IGF-1 Update

If you have been following this blog for some time, you know I have mentioned Dr. Maria Pennuto (lead researcher) and IGF-1 in several articles.  Her initial research allowed the nicknaming of the project “Might Mouse” because of the positive results the mice models had when given IFG-1.

 

rom everything I have read it appears to have great potential, especially if the treatment program is started pre-or-early onset.  This week another update was written on this promising research.  The article is a little too technical for my liking, but it is not written for people like me.

Insulin-like growth factor 1 and androgen signaling crosstalk in the pathogenesis of spinal and bulbar muscular atrophy

Article Excerpt:  “The rationale of this research is that once we know how phosphorylation of AR is regulated we will be able to identify agents that promote such modification for therapeutic purposes. We anticipate that we will elucidate how phosphorylation of AR is influenced by tissue-specificity, age, polyglutamine expansion as well as by methylation and palmitoylation. With this information in our hands, we will be able to screen for agents that affect these modifications to enhance phosphorylation.”

Dr. Maria Pennuto works out of the Department of Neuroscience at the Italian Institute of Technology in Genova. Dr. Pennuto's lab focuses on elucidating the molecular mechanisms of disease pathogenesis in neurodegenerative disorders, such as spinal and bulbar muscular atrophy and Huntington’s disease, using molecular and cellular biology, biochemistry, and behavioral analysis. She previously worked with Dr. Kenneth Fischbeck at NIH. Her current work is based upon results that Maria discovered when she worked at NIH. She found that a specific modification of the mutant androgen receptors results in decreased toxicity. This modification was due to the activation of an enzyme known as PKA. She is also a 2009 recipient of a KDA Research Grant for $20,000.

Ms. Pennuto has been a guest on our KDA chat room and also attended a couple of KDA conferences.  If you want to know more about her research check out  the chat room transcript, “Research Update and IGF-1”. 

I always enjoy writing about research update.  I realize the research (discovery) process is a long one, but it is a necessary one for all of us living with Kennedy’s Disease.  J-9 or IGF-1 might just be the treatment that will change people’s lives.

Good News on the Research Front

In several articles over the last eighteen months I have mentioned ASC-J9 as another potential treatment for Kennedy’s Disease.

Background:  In 2006, the KDA’s Scientific Review Board recommended the awarding of a research grant to Chawnshang Chang, Ph.D., of the University of Rochester.  Dr. Chang’s research was focused on developing a treatment regimen for Kennedy’s Disease targeting the poly Q-expanded mutant AR.  A few years later, AndroScience purchased the rights to this technology.



Tuesday, AndroScience and NIH announced a grant to move this potential treatment’s research along.  Follow this link (ASC-NINDS) to the PR-Newswire site to read the entire press release.  A summary of the release can be found below.

“AndroScience Corporation Awarded a $3.8 Million, 3-Year Milestone-Driven, Cooperative Translational Research Grant from the NIH to Develop an Oral Treatment for Spinal Bulbar Muscular Atrophy (Kennedy's Disease)

 

SAN DIEGO, Jan. 25, 2011 /PRNewswire/ -- AndroScience Corp. (ASC), based in San Diego, California, announced receiving a $3.8 Million, 3-year milestone-driven, cooperative translational research grant from the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH).  Through a joint research effort with the Neurogenetics Branch of the NINDS, ASC will use the funding to pursue development of an oral drug treatment for spinal and bulbar muscular atrophy (SBMA) or Kennedy's Disease, a rare hereditary neurodegenerative disease, which currently has no approved drug available to patients.  Key pathological features of SBMA include progressive motor neuropathy and androgen insensitivity syndrome caused by a distinctive mutation within the androgen receptor (AR) gene.  ASC has developed a unique platform of therapeutic small molecule drugs, which selectively and potently enhance degradation of the AR protein, termed AR degradation enhancers (ARD enhancers).
 
"Given encouraging pre-clinical results and the clear need for a new therapeutic option for SBMA patients, ASC is excited to continue advancing preclinical development of this promising novel drug candidate," said ASC President Charles Shih, Ph.D. "The funding provided by the NINDS/NIH will significantly propel our efforts in validating ARD enhancers as a disease-modifying therapeutic intervention against such a rare and devastating neurodegenerative illness."
 
