Huntington’s Disease

Overview – Huntington’s Disease

Huntington’s disease is a progressive, autosomal dominant neurodegenerative disorder caused by excessive CAG trinucleotide repeats in the Huntington gene. It leads to a toxic gain-of-function mutation in the huntingtin protein, primarily affecting the basal ganglia and cortex. The classic clinical triad includes dementia, depression, and chorea. This condition is fatal, with no cure, and has complete penetrance when pathogenic repeat thresholds are reached.

Definition

• Huntington’s disease is a genetic disorder resulting in progressive neurodegeneration, particularly of the basal ganglia and cortical structures.
• Caused by a CAG repeat expansion in the Huntington (HTT) gene on chromosome 4.

Aetiology

• Inherited in an autosomal dominant pattern.
• Caused by a gain-of-function mutation in the HTT gene, which encodes the huntingtin protein.
  • The huntingtin protein is essential for normal neuronal function, especially in the brain.
• Characterised by expanded CAG (glutamine) repeats:
  • Normal: 10–26 repeats
  • Intermediate: 27–35 (asymptomatic, but can expand in offspring due to slippage)
  • Pathogenic: 36–121 repeats
• Anticipation: Repeat number may increase in successive generations, leading to earlier onset.

Pathogenesis

• Excessive CAG repeats → mutant huntingtin protein production in the brain.
• This protein leads to:
  • Neuronal dysfunction and accelerated decay, especially in:
    • Basal ganglia (caudate, putamen, globus pallidus, substantia nigra)
    • Cerebral cortex
• Results in a combination of movement disorder, cognitive decline, and psychiatric symptoms.

Morphology

Macroscopic Changes

• Marked atrophy of basal ganglia, especially the striatum.
• Cortical atrophy also present.
• Lateral ventricular dilation due to compensatory hydrocephalus.

Clinical Features

Classic Huntington’s Triad

• Dementia: Progressive intellectual decline.
• Depression: Often precedes motor signs.
• Chorea: Involuntary jerking movements → unsteady gait.

Additional Features

• Onset usually in the fourth decade (age ~40).
  • More CAG repeats → earlier onset and more rapid progression.
• Late-stage features:
  • Slurred speech
  • Dysphagia (difficulty swallowing)

Treatment

• No cure available.
• Symptomatic relief:
  • Tetrabenazine: Reduces chorea.
  • Neuroleptics and benzodiazepines: May improve movement and mood symptoms.
• Supportive care is critical: speech therapy, nutrition, and psychiatric support.

Prognosis

• Life expectancy: ~15–20 years after symptom onset.
• Progressive loss of function → death typically from complications such as aspiration pneumonia or infections.

Genetic Transmission and Penetrance

• 50% inheritance risk for children of an affected parent.
• Penetrance is complete: if pathogenic repeat threshold is met, disease will occur.
• Age of onset inversely correlates with repeat number:
  • Higher repeats → earlier onset
• However, symptom severity post-onset is typically consistent regardless of repeat count.

Summary – Huntington’s Disease

Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the huntingtin gene, leading to progressive degeneration of the basal ganglia and cortex. The condition presents with a triad of dementia, depression, and chorea, and has 100% penetrance once the pathogenic repeat threshold is reached. For a broader context, see our Genetics & Cancer Overview page.