Neuro: 1:00 - 2:00
Monday, January 23, 2009
Dr. Dure
HD = Huntington’s Disease
NII = neuronal intranuclear inclusion
HSG = Huntington Study Group
Huntington’s
Scribe: Marjorie Hannon
Proof: Caitlin Cox
Page 1 of 6
The audio didn’t pick up until slide 4, so slide 2 and 3 are my own notes.
I. Introduction [S1]
II. George Huntington and Huntington’s Disease [S2]
a. Disease was named after this doctor on Long Island (George Huntington).
b. He wrote a paper on chorea.
III. Huntington’s Disease [S3]
a. The paper was noteworthy because this type of chorea appeared to be hereditary, appearing in the adult life.
b. He read from the slide:
i. Unique among choreas:
1. Hereditary, presenting in adult or mid-life.
a. Escapees - “the thread is broken.”
b. Never skips a generation.
ii. Tendency to insanity and suicide.
iii. Manifests only in adult life.
iv. Distinct from post infectious or other choreas.
IV. Chorea – Historical Aspects [S4]
a. Chorea was originally associated with St. Vitus (St Guy) – a young man who in prison and thrown to the lions,
but with the help of an angel escaped from the lions. He was recaptured by the Romans and was boiled in oil
with a rooster (when the rooster was dead it ensured that he too was dead).
b. Saying prayers to him was notable in Medieval Germany. It was thought that dancing at his statue would
ensure health. He is also the Patron saint of dancers for people with chorea, epileptics, actors, comedians, and
people who oversleep.
c. People have always associated Chorea with St. Vitus.
V. Chorea - Definition [S5]
a. Chorea is an adjective-laden type of involuntary movement. It is described as frequent, brief, sudden, twitchlike, and chaotic (not much organization to it).
b. It is like a flow of movement from one body part to another. There may be an intrusion of “movement fragments”
for people who try to carry out purposeful activities.
VI. Sydenham’s Chorea [S6]
a. This is a video of someone who had what is called Sydenham’s Chorea.
i. There are bedrails and padding on the bed because he can’t really control his movement.
ii. There is lots of uncontrolled and extra movement here. A person holds out a finger for him to touch, and
he is able to execute a smooth purposeful movement but there is so much intrusion of these other types of
movements.
b. Showed a second video of a young lady with the same disorder, but not as severe. Many people with
Sydenham’s Chorea actually have fairly mild symptoms.
i. An inability to carry out the activities: She can’t keep her eyes shut for a long period of time or can’t keep
her tongue out for a long period of time. When she holds her hands out, there is a lot of movement of her
fingers; you see how her legs start to move. Her gait is pretty normal although her left leg “scoots” along a
bit. That is a little bit of Chorea intruding in on her normal activities.
c. They experience problems with handwriting, drinking, and eating.
d. Those are examples of postinfectious chorea, consequences of Rheumatic fever.
e. [SQ]: Will the symptoms get progressively worse? [A]: That is a self-limiting type of Chorea that actually goes
away after a period of weeks to months.
VII. Clinical Features of HD [S7]
a. HD is relatively rare, maybe 4 to 10 of 100,000 people.
b. The inheritance is of the dominant type. Anticipation refers to the fact that when there is succeeding
generations of dominant disease, the age of onset gets earlier and earlier.
c. Age of onset is typically in midlife (35-30 years) although there is a lot of variation, anywhere from 2 years of
age to 80. Fewer than 10 % present at less than 18 years of age.
d. Duration is anywhere from 15-30 years. Someone who gets diagnosed at the age of 35, they may only live to
be about 50 or 60 years of age.
VIII. Clinical Presentation of HD [S8]
a. Initial signs and symptoms:
Neuro: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, January 23, 2009
Proof: Caitlin Cox
Dr. Dure
Huntington’s
Page 2 of 6
i. People present with symptoms of chorea similar to what we saw in the video of the little girl, it is fairly
subtle. They may describe incoordination- takes a long time to tie shoe, can’t work on car any more, etc.