This $3.8 Million cooperative translational research grant will leverage expertise from the NINDS and draw upon ASC's innovative approach to targeting the mutant androgen receptor (AR).  The goals of the grant will be to first validate an orally administered ARD enhancer drug is efficacious in the SBMA transgenic animal model, and further, to complete preclinical toxicology, safety pharmacology, and ADME studies necessary in supporting of an IND filing to commence human clinical studies.  To date, ASC has provided robust proof of concept data using an ARD enhancer compound; demonstrating treatment ameliorates cardinal features of SBMA neuromuscular pathology, restores functional activity, and improves survival in a SBMA transgenic mouse model.”
 
This is very good news for those of us living with Kennedy’s Disease because it moves another major project forward to the pre-clinical testing phase.  I will be watching this project closely.

Necessity is the mother of invention

This last year I wrote a couple of articles about my new wheelchair.  My Permobil C300 is great and has made life much easier for me.  The seat lift is wonderful and makes transferring to other chairs effortless and worry free.  Last week, however, I discovered a new use for the seat. 

 
I was in the office sitting in my desk chair working on the new KDA website.  The chair height is a little less than needed, so I use a cushion to raise it a few more inches.  The chair is also on wheels and this normally does not create a problem. 

This morning, however, I was not feeling quite as strong and when I pushed off with my arms and leaned forward, the chair slid backwards.  I could not catch myself and ended up sitting on the floor.  I tried getting up, but just did not have the strength.  My wife was gone for the day and my options were limited. 

I was wearing myself down quickly trying different positions and angles.  If I did not come up with a solution soon, I would have to dial “H” for help (i.e., call a neighbor or friend who was available).



As I sat there considering what else to try I looked at my wheelchair and thought, “What if …”  I crawled over to the chair and lowered the seat.  I then moved a folding chair so that it was near the front of the wheelchair.  I laid my upper torso on the wheelchair seat and pushed the “up” button.  Walla!  My body rose up and up and up.  I reached behind, pulled the folding chair closer, and leaned back. 

EUREKA!  I was sitting comfortably on the chair and could get up without a problem.  Afterward as I wiped down the Permobil, I muttered “sweet nothings” to it.  It seemed to sense how I was feeling.  The whirl and hum of the electric motors seemed to say it was pleased with itself.  Mission accomplished!

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.

Are you still the driver?

I always believe there are choices in life.  I am not talking about simple, easy choices (like what should I eat for dinner); I am talking about “life changing” choices.  Often these choices are not always evident.  Some have to be looked for (discovered) before they can be made.  It is just important that you do not close the book on yourself because of your situation.  You never know what could happen in the next few weeks, months or years.  
 


Fortunately, and I do mean fortunately, Kennedy’s Disease is a slowly progressing disorder.  It is often ten or twenty years between the time of onset and your first real life-changing issues.  During that time, you will have the opportunity to make several choices.  As the severity of the condition increases, even more choices will have to be made.  Yet, you must continue to seek out alternatives and recognize the choices and opportunities that are available.  You cannot just shut down.
 


For those of us living with Kennedy’s Disease, it might often appear that someone else is driving the bus and we are now just a passenger.  Yet, the minute we do give up (stop fighting, stop exercising, or lose hope), we become a passenger.  
 
For me, I am a man and I like driving.  I also like knowing where I am going.  I might not always ask for directions, but that does not mean I am lost.
 
I have a saying, "A bad attitude is the only handicap in life."  What I mean by that is that you have to believe that there is a light at the end of the tunnel.  You have to also believe that there is hope.  You cannot give up on yourself because of your situation.  When you do, you no longer have any choices and someone else will decide your future.  
 
I also believe that those of us living with this condition need a good co-pilot.  Your spouse, significant other, or soul mate is a critical element in your future success.  She, or he, needs to be involved in the decision-making process because at some point you will be switching roles.  A partnership in the truest sense is needed because you cannot do it all yourself.
 
The KDA has a saying, “Working together to find a cure … for our generation, and for our children and our grandchildren.”  Many of us living with Kennedy’s Disease are driving the bus because we do not just want to be passengers, or bystanders.  Finding a treatment or cure as well as helping others who are searching for answers keeps me motivated.  It acts like a cup of hot, strong coffee when I am fatigued.  It helps me realize that without hope, we have nothing to look forward to.
 


