Huntington's Disease

Overview

Huntington's disease (HD) is an inherited, progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, which makes a protein called huntingtin. It causes a slow triad of motor symptoms (chorea first, then bradykinesia and dystonia later), cognitive changes, and psychiatric symptoms, typically starting in mid-adulthood and leading over years to severe disability.

Impact

HD reaches deep into families, with a 50% inheritance risk per child, decades of anticipatory anxiety, and hard decisions about predictive testing, having kids, and end-of-life care. The gradual loss of independence, personality shifts, psychiatric symptoms, and eventual need for full-time care creates a massive caregiver load with well-documented mental health effects across generations.

Medical Overview

HD is caused by expansions of 36 or more CAG repeats in exon 1 of HTT, which makes a faulty huntingtin protein that drives a toxic gain-of-function through things like transcriptional dysregulation, mitochondrial dysfunction, failure of protein quality control, excitotoxicity, and neuroinflammation, with the medium spiny neurons in the striatum being especially vulnerable. Early presentation often includes subtle motor, cognitive, and behavioral changes before obvious chorea shows up. Age of onset tends to run younger with longer repeat lengths, and modifier genes can shift things too. Diagnosis is clinical and confirmed by HTT CAG-repeat genetic testing, and predictive testing in at-risk relatives follows established genetic counseling protocols. There's no disease-modifying therapy approved yet, so current care focuses on treating chorea (with tetrabenazine, deutetrabenazine, or valbenazine), depression, obsessive-compulsive symptoms, and psychosis, alongside physical, occupational, speech, and swallowing therapy. Multiple huntingtin-lowering strategies are in clinical development, including antisense oligonucleotides, RNA interference, splicing modulators, and CAG-repeat-targeting small molecules.

References

1. Jiang A, et al.. From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington's Disease Research . International Journal of Molecular Sciences . 2023.
2. Saade J, et al.. Huntington's Disease: Latest Frontiers in Therapeutics . Current Neurology and Neuroscience Reports . 2024.