I am a 65 year old female recently diagnosed as a carrier. I was tested because I was having some of the symptoms that were occurring in maternal family members (male cousins and a female cousin). To date we have identified 12 of us who are positive males and assumed female carriers (I am the only female that has been DNA tested). I am new to this site and the literature but I find virtually nothing about the frequency of female carriers exhibiting symptoms. Most of what is said is dismissive and minimizes the issue. And nothing in this "Carrier Discussion" has been posted since 2014. Both my female cousin and I have muscle cramping, tremors, weakness, fatigue and in my case elevated CK. I would like to know if there are many other carriers out there who have active symptoms? I also wonder if the medical community is addressing this issue? Thank you!

Hi Linda,

A few years ago on this forum, we discussed the subject of symptoms in females very extensively. Title of the thread was "Any females that have this?" Details at this link: http://kennedysdisease.groupee...017074695#3017074695

The conclusion was, it is possible for women to have symptoms of SBMA, but extremely rare. If the rate of KD among men is about one in every 40,000 people, our conclusion was the rate among women would be about one in 1,600,000 people. Also please note that simply being a carrier isn't sufficient to have symptoms. To have symptoms, a woman would have to be homozygous for the KD gene; that is, BOTH her mother would have to be a carrier AND her father would have to be a person with KD. That is very rare, but not impossible, especially in isolated rural communities.

There were also links to a peer-reviewed scientific journal article concerning two Canadian sisters who both came from a family where the men had KD, and both sisters had symptoms. Links to the article: Neurology 59:770 and NIH 12221177
The complete citation is:
Neurology. 2002 Sep 10;59(5):770-2.
Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women.
Schmidt BJ, Greenberg CR, Allingham-Hawkins DJ, Spriggs EL.

Concerning your question about whether the medical community is addressing the issue, the answer is: "No." Most doctors don't even believe that women can get KD for the same reasons you cited. If you are having trouble convincing your doctor, I suggest you print out the articles mentioned above and show them to the doctor. At least that will help to establish your credibility.

Good luck.

This message has been edited. Last edited by: Dan B,

Here are two that are even better. In the original 1968 paper on KD, Dr. William R. Kennedy who identified the disease made note that women had symptoms. Here's a snip from the article.

quote:

The nonaffected members of each family...were examined. [O]ne female...had weakness of the proximal muscles of the lower extremity and had difficulty arising from the squatting position. Other females complained of muscle cramps after exercise but muscle twitching was rarely, if ever, noticed. Electromyographic studies were performed on some of these and were normal.

The reference can be found at this link. http://www.neurology.org/content/18/7/671.citation
The citation is Neurology Volume 18, July 1968, p. 671.

Another scientific paper cited both the Schmidt paper (mentioned above in this thread) and the Kennedy paper. Here's a snip (with emphasis added in boldface).

quote:

Female Homozygotes
Schmidt et al. (2002) described 2 sisters, aged 34 and 42 years, homozygous for the CAG expansion in the AR gene causing Kennedy disease, in whom symptoms were limited to occasional muscle cramps and twitches. Both sibs had mild hand tremor, and the elder had rare perioral fasciculations and mild motor axonal loss in the sternocleidomastoid muscle. Both parents were deceased, but each was thought to have contributed an X chromosome containing the CAG expansion to the sibs. This was supported by a history of muscle disease in the father and the diagnosis of Kennedy disease in a maternal cousin. Women heterozygous for the Kennedy disease gene are generally asymptomatic; however, Kennedy et al. (1968) noted in their original report that 'several female siblings of affected males had muscle cramps.' One of the remarkable features of the homozygous sisters reported by Schmidt et al. (2002) was the mildness of their manifestations. The authors suggested that the increased severity of Kennedy disease in men is due to higher levels of androgen receptor stimulation compared to women, which may produce higher levels of abnormal transcriptional regulation.

Link to the article: https://omim.org/entry/313200

(However, please keep in mind that we think heterozygous carriers don't get symptoms. Only women who are homozygous for the KD gene would get symptoms. That means they have two copies of the gene, one from each parent.)

This message has been edited. Last edited by: Dan B,

quote:

(However, please keep in mind that we think heterozygous carriers don't get symptoms. Only women who are homozygous for the KD gene would get symptoms. That means they have two copies of the gene, one from each parent.)

I think this is an assumption rather than scientific research. I just spoke with my 93 year old mother who is a carrier along with at least 2 of her sisters and they all discount possible symptoms as simply 'old age', arthritis, etc. - which of course may be true but also may be mild symptoms.

Thank you for responding. best Linda

Hi Dan. somehow my earlier post wasn't registered. but I wanted to point out that one of my X chromosomes had a reading of 45, higher than one of my affected male cousins, and my other X had a normal reading of 23. My symptoms include a hand tremor, worsening muscle cramps both in severity and frequency, recently elevated CK level, throat tightness, perceived muscle weakness and fatigue. My female cousin who is the sister of the above male and mother of 2 affected males has similar symptoms to mine but hasn't been tested. So are you saying that these cannot be symptoms of Kennedy's? Luckily my PCP did take my symptoms seriously and referred me to a geneticist who had my blood tested at Mayo and has referred me to a neurologist. Best, Linda

The results from my DNA test from the Mayo Clinic in which one of my X chromosomes was positive (full penetrance) and the other X was normal, states "This result is consistent with this individual being a carrier of SBMA. Of note, female carriers of expansions in the AR gene may be at risk for developing symptoms associated with SBMA....."