Spouses may describe personality changes. There may be frank psychiatric diagnoses as well: anxiety,
depression, etc.
b. Later signs and symptoms
i. Disease progresses with a worsening of Chorea, dystonia, dysarthria (difficulty speaking), and ultimately
dementia with procedural type of memory loss: difficulty carrying out tasks. They don’t forget who they are
or who their relatives are; they forget for example how to make cookies.
ii. May also have fairly significant psychiatric disturbances.
IX. “Typical” HD [S9]
a. Typical new patient is someone in the mid 30’s-40’s.
b. They describe difficulty with their job. May be having trouble with their job or have lost their job, or if they are a
homemaker, they are having greater problems carrying out those typical tasks.
c. They describe behavioral changes/problems. Just as they have difficulty controlling their movements, they have
difficulty controlling their moods. They may be very impulsive, have mood swings, and have altered judgment.
X. Adult HD Clinical Features [S10] (Video)
a. This is a typical adult with HD. He was asked to keep his eyes shut for 10 seconds and he can’t do it. The next
task is to keep his mouth wide open and to stick his tongue out. He can do it, but he can’t keep it out for 10
seconds. This is an example of motor impersistance which is a typical feature of Chorea.
b. He is being asked to hold his arms out at the same elevation and keep them as still as possible. We see that
there is movement.
c. People with HD have problems with fine motor activities.
d. Carrying out sequential movements or alternating tasks are difficult to do and the movements are slow.
e. Problems walking heel to toe (the tandem gait). He has much more chorea when he tries to walk. He may fall
over if you pull on him.
XI. JHD Clinical Features [S11]
a. Juvenile disease is a little bit different.
b. These young adults look like they have Parkinson’s.
c. In the video, the boy has very little facial movement, and tremor of tongue.
i. He is able to hold himself still – he doesn’t have Chorea at all.
ii. He has dystonia: holds himself in an odd posture. This is a fairly typical picture of someone with JHD.
d. Shows another video of the same boy several years later:
i. He has profound tremor of the tongue, he cannot carry out the task asked of him with his hands, he has
more dystonia. He has tremor with action (tries to touch nose and tremors while doing it).
e. This looks very different from the typical adult onset Huntington’s.
f. Juvenile HD is usually inherited from a father who is affected with HD.
i. The description of this is what’s called the Westphal Variant (a type of genetic HD).
g. Problem with dystonia, tremor, dysarthria.
h. JHD is also distinct because they have seizures which are very difficult to control. Unlike adult HD, where the
course is 15-20 years, the course here is usually measured less than a decade.
i. Occasionally you may see a juvenile who has more Chorea.
j. [SQ]: What is the mental capacity of someone with JHD or HD? Do they realize that they can’t carry out these
tasks normally? [A]: For everyone with HD, they maintain a great deal of awareness of what they can’t do
anymore which may be a cause of a lot of the behavioral issues that they face. For example, an adult who can’t
cook anymore, or is doing poorly at their job, or can’t get themselves dressed is very aware of the problem, so
this dementia is a lot different than the dementia that we see in something like Alzheimer’s.
XII. Variability of JHD [S12] skipped video.
XIII. HD/JHD Genetics [S13]
a. The genetics of this disorder is of interest because it is an example of a trinucleotide repeat disease.
b. This is the Huntingtin gene, which is on the short arm of chromosome 4. There is a motif of repeated CAG
elements or triplets. The typical length of these is around 10-15 in people without HD.
c. The average here is 17 with people without HD, but people with HD have a dramatic expansion. The disease
presents when it is 40 or above. There is such a thing called incomplete penetrance for people who are at risk
for developing the disease where the repeats are around 35-39.
d. The average disease allele for adult onset HD is 44 repeats. Juvenile onset is usually 60 or above, and the
longest repeat ever found was around 250.
e. This is a similar process to what is seen in a number of other neurological conditions. Basically a CAG repeat
greater than 39 correlates with clinical disease.
