hard evidence yet.
At the moment there are no exon 44 skipping compounds in clinical development, so for now this is unfortunately only theoretical.
12 November, 2018 at 10:36 am
Exonskip
In theory exon 45 skipping would restore the genetic code for your sons. This is currently evaluated in a clinical trial by Sarepta – the compound is called casimersen. It is not yet clear whether this treatment is safe or whether it leads to benefits.
You can find an overview of this approach and other approaches in clinical developments here: https://treat-nmd.org/research-overview/dmd-research-overview/
30 September, 2019 at 3:05 pm
Federico
What would be the prognosis for an in frame deletion of Exon 26-29?
22 October, 2018 at 8:09 am
Exonskip
I would expect this to lead to a mild Becker disease. However, notably, there is a lot of variation observed between individuals – even with the same deletion – and there are also always exceptions to the rules. So possibly the prognosis is different
30 September, 2019 at 3:06 pm
Simona
Hello my son who is 5 yr old has been diagnosed with problem of exon 57 of the DMD gene, is there any cure or medicine in the pipiline to correct this dysfunction of exons? C.8479G>T
5 October, 2018 at 4:20 pm
Exonskip
I think this is a so called nonsense mutation. If this is indeed the case, ataluren would be an approved therapy in Europe (not available in all countries though).
The company developing this compound is called PTC Therapeutics.
30 September, 2019 at 3:07 pm
Mehwish
Dear doctor,
Can you kindly guide how can we determine whether a point mutation in DMD gene is in frame or out of frame mutation? and if a particular nonsense mutation can be corrected by ataluren.
I would be grateful if you can provide me literature on the recent mutation spectrum of Duchenne worldwide and the diagnostic methods and therapies available so far.
Thank you,
Mehwish
15 September, 2018 at 6:40 pm
Exonskip
Dear Mehwish,
All nonsense mutations should be correctable by ataluren. Whether a point mutation is in-frame or out of frame depends on how many basepairs are involved (a basepair is a DNA building block). If there is a deletion or insertion of basepairs: if the number is divisible by 3 (e.g. deletion of 6 basepairs or insertion of 3 basepairs) the mutation is in-frame. If it is not divisible by 3 (e.g. deletion of 5 basepairs or insertion of 1 basepair), it is out-of-frame. A nonsense mutation does NOT disrupt the reading frame – however, because the code for an amino acid is changed into a STOP code, it leads to truncation of translation of the code from gene to protein and therefore a non functional protein. So the effect is the same (out-of-frame mutations also lead to a premature truncation of translation, but for a different reason – the code becomes unreadable).
For a paper on diagnostics for Duchenne I refer you to this paper: https://jmg.bmj.com/content/53/3/145.long
An overview of therapeutic approaches can be found here: http://www.treat-nmd.eu/dmd/research-overview/introduction/
More information on mutations and their effects can also be found with the Dove tool: http://www.dmd.nl/DOVE
17 September, 2018 at 3:27 pm
Jelena
Hi, my 4 year old son have DMD/BMD diagnosis and his result of DNA test is Exon deletions 45-53 , “in frame” mutation.I am not a carrier, so his doctor don’t know is this Becker or Duchenne.Can you help me about his diagnose?
5 September, 2018 at 9:19 am
Exonskip
Dear Jelena,
This is an in-frame mutation so I would expect a Becker disease. However, there are always exceptions to the reading frame rules possible. What is leading is how your son clinically develops. If he has a severe progression and symptoms at a very young age, that resembles Duchenne. However, if he has not a lot of symptoms at 4 years, that resembles Becker.
30 September, 2019 at 3:09 pm
julio C Ruiz Gallardo
Thank you very much for your prompt response, I think I have the child well on track because he is enrolled precisely with Kevin Flanigan at the Ohio hospital, where he is working on the subject, what worries me is that he is alone with his team watching this issue of exon 2 duplication.
Anyway, I thank you for your attention and I am happy to know that there are still good people in this world who try by all means to make happy the families that suffer for their children.
Best regard, Julio.
2 July, 2018 at 4:35 pm
Anne Trehu
What is the anticipated prognosis for a duplication of exons 52 and 53?
30 June, 2018 at 2:39 pm
Exonskip
A duplication of exon 52 and exon 53 would be expected to maintain the reading frame. So in theory one would expect this mutation to be associated with Becker muscular dystrophy. However, duplication mutations often have unpredictable impacts on how the gene transcripts are processed and a significant number of duplication mutations that do not disrupt the readin frame result in Duchenne, and vice versa duplication mutations that disrupt the reading frame can also result in Becker muscular dystrophy.
So the ‘prediciton’ is a lot less reliable than with deletion mutations.
2 July, 2018 at 4:06 pm
julio C Ruiz Gallardo
im a father of a 7 years old boy, he have DMD because of exon2 duplication’, is any solution available today to solve this kind of mutation.
27 June, 2018 at 10:07 pm
Exonskip
At the moment there is no cure for Duchenne. There are therapies in development that aim to slow down disease progression. This is done by one in 2 ways: 1) trying to restore the missing protein 2) trying to improve the muscle quality.
