An Experts Take on Huntington's Disease

    On February 4th, 2010 the four of us met with Dr. Richard Dubinsky at The University of Kansas Medical Center to aid in a better understanding of what Huntington's Disease is. Dr. Dubinsky is well qualified to answer our questions about Huntington's Disease, and we were able to learn a lot from him.



    To give a brief background, Dr. Dubinksy attended the University of Missouri Kansas City Medical School and graduated in 1982. He completed an internship in internal medicine at Baylor College of Medicine followed by a neurology residency at the Baylor College of Medicine. His areas of interest include movement disorders, specifically dystonia, myoclonus, Huntington's Disease, and Parkinson's Disease. He is actively involved in clinical research in Huntington's Disease, Parkinson's Disease, and dystonia.

    What was extremely beneficial in interviewing Dr. Dubinsky was that we were able to gain better insight into what Huntington's Disease really is. He was able to clarify some of the misconceptions about the disease and go into more detail about what is currently being done to aid in HD treatment/prevention. He was able to confirm many of the things we were able to find with our prior research on the disease and explain in better detail some of the grey area we were still unsure about.


Unfortunately Brian wasn't with us when we took these pictures; so we just made him there anyway.


We asked Dr. Dubinsky is he had ever heard of grid-computing and he said he was unaware of it, but that it did make sense why it would be so critical for research.


Below are some of the questions addressed during our interview, which really helped us to understand the disease from a clinical and research perspective:


1. In your own words, how would you best describe what Huntington's Disease is?
    There are three domains that are affected of people with Huntington’s disease: behavior, cognition, and motoric. The motor part is the chorea movements which are easy to recognize but seldom cause problems. People with Huntington’s disease will be clumsier, and as the disease progresses they will move less and become stiff and more prone to fall. This is really the least of our problems. The behavioral problems are really the main source of problems. They really run the whole gamut of psychiatric problems. Typically there will be problems with depression, anxiety, irritability, compulsive activity, and obsession thoughts. The cognition is interesting in that it is different from Alzheimer's. With Alzheimer's you don’t make memories. You forget that you forget. With Huntington's Disease it is more like having difficultly completing simple tasks, like doing things in the correct sequence. The social aspects are also typically more problematic. It is a very visible disease when there is onset, and it can be very noticeable.


2. How does Huntington’s Disease affect the physiology of the Brain?
    Huntington’s Disease really does not effect neurotransmission. With Huntington’s Disease you have a loss of cells. The basal ganglia in the middle of the brain have spiny neurons and each make about 100,000 connections, and you lose those interconnections. This is why you may have difficulty trying to put things together. We also think that the cortex may be thinning. There is one genotype, but there are many phenotypes.


3. Is the accumulation of the Huntingtin protein HTT in the basal ganglia what damages the nerve cells?
    There are proteinatious clumps in the cytoplasm and the nucleus which can be stained to show the presence of the HTT protein, but they are being bound with ubiquinone. We don't believe the actual proteins are doing anything. It's the other things in the proteinatious clump that are binding up all of the proteosomes needed for the cell. There could be a toxic loss of function by sequestering normal functioning proteosomes.

Image acquired from: http://www.nyctreatment.com/img/Basal-caudate,thala,puta,globus.jpg

Image acquired from: http://upload.wikimedia.org/wikipedia/commons/6/66/Proteasome.jpg

Proteasomes belong to a class of proteins called proteases and play an important role in the normal function of a cell. They are commonly found in the cytoplasm and nucleus and are primarily responsible for assisting in the degradation of damaged or unneeded proteins. They work by lysing the peptide bonds between amino acids, a process called proteolysis. In relation to Huntington's Disease it is a huge problem for the cell if these proteasomes are being used up because of the HTT protein over expression.  A cell constantly regulates how much protein is present, and when too much builds up it can be detrimental to the cell.

4. If you wanted to be tested for Huntington’s Disease, how would you go about doing this?

    It is about a four month process from start to finish. They come in first to see Dr. Dubinsky and myself for about an hour and a half visit to go over family history, personal medical history, and thorough neurological exam. Then they see a psychologist for two visits. Then they see a genetic counselor for one session and have their blood drawn. It’s about a three week wait for the results.

5. How does a geneticist test the blood to determine the presence of the Huntington allele?

    The name of the gene is called IT15 gene. We all have this gene, but some have the expansion, and some don’t. They will either use western blot or PCR. They can look at the number of repeats and see if it is expanded. If they have one positive result they then use the other method just to be certain.

6. What does your research with Huntington’s Disease focus on?

    Most of our research is through the Huntington’s study group. At the moment were are trying to obtain information for those participating in the group so it can be used to answer a lot of questions about the disease. In terms of treatment protocols we are using high doses of creatine going up to 60 grams a day, which will try to slow down the progression over three years. There is another treatment which is an antihistamine developed in Russia that may have cognitive benefits to improve cognition. 

7. Is gene therapy a future treatment possibility for Huntington’s Disease?

    What is really promising is the possible use of missense RNA and missense oligonucleotides where basically you custom-make RNA, which will bind to the transfer RNA for the mutant allele, which will inhibit transcription of the mutant allele. This is also called RNA interference. 

This is a video we found that illustrates how RNA interference can be used for gene therapies:

What makes the use of RNA interference much better than doing a gene knockout is that with RNAi you can regulate the expression of a certain gene without deleting the gene completely. The problem with Huntington's Disease is not the expression of the HTT protein, but rather the over-expression of the protein. If we are one day able to slow down the translation so the Huntington's gene, so it doesn't get over-expressed, then it could be a very valuable treatment in the future.

8. Everyone has the Huntington's gene…What is the HTT protein used for normally?  Would its complete inhibition cause any side effects?

    The gene is transcribed in the basal ganglia.  It is needed for life.  It is found in the mitochondrial membranes and cell membrane.  Also, the nucleus and cytoplasm.  There is no difference in phenotype between homozygous for mutant alleles and only one mutant allele.  

9. What are the most common types of treatments for symptoms?

    For the cognition, not much has been proven to work.  For the behavioral aspects, the usual medications used to treat those psychiatric disorders work quite well in relatively low doses.  The chorea movements are really not that bothersome.  It is when they are falling out of the chair when it gets to be bothersome.  At that point, some medication can block enough dopamine to take the edge off.  Some medications can slow down the chorea but at an enormous cost: a high risk of depression and suicide.  So it’s not a common treatment.  Simple things like cutting caffeine out of the diet can help a lot.  Any sort of stimulant will increase the chorea.  On the other hand, being stiff and not moving is more of a problem than moving all over the place. 

10. Why should a doctor know about evolution?

    From an evolutionary stand point it is interesting to see how a mutation spreads through a population and how it affects the population

Overall the interview was extremely interesting and eye-opening. After doing our own preliminary research about the disease, we thought we had a decent understanding of what Huntington's Disease was. What the interview gave us that research alone did not was that Huntington's Disease, although ultimately a terrible disease, isn't as bad as people might think. Patients with the disease lead very normal lives with the exception that they must adapt when their conditions change. Having a positive attitude is sometimes the best medicine, and this is what really hit home in our interview. We really appreciate Dr. Dubinsky taking the time out of his busy schedule to meet with us and answer our questions.

If anyone reading our blog is interested in learning more about the interview or something mentioned in the interview, leave us a comment and we can help to clarify and/or better explain it.