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 (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.
Huntington's disease is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene on chromosome 4p16.3[1]. 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 and cortical pyramidal neurons, with prominent atrophy of the caudate nucleus and putamen[2].
The mutant huntingtin protein (mHTT) acquires toxic functions through:[5]
The striatum (caudate nucleus and putamen) is most vulnerable in HD:[2:1]
HTT Lowering: What is the optimal timing, delivery method, and target for huntingtin-lowering therapies?[14]
Mutation Effects: How does the CAG repeat length modify age of onset and rate of progression?[3:1]
Non-Motor Symptoms: What causes cognitive and psychiatric symptoms decades before chorea appears?[15]
Biomarkers: Are there reliable markers to track disease progression and treatment response?[12:1]
Genetic Modifiers: What genetic variants modify disease onset and progression?[4:1]
Therapeutic Targets: Beyond HTT, what downstream pathways offer intervention points?[5:1]
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