You can find an overview of these approaches here: http://www.treat-nmd.eu/dmd/research-overview/introduction/ (will be updated this summer)
Restoring dystrophin is often done in a mutation specific way. For an exon 2 duplication, exon 2 skipping would restore the genetic code of the dystrophin gene. At the moment this is not tested in clinical trials, but Kevin Flannigan is doing preclinical tests to assess exon 2 skipping in cell and mouse models.
28 June, 2018 at 4:11 pm
Akash
Respected Doctor,
Hello my son who is 3 yr old has been diagnosed with duplication of exon from 8 to 11 of the DMD gene, is there any cure or medicine in the pipiline to correct this dysfunction of exons?
25 May, 2018 at 1:16 pm
Exonskip
Dear Akash,
Research is ongoing on genome editing for duplication mutations in Toronto (lab of Ronald Coen) -however, this is in a very early stage (cultured cells). There is a lot of research happening on approaches that improve muscle quality – some of which are in clinical trials and all of which are not mutation specific (i.e. they apply to all patients). Furthermore, there are trials ongoing on bringing back a short version of dystrophin (micro-dystrophin) with viral vectors. You can see an overview of all the research that is in trials or close to trials here: http://www.treat-nmd.eu/dmd/research-overview/introduction/
28 May, 2018 at 7:57 am
Sai
Hi
My son have Exons 45,46 and 47 are deleted. He is 32 months old now,we don’t see any notable symptoms so far. He is ahead to reach his motor skills like crowling and walking.
When he tested for jaundice last year due to some other illness his liver enzymes were elevated and they see liver was normal so they started testing ck and genetic testing.
His ck levels drawn 3 times(Oct 2017- 15k, March 2018- 13k and April 2018- 29k)
His doctor is saying RNA analysis is needed to confirm whether this is mild and severe type though it’s a inframe mutation.
We are so scared what will be the outcome of RNA tests.
Can you please help to confirm is this kind of mutation happened to anyone already ( Exons 45,46 and 47 deleted) and what will be the type of their disease whether it’s mild or severe.please help.
28 April, 2018 at 6:18 am
Exonskip
Dear Sai,
Sorry to hear your son has a mutation in his dystrophin gene, but glad to hear he has no notable symptoms so far.
For mutations that are in-frame, one would expect the milder disease (Becker) rather than the severe disease (Duchenne). Note that RNA analysis requires a muscle biopsy – which is a painful and invasive procedure. As such, this is only recommended when the symptoms do not match the genetics (e.g. in-frame with severe symptoms or out-of-frame with mild symptoms). This does happen sometimes (in about 10% of cases) and the mutation you describe has been found in Becker patients but also in some Duchenne patients.
When the symptoms match the genetics (90% of cases), the international guidelines for Duchenne diagnosis, care and management (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869704/figure/F2/ – from this paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869704/) do not recommend RNA analysis.
So I recommend that you ask the doctor why (s)he thinks RNA is needed. Is the disease more severe than expected for a Becker patient? If so, then the analysis makes sense. However, if your son does not have the typical Duchenne symptoms, I do not think the RNA analysis is needed.
30 April, 2018 at 12:49 pm
Sai
Thank you so much for your response
Doctor mentioned it’s a blood test for RNA analysis not the muscle biopsy.
They say in particular in frame deletions (like my son’s) needs RNA analysis to confirm whether it’s a Becker or Duchene.
Does CK elevation (as it was around 30k ) matters to confirm Becker Vs Duchenne.
30 April, 2018 at 1:49 pm
Exonskip
CK elevation means there is something wrong with the muscle – in case of muscular dystrophy the muscular dystrophy is ‘what is wrong’ and why the enzyme leaks from the muscle into the blood. The elevation points to a problem with muscles, but it does not tell you which problem there is (i.e. which protein is missing or not only partially functional) – this is why the genetic tests are needed. One cannot say which muscular dystrophy a person has based on how high the CK levels are because CK levels also vary due to e.g. time of day, how active you have been and how muscular you are etc.
RNA analysis in the blood will not be informative at all. Dystrophin is not expressed in the blood, which will make the analysis very challenging and has the risk of misinterpretation. The guidelines (internationally recognized, published in The Lancet) say that DNA analysis by MLPA is sufficient for deletions involving multiple exons. There is never a need for RNA analysis in the blood (because this is not informative) – if the symptoms do not match the genetics, RNA anlaysis can be done on muscle.
Feel free to direct the doctor to me for his/her questions about this (a.m.rus@lumc.nl)
30 April, 2018 at 2:07 pm
Sai
Thank you!
I had a discussion with doctor and currently hold on RNA analysis. We have in person appointment scheduled for next week to talk more on this.
Earlier you mentioned exon 45-47 deletion shows in both Becker and Duchenne.
