Huntington disease – causes, symptoms, diagnosis, treatment & pathology

Huntington disease – causes, symptoms, diagnosis, treatment & pathology


Learning medicine is hard work! Osmosis makes it easy. It takes your lectures and notes to create
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much more. Try it free today! Huntington disease, or HD, is a rare neurodegenerative
disease that involves a repeated sequence of DNA that causes an abnormal protein to
form, leading to abnormal movements and cognitive problems. Huntington disease is an autosomal dominant
genetic disorder, which means that one affected copy of a gene is enough to cause disease. Affected people are typically present in each
generation, because an affected person (male or female) has a 50% chance of passing on
the affected gene to a child, which causes that child to have the disease. In most people, a gene called huntingtin or
HTT on chromosome 4, contains a triplet repeat, where the nucleotides C, A, and G are repeated
10-35 times in a row. In people with Huntington disease, this repeat
goes on for 36 or more times in a row. CAG codes for the amino acid glutamine, so
people with Huntington disease patients will have 36 or more glutamines in a row in the
huntingtin protein. So, in addition to being a triplet repeat
disorder, HD is, more specifically, a “polyglutamine” disease. The specific way in which extra glutamines
causes HD symptoms isn’t fully worked out, but some clues are that the mutated protein
aggregates within the neuronal cells of the caudate and putamen of the basal ganglia causing
neuronal cell death. Cell death might be related to excitotoxicity
– which is excessive signaling of these neurons, which leads to high intracellular
calcium. The expanded CAG repeats not only affect the
huntingtin protein – they affect DNA replication itself. When copying the HTT gene, DNA polymerase
can basically lose track of which CAG it’s on and accidently add extra CAGs. Since as a zygote develops into a fetus and
eventually into a full adult, by the time sperm and eggs are created, several dozen
cell divisions, each with a round of DNA replication have taken place, and so there have already
been ample opportunities for repeat expansion, and the more repeats that’re added, the
more unstable it gets. This expansion of the originally inherited
gene means a child of a parent with HD can inherit even more CAG repeats than the parent
did. The higher the number of repeats in the protein,
the earlier the age when a person starts having symptoms. This phenomenon is called anticipation, which
means that Huntington disease families often show earlier symptom onset with each generation. Even repeats of 27-35 CAGs can expand occasionally;
these are called “pre-mutation” alleles, since they don’t cause the disease, but
they’re set-up for developing a mutation of 36 or more CAGs. This process of adding more repeats is called
repeat expansion and it happens way more in the production of sperm than of eggs, so both
anticipation and new disease alleles generally happens when the father is the affected parent. When a person has 40+ repeats, they show 100%
penetrance and they will have the disease. For reasons that remain unknown, people with
36-39 repeats can show reduced penetrance; some may have symptoms while others may not. Because of this penetrance, the test for HD,
which counts the number of CAG repeats, is really good at determining whether HD will
develop in an at-risk individual. Now the symptoms of HD involve progressive
CNS disturbances including movement, cognitive, and mood symptoms. The average is around 40 years old, although
remember the age of onset depends on the number of CAG repeats. Over time, if enough of the neurons die in
the caudate and putamen, which together form the dorsal striatum, then it can cause actual
loss of brain tissue volume in that area and expansion of the lateral ventricles. These areas play an important role in movement
(particularly inhibiting it), and that’s why neuronal death in the basal ganglia causes
movement problems like chorea which are purposeless, dance-like jerking movements, and athetosis
which are slower, writhing, “snake-like” movements mainly affecting the hands. These involuntary movements can’t be consciously
suppressed and stop only with sleep. Other motor problems include abnormal eye
movements and poor coordination. Loss of tissue in these regions can also lead
to psychological problems as well, like dementia, personality changes, and depression. Even though this might be oversimplifying
things a bit, the brain regions affected by HD have decreased GABA and acetylcholine,
and increased dopamine levels. This increased dopamine helps explain why
neuroleptics, which are dopamine receptor antagonists, and tetrabenazine which depletes
dopamine, are used to treat chorea in patients with Huntington disease. Unfortunately, these and other pharmacologic
treatments don’t affect overall survival, and death usually happens within 10-20 years
of diagnosis, often by aspiration pneumonia on account of discoordinated swallowing, or
suicide. There are actually several dozen other triplet
repeat disorders in addition to Huntington disease, some of which also have CAG as the
repeated nucleotides but in a different gene, others of which, though, have different repeats,
like myotonic dystrophy (a CTG repeat), Friedreich ataxia (a GAA repeat), and fragile X syndrome
(a CGG repeat). Alright so as a quick recap – Huntington disease
is an autosomal dominant disease caused by having 36 or more trinucleotide repeats of
CAG in the huntingtin gene, which causes neuronal death in the basal ganglia, causing movement
symptoms like chorea and athetosis as well as mental symptoms like depression
and dementia.

21 Replies to “Huntington disease – causes, symptoms, diagnosis, treatment & pathology”

  1. Great video, thanks! I`m sad that I don`t know Eng well to repeat this vid for my university at Russia(

  2. There's an interesting story about a doctor who killed his dad with Huntington, it turns out the doctor also had Huntington. :-O

  3. Thank you for this video! It is May which is HD awareness month and I have a hard time explaining what HD is to people. I'm the first person in all generations of my family to not have inherited the HD gene. My brother, mum, both aunts and grandfather all had it within my lifetime and it's an awful thing to witness and I carry a lot of survivors guilt because of that. The only living relative I have is my brother who has the Juvenile form of HD and is not expected to make it to my age (23) and he is already 15. My mum and both aunts passed away around the age of 40 with onset for them happening around 10 years prior. I have decided to enter into neurodegenerative medicine because of this. Thank you for posting!

  4. My boyfriends mom has it. She just lays there in the hospital all day. She can't talk or move on her own.
    My bf and his sister haven't been tested yet.

  5. nice video i have a question is possible siamese twins one of 2 siblings have huntington disease and not the other and does the lifespan of one maybe effect the other?

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