So, I will ask again, are you still the driver?

Dutasteride Clinical Trial; Another perspective on the

The official summary report of the Dutasteride clinical trial came out this month.  It is an interesting report.  Since the original report came out over a year ago, there has been a lot of discussion from those who were in the trial on whether to continue taking Dutasteride since there appears to be no side effects and an upside benefit potential.



With this latest report, the emails have been flying back and forth about this subject again.  Several who have taken dutasteride commented that they saw an improvement in strength.  The report also reflects a small improvement in the dutasteride group versus the placebo group.  Since I am of the believe that any slowing in the progression is a win … especially at my age, I might be ready to discuss this subject with my doctor.

The section of the report on “Findings” gives me hope.  “At 24 months, the placebo group showed a decrease of 4·5% from baseline in weight-scaled muscle strength as indicated by QMA, and the dutasteride group had an increase in strength of 1·3%; the difference between groups (5·8%, 95% CI -5·9 to 17·6; p=0·28) was not significant.”   I recognize that researchers are looking for significant evidence of improvement while I am just looking for any improvement at all, or a lessoning of the progression. 

Also interesting was, “Quality of life, as measured by the physical component summary of the Medical Outcomes Study 36-item Short Form version 2, favored dutasteride (change in score from baseline: placebo, -3·6%, vs dutasteride, +2·1%; p=0·01), whereas the mental component summary favored placebo (3·3%vs -3·2%; p=0·03). The dutasteride group had fewer patients reporting falls than did the placebo group (9 vs 16; p=0·048); there were no other significant differences in reported adverse events.”

The interpretation of the trial from a researcher’s perspective reads, “Our study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA, although there were secondary indications of both positive and negative effects compared with placebo. A longer trial duration or larger number of patients might be needed to show an effect on disease progression. Performance testing, QMA, and quality of life measures were identified as potentially useful endpoints for future therapeutic trials.”



As a result of the recent emails of those who were or continue to take Dutasteride, and the rereading of the report, I am ready to discuss this potential opportunity with my doctor.  I am not one to start taking just any drug or therapy with hopes that it will help.  I am especially concerned about those individuals that will try anything without it being properly tested and approved.  At the same time, I do not want to “look a gift horse in the mouth” either.  It appears that the worst case scenario is I find out that it does not work for me.

If any of you were involved in the trial and were taking Dutasteride, I would be interested in your thoughts on the subject.  Did you have any side effects?  Did you notice any benefit?  Are you still taking dutasteride today?

The new KDA website; We are getting close to publishing …

My focus the last several months has been in supporting our web site designer as she develops our new website.  Except for a couple of setbacks by our service provider, we have made great progress.  We hope to be publishing the new site in February.

I thought I would take a moment today and show you some of the new looks you will see once the site is up and running.

This is the new home page.  The sub-sections are now divided into articles focused around the KDA’s mission statement as well as “What is Kennedy’s Disease”, “Help us find a cure”, and “About the KDA”.



The lead page in the “What is Kennedy’s Disease” looks like this.  Down the left side is the menu showing all the categories and articles you can access in this section.



This is a picture of the “Promote Research” lead page.



Below is the right portion of the “Provide Support” section lead page.



The right portion of the “Share Information” section looks like this.



The right portion of the “Worldwide Contacts” is shown below.



The right portion of the “Frequently Asked Questions about Kennedy’s Disease” looks like this.



As you can tell, I am excited about this new website.  It is using current technology and will allow us to do things our original website would not allow because of the proprietary coding that was used.

When, What and How?

There is a question I am often asked and one that I continue to struggle with because I am not sure there is one right answer.  I believe there are far too many dependencies to say what, when and how.

The question:  “When should I tell my daughter or son that he/she possibly has the defective gene?”



In my opinion, there is no particular age that anyone is fully ready to hear this news.  I believe a parent should wait …

1. until symptoms appear (in the case of a son),
2. or if a son or daughter start discussing having children with their spouse,
3. or if a treatment is made available and the earlier a patient begins treatment the slower the progression.

Prior to that, what is the value of discussing this issue?  It will not change anything and will probably just make the son or daughter worry about something needlessly.

Once you think you have the above answer, you next have to tackle, “How much should I tell them?”  What level of detail is important at this time?  Should I really get into the disease or just provide an overview and be ready to address additional concerns?