Without RNA analysis what decides the disease is mild (Becker) or severe (Duchenne), is it symptoms? or based on the age symptoms occurs?
can you please give more details like in Duchenne at which age age typically symptoms start and is developmental growth (motor skills) is always delayed with this case.
And with Becker what will be the symptoms and usually at which age symptoms start.
Thank you!
7 May, 2018 at 6:56 am
Exonskip
The severity of the disease is determined by the symptoms and when they occur. Duchenne is the more severe form, and symptoms occur already early in life, at around the age of 1-3 years old. Patients e.g. will have difficulty with walking, hopping/jumping, climbing stairs and will fall frequently already before the age of 4 years.
For Becker there is a lot more variation in when the disease starts – in some patients this is in childhood, in some patients this is in adolescence or even adulthood. So here it is not possible to give a specific age – it varies – even when several patients are affected in the same family, when the symptoms start and how severe they are can differ between the patients.
Note that I am NOT a medical doctor – what I write about the symptoms is what I know from the literature and what I have heard from clinicians treating Duchenne and Becker patients.
7 May, 2018 at 8:27 am
Jaydeep Bhatt
My son is 5 years old and gene 49, 50, 51 and 52 are delete, I would like to know more about possible treatment and institutes where I can contact for cure of his DMD illness, I really need guidance please help.
18 April, 2018 at 7:51 pm
Exonskip
Dear Jaydeep
Unfortunately there is no cure yet for DMD – not anywhere in the world.
There is good care which can help slow down the progression of the disease – you can find out more about this here: http://www.treat-nmd.eu/care/dmd/diagnosis-management-DMD/ It is important to find a hospital with experience in caring for Duchenne patients so that your son can receive the care he needs.
Also there are therapies in development and two therapies have been approved now. However, these are mutation specific and your son is not eligible for those. He would be eligible for “exon 53 skipping”, which is tested in clinical trials. This means that as yet we do not know whether this appraoch is safe and/or effective. Also know that the therapies currently in development are unfortunately not cures – they aim to slow down the progression of the disease.
More information on this can be found here: http://www.treat-nmd.eu/dmd/research-overview/introduction/
I am sorry I cannot give you more positive news. Know that there are many people world wide who work hard to find a better therapy for Duchenne, but that this is challenging.
19 April, 2018 at 8:20 am
Julia
Hi, I would like to ask which mutation (deletion, duplication and point) is/are not suitable for exon skipping and why?
Thank you so much
2 April, 2018 at 10:42 am
Exonskip
The dystrophin that is produced after exon skipping needs to have all its functional domains.
The dystrophin has one dystroglycan binding domain encoded by exon 64-70. This is absolutely crucial. So if a mutation is located/includes exon 64-70, exon skipping will not result in functional dystrophins. This goes for all types of mutations (deletions, small mutations and duplications). With deletions parts are missing, while with duplications parts are double. However, the extra parts of dystrophin can affect the folding of the protein, so that while they are present, they are not functionally active.
The dystrophin has 3 actin binding domains, two encoded by exons 2-10 and one encoded by exon 32-45. To be functional dystrophin needs at least one actin-binding domain. So mutations that remove all three are not eligible for exon skipping, since the resulting dystrophin will not be functional. Note that the first two actin binding domains are “better binders” than the third one. So a dystrophin that lacks the first two domains is less functional (associated generally with more severe Becker) than a dystrophin lacking the third actin binding domain (associated with typical Becker). For small mutations (point mutations) it is not possible to affect all three domains – only for large deletions and duplications this can be an issue. With deletions parts are missing, while with duplications parts are double. However, the extra parts of dystrophin can affect the folding of the protein, so that while they are present, they are not functionally active.
The dystrophin has a connecting domain that is encoded by exons 11-63. This domain is largely dispensable. However, when deletions are longer than 36 exons, the domain probably becomes too short. For duplications it is not known how large they can be and still result in a functional protein. For small mutations of course the exons deleted after exon skipping will never involve more than 36 exons.
3 April, 2018 at 11:14 am
Julia
Thank you so much
5 April, 2018 at 8:49 am
Janice Fields
My 6 months grandson was found to be missing exon 46-47. We were told it is Duchenne. Is there any chance this could change as he gets older? What about skipping therapy?
20 February, 2018 at 5:48 pm
Exonskip
Dear Janice,
I am sorry to hear about your grandson. For a deletion of exon 46-47 indeed Duchenne muscular dystrophy is expected, because this mutation disrupts the genetic code. There are sometimes exceptions (i.e. patients who have a milder progression than anticipated), but unfortunately these are few.
