New Research Could Fine-Tune the Gene Scissors CRISPR

If you are a follower of this blog, you know I am following CRISPR research closely in regards to a potential cure for Kennedy's Disease (SBMA). If this process could reduce the number of CAG Repeats, we might have the cure. One issue that researchers are looking at is how to identify and minimize the potential side effects. Below is a link to the latest article on the fine tuning of the process.

New Research Could Fine-Tune the Gene Scissors CRISPR

GENETIC RESEARCH

When researchers and doctors use the tool CRISPR to correct genetic errors, it may have side effects on the human genome. Now, researchers from the University of Copenhagen have learned how the molecular machinery behind CRISPR works and thus expect to be able to fine-tune CRISPR and remove the undesired effects.

The introduction of the tool for gene editing, the so-called gene scissors CRISPR, in 2007 was a revolution within medical science and cell biology. But even though the perspectives are great, the launch of CRISPR has been followed by debate, especially focussing on ethical issues and the technology’s degree of accuracy and side effects.

However, in a new study published in the scientific journal Cell researchers from the Novo Nordisk Foundation Center for Protein Research have described how one of the CRISPR technologies, the so-called Cas12a, works – all the way down to the molecular level. This makes it possible to fine-tune the gene-editing process to only achieve the desired effects.

‘If we compare CRISPR to a car engine, what we have done is make a complete 3D map of the engine and thus gained an understanding of how it works. This knowledge will enable us to fine-tune the CRISPR engine and make it work in various ways – as a Formula 1 racer as well as an off-road truck’, says Professor Guillermo Montoya from the Novo Nordisk Foundation Center for Protein Research....

Molecular Film 

The researchers have used a so-called cryo-electron microscope to map the technology. The recently inaugurated cryoEM facility at the University of Copenhagen has established the state-of-the-art technology enabling the researchers to take photographs of the different shapes of the molecule when CRISPR-Cas12a cuts up the DNA strand.

They combined it with a fluorescent microscopy technique called ‘single molecule FRET’ that directly observes the motions of the molecules and the sequence of events for each individual protein.

Among other things, this sequence of events revealed to the researchers that three “pieces” of the CRISPR tools must change form for the DNA to be cut properly.

‘Our new study shows the precise series of events in the genome leading to gene editing. These three “pieces” that change, work like airport security checks. You have to complete all checks and in the right order to proceed’, says Associate Professor Nikos Hatzakis from the Department of Chemistry and the Nano-Science center.

[Click on the link above to read the entire article]

It Was A Coin Flip...

And, I lost. 

[ This is an update to a 2009 post ]

Spinal Bulbar Muscular Atrophy, aka Kennedy's Disease, is an X-linked disorder. In other words, an X-chromosome is defective (mutated). Kennedy's Disease is caused by a trinucleotide repeat expansion in the androgen receptor gene. This means that the cytosine-adenine-guanine (or CAG) that are normally repeated 10–36 times mutate (expand in our DNA string) to produce a larger repeat size of approximately 40–62.

This CAG sequence is unstable and can change from one generation to the next leading to further expansions. If the person with the defective gene is the father, he cannot pass the gene on to any sons. However, he will pass the defective gene on to any daughters. If the person with the defective gene is the mother, she is a carrier. With a carrier, there is a 50% chance that the defective gene will be passed to any of the offspring.

50% Means One of Two - Right?

Often, there is a misconception that 50% means half of the offspring will have the defective gene. 50% does not mean one out of two chances. It does not work that way. As with any coin flip, heads or tails could come up five, six, or seven times in a row. The 50% means nothing more than over a very large number of flips, half of the time it will be heads.

My mother was a carrier. Her mother had five children and only passed along the defective X-chromosome to my mother. Then, my mother gave birth to ten children (3 girls and 7 boys). Only three of the ten children have the defective gene. I know of other cases where most of the children have the defective gene. The only way to be sure is to take the DNA blood test for Kennedy's Disease.

Now, there is another misconception. Kennedy's Disease does not manifest itself in the same way with everyone. Even if you have the mutated gene, that does not mean that you will have all the symptoms or when the onset of the disease will occur. Not everyone with the defective gene is going to respond the same. Onset could start as early as the teens (this is rare, however), or it could also start in the late sixties. Normally, the onset will occur in the thirties or forties. One person in the family might have most of the symptoms, while another might have only some of the symptoms. The severity of the disorder is also not the same within a family. Researchers currently believe the higher the number of CAG Repeats, the earlier the onset.

So, when my father's sperm fertilized my mother's egg, I lost the coin flip (it came up tails = defective gene). No wonder I have never won the lottery.