Also, it is important to consider how your daughter or son might receive the information (maturity level).
From there you can drive yourself crazy with other questions including …

• Do I say “possibly” (or a 50-50 chance) even if you are certain they carry the mutated gene?
• Should I provide additional reading material on Kennedy’s Disease or sit with them as they search the internet for information and answers?
• Should I discuss my pending conversation with a genetics counselor asking for guidance as to the best way to explain the situation?  Or, do I break the news while we are both sitting in front of a counselor?
• Should I recommend testing or have them wait until they want to know for certain?
• If they do decide to be tested, how will this information impact their health insurance and employment now and in the future?
• If they son or daughter plan on having children, do I provide information on prenatal testing or schedule an appointment with a genetics counselor?

The above are just some starter questions.  I am sure there are more and perhaps some that are more important.

As a parent or potential parent, your opinion on this important subject is important.  Let other readers know your perspective and reasoning.  It just might help others when they wrestle with these questions.

A lay persons guide to the results of a recent research paper - Part II

Today’s article is Part II of a guest post from Ms. Karia Orr. 

There are different types of nuclear receptors but AR belongs to Class I and behaves as shown the diagram below. The cytoplasm is the cytosol (liquid) plus all the other organelles (intracellular components/structures) contained within the cytosol. Ribosome’s are the organelles in cells that make protein following the instructions in mRNA which is a kind of copy of DNA. AR binds to DNA in the nucleus as mentioned and as a result turns genes either on or off. This then results in changes to the copies of the mRNA which head off outside the nucleus to the Ribosome and provide blueprints for the manufacture of proteins. The proteins then have different roles depending on what they are made of and what their destination is. Think of the ribosome’s as a Global distributing car manufacturing plant that makes different models of cars and car components each with a specific blueprint coded in the mRNA.

Basically, the researchers needed to look at every bit of the AR at the amino acid level and this is one heck of a long rosary chain! In essence you need to change one bead (amino acid) at a time and then see what happens. Change a different bead on a fresh new identical chain and do the same ad infinitum. This takes ages as you need to look at the adult creature (so change a bead, wait for the organism to mature in the case of KD then test) but as a fruit fly matures quickly, they utilized this well studied creature. There are some mammalian models out there being used to study KD but this would have taken the researchers 2 decades and a few billion. The research behind this paper took 5 years. Moving on, what have they found using our friend the fruit fly?

Well, previous findings were confirmed, i.e. the androgen has to bind to the receptor for the whole toxic business to begin. In science things have to be confirmed quite a few times and in different ways for them to become fact so this is good! The really interesting stuff to a geek like myself is that the researchers found that:

• Nuclear translocation of mutant AR is insufficient to initiate neurodegeneration, it is necessary for the receptor to head off to the nucleus as it does normally but this does not cause the neurodegeneration. Knowing that activation of the mutant receptor does not create some yucky stuff in the cytoplasm of the cell that causes the toxicity is good to know.
  
• So what next? They found out the step that initiates the neurodegeneration- DNA binding by mutant AR (remember normal AR normally binds to DNA anyhow and is doing it as you read this!).
  
• They also identified and pin pointed coregulators that assist the mutant AR in its toxic dirty work once it has bound to the DNA.

Co-regulators are all over the place in the body and they are specific wee beasties. Think of the way vitamin D is needed by our bodies to absorb calcium. It is, and if you don’t have enough vitamin D you could eat calcium till the cows come home and you will not absorb much. In this example vitamin D could be classed as a co-regulator in calcium absorption. The researchers identified co-regulators to mutant AR dirty work called AF-2 that comes along after AR has bound to the DNA. Remember we talked about locks and keys earlier? Well, Mutant AR has an interaction site where AF-2 binds once AR had bound to the DNA and the researchers disrupted this binding site to show that it was essential for mutant AR to initiate neurodegeneration. If AF-2 doesn’t bind or you stop it binding to mutant AR bound to the DNA, you don’t get toxicity. Additionally if you stop mutant AR binding to the DNA you do not get the toxicity. So, what does this mean in plain English? In essence, it means the researchers have found a potential drug target and this is discussed below. Basically, in discovering drugs it really helps to know what your target is. This does not always happen in drug discovery but it seriously makes life a lot easier. Drug discovery is like a giant 3D complicated jigsaw puzzle with only a very basic diagram to follow and the more knowledge you have, the easier (relatively speaking) it is.

