Huntington disease

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 cause 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.The diagnosis of Huntington disease is based on the person’s history and physical assessment, followed by genetic testing to confirm the diagnosis.

Additionally, brain imaging tests, such as CT scan or MRI, can be used to assess the atrophy of the basal ganglia.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.

quick recap Huntington disease is an autosomal dominant disease caused by having 36 or more trinucleotide repeats of ca in the Huntington gene which causes neuronal cell death in the basal ganglia causing movement symptoms like chorea and athetosis as well as mental symptoms