No, wait, perhaps it is because I never play the lottery.

Egg-Sperm - https://www.livescience.com/13264

The Genetic Home Reference Library

The United States Library of Medicine has published the “Genetic Home Reference - Your Guide to Understanding Genetic Conditions.” I found this website to be a very user-friendly, yet a comprehensive guide to most genetic disorders including Kennedy’s Disease (SBMA). The explanations are well written and for the layperson. Below are a series of screenshots of the main pages of the guide. Check it out and let me know what you think.

(Note:  Click on the pictures for easier reading)

Home Page
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spinal Bulbar Muscular Atrophy

InfoSearch for Diseases Launched

The Genetic Alliance launched their website today.  It is an information resource on over 13,000 health conditions including Kennedy’s Disease (spelled ‘Kennedy Disease’ in their database).  The website also lists the KDA as an Advocacy and Support Organization.  There are more detailed explanations under the general explanation in the ‘Jump to Topics’ section.

The press release states:

One Stop Shopping for All Diseases:

Genetic Alliance Launches Disease InfoSearch

WASHINGTON, DC – March 19, 2013 – Disease InfoSearch (www.DiseaseInfoSearch.org), a one-stop shop for information and engagement on more than 13,000 conditions, launched today. Disease InfoSearch connects healthcare providers, researchers and the general public with support groups, relevant and timely peer-reviewed articles, open and appropriate IRB-approved clinical trials, and general disease information. Each condition page also features an interactive tool that enables individuals to contribute to biomedical research by securely sharing their health information.

For the past 26 years, Genetic Alliance has connected individuals to advocacy and support organizations. The release of this new online database marks a dramatic expansion in the information available for both common and rare diseases. Genetic Alliance takes a novel approach to the management of disease-specific information, calling on experts—disease advocacy organizations—to provide current, quality information on their respective conditions. This tailored information is supplemented with resources from quality federal databases, distilled through consumer-tested algorithms, and presented in an accessible interface. Disease InfoSearch can now be used by the public to answer questions after a family member’s diagnosis, find a clinical trial, and more; by healthcare providers to offer point-of-diagnosis referral to support groups; and by the research community to identify disease advocacy organizations with registries and biobanks, and to facilitate collaboration with other organizations doing similar work.

“Compiling these resources in a single location makes it significantly easier for healthcare providers, researchers and the public to find the information they need about thousands of conditions,” said Sharon Terry, President and CEO of Genetic Alliance. “Empowering individuals and families is a vital component of our vision – a world in which those affected by genetic conditions have everything they need to live fully – and this project brings us one step closer to achieving that vision,” she said.

For more information, please visit www.DiseaseInfoSearch.org and watch our video http://youtu.be/BzUZxQWukVk.

About Genetic Alliance
Genetic Alliance improves health through the authentic engagement of individuals, families, and communities. Genetic Alliance is the world’s leading nonprofit health advocacy organization committed to transforming health through genetics and works to connect consumers to the smart services they need to make informed decisions about their health and healthcare. Genetic Alliance's network includes more than 1,000 disease-specific advocacy organizations, as well as thousands of universities, private companies, government agencies, and public policy organizations. To learn more about Genetic Alliance, visit http://www.geneticalliance.org.

Would you really want to know?

Over the last few years I have published several articles on genetic testing.  Three of these articles are shown below.

• What is Genetic Counseling
• Genetics Counseling Answers Many Tough Questions
• Just Let Them Be A Kid

This morning another board member sent the link below to a USA Today article written by Janice Lloyd on genetic testing.

Genetic testing and disease: Would you want to know?

The story is about Kristen Powers who has decided to have a genetics test to see if she has inherited the DNA for Huntington’s disease.  Since this disease is similar in many ways to Kennedy’s Disease (neurodegenerative, progressive, rare, similar DNA defect, no treatment or cure, etc.), I found the article interesting because it discusses the personal perspective of being tested as well as other considerations.

The article goes into why some people want to be tested and many of the pros and cons of being tested.

Making the decision

“Gone would be the days of waiting to develop a disease. People would know about diseases they are at risk for and could change their living habits or consider treatments. Opponents warn about the potential for invasion of privacy — threatening employment and insurance — and the possibility that people equipped with the knowledge of their genetic makeup might make risky and unhealthy decisions.”

Reasons to know

“Kristen doesn't want the gene to be passed on again. She says she won't have children if she tests positive: "I can be candid with potential partners and be responsible," she says.  Genetic counselors warn about the emotional impact of testing on the person and family.  "Some people like to plan everything out," says Brenda Finucane, president of the National Society of Genetic Counselors. "They think the information is empowering, while some people want to see how life plays out."

