Neuro: 1:00 - 2:00 Scribe: Matthew Davis

Neuro: 1:00 - 2:00 Scribe: Matthew Davis

Wednesday, February 10, 2010

Dr. Dure Huntington’s Disease Page 1 of 7

I. Introduction [S1]:

II. George Huntington and Huntington’s Disease [S2]

a. Huntington’s disease is named after George Huntington

III. Huntington’s Disease [S3]

a. The reason why it was important was that Chorea’s, a type of movement, among movement disorders like that huntington’s disease was somewhat unique. It was hereditary which hadn’t been seen before and like a number of other hereditary condition this tended to present in adult or mid life. This is not something children would often get from their parents. There was also the concept of escapees. The disease was present in a parent, a child, but not present in a grandchild of an affected parent then none of the descendant of that grandchild would every have the diseas. The thread was broke. It does not skip generation.

b. Huntington also mentioned a tendency towards insanity and suicide which is a little bit general but it hints at the degree of psychometric parts of the disorder and it only manifests, in his series, in adult life.

IV. Chorea [S4]

a. Chorea actually is homonymous with St. Vitus (Guy). He was imprisoned, thrown to the lions, and later boiled in oil. His icon is often seen with a rooster because when they boiled him they also boiled a rooster and when the rooster was dead they knew he was dead.

b. Chorea was often called St. Vitus dance. IN medieval germany he was among a group of other saints called the 14 holy helpers and it was felt that dancing in his statue would ensure helath, it was a protection against the plague and other types of illnesses

c. He later became the patron saint of dancers, people with chorea, also people with epilepsy, actors, comedians, and people who oversleep. Kind of a general saint for child neurologists

V. Chorea- Definition [S5]

a. The definition of chorea is hard to understand if you just read about it. It is a very adjective laden definition. It is an involuntary movement, it is described as frequent, brief and sudden. Movements are twitch like and chaotic. Again if any of you can put up a mental picture of that I applaud you. I tend to think of chorea as a flow of movement from one body part to another and the intrusion of movements by other movement fragments

VI. Sydenham’s Chorea [S6]

a. I think the best way to tshow this to you is to give you a video. This is a old video of someone with sydenham’s chorea which is post infectious. You’ll notice this young man has a lot of different movements especially when he tries to carry out a purposeful task but you’ll notice he is able to touch the examiners finger so he is able to carry out meaningful activities but there is lots of intrusions forom other movements.

b. This is a more contemporary case. It is the same Sydenham’s chorea. Children are interesting though because to try to hide the chorea they will cross their arms or sit on their hands. What you need to appreciate3 here is that there is just extra movement. She has trouble maintaining movement so I was trying to get her to close her eyes, stick out her tongue, and keep it out. She can’t do it very well unless she bites down on her tongue. This is called motor impersistance and is another feature of chorea.

c. She is a little cooperative, but if you try to put her hands out in front of her, her legs continue to move and her hands begin to move even though she is holding herself quite stiffly trying to hold still. This is really how chorea presents early on or in mild cases. The gate is normally described as a dancing gate. In her case she has just a little bit of a hitch.

VII. Clinical Features [S7]

a. Now back to Huntington’s disease. Because Huntington’s disease, despite manifesting a similar movement disorder, really has some unique characteristics.

b. Prevalence is low. About 4-10 per 100,000 people. Now that may not sound like a whole lot but those of you going into dentistry or optometry you have a fairly good chance of seeing someone with Huntington’s disease during your career

c. The inheritance patternof this is dominant meaning that a child of an affected person has a 50% chance of inheriting the disease. Another feature of the inheritance pattern is called anticipation, in large pedigree’s where large generations have been studied the age of onset tends to creep down a little bit. The people that are affected get affected earlier and earlier as time goes on.

d. It has been demonstrated the gene has been identified and it is an expansion of a part of the HTT or Huntington Gene. It also has a very high penetrance, if someone inherits the abnormal gene you will most likely exhibit the disorder.

e. The age of onset is mid life, between 35 and 40 years is where the peak is although the range is very broad. From 2 years to 80. About 10% present under the age of 18 and we’ll talk about that specifically because it is a very different looking condition. The duration of the illness is usually anywhere from 15-30 years of survival after diagnosis but it varies quite a bit depending on the quality of care the patient gets after they have been diagnoses.

VIII. Clinical Presentation of HD [S8]

a. Now the initial signs and symptoms of Huntington’s disease are subtle. They typically present with some chorea but if you saw the little girl from the video it is likely you won’t notice any big problems with her. You might think she is just a fidgety kid. That is how adults will often start out, they will seem somewhat fidgety. They may have some coordination or trouble with fine motor activities. Things like tying your shoes, working on small instruments and things like that can be difficult.

b. Another feature is that of personality change. These are common complaints, but not very specific. There are also some patients who present early on with frank psychiatric diagnosis. They may have been diagnosed with an anxiety disorder, depression, bipolar disorder. What it really is is their Huntington’s disease. The disease is relentlessly progressive. What you see is a progression of chorea as well as the onset of another movement disorder called dystonia. They get a fairly significant dysarthria, difficulty talking and trouble swallowing. They can become demented in later life although the dementia is not the same that one sees with Alzheimer’s disease. People with Alzheimer’s disease forget facts. They loose their memory. People with Huntington’s disease loose their executive function, they have difficulty planning activities. Their memory has no problem at all, they know who everybody is, what date it is, and etc. They have trouble sequencing different types of activities. If they have any other psychiatric disturbances at the onset of disease usually gets worse with time as well

IX. Typical HD [S9]

a. So the typical case that would come in to us is an individual in their mid 30’s to 40’s. They have been experiencing troubles with their job or employment. If they are employed within the home they have problems with household management. The spouse usually reports problems with behavior and their judgment may be a bit altered, they are impulsive and have mood swings.

