Huntington Disease (HD) is a progressive, hereditary, neurodegenerative disorder.

Epidemiology

• Incidence - 1/15,000 in Western Europe
• Age - onset usually between 35-45 years

Inheritance

• Autosomal dominant
• Greater than 99% of cases result from an expanded number of CAG repeats in exon 1 of the Huntington gene (HD)
• The encoded protein, huntingtin, is expressed in neural and non-neural tissues; the mutant protein is suspected to cause neuronal loss in the caudate and putamen
• Allele sizes are classified by the number of CAG repeats
  • Normal
    • less than or equasl to26 CAG repeats
    • Not at risk for developing or transmitting HD
  • Mutable normal
    • 27-35 CAG repeats
    • Unaffected, but males have 2.5% risk for CAG expansion in offspring to disease-causing range
    • Approximately 1-2% of the general population carry an allele of this size
  • Reduced penetrance
    • 36-39 CAG repeats
    • At risk for developing symptoms of HD
    • Offspring also at risk for HD
  • Full penetrance
    • greater than or equal to 40 CAG repeats
    • Disease causing
    • Offspring at 50% risk for developing HD
• Longer CAG repeat lengths are associated with earlier disease onset; however, it is not possible to predict the specific age of onset, severity, symptoms, and rate of disease progression from CAG repeat length
• Most individuals with HD have an affected parent; apparent de novo cases may be explained by the death of a parent before symptom onset, unrecognized diagnosis in family, intermediate or reduced penetrance allele resulting in absent or late-onset symptoms in a parent, or nonpaternity
• Allele sizes may increase during paternal transmission (anticipation) resulting in earlier age of onset in an affected male's offspring

Clinical Presentation

• Motor symptoms
  • Tremor
  • Chorea/choreoathetosis
  • Slow ocular saccades
• Cognitive symptoms
  • Cognitive speed impaired initially (executive function)
  • Mood disorders
  • Suicidal ideation
  • Dementia
• Relentless progression of disease with death 15-20 years after onset
• Juvenile onset symptoms (before 21 years in 5% of patients)
  • Clumsiness
  • Hyperreflexia
  • Occulomotor disturbances
  • Physical instability
  • Rigidity
  • Mental deterioration
  • Epilepsy
  • Rapid decline

Diagnosis

• Presence of an expanded HD allele and compatible clinical presentation

Differential Diagnosis

• Neuroacanthocytosis
• Slow virus prion disease
• Sydenham’s chorea
• Tardive dyskinesias