What about insurance?

“Ed Powers backs his daughter Kristen’s decision to find out whether she inherited the gene for Huntington’s disease, but he also wonders how a positive result might affect his family’s health insurance. “I hope ObamaCare takes care of us,” he says. The Supreme Court is expected to rule on the fate of the Affordable Care Act in June.  About 30 million Americans live with rare diseases, many of them chronic. People afflicted with these diseases often have difficulty obtaining coverage, or the policies are cost-prohibitive. The health care law created the pre-existing condition insurance plan (PCIP) for Americans denied coverage by private insurance companies for health reasons. PCIP is currently in effect.  If the law is upheld, all Americans, regardless of health status, will have access to insurance by 2014 through an employer or in the marketplace, says the Department of Health and Human Services. Insurers will be prohibited from charging more or denying coverage to anyone. The law also eliminates annual and lifetime insurance caps.”

I encourage you to read the USA Today article.  ‘Knowing or not-knowing’, that is the question. Since there currently is no treatment or cure, what would you do differently if you knew that you or one of your children had the defect?

More importantly, if one of your children is going to be tested (their wish or yours),  I would highly encourage both of you to discuss the issue with a genetics counselor ahead of time.  A counselor can:

• Answer your questions
• Address concerns
• Review expectations
• And, discuss possible next steps ... should the test be positive.

What is Genetic Counseling and should my family be tested?

The MDA recently sponsored an online presentation on genetic counseling. Afterward a YouTube video was made available of the presentation as well as a Quest online magazine article. Both are well presented in layman’s terms. I highly recommend viewing the presentation or reading the article since it is so applicable to Kennedy’s Disease (and Kennedy’s Disease is even mentioned).

“Article Highlights:

• MDA’s Genetic Counseling Webinar, which occurred Feb. 22, 2012, covered the basics of genetics and genetic testing, and answered questions from participants.
• Knowing your exact genetic diagnosis has advantages in terms of family planning and testing of other family members who may be presymptomatic, or may be carriers of the genetic mutation.
• An exact diagnosis also improves disease management by alerting doctors to associated health problems, such as cardiac issues.”

“Knowing your exact genetic diagnosis does more than just satisfy your curiosity — it can impact family planning, disease management and participation in clinical trials.”

There is even a Frequently Asked Questions section that addresses:

• What happens at a genetic counseling session?
• What are the limitations to genetic testing?
• What does it cost?
• When should unaffected family members be tested?
• How can I find a genetic counselor who is familiar with my disease?

Link to Quest Article: http://quest.mda.org/news/mda-genetic-counseling-webinar
Link to YouTube presentation: https://www.youtube.com/watch?v=JvkvkzBjk3A

Back in the early 80s my entire family was tested. At that time there was no test for Kennedy’s Disease and when the results came back three of us were shown to have Familial ALS. There was no genetic counseling offered at the time so we were left with a large void as to what does all this mean. About fourteen years later I was given another DNA test and officially diagnosed with Kennedy’s Disease.

“Life is often out of our control”

I read this article today at Scotsman.Com because Kennedy’s Disease was mentioned. The title was: On Christmas Day I smiled but I couldn’t help but look at Vanessa and wonder if this was her last Christmas - it was heartbreaking.

The story is about a couple’s daughter who was diagnosed with cancer. The subject struck too close to home.

The article caught my interest from the beginning with this lead: “The only hope Connie and Chris Riddle have of saving their daughter from a rare form of cancer is treatment in the USA costing £500,000. Maria Croce meets a couple determined to give their little girl the best chance they can.”


I have mentioned before that there are far worse things than Kennedy’s Disease and cancer is always near the top of the list. And, even worse, it attacks your child. “Just a few days earlier life had seemed to be getting back to normal. It looked like Vanessa had beaten a rare form of childhood cancer, neuroblastoma, after extensive treatment, because she’d been in remission for 16 months. But just before Christmas a scan revealed the cancer was back.”


“Connie had already realized the fragility of life after her father was in 1995 diagnosed with muscle-wasting Kennedy’s Disease and spent his later years in a wheelchair until he died, four years ago, at the age of 72. It is completely unrelated to Vanessa’s cancer – but Connie discovered she is a carrier of the hereditary disease that only affects males in adulthood. “I chose not to have the tests when I was pregnant with Olivia or Vanessa,” she says. “I thought even if I’d discovered I was carrying a baby boy with the condition I would still have had him.”