Neuro: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, January 23, 2009
Proof: Caitlin Cox
Dr. Dure
Huntington’s
Page 3 of 6
f. JHD is associated with very large expansions. It is typically inherited from the father unless the mother herself
was a juvenile onset patient.
XIV.
CAG Expansion and Age of Onset [S14]
a. This is a graph from the early days when people first found out about these triplet repeats. You can see the
relationship of repeat size and age of onset.
b. When the repeat gets above 50, the age of onset begins to drop off.
XV.
CAG Repeats in Other Disorders [S15]
a. This is also seen in other disorders. You don’t really need to know these other than the fact that these are
neurological diseases that are often associated with movement disorder and they are all associated with an
expansion of CAG repeat on some gene. This is a fairly consistent pattern of the disease process.
XVI.
CAG Expansions [S16]
a. The general rule is that the lower number relates inversely to rate of decline and severity. Basically, the shorter
the length, the better off you’ll be.
b. Younger people who have symptoms have higher repeat lengths.
c. There are older people who may not present until they are 75 or 80 years of age and they are typically right at
40 or 41 repeats; they have milder symptoms.
d. It is unclear why the large expansions (over 100) are occurring. It is a phenomenon of meiosis, and is probably
related to spermatogenesis; however no one really knows for sure why these occur. This is thought to be the
cause of JHD.
XVII. Genetic Testing - Types [S17]
a. Back in the 1980s, the genetic testing for HD was cumbersome. It wasn’t until about 1993 that a fairly simple
test was available where you only had to draw blood from the person of interest. (In the past you had to get
blood from an affected relative, an unaffected relative, and yourself).
b. The types of genetic testing that one can do (all involve drawing blood from one person):
i. Confirmatory - people who have symptoms consistent with HD, adults and children.
1. Draw blood to confirm that they have HD.
ii. Predictive – for someone without symptoms but may have a parent with HD.
1. This person is at 50% risk of HD so they can get tested. This test is reserved for adults. This is not
an appropriate test for children (who can’t give consent).
iii. Prenatal Testing- done very early in pregnancy (the first 10 weeks).
1. This test is done with the understanding that if the test is positive the pregnancy will be terminated.
iv. Unaffected children are not tested (usually).
XVIII. Testing for HD [S18]
a. Skipped because he said he sort of already went through this.
XIX.
HD Testing in Children [S19]
a. It is very tempting as a physician to order the test for a child who may have behavioral problems. However, that
is misguided.
b. Before you test any child for HD, they should look like they have the disorder. They should have some of the
cardinal features of the disorder such as rigidity or dystonia in order to be tested; as opposed to just having
psychiatric or behavioral manifestations alone.
c. Psychiatric/behavioral manifestations alone are insufficient to warrant testing in a child.
i. Part of the reason is that psychiatric disorders are common in these families, but it is not always seen in
people who have the gene.
ii. If you grow up in a family and one parent has HD and they die when you are still a teenager, your life has
been disrupted, etc., it’s normal to have a little depression and have problems adjusting. It doesn’t mean
you are going to get HD.
iii. This occurs on a regular basis. Children get tested for the disease, the parents find out that they have an
expanded allele, but their kid isn’t actually going to have any symptoms until they are around 35 years of
age. So it is a difficult situation.
XX.
Treatment of Chorea [S20]
a. The bottom line is that there is no effective treatment for this disease. You can treat the symptoms though.
b. In terms of Chorea, benign neglect is probably the best thing.
c. Most people accommodate to their chorea well. They limit their activities, they don’t engage in very complicated
manual tasks, and they actually do quite well for a long period of time.
d. There is a class of medications that are helpful for Chorea – these are called neuroleptics (major tranquilizers).
They can temporarily help chorea, but remember that this is a progressive disorder so eventually they will not be
able to take anything for this; the drugs actually may do more harm than good.
e. People respond very well to occupational and physical therapy for their chorea, which basically help them make
these adjustments in order to get by a little easier.
