Thursday, January 6, 2011

Why do some carriers have symptoms?

Normally, women that have the defective gene that causes Kennedy’s Disease are only carriers.  However, we occasionally hear about a carrier experiencing some symptoms … usually later in life.  Hand tremors, weakness in the legs, and difficulty swallowing are the most common symptoms exhibited.

X-inactivation or Lyonization

Tuesday, in our KDA Forum, Dan posted a comment that provided a possible explanation.

“I found a reference to another reason why women can have SBMA symptoms. As you may know, women have two X-chromosomes. There is a natural process by which one X-chromosome can be "turned off" or inactivated. The process is called "X-inactivation" or "lyonization." 
So, assuming the woman carrier had two X-chromosomes, one with the SBMA gene and second one without, and then the second X-chromosome became inactivated, then the first one with the SBMA gene would be more likely to be expressed. 

Here's a quotation from Wikipedia:
"X-inactivation (also called lyonization) is a process by which one of the two copies of the X chromosome present in female mammals is inactivated....The choice of which X chromosome will be inactivated is random in placental mammals such as mice and humans, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants in the organism."

nucleus-x-chromosome-inactiveNucleus of a female cell. Top-left: Both X-chromosomes are detected, by FISH. Bottom-left: The same nucleus stained with a DNA stain (DAPI). The Barr body is indicated by the arrow, it identifies the inactive X (Xi).

The article that Dan references can be found in Wikipedia.  I read the article and it was interesting.


Ed, our resident biology professor, responded to Dan’s finding with the following:

“I am not sure if the X inactivation is the cause of the appearance of symptoms in females. There have been several cases in which both X chromosomes in women are the SBMA form of the gene (this is known as homozygous for SBMA) and these individuals do not show the symptoms as men do and are not really different from women who are simply carriers ( these are heterozygous). 

This paper was referenced in the post by Dan on this thread, I think the main reason women tend to have few symptoms is due to the low levels of testosterone. Since women do have testosterone, albeit low levels, it is possible that even these low levels of testosterone can lead to some of the minor (compared to men) symptoms. Still, I do not know of any report in which a woman has had the severity of symptoms seen in men.”


So the jury is still out on this question.  In my opinion, Ed is correct about testosterone being the main factor in causing the severity of the symptoms.  Yet, the “X-inactivation” factor is interesting also. 

What do you think is the cause?

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