Yes, much of our life is out of our control

Those of us living with Kennedy’s Disease know that some things in life are just totally out of our control. At the same time, there is hardly anything worse than the totally helpless feeling that overwhelms your body, mind and spirit when your child is diagnosed with cancer. I know, because at two years old, my son was diagnosed with an aggressive (malignant) brain tumor that was strangulating his upper vertebras causing seizures.

Fortunately, they caught it early, we had a great neurosurgeon, and after surgery and 33 massive cobalt treatments the doctors felt they got it all. Five years later he was given a clean bill of health. My son is now forty-one and even though he doesn’t remember much about that time in his life, it is still a vivid memory to me.

Can women have Kennedy’s Disease?

Over the last couple of weeks I received two emails from women asking if they could have Kennedy’s Disease. Both women thought that it only affected men.  One woman had previously been diagnosed with ALS.
 

Not Gender Specific

Kennedy’s Disease is not gender specific. Both men and women can have the defective X-chromosome gene. It is rare, however, for women to show symptoms until later in their life. Also, symptoms for a woman are generally less severe.  My mother, for example, began to experience leg weakness and twitching in her early 70s. She also began experiencing swallowing issues.

The symptoms are caused because the mutated gene cannot process testosterone correctly (do its job). And, since men normally have higher levels of testosterone, the symptoms are more severe and begin to show up earlier in life.
 

DNA Test

Women are tested for Kennedy’s Disease the same way as men. Your family doctor can draw the blood and send it to a DNA lab for analysis.  If your doctor is unfamiliar with Kennedy’s Disease, you might want to print this web page that explains the DNA test (http://www.athenadiagnostics.com/content/test-catalog/find-test/service-detail/q/id/61 ). A DNA blood test normally takes about 4-6 weeks. 
 

Genetics

Since the disease is genetic, both men and women can pass the defective X-chromosome gene on to their children. Women are considered carriers. Normally, they have one healthy and one defective X-chromosome. There are very rare cases where a woman has two defective X-chromosomes. A carrier can pass either a healthy or a defective X-chromosome on to her children (son or daughter). A man with the defective gene can only pass the defective chromosome on to his daughters.
The genetic chart below shows how this can happen.


Should you have any questions, please don’t hesitate to ask.  If I don’t know the answer, I will try to find someone that can answer it for you.

Rare Disorders - Raising public awareness

A special insert in the Washington Post this week highlighted rare diseases, the need for more treatments, and the challenges of having a rare disease.  Below are two of several good articles that appeared in the Post.  If you want to see the entire insert, send the KDA an email (info@kennedysdisease.org) and I will forward you the PDF document.



According  to the National  Institutes  of  Health  (NIH),  there  are nearly  7,000 diseases defined as rare, or affecting  fewer than  200,000  Americans by U.S. definition.  

Somebody  you  know  has one  of  these  diseases,  and  the patients and families coping with them  need  our  help.  They  live with  day-to-day  challenges  that are  vastly  underserved  at  this time  by  our  medical  and  public health systems. 

This results in shattered dreams,  unnecessary  expense,  lost  productivity,  and  all  too  often,  premature death.

 

What are the challenges?

 

Even  though  each  disease  is unique, the problems associated with having a rare disease tend to be consistent. They include:

• Delayed or inaccurate diagnosis
• Difficulty finding a medical expert
• Too little research
• Few, if any, treatment options
• Insurance  or  other  reimbursement problems
• Lack of awareness and understanding of the patient’s needs
• A sense of isolation.

Rare  diseases  are  often  called  “orphans”  because  they  are  forgotten  and  “unclaimed.”  Many  rare  diseases  are  not  being  studied  by  any  researchers  because  there  is  little  or  no  public  funding  for research.

In  fact,  much  of  the  research on  rare  diseases  today  is  being funded  by  patients,  families, and  patient  organizations  raising money through golf tournaments,  bake  sales,  and  other  means  to provide grants for researchers at universities and hospitals.

Seek Treatment

 

Only  about  200  rare  diseases  currently  have  treatments  approved  by  the U.S. Food and Drug Administration (FDA). That leaves many patients  and  their  families  in  the  position  of being treated with products not specifically approved for their disease or  not being treated at all. 

Furthermore,  more  than  half  of  the patients are children. The organization  I  represent—the  National  Organization  for  Rare  Disorders  (NORD)—receives phone calls and  emails on a daily basis from parents  who are coping simultaneously with  the  challenges  of  having  a  desperately sick child, appealing insurance denials, finding appropriate medical  care,  and  educating  their  families  and   friends  about  their child’s disease.  It’s  a  lot  to  deal  with,  and  no  one should have to do it alone.

