Huntington’s Disease

Pathophysiology

Huntington’s Disease (HD) is a genetic neurodegenerative disorder. It is caused by a CAG triplet expansion repeat in the huntingtin gene. The number of repeats determines the phenotype:

Number of CAG repeats Phenotype
< 29 Normal
29 – 35 Unstable: not pathogenic, may expand
36 – 39 Reduced penetrance
>39 100% penetrance

HD is inherited as an autosomal dominant trait. The penetrance depends on the number of CAG repeats as shown in the table above. HD demonstrates anticipation – the number of repeats usually expands with each generation, leading to earlier and more severe disease in each subsequent generation. The number of CAG repeats is more likely to increase with paternal rather than maternal inheritance.

Mutant huntingtin leads to progressive degeneration of the striatal medium spiny neurons, loss of corticostriatal connections, and generalised cortical atrophy. How precisely the mutant protein leads to neuronal death is not known.

Epidemiology

Prevalence: 3 / 100 000

Age of onset: variable. Usually 30s – 40s. Juvenile-onset (Westphal variant) has a poor prognosis. Elderly-onset has a good prognosis.

Classic presenting complaint

Progressive personality change, behavioural abnormalities, depression, cognitive impairment, and movement disorders (most commonly chorea).

Symptoms

The symptoms of HD can be grouped into motor, psychiatric, and other features.

Motor

  • Chorea
  • Parkinsonism
  • Dystonia
  • Oculomotor abnormalities:
    • slowing of saccades

Neuropsychiatric

  • Cognitive impairment
  • Mood disorders:
    • Depression
    • Anxiety disorders
  • Personality change
  • Psychosis

Other

  • Weight loss

On examination

  • On inspection
    • Walking aids
    • Chorea
    • Other hyperkinesias
  • Eyes
    • Impairment of voluntary saccades
    • Loss of smooth pursuit
  • Arms & legs

Diagnosis

The definitive diagnostic test is genetic sequencing of the huntingtin gene to assess CAG repeat number.

Treatment

There is no disease-modifying therapy to slow the progression of HD. Management is therefore primarily supportive. Drug treatments can be used for symptomatic relief. Atypical antipsychotics are particularly useful because of their dual effects on chorea and psychosis.

  • Chorea:
    • Atypical antipsychotics
    • Tetrabenazine
    • Amantadine
  • Depression:
    • SSRIs
    • Tricyclics
  • Psychosis:
    • Atypical antipsychotics