Genetics of Duchenne Muscular Dystrophy

[Babbocat]

My son is being tested to see if he has this or another form of Muscular Dystrophy. I have read that it is an x-linked genetic disease, which is usually inherited from the mother but that spontaneous mutations can also happen, plus there is "germline mosaicism". I am familiar with a case of Apert Syndrome which is often caused by a spontaneous mutation in a certain chromosome (10 I think) and often due to the father. I wonder if anyone could tell me if given that Duchenne concerns the dystrophin gene, which is on the x chromosome, whether the father's genetic input could be somehow involved in Duchenne developing (if it were a spontaneous mutation). I have seen references to spontaneous mutations occurring through the grandfather/grandmother and being passed on to the mother and then the grandchild, but so far I haven't seen much information about the father. Can we assume that the X chromosome in the child is exactly as it should be in the mother? Obviously the tests will clear this up, but they may take quite a while.

Thanks.

[Dagl1]

Spontaneous mutation can of course happen, however this will be independent of the fathers chromosomes. If, as the mother you are carrying a DMD-causing error, there is a chance you will have light symptoms, however this is rare and may be even difficult to notice without exact testing.

I am not entirely sure what you mean with "Can we assume that the X chromosome in the child is exactly as it should be in the mother?"

Hope it turns out that your son doesn't have DMD!

-Dagl

[Endy0816]

The father would have passed on a Y chromosome to a son(assuming normal chromosome inheritance).

ie. Mother XX, Father XY, Son XY

 

Hopefully not needed but there are promising gene therapies in the works now.

[Babbocat]

Thank you Dagl1. I don't really know much about genetics. What I mean is if father's chromosomes or his DNA can somehow get mixed up with the x chromosome inherited by the child. If it is Duchenne it is definitely the dystrophin gene which is on the x chromosome. There is another type called limb-girdle muscular dystrophy where the mutation is on chromosome 15, for example, it is autosomal recessive, I understand that in this case both our genes would come into play. It might possibly be limb girdle but at the moment it all points to DMD.

As you can see, my knowledge about this field is quite limited.

As you have said "it will be independent of the father's chromosomes" I think this more or less answers it.

5 minutes ago, Endy0816 said:

The father would have passed on a Y chromosome to a son(assuming normal chromosome inheritance).

ie. Mother XX, Father XY, Son XY

 

Hopefully not needed but there are promising gene therapies in the works now.

Can I ask what you mean by "assuming normal chromosome inheritance"? Thanks.

[Dagl1]

A quick explanation; 

Genes are just the code or blueprint that cells use to make proteins, which are in all essentially little machines that can do almost anything. 
There is gene for a protein that helps with a specific chemical reaction, there are proteins that work as little pumps, there are proteins that look at how much energy is available in the cell and if needed they can then increase energy production if there isn't enough. Dystrophin is a structural protein, it acts as the beams or pillar within a building to give muscle cells their strength (and other things but this is a good analogy). Dystrophin is only present on the X chromosome and thus will either come from the mother or have happened spontaneously.

Unfortunately, because males only have 1 X chromosome, there is not such a thing as autosomal recessive for them. They either have a mutation in dystrophin gene, or they don't. However there are several types of mutations; some will reduce the amount of dystrophin, others make it less functional (think instead of having steel beams, they are now a little shorter and made of a weaker metal). Some of these are not as bad as others, please take a look at this section of the following article (also check out Becker's Muscular Dystrophy).

https://www.hindawi.com/journals/bmri/2009/325210/ 

BMD = Becker's muscular dystrophy
In DMD patients, immunohistoanalysis shows total absence of dystrophin; whereas BMD patients have 10% to 40% of the normal amount or produce a partly functional dystrophin protein with an altered size [12]. 

During healthy conception, 23 chromosomes will come from the father and 23 from the mother, 22 of these pairs will contain the same genes (although the exact protein may be slightly different (think of, pump with 500 bolts and 1 motor vs pump with 488 bolts and 2 motors)). The last pair is either X X (so both from the father and the mother, in which case it is a girl) or X Y, where the Y is given by the father. While all the other chromosomes allow for 2 variants of each protein (and thereby autosomal recessive mutations can exist) this is not the case for a mutation on chromosome X when the child (boy) only has 1 X chromosome. If you are a carrier of one of these mutated proteins, then there it most likely is autosomal recessive for you, but unfortunately not for him. 

I hope that gives a bit more clarity, I can imagine this is a worrying time and having a bit more knowledge about the subject may help with further understanding as well.

-Dagl
 

[Babbocat]

Thanks again Dagl1. He has a normal set of 23 pairs, 22 and X/Y.

 

Obviously it would be better if it were not this x-linked disease. With limb girdle MD, the autosomal recessive type, people can have more or less normal lifespans.

 

This has come completely out of the blue. He is our eldest son. His brother, who is only a few months old, appears totally normal. But the eldest did not suckle well from birth, did not move much, and also had a clubfoot (left side and operated successfully). For a long time, we have thought that his problems just came from the club foot, but he recently had a blood test with a very high CK which is what has prompted the genetic test for muscular dystrophies.