Neuro: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, January 23, 2009
Proof: Caitlin Cox
Dr. Dure
Huntington’s
Page 4 of 6
f. Speech therapy is quite helpful for swallowing issues.
g. There are a lot of other medications that one can try for the treatment of chorea:
i. Atypical antipsychotics, amantidine, and tetrabenazine (a newer drug with mixed success).
h. There are some ways to treat chorea, but you might try to wait a while before you do that.
i. [SQ]: What does HSG stand for? [A]: I’ll tell you what that is later. I realize I skipped that.
XXI.
Tetrabenazine in HD [S21] skipped
XXII. Behavioral and Psychiatric Care [S22]
a. More time is spent in the Huntington population dealing with certain behavioral and psychiatric issues. The
disease itself is associated with significant psychiatric problems. There is a lot of emotional lability or dyscontrol.
It is hard to tell if it is a cause of the disease or is it a consequence because the patients are completely aware
of what is happening with this neurodegenerative disease that has no cure.
b. There is occasionally more serious psychopathology associated with these patients such as depression,
obsessive compulsive disorder, and anything else a psychiatrist might see can be manifested in a Huntington’s
patient. You should treat the Huntington patients as you would any other patient; essentially anything that you
would use in a patient without disease, you would use in a Huntington patient, typically with good effect.
XXIII. Management of JHD [S23] skipped
XXIV. Neurobiology – What have we learned? [S24]
a. (Side note: he stated that his questions are usually pretty simple that if you paid attention you would be fine)
b. This is a trinucleotide repeat disease. Because of the phenomenon of expansion of the mutation, we have an
explanation for anticipation (why we have younger people getting the disease is because they have a greater
expansion and it always seems to occur in children of an affected father).
c. Huntingtin, the translated protein, what does it do? We know it is translated and we presume that this is a gain
of function that there is some new capability conferred onto the cell—it may not be a good function, it could be
an impaired function but the point here is that it seems to explain a number of issues related to the genetics.
d. In terms of understanding the neuropathology, it is helpful to compare the contrasts between JHD and HD.
i. We know that HD lasts anywhere from 15 to 30 years before people die, but JHD is a much more
malignant progressive process.
ii. If you look at sliced preparations of a human brain of someone with HD, you see that it is a disease that
affects the entire brain (pathology is everywhere) but the most extensive area of regional damage is in the
basal ganglia: caudate and putamen. The earliest cell loss is in the subthalamic nuclei that project to the
lateral globus pallidus.
iii. In contrast in someone with JHD, it is not as discrete. Again, it is a global process but it is serious
everywhere.
XXV. Functional Pathology [S25]- he talked really fast here and the audio was of poor quality. We listened to it
over and over and still couldn’t figure out some things that he was saying. It is around minute 25 in the audio
if you would like to try to listen to it on your own.
a. This is an axial cut of a hemisphere of the brain. (He then points out the front, back, and lateral ventricle, the
putamen, the caudate, and the globus pallidus.)
b. The caudate is wiped out in someone with HD. This is hallmark pathology.
c. What do we think happens?
i. We know that there are projections from the caudate/putamen to the lateral globus pallidus (LGP), these
are enkephalinergic and inhibitory. Then there are projections from the lateral globus pallidus to the subthalamic nucleus. Then the sub-thalamic nucleus is tonically active on the medial globus pallidus (MGP).
The medial globus pallidus is the main output nucleus of the basal ganglia and there is an inhibitory
influence from the caudate/putamen that is from MSN (couldn’t hear what this stands for - minute 26:56)
that contain substance P. (next sentence was inaudible) Last part says “from the medial globis pallidus to
the thalamus.”
d. MGP is direct motor pathway. LGP is indirect motor pathway.
e. The first thing to go in adult onset HD is the projection from the caudate to the lateral globus pallidus. Then you
have this inhibitory output here and you also have tonic activity from the lateral globus pallidus which in turn
inhibits the sub-thalamic nucleus, so really all you have is this direct motor pathway. We presume that this is
why people with HD develop a hyperkinetic movement disorder.
