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Huntington disease (HD) is a progressive, hereditary, neurodegenerative disorder that is characterized by abnormalities in motor skills, cognitive skills, and psychiatric changes. HD is typically diagnosed based on clinical symptoms, including the presence of chorea, and a family history of HD, and is confirmed by genetic testing. Although there is no known cure for HD, a diagnosis may enable treatment of some of the physical and psychiatric symptoms, which can be managed with pharmacologic therapy in the earlier stages of the disease. Additionally, at-risk family members of individuals with HD may choose to undergo predictive genetic testing after thorough genetic counseling.
Quick Answers for Clinicians
Huntington disease (HD) is caused by an expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats within the HTT gene. A higher number of CAG repeats is associated with an earlier age of onset. The age of symptom onset varies but is usually between 35 and 44 years, although juvenile HD presents earlier. Once HD manifests clinically, the median survival time is 15 to 18 years. However, the number of CAG repeats is not indicative of the duration of the illness or the rate of deterioration.
Individuals with intermediate alleles (27-35 cytosine-adenine-guanine [CAG] repeats) typically do not have symptoms of Huntington disease (HD). However, large expansions of the CAG repeat region can occur during sperm formation. Those with intermediate alleles are prone to this repeat instability and may have children with an HD-causing allele.
Asymptomatic individuals should be tested for Huntington disease (HD) only if they have a family history of the disease, and only after genetic counseling. Predictive genetic testing is discouraged for asymptomatic minors because a positive result could diminish their autonomy and cause anxiety with no meaningful benefit.
Indications for Testing
Testing for HD is indicated for individuals with symptoms of HD (eg, chorea, tremor, and other motor changes; cognitive decline; and emotional and behavioral changes) and for asymptomatic adults with a family history of HD.
Laboratory Testing
Although a diagnosis of HD is largely based on clinical symptoms, the gold standard for diagnosis is genetic testing.
Diagnostic genetic testing is indicated for individuals with or without a family history of HD after the onset of motor symptoms, particularly those severe enough to receive a score of 4 on the Unified Huntington’s Disease Rating Scale (UHDRS). Symptoms with a score of 4 are considered unequivocal signs of HD. Predictive genetic testing may be indicated for asymptomatic individuals with a family history of the disease.
Genetic Testing
Polymerase chain reaction (PCR) testing and size analysis for an expanded number of cytosine-adenine-guanine (CAG) trinucleotide repeats in the HTT gene may be performed for both symptomatic individuals and asymptomatic individuals with a family history of HD. The number of repeats determines the risk and likely age of onset for symptom development.
| Phenotype | Number of CAG Repeats | Clinical Significance |
|---|---|---|
| Normal alleles | ≤26 | n/a |
| Intermediate alleles | 27-35 | Not at risk for HD; instability of CAG repeat may lead to HD allele in offspring |
| HD allele with reduced penetrance | 36-39 | At risk for HD, but may not develop symptoms; instability of CAG repeat may lead to full-penetrance HD allele in offspring |
| HD allele with full penetrance | ≥40 | Increased certainty of developing HD, assuming normal life span |
|
n/a, not applicable |
||
ARUP Laboratory Tests
Polymerase Chain Reaction (PCR)/Fragment Analysis
References
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