Treatment in the Future
 
First of all it is impossible to put defined timeframes on gene therapy or drug discovery. Gene therapy is the golden goose and with something like KD we are definitely at least a minimum of 15years away as gene therapy is in its infancy.

So what about drugs? Well, the future is a bit brighter here as the paper has identified areas of mutant AR that confer toxicity to your neurons. This had to be confirmed more in higher species but the data is very promising and has identified some pharmacological targets. Also bear in mind that KD belongs to a family of other disease’s so as we find out more about one, it adds to the overall jigsaw of drug discovery in this area and everything moves forward. Experiments and/or trials that fail are also good as it means we have eliminated something and therefore re-evaluated our jigsaw pieces if you like.

So, what about this AF-2 stuff we talked about earlier? As it happens AF-2 is being studied in other disease areas (prostate cancer, hyperandrogenic syndromes and male pattern baldness amongst others) so we know a bit about it and have some drugs that wreck its plans! Therefore, the next steps of research are likely to take some of these AF-2 drugs and see what happens when you put them into a genetically modified mutant AR mouse. Will they halt or slow down the toxicity? Well there is a drug that has been put into a mouse model of KD and did show promising results but this needs to be repeated and replicated in species a bit higher up the evolutionary tree than our other friend, the mouse (see http://www.nature.com/nm/journal/v13/n3/abs/nm1547.html for more info). This waits to be seen but it’s a good step forward to have a pharmacological target to test. Remember your AR does lots of good things so you really don’t want to block its effects all together. What we want to do is let it do what it normally should do but stop this toxicity business which is only a fraction of what it does.

In summary this research paper is quite exciting, we have found out more information and have a pharmacological target to test. This target has been studied in other diseases and we know some information about it and we have some established tool to use to investigate. This opens up a lot of areas for research and as KD is related to other diseases’ the information overlaps and will assist other areas which will in turn assist knowledge on KD. The future is promising.

A lay persons guide to the results of a recent research paper – Part I

Today’s article is a guest post from Ms. Karia Orr.  Her friend, a man with Kennedy’s Disease sent me the article last week.  I thought it was well written and asked if I could post it in this blog.  The article helped me better understand how the Androgen Receptor (AR) works as well as what does not work when a person has the defective gene.  
 
Note:  Because of the length of the article, I am breaking it into two parts.
 
About the Author: My name is Karia Orr and I wrote this article for a friend. I am a Pharmacologist by training with over 10 years experience in various aspects of Drug Discovery and I currently live in Holywood, Northern Ireland. I would like to highlight that this article is written to be read by a lay person with an interest in Kennedy's Disease and the aim of the article is to give a basic overview of the papers’ results with some background information on receptors and some implications of the results for potential pharmacological interventions in the future treatment of KD. The real credit lies with the Researchers who carried out the research itself, analyzed the results, produced the data and interpreted it.
 
Disclaimer: This article was written by Karia Orr and the views expressed herein do not necessarily represent the views of the Research Paper Authors. Of note, the section on receptors and future treatment of KD are not from the research paper and diagrams and links have been obtained from publically available sources.


Native Functions of the Androgen Receptor Are Essential to Pathogenesis in a Drosophila Model of Spinobulbar Muscular Atrophy  Neuron 67, 936-952, September 23, 2010

A lay persons guide to the results of this research paper and some background information.
 
Kennedys Disease (KD) aka Spinobulbar muscular atrophy (SBMA): Neurodegenerative (neurons/nerves degenerate) disease caused by a mutation in the building blocks of the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. AR has lots of biological duties, but unfortunately in KD it does additional something(s) that gives rise to degeneration of the neurons innervating muscles. As such, the nerves are unable to communicate to the muscles and ask them to move.

Although some mouse models are being used to study KD, the Fruit fly was used to speed up the identification process of which parts of the AR are required for toxicity, and to therefore identify the mutant parts on the androgen receptor. NB, remember we are using mutant in the biological sense (http://www.biology-online.org/dictionary/Mutation) rather than X men definition here so do not freak out!! We are all biological mutants in one way or another. First of all, a bit of information on receptors:

Receptors are proteins themselves and basically proteins are made of amino acids that are linked to together (think of the beads on a rosary chain where each bead is an amino acid) and then the whole chain twists like a telephone cable and comes together into a big 3D structure like a jumbled up telephone cable mass- the receptor in quaternary structure. 