Just by becoming more aware of  rare diseases and the needs of the  children and adults who have them,  you  can  help.  The  word  “rare”  is  misleading.  These  diseases  touch  lives all around us, and as a society  we need to pay more attention.  It  could  be  your  son  or  daughter,  or  your  elderly  parent,  who  is  affected. 

If we all focus a little more  on these issues, we could improve millions  of  lives,  reduce  unnecessary  healthcare  spending,  and  put meaning  in  the  phrase:  Alone  we  are rare. Together we are strong.

Peter  L .  Saltonstall
President and CEO, National Organization for Rare Disorders (NORD)

 

Mothers lead the way in researching rare disorders

 

Few  medical   conditions a re as difficult  to  diagnose  as  rare  disorders. Many patients wait seven to  10  years  before  receiving  a correct  diagnosis,  and  when  the disease is finally given a name, 
the  person  behind  that  diagnosis  is  often  a  mom.  Why? 

• First, 80  percent of all rare disorders including  cystic  fibrosis,  childhood  cancers,  and  numerous unnamed  diseases  are  diagnosed  during  early  childhood. 
• Second,  physicians  receive  little medical training in rare disorders and  can  spend  an  entire  career without  ever  encountering  one. 
• Third,  and  most  importantly,  is the strength of a mother’s instinct  to  protect  her  young  –  she  is  literally  fighting  for  her  children’s lives.  Empowered  by  the  inter-net, these mothers research and network  with  unmatched  skill.

“The  Internet  gives  patients  and  caregivers  access  to  medical journals , clinical trial investigators,  advocacy  organizations and  government  officials.”  Additionally, mothers employ the  use of social media for sharing news,  experiences  and  resources.

“Having support and encouragement  right  at  their  fingertips  can transform  a  family’s  solo  ordeal into  a  shared  journey;  stripping away  feelings  of  isolation  and bolstering  their  faith  and  determination.”  A  simple  click  of  a  mouse  can  make  a  world of difference. 

Wendy White 
Founder and President, Siren Interactive

Preimplantation genetic diagnosis (PGD)

The subject of PGD has come up several times in the last couple of years regarding the potential parent’s concerns with Kennedy’s Disease. At the KDA conference this year, attendees heard of the success of one family using PGD to terminate the defective gene in their lineage.  

Since I know very little about the subject, I went to Wikipedia to learn more.  From there I read more about it at Suite 101 and the Advanced Fertility Center of Chicago. Below are excerpts from these three websites. I can understand why potential parents might want to know if their child has the defect, but I also can see the possible risks of the process since it is a relatively new technology and appears to be not always accurate.

Because I know so little about this procedure and am somewhat biased, I will just provide information that I found on the internet and let you, if interested, investigate the process further.



Wikipedia
In medicine and (clinical) genetics pre-implantation genetic diagnosis (PGD or PIGD) (also known as embryo screening) refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis. Its main advantage is that it avoids selective pregnancy termination as the method makes it highly likely that the baby will be free of the disease under consideration. PGD thus is an adjunct to assisted reproductive technology, and requires in vitro fertilization (IVF) to obtain oocytes or embryos for evaluation.

Suite 101
PGD Testing for Familial Disease
It’s understandable that a family that carries a devastating disease would want to eliminate this from future children. But the problems of using PGD in these cases are similar to those for gender selection; the results may not be accurate, and there’s a chance of damaging a normal embryo. Genetic testing laboratories can only test for some genetic abnormalities, not all, so it’s possible an embryo that doesn’t have a test for disease could have another disease. Parents should also consider that the deadly diseases of today may have cures by the time their child needs them.
 
The Unknowns of PGD Testing
Some studies have shown that embryos with abnormal chromosomes on day three, when the cell is removed for PGD testing, may "self correct” and have normal chromosomes by day five. Obviously, this isn’t always the case, but it could mean that normal embryos are destroyed. 
 

Advanced Fertility Center of Chicago
What is PGD, or preimplantation genetic testing?
Preimplantation genetic diagnosis involves testing done on in vitro fertilization IVF embryos prior to transferring them to the mother's uterus. The testing is done either to check for a specific genetic abnormality (such as a disease like cystic fibrosis), or it can be done to determine if the embryos are chromosomally normal (also called aneuploidy screening). 
 