The genetic code for your grandson could be corrected by the skipping of exon 45. This is currently tested in clinical trials, but is not yet available as a therapy (because the trials are needed to test if the approach works and is safe). For more information see http://www.treat-nmd.eu/dmd/research-overview/mutation-specific-approaches/exon-skipping/
Annemieke
22 February, 2018 at 6:18 am
Shady Youssry
Dear Doctor Aartsma-Rus,
I heard about crispr cas 9 can correct mutations between exon18 and 58,
My question is that means both deletions and duplications or only deletions, noting that my 7 years old son has a duplication of exon 53 to 57 and I am searching for ongoing trials meeting his mutation (duplication)
Thanks in advance
13 December, 2017 at 12:33 pm
Exonskip
Genome editing (using CRISPR/Cas9) can in theory correct both deletions and duplications. For deletions, the aim is to restore the genetic code, while for duplications, the aim is to restore the normal code. This can be achieved by cutting out the duplicated parts. However, this work is as yet in a very early stage and only tested in patient-derived cell cultures. So there are no clinical trials ongoing specifically for duplications at the moment.
You can read more about genome editing here: http://www.exonskipping.nl/whats-hot/blog-crispr-technology/
You can read more about therapies in development here: http://www.treat-nmd.eu/dmd/research-overview/introduction/
Note that all therapies that are not mutation specific would apply to all patients (so also patients with duplications).
14 December, 2017 at 9:55 am
Ziggy Ören
Hello, the 5 year old son of our very good friends has just been diagnosed with DMD with duplications of Exon 6 and 7. We live in Turkey and I wondered if you could give us any information on clinical trials or treatment options available in this country?
Also, if they were able to travel would there be any other trials you could recommend?
Kind regards
Ziggy
20 November, 2017 at 8:41 pm
Exonskip
Dear Ziggy,
I am sorry to hear about your friends’ son. Note that Turkey has a very good Duchenne specialist, Dr. Haluk Topaloglu and that he is involved in multiple clinical trials. I do not know by heart which ones are currently happening and whether your friends’ son would be eligible to participate, but I am sure his team will be able to inform you about that.
Note that participation in clinical trials is a burden. Clinical trials are experiments in humans. There is no guarantee that the test drug will work and they may be unsafe. Also trials generally mean many hospital visits – so this in and of itself is a burden as well. It is best to participate in a trial that is local – this reduces the travel burden for the patient and the family (e.g. weekly hospital visits are more rule than exception) and trials may be daunting to the patient, especially when he is young and when the trial is in another country where they speak a different language. So when possible I would recommend a local trial.
Annemieke
24 November, 2017 at 9:40 am
Alexander
Dear Doctor Aartsma-Rus,
My son has a single base deletion in exon 56 (c.8375delA). Is exon skipping working with such small deletions. Which exon needs to be skipped to restore a truncated dystrophin for him?
Best regards
Alexander
16 October, 2017 at 9:29 pm
Exonskip
Dear Alexander,
Exon skipping is in theory possible also for small mutations. Then the point is not so much to restore the reading frame (or genetic code) but to bypass the mutation. The challenges here are twofold:
1. For the majority of exons if you skip them this will disrupt the reading frame. Exon 56 is such an exon, so skipping this exon will bypass the mutation but this will disrupt the reading frame. As such TWO exons would need to be skipped (either exon 55 and exon 56 OR exon 56 and exon 57). This way the mutation is bypased while the reading frame is not changed. Skipping two exons is a lot more challenging than skipping one exon
2. While the larger deletions that remove one or more exons are clustering in the area of exon 45-55, small mutations (like the one of your son) occur in all exons. This means that exon skipping for small mutations applies to very small groups of patients (less than 0.1% of all patients generally).
So exon skipping as it is currently in development for DMD will not be applicable to your son, unfortunately. However, all the mutation independent approaches in development (anti-fibrosis, anti-inflammation, pro-regeneration, mini-dystrophin, utrophin upregulation etc) do apply.
Best regards
Annemieke
19 October, 2017 at 10:58 am
Alexander
Dear Annemieke
Thank you very much for this explanation.
Best regards
Alexander
19 October, 2017 at 7:19 pm
Adriana
Dear Doctor Aartsma-Rus,
I’ve sent you an email about the twin boys of a friend of mine. Is there a clinic you work in The Netherlands? By any chance can we contact you for an appointment? Please, my friend is desperate specially becouse in the city he lives in Brazil doctors know very little about it.
Kind regards,
Adriana
22 September, 2017 at 2:06 pm
Exonskip
Dear Adriana,
I am not a medical doctor so I cannot see your friend’s sons. I will email you about options in Brazil.
Best regards
Annemieke
22 September, 2017 at 3:17 pm
Adriana
That would extremely helpfull!!! Thanks a lot!!! Looking forward to your e-mail.
Kind regards, Adriana
22 September, 2017 at 4:15 pm
Abdul Salam K.
Dear Doctor,
Hi
The results of the Gene / DNA has showed the below :
The MLPA results suggest there is deletion of exon 48 to 52 of the DMD gene at hemozygous state. However this test will not detect any alteration that lie outside the target probe sequence.The deletion within the DMD gene results in frame-shift and therefore premature dystrophin , which agrees with the DMD diseases. diagnosis.
