Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the HTT gene, resulting in a mutant [huntingtin protein](/proteins/huntingtin) (mHTT) with toxic gain-of-function. The disease manifests with progressive motor, cognitive, and psychiatric symptoms, typically onsetting in middle age. HD affects approximately 5-10 per 100,000 people worldwide, with higher prevalence in populations of European ancestry.
Overview
Huntington's disease is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene on chromosome 4p16.3[@the1993]. The mutation results in an expanded polyglutamine tract in the huntingtin protein, leading to toxic gain-of-function that disrupts neuronal function and survival. The disease is characterized by progressive motor, cognitive, and psychiatric disturbances, with an insidious onset typically in the third to fifth decade of life. Neuropathologically, HD is characterized by selective degeneration of striatal GABAergic medium spiny [neurons](/entities/neurons) and cortical pyramidal neurons, with prominent atrophy of the caudate nucleus and putamen[@vonsattel2011].
Epidemiology
...
Huntington Disease
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the HTT gene, resulting in a mutant [huntingtin protein](/proteins/huntingtin) (mHTT) with toxic gain-of-function. The disease manifests with progressive motor, cognitive, and psychiatric symptoms, typically onsetting in middle age. HD affects approximately 5-10 per 100,000 people worldwide, with higher prevalence in populations of European ancestry.
Overview
Huntington's disease is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene on chromosome 4p16.3[@the1993]. The mutation results in an expanded polyglutamine tract in the huntingtin protein, leading to toxic gain-of-function that disrupts neuronal function and survival. The disease is characterized by progressive motor, cognitive, and psychiatric disturbances, with an insidious onset typically in the third to fifth decade of life. Neuropathologically, HD is characterized by selective degeneration of striatal GABAergic medium spiny [neurons](/entities/neurons) and cortical pyramidal neurons, with prominent atrophy of the caudate nucleus and putamen[@vonsattel2011].
Epidemiology
Prevalence: Approximately 5-10 per 100,000 people worldwide
Population: Higher prevalence in populations of European ancestry (5-10/100,000) compared to Asian populations (0.5-1/100,000)
Age of Onset: Typically 30-50 years, but can present at any age
Sex: Equal prevalence in males and females
Disease Duration: 15-20 years from onset to death
Genetics
Causative Gene
HTT (Huntingtin): Located on chromosome 4p16.3; CAG repeat expansion causes HD[@the1993]
Normal: < 26 CAG repeats
Intermediate (reduced penetrance): 27-35 repeats
Full penetrance: ≥ 36 repeats
Juvenile onset (Westphal variant): > 60 repeats, usually paternal inheritance
Genetic Modifiers
CAG Repeat Length: Strong inverse correlation between repeat length and age of onset[@gusella2023]
DNA Repair Genes: MSH3, FAN1, and other DNA repair pathway genes modify age of onset[@hong2023]
HTT haplotypes: Different haplotypes affect disease progression
Pathophysiology
Mutant Huntingtin Toxicity
The mutant huntingtin protein (mHTT) acquires toxic functions through:[@ross2014]
[Huntington's Disease Society of America](https://hdsa.org/)
[CHDI Foundation](https://chdifoundation.org/)
References
[The Huntington's Disease Collaborative Research Project, A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes (1993)](https://pubmed.ncbi.nlm.nih.gov/8351231/)
[Rawlins MD, et al, The prevalence of Huntington's disease (2016)](https://pubmed.ncbi.nlm.nih.gov/26876675/)
[Vonsattel JP, et al, Neuropathology of Huntington's disease (2011)](https://pubmed.ncbi.nlm.nih.gov/21311640/)
[Gusella JF, et al, Genetic modifiers of Huntington's disease (2023)](https://doi.org/10.1038/s41576-023-00619-2)
[Hong EP, et al, Genetic modifiers of Huntington's disease: from GWAS to sequencing (2023)](https://doi.org/10.1038/s41588-023-01507-5)
[Ross CA, et al, Huntington disease: molecular mechanisms of disease and therapeutic strategies (2014)](https://doi.org/10.1016/j.cell.2014.08.013)
[Huntington Study Group, A randomized, double-blind, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease (2001)](https://pubmed.ncbi.nlm.nih.gov/17210854/)
[Huntington Study Group, Unified Huntington's Disease Rating Scale: reliability and consistency (1996)](https://pubmed.ncbi.nlm.nih.gov/8559188/)
[Huntington Study Group, Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial (2006)](https://pubmed.ncbi.nlm.nih.gov/16476934/)
[Huntington Study Group, Deutetrabenazine for chorea in Huntington disease (2017)](https://doi.org/10.1056/NEJMoa1508489)
[Factor SM, et al, Valbenazine for the treatment of chorea in Huntington's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/31945179/)
[Tabrizi SJ, et al, Targeting huntingtin expression in patients with Huntington's disease (2019)](https://doi.org/10.1056/NEJMoa1900907)
[Weir DW, et al, Neurofilament light chain as a biomarker in Huntington's disease (2024)](https://doi.org/10.1038/s41582-024-00835-0)
[Zhang N, et al, Stem cell therapy for Huntington's disease: a mini-review (2017)](https://pubmed.ncbi.nlm.nih.gov/28986159/)
[Tabrizi SJ, et al, Huntingtin-lowering strategies for Huntington's disease (2023)](https://doi.org/10.1038/s41572-023-00468-5)
[Paulsen JS, Long JD, Cognitive decline in Huntington disease (2023)](https://doi.org/10.1038/s41582-023-00760-3)