What is the pathophysiology of Huntington's disease?

Pathophysiology of Huntington's Disease

Genetic Mechanism

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 produces an abnormally long polyglutamine tract that triggers protein misfolding, toxic aggregation, and selective neuronal death. 1

• The HTT gene spans approximately 170 kb, contains 67 exons, and encodes a 3,144-amino-acid huntingtin protein with a molecular weight of ~350 kDa. 2
• Normal alleles typically contain 17–19 CAG repeats and are never associated with disease. 2, 1
• Alleles with ≥40 repeats demonstrate full penetrance and 100% diagnostic specificity, accounting for >99% of HD cases. 2, 1
• The mutation follows autosomal-dominant inheritance with meiotic instability, particularly during paternal transmission, where intermediate alleles (27–35 repeats) carry a 6–10% risk of expanding to pathogenic length. 2, 1

Molecular Pathogenesis: Toxic Gain-of-Function

The expanded polyglutamine tract causes the mutant huntingtin protein to misfold and adopt abnormal conformations, initiating a toxic gain-of-function mechanism that drives neurodegeneration. 2

Protein Misfolding and Aggregation

• The abnormal polyQ stretch induces structural alterations in the huntingtin protein, leading to protein misfolding that cannot be cleared by cellular degradation systems (lysosomes and ubiquitin-proteasome system). 2
• Proteolytic cleavage generates N-terminal fragments containing the polyglutamine expansion that are especially prone to aggregation. 1
• These misfolded proteins and fragments accumulate as intranuclear inclusions in neurons, forming deposits that aberrantly interact with other proteins and disrupt their normal functions. 2

Cellular Dysfunction Cascade

The protein aggregates disrupt multiple critical cellular processes, ultimately resulting in neuronal damage and death. 2

• Proteostasis disruption: Impaired protein quality control and degradation pathways. 2
• Nuclear pore complex dysfunction: Altered nucleocytoplasmic transport. 2
• Transcriptional dysregulation: Abnormal gene expression patterns. 2
• Mitochondrial dysfunction: Impaired energy production and increased reactive oxygen species. 2
• Axonal transport defects: Disrupted intracellular trafficking. 2
• Synaptic signaling abnormalities: Impaired neurotransmission. 2
• Altered post-translational modifications: Abnormal protein processing affecting function and degradation. 2, 1

Selective Neurodegeneration Pattern

Despite ubiquitous expression of mutant huntingtin throughout neural and non-neural tissue, neurodegeneration is highly selective for the caudate nucleus and putamen (striatum), which are the primary sites of neuronal loss. 2, 1, 3

• The mechanism underlying this regional selectivity remains incompletely understood, as the mutant protein is expressed throughout the brain and body during the entire lifetime. 3
• Other regions including basal ganglia, hypothalamus, cortex, and brain stem are also involved but to a lesser degree. 2

Clinical Manifestations Linked to Pathology

Striatal degeneration produces the characteristic triad of motor, cognitive, and psychiatric symptoms through disruption of basal ganglia-cortical circuits. 1, 3

Motor Symptoms

• Choreic (involuntary) movements result from striatal degeneration disrupting motor-control circuits. 1

Cognitive Decline

• Progressive loss of neurons in basal ganglia and their cortical connections underlies cognitive deterioration. 1

Psychiatric Manifestations

• Involvement of limbic and cortical networks leads to behavioral changes and affective symptoms. 1

Disease Course

• The disease produces a devastating progression over 15–20 years with no effective disease-modifying treatment currently available. 3, 4

Common Pitfalls

• Do not confuse intermediate alleles (27–35 repeats) with disease-causing alleles: These do not cause disease in carriers but carry transmission risk, particularly with paternal inheritance. 2, 1
• Recognize that reduced penetrance alleles (36–39 repeats) have variable clinical expression: Not all carriers will develop symptoms, though the alleles are meiotically unstable. 2, 1
• Understand that HD is not an immune-mediated disease: Immunosuppressive therapies have no role in management, as the pathology results from direct neurotoxicity of the mutant protein. 1