The Core Issue with Huntington's Disease
The fundamental problem in Huntington's disease is an expanded CAG trinucleotide repeat (≥40 repeats) in the HTT gene that produces a mutant huntingtin protein with an abnormally long polyglutamine stretch, causing direct neurotoxicity and progressive neuronal death, particularly in the caudate nucleus and putamen. 1
Genetic Mechanism
The disease is caused by expansion of a polymorphic CAG repeat in exon 1 of the HTT gene on chromosome 4, with full penetrance occurring at ≥40 repeats and variable penetrance at 36-39 repeats 1
This CAG expansion is inherited in an autosomal dominant manner, meaning a single copy of the mutated gene from either parent will cause disease 1
The expanded CAG repeat translates into an abnormally long polyglutamine (polyQ) stretch at the N-terminus of the huntingtin protein, which is the molecular basis for protein toxicity 2, 3
Pathophysiological Consequences
The mutant huntingtin protein (mHTT) causes direct neurotoxicity through abnormal protein processing and aggregation, leading to selective neuronal vulnerability and death 4, 3
Neuronal loss occurs most notably in the caudate nucleus and putamen (the striatum), though the mutant protein is expressed throughout the brain and body during the entire lifetime 1
This is NOT an autoimmune or immune-mediated disease—the pathology results from direct cellular toxicity from the mutant protein, not immune system involvement 4
Clinical Impact on Morbidity and Mortality
The disease produces a devastating triad of progressive motor dysfunction (choreic movements, rigidity), cognitive decline, and psychiatric disturbances over a 15-20 year course 1, 5, 2
There is currently no effective disease-modifying treatment—all available therapies are purely symptomatic 1, 4
The disease is uniformly fatal, with relentless progression once manifest symptoms appear 5, 2
Critical Pitfall to Understand
The disease begins many years before diagnosable symptoms appear—neurodegeneration and subtle prodromal changes in cognition, motor function, and behavior occur long before clinical diagnosis 3
Genetic testing with CAG repeat quantification provides 100% specificity for diagnosis when ≥40 repeats are present, making this a definitive molecular diagnosis rather than a clinical one 1, 4