Carriers with two defective genes

The KDA Forum had some interesting posts this week about ‘carriers’.  Specifically, carriers that have two defective “X” chromosomes … a rarity. 



Normally, a carrier has one good “X” chromosome and one bad one.  Along with low testosterone levels in females, the good one helps mitigate some of the impact of the defective gene.

In this forum topic, a person heard that two women, both with two defective genes, had full blown symptoms.  She asked, if this is the case, why are carriers not included in clinical trials.

Ed, our illustrious biology professor and resident researcher, provided the following explanation.

“… there have been two cases in which women are homozygous for KD (meaning that both copies of their AR gene are the mutant ‘KD’ form). However, these women did not have the major signs or symptoms associated with KD (see http://www.neurology.org/content/59/5/770.abstract) and had similar symptoms/signs as did other carriers.

… as far as I know, there is no reported case of a woman having "full blown" KD. Such a finding would be published and there is no such paper that I know of. ...

As far as our current understanding goes, one must have two conditions to have KD; a copy of the mutant form of the AR gene and high testosterone levels. Carriers only have the former and without the latter, that is why the symptoms will be less severe than in men. Different women have different levels of testosterone (but typically much lower than men) and it would appear that even this low level could cause the effects that seem to be felt by carriers.

With regard to why there are no clinical trials for women, I would guess that is primarily due to the lack of severe symptoms and the slow onset of the symptoms. It is difficult enough to try to determine the efficacy of a treatment with the men who have a faster progression and more severe symptoms. It would be almost impossible to identify success in carriers. It is hoped that if a treatment is discovered that works for men, it may also work with carriers.”



This subject brings up something else worth noting.  If a carrier does have two defective genes, then the 50-50 probability is thrown out the window in regards to children.  Every child would have the defective gene.  Fortunately, there are only two known cases where this condition exists.