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- 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
- 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
- Juvenile form (Westphal variant), 6–8% of cases
- 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
- Predominant age: onset typically 30 to 50 years but can occur at any age
- Predominant sex: male = female
- 1.8 to 4.7 per million per year
- 6–8% of cases are sporadic.
- 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.
- 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
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)