Can you please let me know if the exon 51 skipping is valid in this case
Thank you.
probe
22 July, 2017 at 3:12 pm
Exonskip
Dear Abdul,
The MLPA will test for each part of the genetic code of the dystrophin genes (the so called exons) whether they are present or not. In case of your son, exons 48, 49, 50, 51 and 52 are missing. This disrupts the genetic code, so starting at exon 53 this becomes unreadable for the machinery that translates gene to protein. He therefore cannot produce functional dystrophin.
Exon skipping aims to restore the genetic code by making the deletion one exon larger. In case of your son’s mutation, exon 53 skipping would restore the genetic code. Exon 51 skipping will not work because your son does not have exon 51, so it cannot be skipped.
24 July, 2017 at 7:49 am
Exonskip
Dear Shady,
I am not a clinician but a researcher so I cannot provide you advise on the care of your son. I can point you to the standards of care for DMD which have been published also in a family friendly version: http://www.treat-nmd.eu/care/dmd/family-guide/
There are no clinical trials ongoing specifically targeting your son’s mutation. However, there are multiple trials ongoing for which mutation type is not an issue. See for an overview: http://www.treat-nmd.eu/dmd/research-overview/introduction/. The mutation specific approaches currently under evaluation (exon skipping and nonsense codon readthrough) will not apply to your son’s mutation. However, approaches aiming to reduce fibrosis, improve regeneration, decrease inflammation will apply to all DMD patients.
Best regards
Annemieke
20 July, 2017 at 9:23 am
Shady
Dear Annemieke
Thanks for your valuable information ,
Could you please tell me what is the difference between non sense (stop codon) mutation and large duplication that alter the reading frame like my son’s case,as i know that both disrupt the reading frame but do both have the same severity phenotype? And different propability of the total absence of the dystrophin protein?
Thanks
Sh.y
20 July, 2017 at 12:49 pm
Exonskip
Dear Shady,
A nonsense mutation does not disrupt the reading frame. It changes the genetic code at one position so that the code reads “stop” rather than genetic information. These stop codes are normally only present at the end of the genetic code, so the translation machinery knows the protein is complete. When a mutation changes the genetic code into a stop earlier in the gene, the translation stops too early and the protein is not functional. So the consequence is the same as with frame-shifting mutations (translation stops too early and protein is not functional). As such, these nonsense mutations cause DMD, like the frame shifting mutations.
24 July, 2017 at 7:45 am
Shady
Hello Dr.
Mlpa was done for my 7 years old son, showed a duplication from Exon 53-57 that disrupt the reading frame ,
The question is the said mutation disrupted the whole function of the gene or only the site beyond or below the mutation site(exons)in other words the gene is functioning till Exon 52 only that can translate the proteins before the duplicated exons or not functioning at all?
Another question if the site (region) of mutation in specific area of the gene differs in severity than other parts of the gene even if disrupt the reading frame for example if I have 2 patients,1 with duplication of Exon 18-22 (out of frame) and the other patient has duplication of Exon 53-57 ( out of frame also) do both of them have the same severity or not?
Thanks in advance
14 July, 2017 at 1:00 pm
Exonskip
Dear Shady,
I am sorry to hear your son has Duchenne. I will try to explain some of the genetics to you – hopefully this will answer your questions.
Duchenne is caused by a failure of patients to produce a functional dystrophin protein. The dystrophin protein fulfills a linker function in the muscle. One side of it connects to the skeleton/internal structure of the muscle fiber, the other size connects to the connective tissue surrounding the muscle fiber. In between there is a spring like system consisting of 24 similar domains. The connection stabilizes muscle fibers upon contraction.
Duchenne patients have a mutation that disrupts the genetic code of the dystrophin gene (out-of-frame mutations). Consequently, the code becomes unreadable after the mutation. Because the important domains of dystrophin are located at the start and the end of the protein, the resulting dystrophin will not be functional. It will lack the domain that connects to the connective tissue. As such it does not matter whether the mutation is at the start or in the middle are even close to the end – the crucial domain at the end will be missing and therefore the dystrophin is not functional.
In fact, the part in the middle of dystrophin is redundant. We know this because in-frame mutations affecting the middle of the protein keep the genetic code readable. As such dystrophins can be produced that have the important domains at the start and the end, but are shorter in the middle. These proteins are found in the less severe Becker muscular dystrophy.
In summary, for out of frame mutations it does not matter where the mutation is located – if the domain at the end of the protein (encoded by exons 64-70) cannot be produced, the protein will not be functional. As such they will both cause Duchenne.
Please do not hesitate to ask for clarification if this is not clear to you or ask follow up questions.
19 July, 2017 at 8:42 am
Shady
Thanks for your kind reply,I just need to ask some questions
First:is there any trials currently recruting regarding the mentioned mutation for my son(duplication 53-57)?
Second:what is the best treatment should I start with my son ,noting that my son is 7 years old,he is active and still ambulant in good condition except for climbing stairs with support by himself and Gower’s sign
Third: which is better “Prednisone or deflazacort” noting that our neourlogist has recommended Prednisone 15 mg/d in addition to multivitamins,but we didn’t start steroids yet?
Fourth:she recommended swimming 1hr a week but didn’t recommended physiotherapy right now?
