What is the pathophysiology of Huntington's disease?

Pathophysiology of Huntington's Disease

Huntington's disease is caused by an expanded CAG trinucleotide repeat (≥40 repeats) in exon 1 of the HTT gene on chromosome 4p16.3, which translates into an abnormally long polyglutamine tract in the huntingtin protein, leading to protein misfolding, toxic aggregation, and selective neuronal death primarily in the caudate nucleus and putamen. 1, 2

Genetic Mechanism

• The HTT gene spans 170 kb with 67 exons, encoding a 3,144 amino acid huntingtin protein (350 kDa) that normally functions as a housekeeping protein. 1
• The polymorphic CAG repeat in exon 1 becomes pathogenic when expanded beyond normal limits (normal alleles contain 17-19 repeats most commonly, with ≤26 repeats never associated with disease). 1
• Alleles with ≥40 CAG repeats show full penetrance and 100% specificity for disease, while 36-39 repeats show reduced penetrance with variable clinical expression. 1, 2
• The mutation follows autosomal dominant inheritance, with the abnormal allele being meiotically unstable and capable of further expansion during transmission (particularly through paternal inheritance). 1

Molecular Pathogenesis

The expanded CAG repeat creates a toxic gain-of-function through multiple interconnected mechanisms: 2, 3

Protein Misfolding and Aggregation

• The expanded polyglutamine tract causes the mutant huntingtin protein to misfold and form abnormal conformations. 1, 3
• The large huntingtin protein undergoes proteolytic cleavage to produce shorter N-terminal fragments containing the polyglutamine expansion, which are particularly prone to aggregation. 3, 4
• These misfolded fragments accumulate and form intranuclear inclusions and aggregates in neuronal nuclei and processes, which have been identified in HD patient brains. 1, 3

Cellular Toxicity Mechanisms

Neurotoxicity results from the mutant protein in multiple forms—soluble misfolded protein, protein aggregates, and/or the active process of aggregation itself—through direct neurotoxicity rather than immune-mediated damage. 2, 3

The pathogenic cascade involves:

• Caspase activation leading to apoptotic cell death pathways. 3
• Dysregulation of transcriptional pathways affecting gene expression critical for neuronal survival. 3, 4
• Increased production of reactive oxygen species causing oxidative stress and cellular damage. 3
• Inhibition of proteasome activity, impairing the cell's ability to clear misfolded proteins. 3
• Altered post-translational modifications of the huntingtin protein affecting its function and degradation. 1

Selective Neurodegeneration Pattern

Despite widespread expression of mutant huntingtin in both neural and non-neural tissues throughout the body, there is highly selective, region-specific neuronal loss predominantly affecting the caudate nucleus and putamen (striatum). 1

• This selective vulnerability remains incompletely understood but involves both cell-autonomous mechanisms (intrinsic to affected neurons) and cell-cell interaction mechanisms. 4
• The disease produces progressive neurodegeneration over 15-20 years from symptom onset. 2
• Neurodegeneration begins many years before diagnosable clinical signs appear, with subtle prodromal changes in cognition, motor function, and psychiatric status. 4

Clinical Correlation

The pathological changes result in:

• Choreic movements from striatal degeneration affecting motor control circuits. 1
• Cognitive decline from progressive neuronal loss in basal ganglia and cortical connections. 1
• Psychiatric manifestations including behavioral changes and affective symptoms. 1, 5
• Juvenile-onset HD (before age 20) presents with rigidity, spasticity, and rapid intellectual decline, occurring in approximately 5% of cases. 1

Important Caveats

• The CAG repeat expansion accounts for >99% of HD cases, making genetic testing highly sensitive and specific for diagnosis. 1, 2
• Alleles in the 27-35 CAG repeat range (mutable normal/intermediate alleles) are not associated with disease phenotype but carry 6-10% risk of expanding to pathogenic range when paternally transmitted, particularly at the upper end (35 repeats). 1
• The disease mechanism is purely neurodegenerative without immune system involvement, meaning immunosuppressive therapies have no role in management. 2