X. Adult HD Clinical Features [S10]

a. Now this is a gentleman who is older but I want to give you a strong case of Huntington’s. You’ll notice he moves around quite a bit. He moves around a lot so it is hard for the camera to keep him in the picture because he is always swaying. The first part of the examination is trying to get him to sustain an activity, in this case to stick his tongue out. He is unable to do it without some movement of the tongue and he tends to bite it. This is called motor impersistance and is a key feature of chorea. Same thing with the hands outstretched. The eyes closed trying to distract their movement. You’ll see some movements at the shoulders and fingers. This is not subtle chorea.

b. If you haven’t seen it it is hard to describe chorea-using words.

c. As a consequence of motor activity there is significant problems with sequencing motor activities. There is a problem with speed. There are also problems with rhythm as well. If you look carefully at the mans hands while he is walking you will notice they become very choreic as he walks.

d. These are typical features of adult HD

XI. JHD Clinical Features [S11]

a. Now I mentioned earlier that Juvenile HD is quite different. We have a fairly high number of juvenile HD patients in Alabama and I get calls often from the dentist at Children’s for help managing these kids. This guy had an onset before the age of 18. If you have seen people with Parkinson’s disease this kid looks similar. There is vary little facial expression, he is slow in his movement, and has odd posture. This is dystonia

b. This pattern of activity is what we consider hypokinetic. It is a Westphal variant of HD , they mainly have dystonia, the have tremor and dysarthria, but they do not have chorea.

c. This is this young man a few years later. When he sticks his tongue out he can do it but he has a remarkable tremor associated with mouth opening. One shoulder is higher than the other with his neck cocked over. This is dystonia. The posture of his hands is suggestive of dystonia. This is a typical case of juvenile HD. These videos were only a couple years apart, and he declined over a period of 5 years and ultimately died of the disease. His gate is much more wide based, his hands are very stiff. This is more typical of the juvenile course of the disease

d. They can also have seizures which is distinct in juvenile HD

XII. HD and JHD Genetics [S12]

a. For a long time we were left with just a clinical diagnosis, examining patients, looking at their family history, and deciding if it was consistent with HD. It wasn’t until the early 80’s and finally in 1993 the gene for HD was actually discovered. It was found on the short arm of chromosome 4, a gene called the Huntingtin gene which codes for the Huntingtin protein. The abnormality seen is in the 5’ end of the gene and is a stretch of CAG repeats that normally exist. The average length of the repeats is 17 CAG triplets but in people with HD there is a marked expansion. The diagnostic threshold for that is 40. If you have 40 repeats or above you will manifest the symptoms of HD at some point during your life. The average disease allele is 44 and juvenile HD is associated with a much higher number of 60 or above.

b. This group here between 35 and 39 is referred to as incomplete penetrance. What it really refers to is a big expansion, but if you live a normal life span like 80 you have a good chance of never developing symptoms of the disease. But if you make it into your 90’s you will probably manifest HD at the latter part of your life.

c. This motif of an expanded CAG repeat which is subsequently translated is actually similar to other conditions that effect basal ganglia that result in movement disorder and some demntia. I think I mentioned already that juvenile HD is typified by these large expansions, the other interesting thing is the only other way to get juvenile HD is if you have an affected father or a mother who herself was a juvenile case. Why was that? Why did affected children only come from affected fathers. It has to do somehow with somatogenesis. If you have a father who has 44 repeats he has a possibiltity of producing sperm that has repeats from 70 to a couple 100. If you are unlucky the child might inherit that allele and develop early onset disease.

XIII. CAG Expansion and Age of Onset [S13]

a. This is just a scatter plot that was taken from one of the early papers about looking at the age of onset and repeat size and there is a big group here, the onset again between 40 and 50. There is a big spread here in the age of onset, anywhere from 35 up to like 70 depending on these lower numbers. Where it really gets interesting is repeat lengths of 60 or above because these are people who present under the age of 20.

XIV. CAG Repeats in Other Disorders [S14]

a. As I mentioned before this motif is very similar to other diseases. There is some spino-cerebellar ataxia Type II and I, here is HD, DRPLA, and SCA3. These again have the same sort of pattern of age of onset associated with a repeat length. There is a correlation between age of onset to longer repeats. It sort of suggests a explantion for anticipation.

XV. CAG Expansions [S15]

a. The general rule for these expansions is that a lower number relates inversely to the rate of decline and severity of the disease. If you present as a younger person with symptoms you probably have a higher repeat length. Older people who present probably have a lower repeat number.

b. These really large expansions that explain juvenile cases are phenomenon of miosis. We do know that DAG repeats are quite unstable in spermatogenesis.

c. Once this gene was really well characterized, it became possible to obtain genetic testing. Your generation, genetic testing is something that is obvious and readily available for a variety of conditions.

XVI. Genetic Testing Types [S16]

a. You can even get your own genome looked at for 900 dollars. HD is important because it is one of the first tests that was predictive of the disease before you would actually have symptoms.

b. 1 type of testing that can be done is called confirmatory testing. IF you have somebody manifesting symptoms you can go ahead and draw blood to see if they have the mutation. What was different about HD was that you had a disorder where you could do predictive testing. You could take people who never had symptoms, but had a parent who had HD, but they could be tested for the disease that would not present for some time.

c. With advantages in technology we can do prenatal testing in unborn children. WE typically try to stay away from testing unaffected children even though it can be done. We don’t like to do it primarily because of questions relating to informed consent and what do you do with the information in a 10 year old who may not develop the disease until they are 35 or 40. These are the kind of types of genetic testing one can do and predictive testing is the most common.