Last question:shall we start using night splint and hand braces for him now or later?,also shall we delay steroids or start now?
Thanks for your time
19 July, 2017 at 4:59 pm
Magdi
My grandson is 7 years old and was diagnosed as having DMD ( most probably )due to duplication of exons 53 to 57 .He is ambulatory and does physiotherapy is specialized center . we give him Tamoxifen 10 mg daily for 1.5 months now . He is doing better since then . What is your comment on the duplication regarding prognosis and treatment . Also ,if you have any comments on Tamoxifen ( I know that it is in clinical trial but I took the risk because I cannot wait till I see him helpless and not moving so early ) .
4 July, 2017 at 11:04 pm
Exonskip
I am sorry to hear about your grandson. Good care is really the best thing that can be doen for him – this means physiotherapy but also has other aspects (see http://www.treat-nmd.eu/care/dmd/family-guide/). I cannot comment on tamoxifen other than that it is a therapy that has yet to be tested in Duchenne patients. It has yet to be shown that this drug is effective and that it is safe in Duchenne patients. The fact that it works in mice is no guarantee that it will work in patients. The fact that it appears to be safe in mice is no guarantee that it will be safe in Duchenne patients.
Regarding the duplication: it is expected to disrupt the genetic code of the dystrophin gene and as such is a “Duchenne type” of mutation. The milder disease course of Becker is expected for mutations that do NOT disrupt the genetic code. However, how your grandson will progress exactly is difficult to predict since every patient is unique. This will depend on how well his muscle regenerates, how well his immune system works, how muscular he is to begin with etc.
Coming back to the start: the best thing to do is to make sure he has good care – this is the best way to slow down the breakdown of muscle as much as possible.
5 July, 2017 at 7:48 am
Valerie Heylen
Beste,
Bedankt voor de snelle reactie.
Vriendelijke groeten,
Valerie
3 July, 2017 at 5:12 pm
Valerie Heylen
Beste,
Mijn zoontje is 19 maanden en heeft Duchenne, hij heeft deletie 51. Kan hij met deze deletie in aanmerking komen voor exon skipping of is dit niet voor deletie 51 van toepassing?
Vriendelijke groeten,
3 July, 2017 at 2:23 pm
Exonskip
Beste Valerie,
Exon skipping is een mutatie specifieke aanpak waarbij gepoogd wordt om Duchenne patienten een deels functioneel dystrofine eiwit te laten maken in plaats van een niet functioneel eiwit. Hiervoor moet tijdens het verwerkingsproces van gen naar eiwit dus een exon geskipt worden. WELK exon hangt af van de locatie van de mutatie. Een exon 51 deletie komt in theorie in aanmerking voor deze aanpak. Om de leesbaarheid van het gen te herstellen moet exon 52 OF exon 50 worden geskipt. Momenteel wordt er geen klinisch onderzoek gedaan met middelen om deze exonen te skippen. De focus ligt vooral op het skippen van exon 51, 45 en 53 momenteel omdat dit toepasbaar is op de grootste groep patienten.
3 July, 2017 at 4:26 pm
Manohar
Hello Dr.
My Son is 7-years, Muscle Biopsy says consistent with DMD but MLPA ( Genetic Test ) reveals point mutation at 46 chromosome.
He is on protein diet and also physiotherapy, swimming etc. going regularly
Please guide me regarding any treatment pertaining to point mutations ( exon skipping, ataluren ( translarna)
awaiting for your reply
Regards
Manohar
20 June, 2017 at 2:50 am
Exonskip
Dear Manohar,
I am sorry to hear your son has DMD. The mutation you describe however, does not make sense to me. Do you mean a deletion or duplication of exon 46? A small mutation in exon 46? Feel free to email me privately if you prefer (you can find my email address on publications). I will need this information to provide information about mutation specific appraoches.
Very good to hear your son is doing physiotherapy – good care is the most important thing you can do for him!
26 June, 2017 at 10:03 am
Shenoy john Rajan
Hi,
My son is 4 years old and has exon deletion from 48 – 52 . How feasible is an exon 53 skipping and i have read that trial results are due only in 2019 . What other treatments can be done in the mean time ?
26 April, 2017 at 10:56 am
Exonskip
Exon 53 skipping is indeed tested in clinical trials at the moment. As yet we do not know whether it is effective or safe (of course we all hope it is both effective and safe, but the trial is done to evaluate this).
What can be done already is provide good care to your son to keep him in as good a condition as possible for when hopefully a therapy is available. More information on care guidelines for Duchenne can be found here: http://www.dmd-guide.org/. This is based on two scientific papers published on this topic, but ‘translated’ into more accessible language non medically trained individuals.
1 May, 2017 at 4:01 pm
Abdul Salam K.
Dear Doctor ,
Referring to deletion exon 48 -52 my son was diagnosed based on DNA Results .
Can you explain please the difference as part of symptoms and progression of the disorder would it slow or fast.
is milder or sever !