Receptors have lots of bits that are kind of like locks or keys as a result of all this twisting and folding. For something (e.g. drug, hormone, transmitter, endogenous ligand) to interact with a receptor it has to fit right with the receptor and this is known as the lock and key model. Put simply, locks and keys are required for things to bind to receptors and for other things to then occur as a result of this interaction.
 
This diagram is the structure of the human androgen receptor with bound testosterone (white left off centre bit). The blue, red and green bits are the AR and the colors represent different types of secondary and tertiary protein structure folding. Note, these colored bits could represent 1000’s and 1000’s of amino acids and by changing 1 amino acid you can change a heck of a bit. Believe me, you do not want to know why. ;-)

There are lots of types of receptors that respond to many things such as chemicals, sound, osmolarity, pressure etc and the human body can be broken down into systems, organs, tissues and cells. All of these have receptors. Some receptors live outside cells, some float about inside the cell in what is known as the cytosol of the cell (the cytosol is the intracellular fluid or the liquid component inside a cell if you like). In the case of nuclear receptors, like AR, they float about inside the cell, the androgen (male hormone, the key) enters the cell, finds a lock on the receptor it fits to, the key binds to the receptor forming a complex and stuff happens.

The main thing that happens with AR when an androgen binds to it, is that new areas on the receptor open up (think of like new locks appearing as a result of a shape change in the receptor) therefore creating new locks and keys to attract things and the receptor androgen complex head off to the nucleus, meet other things floating about in there and bind to DNA. Binding to DNA either activates genes or switches them off. All nuclear receptors do this, it’s just what they do.

Part II will be Tuesday’s articles.

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 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.

Testosterone

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?

Protecting yourself around the house

You have heard of “child-proofing” your home.  Well, as Kennedy’s Disease progresses, you need to consider how to make your home safer to live in while you are still mobile.  Since most falls occur when we are stepping up or down, turning, twisting, reaching or bending, it is important to perform a “walk-through” of the house looking at every room to determine potential safety concerns/hazards.

Below is a list of things to consider.  Many modifications can be made for little or no cost. 

• Add handrails:  Add a second handrail to any steps.  The leverage can make all the difference in the world for safety and navigation.

• Add entranceway grab bars:  Add grab bars on both sides of the door going into the house from the garage if you have more than one step to navigate.  Many falls occur as you are entering or exiting the house.
  
• Remove throw rugs:  Tape down or remove them.
  
• Replace other rugs:  Replace rugs, if needed, with the non-skid type especially in front of any stairs.
  
• Secure electrical cords:  Tape down or remove/reroute electrical cords that might be a tripping hazard.
  
• Add rug strips to stairs:  If your stairs are not carpeted, consider adding non-skid rug strips on each step.
  
• Add grab bars to bathrooms:  Add grab bars near the shower, tub, and toilet to help you sit down, get up and safely stand. 

• Add shower/tub grab bars:  Add grab bars to the interior of your shower or around the tub.  Removable suction grab bars often work quite well and can be taken on trips.
  
• Make shower/tub surfaces safer:  Make certain you have skid-free surfaces on the floor or a high quality bath mat.
  
• Add a shower/tub stool:  Slip-free shower and bath stools with adjustable height legs make for easier and safer bathing.
  
• Change out the shower/tub hardware:  Add a hand-held nozzle for easier rinsing from the seated position.
  
• Raise the height of the chairs:  Add raisers to the legs of the chairs and sofa you use.  They can be as simple as 2x4 or 4x4s inserted under the legs.  When this no longer works, consider using an uplift-seat or go all the way and buy a chair than can lift you to an upright position before exiting.
  
• Use dining room chairs with arms:  Or, use sturdy pillows/cushion or an up-lift seat.
  
• Raise the bed height:  Add raisers to the legs of your bed to make it easier and safer to get up.  Most bedding stores have these raisers for sale.
  
• Raise the height of the commode:  Install a handicap commode.  It can raise the height of the seat by 2-4 inches.  If that will not help, use an elevated seat (“tallette” device) to increase the height of the seat 4-6” and it is portable.  If that does not work, consider a seat-lift device.  If possible, add arms to the device to get better push off.
  
