Huntington Disease

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Basics

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)

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