Thank you
21 July, 2017 at 3:16 pm
Exonskip
Dear Abdul,
A deletion of exon 48-52 unfortunately disrupts the genetic code of the dystrophin gene. That means your son cannot produce functional dystrophin and he would be expected to have Duchenne muscular dystrophy – the more progressive form of the disease.
24 July, 2017 at 7:46 am
Sonia Kher
Hi,
I have come across a child who is 7 yrs old and has exon 48-52 deletion. Can you let me know when the trial is going to come up. The patient is in India..I am wondering how can he be a part of the trial
8 June, 2017 at 7:22 pm
Exonskip
You can see an overview of therapies in clinical development at many places, e.g. the TREAT-NMD website: http://www.treat-nmd.eu/dmd/research-overview/introduction/
Here you will see that there are approaches in development that apply to all Duchenne patients regardless of their mutation. In addition there are mutation specific therapies in development. The latter have been developed furthest and two compounds have been approved: Translarna (in Europe) and Eteplirsen (in the USA). Translarna only applies to nonsense mutations – so the child you mention would not be eligible since he has a frame-shift. Eteplirsen is an exon 51 skipping compound, aiming to restore the reading frame. However, this would also not work for the child you mention since exon 51 is deleted already. Exon 53 skipping would restore the reading frame for this patient. Exon 53 skipping compounds developed by Sarepta therapeutics are in clinical development in the USA and Europe. To my knowledge no trial is currently going on in India, but I know DART (Duchenne Annihilation Research Trust, located in Bangalore) is preparing clinical trials in India.
15 June, 2017 at 8:07 am
Annemieke
Most treatments in development are mutation agnostic. You can find an overview of therapies in or close to clinical development for DMD here: http://www.treat-nmd.eu/dmd/research-overview/introduction/
27 February, 2017 at 11:12 am
Mangesh
Thank you for your reply what are the future treatment which will be available for gene duplication please let me know if any so that I can follow theme
26 February, 2017 at 7:24 pm
Mangesh
My nephew is suffering from Dmd duplication of Gene 57 to 60 what does duplication means is the prognosis same as deletion.
16 February, 2017 at 7:21 pm
Exonskip
Dear Mangesh,
I am sorry to hear about your nephew. The dystrophin gene has 79 exons. A deletion means that part of the gene is missing (e.g. exon 57-60). A duplication means that part of the gene is ‘doubled’, in case of your nephew he has exon 1-60, but then instead of exon 61, he has an extra copy of exon 57, 58, 59, and 60, and only then exon 61-79. The consequence of deletions and duplications can be two-fold: 1. They can disrupt the genetic code. This means that dystrophin protein cannot be produced and patients have Duchenne. 2. They can maintain the genetic code, allowing the production of a dystrophin that is slightly shorter but has its functional domains. These proteins are partially functional and are found in Becker patients (less severe disease).
A duplication of exon 57-60 is unfortunately of the type that disrupts the genetic code. So you would expect him to have the severe type of the disease. There are exceptions to this rule however, so it is not possible to say this with 100% certainty.
20 February, 2017 at 3:53 pm
Amir Scetic
Hello,
I have son with DMD and we recive genetic test which shows c.3151C>T in exon 23coresponding to the mutation p.Arg.1051.
What these mean? Can he take some terapy?
23 January, 2017 at 12:04 pm
Exonskip
Dear Amir,
I am sorry to hear about your son.
The mutation you describe is a so called nonsense mutation (also called stop mutation). Genes contain the genetic code for proteins. Each gene has a start and a stop signal so the translation machine knows where to start translating the gene into protein and when the protein is finished. For most Duchenne patients part of the genetic code is lost (deleted) and therefore the code becomes unreadable, so it is not translated. However, for some patients, like your son, there is a very small change that changes the code for a part of the protein into a stop signal. This means that translations is stopped prematurely and no functional protein is produced.
There is a therapy that addresses this type of mutations. It is called stop codon readthrough and the drug that achieves this is called Ataluren (tradename Translarna). Ataluren is approved for treatment of ambulant Duchenne patients 5 years and older in Europe by the European Medicines Agency. It is on the market in several countries in Europe. In addition there are access programmes for patients outside Europe. It is a treatment, not a cure. It does not stop the disease, but slows down its progression.
For more information I refer you to: http://www.treat-nmd.eu/dmd/research-overview/mutation-specific-approaches/exon-skipping/ and to the website of the company producing Ataluren (PTC): http://www.ptcbio.com/en/
23 January, 2017 at 2:22 pm
Amir Sceric
Thank You very much for Your qucik replay. Can You tell me which clinic in Europa I can contact and go with my son. Ina our country, Bosnia, we do not have good doctors. Nobody tell as about this tretman. They do not know abou it. If You have some contacts please send me. Thank You very much.
23 January, 2017 at 8:06 pm
Mohammad Yunoos
Hi,
I ‘ m father of a child With dmd due to a deletion Of exons 45 to 53 .My son is 7 Years old What you Can’ do today for this
Type of mutation?