• Add stools:  In the garage, nook, or hobby room add stools to make it easier to work and get up afterwards.  Stools with a swivel seat are especially nice in work areas.
  
• Improve lighting:  Some hallways or rooms are darker than others.  Add lights or increased wattage bulbs in these rooms.
  
• Get rid of clutter:  Over time certain rooms collect things (clutter) that could become a tripping hazard.  Make a point of picking up or moving aside potential hazards such as newspapers on the floor, a foot stool in a traffic area, a small table in a hallway, etc.

• Rearrange your stuff:  In the garage, nook, kitchen, and bathroom rearrange the shelves, cupboards and tables to make it easier to reach items you use regularly.
  
• Invest in a reacher-grabber:  Many falls occur when we lose our balance while trying to pick something up from the floor.  These reachers are great for picking up many things.

And, most importantly, do not be afraid to ask for help.  There are resources available.  County services and some independent companies will perform assessments and can also provide recommendations and information on needed modifications.  Also consider contacting your regional MDA office for assistance.  Most MDA offices have a “loaner locker” of home aides that could help you determine what would work best before performing modifications or purchasing something.

Three keys:  (1)  In your walk-through, look for “potential” hazards or conditions that might cause a trip, a fall, or an unsafe situation.  (2)  Consider “worst case” scenarios and then consider intermediate and long-term options.  (3)  If you are not already exercising, begin a program that will help maintain your mobility.

The above list is a lot to consider, but it is not everything.  I would appreciate your thoughts to additions to this list. 

Not every health issue is related to Kennedy’s Disease

If you are a frequent reader of this blog, you have heard me mention, “Just because you have Kennedy’s Disease does not mean you are immune to other health issues.”

Colon and prostate cancer probably have the same stigma associated with them.  They are both topics that you do not want to even think about, let alone discuss.  Yet, they are two topics that you need to discuss with your family doctor regularly as you age.

PROSTATE CANCER  



Prostate cancer is the second most common cause of cancer-related deaths in men.  It is estimated that one in six men will be diagnosed with prostrate cancer sometime in their life.  Anyone substantially overweight also increase the potential of having serious prostrate cancer issues.

Fortunately, most prostate cancers are slow-growth, but it is still something that needs to be checked for especially if a father or brother has been diagnosed with this health issue in the past.  Early detection and treatment is important.  Treatment options vary depending upon the age and health of the patient.



Unfortunately, detecting prostrate cancer early can be difficult.  The PSA (prostate specific androgen) test is a simple blood test that can be administered by your doctor.  It is helpful in determining potential issues with the prostrate if checked at least annually in men in their 50s and 60s.  If there is a history of prostate cancer in the family, your doctor might recommend starting PSA testing earlier.  The PSA test is not exact, however.  There are often false-positives due to non-cancer related elevations in PSA levels.  Yet, it can be a ‘red flag’ that tells your doctor that further testing might be necessary.

As men age, the prostate naturally enlarges.  This also means that the PSA levels increase.  That is why it is important to have annual PSA tests so that your doctor can track any trends in PSA elevation.  Sudden spikes in PSA levels could mean trouble.  If warranted, your doctor might recommend a digital rectal examination that would include a biopsy.



EAT YOUR VEGIES

Doctors and dieticians for years have recommended the following foods to help reduce your risk.

• Tomatoes
• Broccoli, cabbage, brussels sprouts, cauliflower, arugula, bok choy, collards, kale, mustard greens, rutabaga, turnip greens, and watercress.
• Soy base products (a protein substitute)
• Anything with a good supply of vitamins A, D, and E
• Salmon
• Walnuts
• Red wine (small quantity)
• Dark chocolate (small quantity)

Doctors also recommend that you reduce your red meat intake and begin a regular physical exercise program.  Not only do these two help keep your weight manageable, but they can also be good for your heart, lungs, muscles, motor neurons, etc.

The Key:  EARLY DETECTION

If you are middle-aged, do not wait to discuss this potential health issue with your doctor.  He can help determine when to begin testing.

For more information, go to the Prostate Cancer Foundation’s website (www.pcf.org).  Other good resources for information include the American Prostate Society (www.ameripros.org) and the American Cancer Society (www.cancer.org).