Huntington's disease is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the HTT gene on chromosome 4. The expanded mutant huntingtin protein produces progressive striatal degeneration — particularly affecting medium spiny neurons of the indirect pathway — with the clinical triad of motor, cognitive, and psychiatric symptoms.
Genetics: the HTT gene normally has fewer than 27 CAG repeats. Repeats 27-35 are intermediate and rarely produce disease. Repeats 36-39 have incomplete penetrance. Repeats 40+ produce HD with full penetrance. Larger expansions produce earlier onset (juvenile HD with very large expansions can present in childhood). Genetic anticipation — expansion tendency through paternal inheritance — produces earlier onset in successive generations.
Typical clinical course:
Prodromal phase — subtle motor signs (mild chorea, eye movement abnormalities), psychiatric symptoms (irritability, depression, apathy), mild cognitive changes (executive dysfunction) may precede clear motor onset by years.
Manifest disease — typical onset ages 30-50. Chorea (involuntary brief writhing movements), dystonia, dysarthria, dysphagia, gait abnormalities, eventual difficulty with all motor function.
Cognitive decline — executive dysfunction, processing speed slowing, eventual dementia. Memory typically less affected than in AD.
Psychiatric symptoms — depression (40-50% of patients, high suicide risk), irritability and aggression, apathy, anxiety, occasional psychosis, OCD features.
Late stages — severe motor disability, dementia, bedridden state, death typically 15-20 years after motor onset, often from aspiration pneumonia or complications.
The neuroanatomy: striatal degeneration begins in the caudate and putamen. Indirect pathway medium spiny neurons are preferentially affected — explaining the chorea (loss of motor program suppression, opposite of Parkinson's). As disease progresses, both pathways degenerate, producing a mixed motor picture with later parkinsonian features.
Treatment is symptomatic — no disease-modifying therapy yet.
For chorea: tetrabenazine, deutetrabenazine, valbenazine (VMAT2 inhibitors that deplete presynaptic dopamine). Reduce chorea but can worsen depression.
For depression and suicidality (high priority): SSRIs, careful safety planning, monitoring.
For irritability/aggression: SSRIs first-line, atypical antipsychotics for severe symptoms, mood stabilizers in some cases.
For psychosis: antipsychotics (atypicals preferred to minimize movement worsening).
Genetic testing and counseling: predictive testing for at-risk individuals requires extensive pre-test counseling. Considerations: psychological readiness, insurance implications, reproductive decision-making, suicide risk on receiving positive results (small but real), absence of disease-modifying treatment. Many at-risk individuals choose not to test. Specialty genetic counseling with HD experience is standard.
Reproductive options for known mutation carriers: preimplantation genetic diagnosis allows unaffected embryos to be selected through IVF. Substantial financial and emotional cost. Decisions are personal.
When you encounter a Huntington's patient or at-risk family member, the framework requires sensitivity. The disease is currently devastating; care emphasizes quality of life, symptom management, and family support. Disease-modifying therapies are in development (antisense oligonucleotides targeting huntingtin mRNA) — the trajectory may change.