PGD is done by removing 1 or 2 cells usually at about the 8-cell stage (day 3 after fertilization). A hole is made in the shell of the embryo, and then a pipette is used to suck the cell(s) away from their neighbors - removing them from the embryo so that testing can be done. This process is called embryo biopsy or blastomere biopsy. Some programs biopsy the polar bodies of the egg, rather than the cells from the early embryo. 
 
Specialized techniques are then used to either check for the genetic disease in question, or to investigate for overall chromosomal normality. The testing can generally be completed in 1 day. Therefore, embryos can be tested on day 3 after fertilization and transferred back to the wife on day 4 or 5 after the results are back. 
 


What are some of the additional problems and concerns with PGD at this time?
The embryos are traumatized with PGD. The question remains unanswered as to how often they can "recover enough from the beating" to retain viability. It seems that many embryos do not recover completely. Said another way, too many normal, strong embryos are weakened to the point of being non-viable by the embryo biopsy procedure.
As with any new technique and technology, there is a "learning curve". Some technicians will be more proficient at the biopsy procedure. Some labs will also be more proficient at the diagnostic component after the cells are removed - giving a higher percentage of accurate results. Therefore, there will potentially be large differences between centers performing these techniques, and possibly even between different technicians within the same center.
 
PGD test results are not always correct

• Sometimes the embryo has abnormal chromosomes, but PGD testing shows a normal result
  
• Sometimes the embryo has normal chromosomes, but PGD testing shows an abnormal result
  
• Therefore, some chromosomally normal embryos will be discarded, and some chromosomally abnormal embryos will be transferred after PGD

IVF and PGD Costs - How much is PGD?

• PGD is expensive and costs about $3000 to $5000 in the US, in addition to all of the other IVF costs

Frequently Asked Questions about Kennedy’s Disease – Part I

Today and Sunday’s posts address many questions asked about Kennedy’s Disease.  This information is also part the “welcome packet” that is sent out to those who join the Kennedy’s Disease Association.



Q: What is Kennedy’s Disease?
A: Kennedy's Disease (also known as Spinal Bulbar Muscular Atrophy, SBMA, or Kennedy's Syndrome) is a rare and currently incurable and non-treatable X-linked recessive genetic progressive neuro-muscular disease. Both the spinal and bulbar neurons are affected causing muscle weakness and wasting (atrophy) throughout the body which is most noticeable in the extremities (legs/arms), it is also especially noticeable in the face and throat, and causes speech and swallowing difficulties, along with major muscle cramps as well as other symptoms.

Q: What are some of the symptoms of Kennedy’s Disease?
A: See the following link: KD Symptoms

Q: When do you first start seeing signs of the disease?
A: Generally, symptoms begin to appear in the late 20’s or early 30’s. However, there have been cases where the symptoms showed up as early as the late teens or not until the 60’s. 

Q: Who gets Kennedy’s Disease?
A: Kennedy's Disease is a genetic disease, passed on from generation to generation in a family.  It is an X-linked recessive inherited gene.  Generally males who inherit the gene exhibit symptoms. Females, who inherit the gene, are carriers and may also exhibit symptoms, usually later in life.

Q: Is there a treatment or cure for Kennedy’s Disease?
A: Currently there is no treatment or cure. Recent research, however, show some promising signs. Read about research that is taking place at this link: Research.  (Note:  You can also search this blog for the most current reports on research) 

Q. What causes the muscle cells to die?
A. The direct cause of the muscle cell death is believed to be the death of the nerve cells that control the contraction of the muscle cells. These nerve cells are known as motor neurons. Motor neurons are the cells that connect the brain to the muscle cells. When you wish to contract a muscle to pick up a pencil, for example, your brain sends signals to the motor neurons that control those muscles. The motor neurons then convey the signal to the muscle cells and the muscle cells contract, performing the movement that you envisioned in your brain.

In KD, the motor neurons die and so the connection from the brain to the muscle cells is broken. As a direct result of the loss of the motor neuron, the muscle cells die as well. Whenever muscle cells lose their motor neuron, they will usually die. It is generally thought that KD does not directly cause the muscle cells to die although there is some recent evidence that KD may result in some changes in the muscle.

Q. What causes the motor neurons to die?
A: This is the million dollar question. The straight answer is that we really do not know for sure. There is a lot of evidence that the motor neuron cell death may be due to the inability of the cell from KD patients to adequately recycle proteins and this results in the build up of old, trashy proteins. This build up of trash is believed to somehow be toxic to the cell.  (Note:  See Dr. Taylor’s research article in this blog for the most current assessment of what happens)

Q. Why can’t the cell recycle proteins?
A: KD is a genetic disease – this means that KD patients have a defective gene. The function of genes is to tell the cell how to make a specific protein and a cell can only make proteins for which there is a gene. For example, we all have a gene to tell our cells how to make hemoglobin, the protein that carries oxygen in our blood. Without that gene, our cells would not be able to make any hemoglobin. Since we need hemoglobin to live, such an individual would never even be born. However, occasionally, a gene for a specific protein may be changed so that the cells would make an altered form of the protein. This altered protein may still work, but possibly not as well. This is what happens in sickle cell anemia. The hemoglobin gene has been altered and the hemoglobin made does not work as well.