XXVI. Cortical Pathology [S26]
a. There have been a lot of studies of neuropathology of human brain with HD. This can now be done in vivo and
you don’t actually have to wait for someone to die.
b. In postmortem studies (used widely in the past), you would see profound cell loss primarily in the basal ganglia
but in the late stages of the disease it is almost everywhere.
c. We now have the capability to use premortem techniques typically with functional MRI.
Neuro: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, January 23, 2009
Proof: Caitlin Cox
Dr. Dure
Huntington’s
Page 5 of 6
i. If you look at an MRI and compare cortical thickness of controls to people with HD, what you see is that the
cortex is thicker in people who have presymptomatic HD. We don’t know what happens next because
these people don’t have symptoms yet and they haven’t been followed long enough. This is however a very
interesting distinction, at least presymptomatically. It may suggest this consequence of the gain of function
in people with HD.
XXVII. Investigative Models of HD [S27]
a. There are also a number of investigational models for HD.
b. The R6/2 mouse is probably the most famous model.
i. This is a knock in mutant where they have taken the human mutation and knocked it into a mouse.
ii. This mouse has a very typical stereotype appearance. They are normal for quite some time and then they
gradually lose a lot of motor skills. These mice develop a progressive phenotype that is also characterized
by seizures and the mice ultimately die.
c. There have been a number of other mice that have been created. As long as you put in the expanded CAG
repeat mutation, you will see a phenotype that is very similar.
d. In Drosophila (the fruit fly), if you knock in the mutation you see macular degeneration in the eye.
e. You can look at yeast, or just plain cell culture. There are a lot of ways that people are now looking at the
effects of this mutation.
XXVIII. Neuronal Intranuclear Inclusions (NII) [S28]
a. One of the first things that was noticed in the mice is something called neuronal intranuclear inclusion (NII).
b. Within a neuron or a cell that is neuron like, you will have these very dense inclusions within the nucleus.
c. Top picture is the normal/control, with 18 CAG repeats. Bottom picture is the abnormal, with 82 CAG repeats.
i. These are stained with ubiquitin.
ii. Can see the differences between the two cells: see the NII when the cell has an expanded CAG repeat.
d. This was initially originally observed in human brain by Kowall and Ferrante, but they didn’t know what it meant.
it wasn’t until there were a lot of mouse brains to look at until they were able to make the link to show that this
occurs in the human as well.
e. These NII colocalize with the huntingtin protein. The only problem is that these do not correspond to regions in
which there is the greatest degree of pathology. This means that you will see these in the caudate/putamen, but
you won’t see nearly as much as you might see in the cortex.
f. It is unclear whether these are protective or are they just what is left over- are there not as many in the
caudate/putamen because those cells are dying? It is still not known.
XXIX. Toxic effects chart [S29]
a. There have been a number of hypothesis of what all of this might mean. We know we have this protein that has
this poly-glutamate area (CAG codes for glutamate).
b. Proteins in the cell are broken down in order to be metabolized and ultimately used for other things. You end up
with a fragment that would be very rich in glutamine. If there are enough of these, these can form fragments
which are misfolded. All the glutamine is not good for the cell and will form inclusions by forming oligomers (or
these big tangles), which is what one sees.
XXX. Mutant Huntingtin [S30]
a. This leads to a number of hypotheses of how the mutant huntingtin will cause problems.
b. We know that it is normally cytoplasmic and it is going to be broken up into pieces. If you can translocate this
down the axon at the nerve terminal, it has been shown to inhibit brain or nerve growth factor effects.
c. It has an effect on the neuron because it is present in the end plate.
d. You also have the proteosome, the apparatus that breaks proteins down into smaller parts. The problem is that
these to be much less efficient.
e. These fragments can also affect mitochondria. It affects their ability to buffer calcium, it causes them to
depolarize. So it has affects on our prime energy creator for the cells.
f. Can translocate into the nucleus itself and will affect gene transcription.
g. These are all areas in which mutant huntingtin can render a cell sick or disabled.
