World-class doctors, researchers, scientists and individuals living with Kennedy’s from around the world met face-to-face for the first time at the Kennedy’s Symposium funded by the generosity of Nathaniel Ginor in memory of his beloved mother Dr. Zvia Ginor and coordinated by Dr. Diane Merry (Thomas Jefferson University, Philadelphia, PA).

Unfortunately, Dr. Fishbeck was unable to attend due to a family emergency. Dr. Diane Merry led the discussion in his absence.

Dr. Merry did a good job making the complex SBMA subject and medical terms simple and easy to understand. Kennedy’s disease is caused by a gene mutation in the androgen receptor which is located on the "X"-chromosome (primarily men are affected and show symptoms, women are carriers who pass the affected gene on to their sons). Women may be protected from the disease because they have two separate "X"-chromosomes (one carrying the Kennedy’s mutation and the other not) or perhaps protected because of lower testosterone levels. Researchers hope to model and find out why women carriers are protected from showing symptoms.

Dr. Merry discussed the genetic basis of SBMA (the expansion of a CAG repeat sequence in the androgen receptor gene), that this expanded DNA repeat is made into RNA and protein, and what is known about the unusual polyglutamine tract within the androgen receptor protein. This string of glutamine amino acids that is a part of the normal androgen receptor protein is much longer than it should be in Kennedy’s patients. What does this unusual mutation do to the protein? It is now known that the expanded glutamine stretch within the androgen receptor protein causes it to become toxic to motor neurons. The basis for this toxicity is unknown; all that is currently know about this toxic function is that the long glutamine tract causes the androgen receptor to fold in an abnormal way. Every protein in the cell must fold in a very particular way in order to function. The expansion of the glutamine tract causes the androgen receptor to misfold and to become very sticky. It forms large aggregated structures within neurons. It is still not known whether these sticky aggregates of protein are themselves bad or if they simply indicate that the androgen receptor is misfolded. There is probably some loss of androgen receptor function over time, which may cause some or all of the signs of androgen insensitivity (the breast enlargement, progressive loss of fertility, and testicular atrophy) that occur. However, this is likely secondary to the toxic gain of function that is caused by the misfolding of the protein. A high priority is to develop the experimental models in order to understand the dysfunction of the neurons and to understand some very basic questions about this androgen receptor mutation and how it specifically affects motor neurons. The neurons affected in Kennedy’s Disease are lower motor neurons of the spinal cord and brainstem. These brainstem neurons enervate the bulbar muscles that control chewing and swallowing. Thus, the involvement of spinal and bulbar muscles helps to distinguish Kennedy’s from SMA III.

After Dr. Merry updated us with the above information, those in attendance living with SBMA asked questions. The questions and answers follow:

Q: Is everyone sharing information and working together for efficiency sakes and culmination of information or is there competition?

A: One of the primary reasons for this symposium is to interact and promote collaboration. Many of the researchers in the room have already been collaborating and some for many years. There are some who are working on similar things, but with slightly different approaches that are complimentary. We are already a cooperative and collaborative group. Today in our research group we are going to present what we have been working on, but we are also going to talk about ideas, brainstorm about direction, talk about ways that we can collaborate in a way that can make the research go faster.

Q: Is there a formal network set up?

A: There has not been one for the researchers, although we do have each other’s e-mail addresses. But I think that this kind of forum once a year (to get this group together) is very beneficial. This is the first time that, I’m aware of, this large of a research symposium has been specifically devoted to SBMA. We have often participated in the Huntington’s Disease meetings because of the common mutation, but there are specific details about SBMA that we do not get a chance to discuss at those meetings. At this symposium we will only focus on SBMA.

Q: What about research funding? Since you are all studying the androgen receptor, where are you receiving funding from?

A: Huntington’s Disease is supported by Hereditary Disease foundation and the Huntington’s Society of America, they support research in SBMA if it is relevant to their disease. The Muscular Dystrophy Association has also funded a few SBMA grants. They support 40+ diseases. In fact, SBMA is not one of their named diseases but they continue to support us because they know this is an important disease that really has, I have to say in terms of individual organizations, fallen through the cracks. Under grant applications it is not listed, but they have given grant money for SBMA research.

Q: Does Repeat length have anything to do with speed of progression?

A: There have been studies that have found yes, and some have found no. There’s no absolute finding yet. SBMA patients’ children can have longer repeat lengths and are likely to have an earlier onset over the generations. The instability of the repeat is not large. It is clear that it is unstable, and that over generations that it can change modestly. There hasn’t been a large enough population to study.

Q: When a cure is found, do they believe it will reverse the process or just stop its progression?

A: We don’t know, but there is recent data published that provide a glimmer of hope that even when neurons are not working correctly due to the proteins misfolding, that it is possible that the cell can get rid of the bad protein if the bad protein stops being produced. That’s encouraging information, that neurons can be very sick, perhaps pulled back from the brink and made to work properly. However, this is being worked on with mouse models and only one experiment has been performed. There has been a strong feeling that you have to lose a lot of motor neurons before you develop symptoms. But that is not clear. It is likely that motor neurons lost may be a late event. And that when you have symptoms, you still have a lot of motor neurons in place, but they are not working properly. There are mouse models with Huntington’s, and even our own mouse models that we are developing for Kennedy’s Disease also, but what we do know is that there is not a lot of neuronal loss.

Q: Once motor neurons are gone, they will not regenerate themselves?

A: If they are gone, they are gone. There might be a way to replace them through stem-cell therapy. Neighboring motor neurons do help pick up the slack for motor neurons that no longer function.

Some other interesting comments made during the symposium:

If a person’s polyglutamine chain has a short number of repeats, they have a higher chance of Prostate Cancer. The longer the chain (such is found in those with SBMA) there is a very low chance of Prostate Cancer.

Two of the doctors were from Japan, where one city has 200 individuals with Kennedy’s Disease. They are performing their studies there.

Many of the individuals with SBMA believe strongly that Kennedy’s Disease is underdiagnosed and misdiagnosed frequently. A majority of those with SBMA have been misdiagnosed more than once. A large percentage of those misdiagnosed were diagnosed with ALS (Lou Gehrig’s Disease) first. Hopefully, the DNA blood test, which costs approximately $200.00, will help others to be diagnosed quickly and correctly.

We found the SBMA Symposium to be not only educative, but liberating. Meeting all the researchers and doctors gave us great hope for the future that a cure will be found.

I’d like to personally thank Families of SMA for their assistance with this SBMA forum, for all their hard work coordinating the FSMA conference, and for helping to support SBMA individuals with a space in their newsletter and allowing us to attend their conference. Without Nathaniel Ginor and Families of SMA’s help, this symposium would never have happened. We owe them our deepest gratitude.