SKY-0515

Huntington's disease is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in HTT. Alleles of 40 or more repeats are fully penetrant, and alleles of 36 to 39 repeats show reduced penetrance. A 2022 meta-analysis of 33 studies estimated a pooled global prevalence of 4.88 per 100,000 and a pooled incidence of 0.48 cases per 100,000 person-years. In the US, a commercial claims analysis of over 67 million enrollees reported an age-adjusted diagnostic frequency of 6.52 per 100,000 persons, and the Huntington's Disease Society of America estimates approximately 41,000 symptomatic Americans and more than 200,000 at risk of inheriting the disease.

Mean age of onset is approximately 45 years, and median survival after onset is 15 to 18 years. In 878 individuals with known ages at motor onset and death, median disease duration was 15 years. In a UK primary care cohort, median survival from first recorded diagnosis was 12.4 years, and risk of death was 4.51 times that of matched controls. Among 147 brain bank records that listed a cause of death, pneumonia was recorded in 81 (55%). In a Norwegian registry, suicide accounted for 2.3% of deaths in people with the disease compared with 1.3% in the general population.

Morbidity spans motor, cognitive, and psychiatric domains. Neuropsychiatric symptoms were present in 98% of 52 participants in one cohort, and suicidal ideation was endorsed by 169 of 2,106 mutation carriers (8.0%) at baseline in the European REGISTRY study. Falls were reported by 27 of 45 participants (60%) with early to midstage disease, and 228 of 3,070 participants (7.4%) with clinically definite disease in a US database resided in skilled nursing facilities. Late-stage disease is characterized by total dependence, mutism, and incontinence.