Since KD is a genetic disease, patients with KD must have an altered gene. The gene that is altered is the one that tells the cells how to make the protein known as the androgen receptor (AR). The normal function of the AR is to mediate the actions of testosterone. Without the AR, testosterone would have no effect on a cell. In men with KD, the AR that is made is altered. It still works but sometimes not as well. The current thinking is that the problem with those with KD, however, is that the altered AR cannot be removed by the cell.
Typically, once used, the AR is destroyed by the cell. This is done by processes that help remove all proteins. Even worse, when the cell tries to remove the AR, the altered form of AR jams up these cellular processes preventing the cells from removing any proteins. Apparently, the nerve cell must be able to remove proteins to survive, so the overall effect of the jamming is to kill the cells. Much of the research on KD right now involves investigating ways to ‘un-jam’ these protein removal mechanisms and prevent the death of the cell.

Can Gene Therapy Work – Part II

Part I discussed the general subject of gene therapy including the pros and cons. In today's article, I will focus on the possible application of gene therapy as a treatment for Kennedy's Disease.

Gene Therapy and Kennedy's Disease

Recently I received the following inquiry. "Please review the article in Quest Magazine on gene therapy success.  My husband and I have been wondering if gene therapy from a healthy relative could be a cure for SBMA."

I thought this would be an opportunity to learn more about the differences between using gene therapy to treat inclusion-body myositis (IBM) (no, not the computer company) and Kennedy's Disease. So, we asked Mr. Science (the biology professor and KDA board member) and, as usual, he came through for me (why didn't I have professors like him when I was in school).

"This is a very interesting study, and if true, demonstrates a new (at least to me) method of gene therapy.  I hope to have the full copy of the paper soon.  I have the abstract and found a bit of info on the disease referenced in the study, namely IBM.  From what I could gather, the inherited form of IBM is a recessive mutation of the GNE gene.  This suggests that the disease is due to the lack of the normal GNE protein.  The researchers injected a good copy of the gene and their technique allowed the cells to take up this good copy of the gene - and the cells apparently were rescued.  However, note that the report in Quest indicates that not all muscles were rescued.   

Now with regard to Kennedy's Disease, this does not have a simple answer.  The problem with those of us with Kennedy's Disease is NOT that we do not have the function of a particular protein (in our case, androgen receptor, i.e., AR), but that the form we have (that still works) has an additional property that kills nerve cells.  This is what the scientists mean as a 'gain of function' mutation. Thus simply giving the patients a good copy of the AR will not help.  The one we have works fine and since we did not remove it during the therapy, cells will now have two copies, one good (the one we added) and the original Kennedy's Disease one.  The cells will still make the Kennedy's Disease version and so the cells will still die even though they now also have a good copy.  In order to be sure that the technique would work, not only would the therapy have to add the 'good' version of the gene, but one also remove the Kennedy's Disease version - and no one knows how to do that.  It is possible, however, that the progression of Kennedy's Disease could be slowed down by gene therapy - but I do not think that it is known that this would occur. 

I am not sure if I explained that well - so let me use a bad analogy.  Imagine that the protein made by the Kennedy's Disease gene is a watchdog.  The normal watchdog only attacks strangers - that's its function.  Most genetic diseases are due to the lack of a protein so in this analogy, this would be as if we lacked a watchdog (like IBM is due to the lack of a protein).  To cure it, all we would have to do is replace it with a new dog (as they did with the gene in the article).  Now if your problem was that you had a watchdog that not only attacked strangers, but also attacked your family; then getting a new dog will not be helpful as you still have the super aggressive one.  It is necessary not only to add a new dog, but also to remove the old one. 

Kennedy's Disease is like the second scenario.  We need to remove the old form of the gene as well add a good one. 

I hope that this makes a bit of sense - the bottom line is that simply adding the 'normal' copy of the gene probably will not be very helpful.  And if it were, it is unlikely that it would have to come from a relative - most anyone's copy would do." 

I also asked a neurologist and researcher, Dr. Paul Taylor, for his thoughts on the subject.