XXXI. Mutated Huntingtin – Possible Roles [S31]
a. There have been a number of proteins that have shown to have been altered in terms of their expression but no
clear leading candidate as to what leads to the true pathogenesis.
b. Metabolic dysfunction:
i. Pathology tends to be greatest in regions prone to oxidative stress. If your mitochondria aren’t working
very well, these regions of the brain will be most quickly affected.
XXXII. Possible Therapeutic Approaches [S32]
a. Skipped
XXXIII. Ambiguity vs. Progress [S33]
Neuro: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, January 23, 2009
Proof: Caitlin Cox
Dr. Dure
Huntington’s
Page 6 of 6
a. We know a fair amount about the genetics and clinical course of this condition and we are still learning about the
neurobiology. The unfortunate thing is that we really don’t have any treatment. So, how would you proceed?
b. The Huntington study group (HSG) has dedicated itself for developing rational treatment options for HD. One of
the things that they have been working on is what is called the high-throughput screening- looking for
compounds that might work for the disease.
i. There are chemical companies that own a bunch of compounds of no use at all. They just synthesize and
package compounds. You can attempt a brute force method (what they are doing here) and just grab a
few thousand of these compounds and see if they work for HD.
ii. The nice thing is that there are a lot of in vitro and in vivo models to look at neurodegeneration in HD. They
can feed these compounds to the animals and see if they alter the phenotype.
iii. This has been done to a certain extent with some hypothesis-driven testing of compounds (creatine,
minocycline, and a few others). These are things that people thought would be helpful for HD and when
shown to be useful in mice, they were used in humans.
iv. The latest technique is to do high-throughput screening in these compound libraries. They are screening
thousands of compounds a year to see what might be helpful on these preclinical models and then be
taken out into a human trial.
XXXIV. Clinical Research [S34]
a. The HSD has been dedicated to developing these clinical trials and so far the results have been somewhat
disappointing. However, there are about 5 Huntington studies with drug treatment that are going to be ongoing
this year.
b. One thing that the HSG has done is to do a better job of trying to characterize the clinical features of the
disease.
c. The study is being done at the University of Iowa for people with pre-symptomatic HD. They now can predict
within 5 years when someone will start to develop motor symptoms in the disease.
d. This has lead to a need to study younger subjects.
XXXV. Recent/New Studies [S35]
a. Two studies that are going to be ongoing here:
i. One is a dopaminergic modulator which has shown some promise for people with HD and Alzheimer’s.
There is a 2 year treatment trial that has been going on here.
ii. One is called Crest-HD which is a creatine study for very high dose creatine and this is also a 2 year
treatment trial.
b. We are moving forward in terms of clinical trials.
XXXVI. Research in Younger Subjects [S36]
a. The goal is to recruit younger people to try to understand the disease better and to try to intervene sooner.
b. Someone who is already severely affected with JHD is not someone you want to enroll in the study. You really
want the people with minimal symptoms or even those before they have symptoms.
c. The problem is in the details. A lot of children with HD have an imperfect understanding of the disease itself and
they may not even know that they are at risk for the disease. We have to be able to consent people, or with a
child you have to get their assent to participate in a clinical study. In HD, if they don’t know about the disease,
you are not going to be able to do it. A problem that we face is: how do we assess the understanding of children
with HD.
XXXVII. Summary [S37]
a. HD is hereditary and progressive.
b. The genetic research has been productive in terms of understanding anticipation, development of screening and
diagnostic testing, and has helped drive the neuroscience investigation. The problem though is that the
neurobiology hasn’t been able to keep up in the past 15 years.
c. All of that together means that clinical research will remain a big challenge for this disorder.
[SQ]: How does the NII affect the neuron? [A]: It doesn’t bother people so much that it shows up throughout the neuron,
but why does it end up in the nucleus? It is a feature that has actually been seen in certain types of cancers- the same
thing happens (a protein in the cytoplasm ends up in the nucleus). It is unclear why it translocates and what affect that
has.
[end 44 min]