 

From what you have said, at least I can console myself with the idea that if it is DMD it is very unlikely to have come from me (if I have understood your explanation correctly).  As I am on the old side, for the father, this is one idea that has troubled me. And I do know of a girl who has Apert where it is clear that the mutation came from her father (who is not young either).  

[Babbocat]

On 5/30/2019 at 6:05 PM, Dagl1 said:

A quick explanation; 

Genes are just the code or blueprint that cells use to make proteins, which are in all essentially little machines that can do almost anything. 
There is gene for a protein that helps with a specific chemical reaction, there are proteins that work as little pumps, there are proteins that look at how much energy is available in the cell and if needed they can then increase energy production if there isn't enough. Dystrophin is a structural protein, it acts as the beams or pillar within a building to give muscle cells their strength (and other things but this is a good analogy). Dystrophin is only present on the X chromosome and thus will either come from the mother or have happened spontaneously.

Unfortunately, because males only have 1 X chromosome, there is not such a thing as autosomal recessive for them. They either have a mutation in dystrophin gene, or they don't. However there are several types of mutations; some will reduce the amount of dystrophin, others make it less functional (think instead of having steel beams, they are now a little shorter and made of a weaker metal). Some of these are not as bad as others, please take a look at this section of the following article (also check out Becker's Muscular Dystrophy).

https://www.hindawi.com/journals/bmri/2009/325210/ 

BMD = Becker's muscular dystrophy
In DMD patients, immunohistoanalysis shows total absence of dystrophin; whereas BMD patients have 10% to 40% of the normal amount or produce a partly functional dystrophin protein with an altered size [12]. 

During healthy conception, 23 chromosomes will come from the father and 23 from the mother, 22 of these pairs will contain the same genes (although the exact protein may be slightly different (think of, pump with 500 bolts and 1 motor vs pump with 488 bolts and 2 motors)). The last pair is either X X (so both from the father and the mother, in which case it is a girl) or X Y, where the Y is given by the father. While all the other chromosomes allow for 2 variants of each protein (and thereby autosomal recessive mutations can exist) this is not the case for a mutation on chromosome X when the child (boy) only has 1 X chromosome. If you are a carrier of one of these mutated proteins, then there it most likely is autosomal recessive for you, but unfortunately not for him. 

I hope that gives a bit more clarity, I can imagine this is a worrying time and having a bit more knowledge about the subject may help with further understanding as well.

-Dagl
 

Hello Dagi, following up on your explanation, I wanted to ask you about something I found on the Duchenneregistry website:

 

"If you have no other affected family members, there is a 66% (or 2 in 3) chance that you are a carrier. Approximately 33% (or 1 in 3) of cases of Duchenne muscular dystrophy are caused by what are called new mutations. These are random changes to the genetic code in the dystrophin  gene that happen in only one egg or sperm. That one egg or sperm could create an affected male; rarely, an affected female; or a carrier female child who could later have affected children."

 

In other websites they refer more generally either to mutation happening in the mother's egg or to the developing embryo.

 

The thing I don't understand here is how the change in the genetic code for dystrophin could happen in the sperm of the father (not just the grandfather) if the father only gives the child the Y chromosome and the dystrophin gene is on the X chromosome.

 

I can understand that the mutation may have happened in the grandfather because he gives his daughter the X chromosome. She would then become a carrier and have a 50% chance of passing it on.

 

Thank you for your time.

[Dagl1]

3 hours ago, Babbocat said:

Hello Dagi, following up on your explanation, I wanted to ask you about something I found on the Duchenneregistry website:

 

"If you have no other affected family members, there is a 66% (or 2 in 3) chance that you are a carrier. Approximately 33% (or 1 in 3) of cases of Duchenne muscular dystrophy are caused by what are called new mutations. These are random changes to the genetic code in the dystrophin  gene that happen in only one egg or sperm. That one egg or sperm could create an affected male; rarely, an affected female; or a carrier female child who could later have affected children."

 

In other websites they refer more generally either to mutation happening in the mother's egg or to the developing embryo.

 

The thing I don't understand here is how the change in the genetic code for dystrophin could happen in the sperm of the father (not just the grandfather) if the father only gives the child the Y chromosome and the dystrophin gene is on the X chromosome.

 

I can understand that the mutation may have happened in the grandfather because he gives his daughter the X chromosome. She would then become a carrier and have a 50% chance of passing it on.

 

Thank you for your time.

Hey Babbocat, 

So that website's description is strange, those chances seem wrong, I wouldn't pay too much attention to them. Regarding the description of the mutations, you are right; As the father of a boy, you do not give it your X chromosome thus you could not give it a mutated X chromosome. I think that website is a little inaccurate.

-Dagl

[Babbocat]

On 6/12/2019 at 11:16 AM, Dagl1 said:

Hey Babbocat, 

So that website's description is strange, those chances seem wrong, I wouldn't pay too much attention to them. Regarding the description of the mutations, you are right; As the father of a boy, you do not give it your X chromosome thus you could not give it a mutated X chromosome. I think that website is a little inaccurate.

-Dagl

Thanks you so much for taking the time to give me your input.