"There are a few obstacles to this approach in Kennedy's Disease. First, the therapy described here is gene replacement therapy. In other words, this type of muscle disease is caused by a deficiency of the gene in question and the therapeutic strategy is to replace the missing gene. Kennedy's Disease is not caused by deficiency of a single gene; rather, it is caused by toxicity of the mutated gene. Second, the disease described here is primarily a problem in the muscle cells themselves. These are an easier target than motor neurons, which are believed to be the primary cell type affected in Kennedy's Disease. 

That said, it is possible that treating muscle may turn out to be beneficial in Kennedy's Disease even if muscle is not the primary tissue affected by the disease. Maria Pennuto's data published last year suggests that possibility. In that case, rather replacement of a deficient gene, Kennedy's Disease mice had benefit from a muscle-boosting gene called IGF-1. Furthermore, it may turn out that primary muscle involvement is more important than we previously thought (we are working on this presently) which would make muscle an even more important target." 

Like anything else with Kennedy's Disease (and my computer when it acts up), a simple fix will not solve the problem. Perhaps that is why we are so unique (and I say that in a most positive way).

I find it interesting that the subject of gene therapy causes such a dichotomy of opinion. How do you feel about gene therapy ... especially if it became a treatment for Kennedy's Disease?

Genetic Counseling Helps to Answer Many Tough Questions

There are so many misconceptions regarding spinal bulbar muscular atrophy, aka Kennedy's Disease. At least a couple of times a month I receive emails asking about who can be passed the gene or if my father has the disease, or can I be a carrier, or if I am a carrier, does this mean my children will also have the defective gene. Because of all the different, but similar questions asked, I feel the need for genetic counseling is almost as important as seeing a neurologist.

Recently I was asked what would be the odds of having both a husband and wife with the defective gene. When I responded that it is possible, but highly unlikely, the person asked another question about how the 50% rule of passing along a defective gene is determined. I pulled the following from the Kennedy's Disease Association web site to use as a starting point:

"Are you wondering if your children are or will be affected by this Disease? Since the defective gene is in the "X" chromosome, if the mother is the only carrier of the defective gene: there is a 50 % chance of passing the affected gene on to male children (in which they would develop symptoms in adulthood). The chance of passing the defective gene on to female children is also 50 % (in which case they would be carriers of the gene, but usually do not ever develop any severe symptoms).

If the father is the only carrier of the defective gene, your chances of passing the defective gene to a male child are 0 %. However, it is 100 % certain that you would pass this gene on to your female child, and she will be a carrier."

The 50% rule is not a perfect one out of every two rule

Since there is no internal monitor within the genes that keeps track of whether a defective or normal "X" chromosome was used when an egg was fertilized, researchers and counselors use averages in determining percentages. Out of a hundred cases reported, for example, you could have one case where every child is passed the defective gene. In another case, perhaps only one child is passed the gene. As you average out the number over 100 cases, however, it nears 50%.

Another example using coins might explain it better. A coin comes up either heads or tails when flipped (50-50 chance). If you have 100 people flipping a coin not every person flipping the coin will have a heads one time and a tails the next. Some might have three heads come up in a row before a tail. Conversely, another might have four or five tails come up before a heads. However, when you average out all of the heads and tails that come up for the 100 people, it should be close to 50% for each.

Using my family, for example, where my mother was a carrier three out of seven boys have the defect (43%). Out of three girls, none has the defective gene (0%). For our family, three defective "X" chromosomes (30%) and seven normal "X" chromosomes were passed to the ten children. And, as many times as I heard that all the males in someone's family have the defective chromosome, I also heard as many stories that only one male has it. In poker terms, it could be called the "luck of the draw."

Was it Adam or Eve?

Reference another question that I am often asked; I do not think anyone knows what actually caused the first defect in the gene and when or where it happened. It is very difficult to trace the lineage of the disorder since for many years Kennedy's Disease had been misdiagnosed. It was not until the 1960s that Dr. William R. Kennedy first named the disease. And, all the way to the 1990s it was still commonly misdiagnosed (most often as ALS). Once a simple DNA blood test was discovered, early detection and correct diagnosis has improved substantially.

Many qualified genetic counselors are familiar with Kennedy's Disease. If you feel there is Kennedy's Disease in your family, I would recommend talking with a counselor. They can help answer your questions regarding how the defective gene is passed through a family. They are also there to discuss the benefits and possible ramifications of having children tested. The National Institute of Health (NIH), for example, has genetic counselors on their staff that are fully versed in Kennedy's Disease. Use these services to help you better understand Kennedy's Disease and the impact it might have on your family.