Thank you
1 November, 2016 at 4:00 pm
Exonskip
Dear Mohammad,
Sorry to hear about your son. At the moment there is no therapy available for Duchenne. There are care guidelines available, see here for a family friendly version: http://www.treat-nmd.eu/care/dmd/family-guide/
Good care is very important to keep Duchenne patients as functional as possible for as long as possible.
The exon skipping approach probably will not apply to your son. The approach aims to restore the genetic code. However, a deletion of exon 45-53 does not disrupt the genetic code (so therefore it cannot be restored). For this mutation we would expect a milder progression (Becker) – However, there are exceptions, e.g. it is possible that while on DNA level the genetic code seems not to be disrupted, it IS disrupted in the temporary RNA copy because parts of the gene that are important for gene processing are missing. Since the protein is translated from this RNA copy (and not directly from DNA), the way the RNA copy looks like, is what determines whether protein can be produced. However, RNA and protein analysis can only be done on muscle tissue. How was the mutation found? Only by DNA analysis? Or was protein analyzed as well?
14 November, 2016 at 1:27 pm
ruud quaars
goede dag
is het nu niet mogelijk dat het medicijn wat nu er is niet te gebruiken voor de patenten die in de proef bij jullie waren
want op de congres zag ik de bij nr 53 goede voorgang zat // groen was kleine doorlatingen van eiwitten // zie foto
ik zag dat ook nu bij mijn klein zoon / nu zie je dat deze toch wat achteruit gaat
daarom vind ik dat als je ziet dat er een kleine tijd verlenging tot stand komt het toch werkt
18 July, 2016 at 2:15 pm
Exonskip
Beste Ruud,
Het is niet mogelijk om dit middel te gebruiken – het is namelijk niet een medicijn want nog niet goedgekeurd. De ontwikkeling van de “Biomarin/Prosensa” exon skip middelen is gestopt omdat de bijwerkingen niet opwogen tegen de zeer beperkte effecten in een klein groepje patienten.
In Amerika is afgelopen week een ander exon skip middel goedgekeurd (Eteplirsen, van het bedrijf Sarepta). In Europa wil Sarepta ook exon 53 middelen testen.
MVG
Annemieke
24 September, 2016 at 10:49 am
Jennifer Batterbee
Hi, we’re desperately trying to find out how to get exon skipping for TJ. He’s a three year old boy who has just been diagnosed. We’ve just started raising funds to help us in our endeavour. However we have no idea where to start in terms of having access to the treatment or how much money we need or even when he might be eligible for the treatment. Please, please help us? Any information on who to contact or how to start on this journey would mean the world to us! Thank you so much for taking the time to read this. I hope to hear from you soon. Warm regards Mrs Jennifer Batterbee.
13 August, 2015 at 10:55 am
Exonskip
Dear Jennifer,
What is TJ’s mutation? Not all mutations are suitable for exon skipping.
Annemieke
24 September, 2016 at 10:50 am
Getjan Lammers
Message for Dr Aartsema.
Dear Annemieke , today i heard the last part of an interview with you on Radio1 about the influence of mobile phones on the well-being of youngsters. What survey or news item did this refer to? Would you also think that such devices have an impact on persons at their workplace? As i am interested in how advanced automation and robotisation will impact the life of people on the workplace.
My interest is therefore both professional and private.
Thank you in advance for your response.
6 May, 2015 at 6:32 pm
Exonskip
The problem with mobile phones and tablets is that they produce a lot of light – especially in the blue spectrum. This is not harmful in itself. The problem is that blue light interferes with the production of melatonin. Melatonin is a substance your body makes that helps you sleep. It needs to accumulate for about 3 hours before there is enough to get you to sleep easily. So if you use tablets or mobiles in the evening, melatonin can not accumulate due to the blue light exposure. This can lead to difficulties falling asleep.
So it is not the mobile phones that are harmful, but the lack of sleep if you use them until very late.
24 September, 2016 at 10:53 am
kumar prashant
what can i do if i want exon skipping….
i am suffering from dmd….
plz help me…..
contact no:+917209851790
17 February, 2015 at 8:05 pm
Exonskip
Dear Kumar
Exon skipping is an approach that aims to slow down disease progression. Muscle function that is lost will not return.
It is also a mutation specific appraoch. Not all mutations are suitable unfortunately.
24 September, 2016 at 10:54 am
Angelo
Ho
I ‘ m father of a child With dmd due to a duplication Of exons 8 9 .My son is 5 Years old What you Can’ do today for this
Type of mutation?
Tank you
27 January, 2015 at 6:47 am
Exonskip
Dear Angelo
Duplications are challenging for the mutation specific type of approaches (exon skipping). However, there are other appraoches in development.
More here: http://www.treat-nmd.eu/dmd/research-overview/introduction/
Furthermore, good care is something to focus on, because this is something that can allow your son to be as functional as possible for as long as possible
More here: http://www.treat-nmd.eu/dmd/care/family-guide/translations/
Annemieke
24 September, 2016 at 10:56 am