Summary
Highlights
Huntington disease (HD) is a rare neurodegenerative disorder caused by a repeated DNA sequence that leads to an abnormal protein, resulting in abnormal movements and cognitive problems. It is an autosomal dominant genetic disorder, meaning one affected gene copy is enough to cause the disease, and there is a 50% chance of passing it to offspring.
The huntingtin (HTT) gene on chromosome 4 normally has 10-35 CAG repeats. In HD patients, this repeat extends to 36 or more times, leading to an abnormal number of glutamines (polyglutamine disease) in the huntingtin protein. The exact mechanism of damage is unknown, but it involves mutated protein aggregates and neuronal cell death in the caudate and putamen of the basal ganglia, possibly due to excitotoxicity.
The expanded CAG repeats also affect DNA replication, with DNA polymerase inadvertently adding more CAGs during cell division. This 'repeat expansion' means subsequent generations can inherit even more repeats. The higher the number of repeats, the earlier the symptom onset, a phenomenon called 'anticipation.' This expansion is more common in sperm production, so anticipation often occurs when the father is affected.
Individuals with 40+ CAG repeats will invariably develop HD (100% penetrance). Those with 36-39 repeats may show reduced penetrance, meaning some develop symptoms while others don't. The test for HD, which counts CAG repeats, is highly effective in determining disease development in at-risk individuals.
HD symptoms involve progressive CNS disturbances, including movement, cognitive, and mood issues. The average onset is around 40, varying with repeat numbers. Neuronal death in the caudate and putamen (dorsal striatum) causes brain tissue loss and ventricular expansion. This leads to involuntary movements like chorea (dance-like jerking) and athetosis (slow, writhing movements), abnormal eye movements, poor coordination, dementia, personality changes, and depression.
Affected brain regions in HD show decreased GABA and acetylcholine, and increased dopamine. This explains why neuroleptics (dopamine receptor antagonists) and tetrabenazine (dopamine depleter) are used to manage chorea. Unfortunately, these treatments do not improve overall survival, and death typically occurs within 10-20 years of diagnosis, often from aspiration pneumonia or suicide.
Huntington disease is one of many triplet repeat disorders. Others include myotonic dystrophy (CTG repeat), Friedreich ataxia (GAA repeat), and fragile X syndrome (CGG repeat), some of which also involve CAG repeats in different genes.
Huntington disease is an autosomal dominant disorder caused by 36 or more CAG trinucleotide repeats in the huntingtin gene. This leads to neuronal death in the basal ganglia, resulting in movement symptoms like chorea and athetosis, as well as mental symptoms such as depression and dementia.