So, this seems to refute the idea that only women carriers who are homozygous for the KD gene would get symptoms.

Linda wrote:

quote:

So are you saying that these cannot be symptoms of Kennedy's?

No, I am not saying that. Certainly if you are having symptoms, and the Schmidt paper said that women had symptoms, the original Dr. William Kennedy paper said that women he observed had symptoms, and even the Mayo Clinic said you were at risk for symptoms, I would not even think about arguing with all of those sources. I believe that you have KD symptoms.

This discussion is quite interesting scientifically because it bears on learning about the true nature of KD. The medical "conventional wisdom" on KD includes these two points:

1. The gene for KD is recessive, which means that your "normal" chromosome of 23 repeats would "override" the other chromosome of 45 repeats. Therefore you "should not" have KD.

2. The binding of testosterone to the androgen receptor is very significant in the onset of KD. Since you are a female age 65, you probably have very low testosterone levels, if any. Therefore you "should not" have KD.

The fact that you do have symptoms would seem to refute both point #1 and point #2. My wish is that your case could come to the attention of not only a medical doctor and maybe a physical therapist who can help you with symptoms, but also a researcher who can address both points and possibly advance our knowledge of KD.

This message has been edited. Last edited by: Dan B,

Hi Dan. I think the symptoms started 8-10 years ago with increasing cramping all over my body and a feeling of weakness in my arms and legs. So I would have been about 55 at the time. I also think it would be worthwhile to work with a researcher about this and that is why I brought this to the forum's attention. I think it's likely that most women don't get tested because of the expense or the assumption that they won't be symptomatic (and they will not think, then, that perhaps some of their 'aches and pains' are actually mild-to-moderate manifestation of KD). It might also be beneficial to test women's testosterone levels at the same time as this test - that might go a long way in advancing this knowledge. Perhaps I have higher testosterone than average? Also I am wondering if there is correlation between the number of repeats and the severity of symptoms? (i.e. I believe the abnormal scale starts at 38 and ends at around 63 - so if a woman had a repeat of 39 or 40, would her symptoms be less?)

I see the neurologist in Sep - he specializes in MS. I live in Vermont where there are no Kennedy specialists in the immediate area. If you know of a researcher that would be interested in exploring this further, please let me know. thanks for your input

quote:

Perhaps I have higher testosterone than average?

If you want to follow up on that, there is a relatively simple blood test for testosterone and DHT.

quote:

so if a woman had a repeat of 39 or 40, would her symptoms be less?

From Bruce's blog, the following posts go into the question of number of repeats vs. progression of KD.
http://kennedysdisease.blogspo...ennedys-disease.html
http://kennedysdisease.blogspo...ennedys-disease.html

This message has been edited. Last edited by: Dan B,

Thanks, Dan; this is very informative. I plan to pass on all of this info both to my doctor and my geneticist as they had not heard of Kennedy's prior to meeting me!

If you would rather see a doctor who is familiar, on the KDA website there is a list of "Doctors Familiar with Kennedy's Disease" at this link http://www.kennedysdisease.org...-disease/kda-doctors
For me, it is reassuring to be talking to a doctor who has seen KD before, as opposed to one who has no idea.

Probably the closest one to you is in the Boston area. Before you make a special trip, I should add that there isn't much doctors can do about KD, since there are no FDA-approved treatments for KD.

However, there are treatments available for specific symptoms such as cramping or swallowing, for example physical therapy, and they can prescribe those.

This message has been edited. Last edited by: Dan B,

Hi Linda, much is being learned about what SBMA truly is and why there is so much variance in symptoms (even within the same family). In the absence of a cure, the standard is to treat the symptoms. In another post, you spoke of diet, it can't hurt. Check your calcium /magnesium balance for the cramping and tremors. I was diagnosed with Prinzmetal's Angina (usually found in women) when chest cramps were severe and Norvasc has taken care of it (and the migraines), seems it works by stopping smooth muscle fasciculations. Read up about mitochondrial dysfunction for the fatigue another symptom KD can have in common with other disorders (I have had great results by supplementing with Acetly L Carnitine). Unless your hair is falling out, its unlikely your testosterone is out of wack and there are studies that show testosterone loss of function is as much a problem as gain of function.
Such a large grouping deserves followup, I wish my mother had had the tests and wonder at the similarity of the her passing and her sister. If you cannot get anyone to follow up, check your closest teaching hospital, and maybe the Rare Disease Clinical Research network. Above all I would call NIH at Bethesda Maryland and talk to Angela in neurology
https://patientinfo.ninds.nih.gov/

Thanks for the info, BC Paul