Description

• Inherited neurodegenerative disease characterized by progressive motor and psychiatric dysfunction, dementia, and ultimately death
  • Onset of symptoms typically occurs between 30 and 50 years.
  • By the time of diagnosis, patients have often passed the disease to another generation.
• Currently incurable
• Adult (most common) and juvenile forms exist.
• System(s) affected: nervous
• Synonym(s): Huntington chorea; chronic progressive hereditary chorea

Geriatric Considerations

• Significant morbidity with early mortality
• Typical life expectancy is 15 to 25 years after symptom onset.
• Affects individuals of all ages
• High risk of suicide, with greatest risk corresponding to loss of function

Pediatric Considerations

• Juvenile form (Westphal variant), 6–8% of cases
• Characteristics:
  • Onset prior to age 21 years
  • Usually a hypokinetic disorder with parkinsonian features
  • Rapid progression
  • Trinucleotide cytosine-adenine-guanine (CAG) repeat expansion
  • Length of repeat is inversely associated with, but is not an accurate predictor of, age of onset.
  • Typically, 100% penetrance
  • Autosomal dominant, juvenile form is typically paternally inherited; otherwise, equal paternal and maternal inheritance pattern

Epidemiology

• Predominant age: onset typically 30 to 50 years but can occur at any age
• Predominant sex: male = female

Incidence

• 1.8 to 4.7 per million per year
• 6–8% of cases are sporadic.

Prevalence

• Estimates range from 4 to 10/100,000 in North America.
• Estimates variable internationally due to populations expressing founder effect, notably certain regions of Venezuela, Scotland, and Tasmania
• Rare in Norway, Finland, and Japan
• Mean onset of motor symptoms among African Americans is 36 years and 42 years in whites.

Etiology and Pathophysiology

Associated with a CAG trinucleotide repeat expansion of the huntingtin gene (HTT) on the short arm of chromosome 4 (4p16.3) causing a toxic gain-of-function mutation

• The gene encodes the protein huntingtin, which plays a role in neural development and neurodegeneration and is conserved across species. Pathologically, it becomes cross-linked and accumulates, producing neuronal intranuclear inclusions.
• RAS homologue enriched in striatum (Rhes) may be involved in the pathogenesis and neuronal toxicity by binding to abnormal huntingtin, but its role in Huntington disease (HD) remains controversial.

Genetics

• Autosomal dominant inheritance
• Expansion of CAG trinucleotide repeats in the HD (HTT/IT15) gene on chromosome 4p16.3.
  • >40 show complete penetrance.
  • 36 to 39 show reduced penetrance.
  • 29 to 35 unstable range with possible expansion in future generations
• Paternal transmission shows greater expansion and stronger anticipation.
• Repeat length inversely correlated with age of onset but has not been consistently associated with disease progression

Risk Factors

Family history

General Prevention

Genetic pre- and postcounseling, as well as complete psychiatric and neurologic evaluations, are recommended for asymptomatic individuals at risk for inheritance.

Commonly Associated Conditions

Similar diseases include the following:

• Huntington disease–like 1 (HDL-1): chromosome 20, prion disease
• Huntington disease–like 2 (HDL-2): chromosome 16, also CAG repeat; junctophilin 3 gene
• Huntington disease–like 3 (HDL-3): chromosome 4, autosomal recessive, single family reported
• Huntington disease–like 4 (HDL-4): also known as spinocerebellar-ataxia type 17 (SCA17)