Huntington Disease

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

What causes Huntington disease?

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. 

Can someone develop Huntington disease without a family history?

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. 

Should asymptomatic individuals be tested for Huntington disease?

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. 

Clinical Significance of CAG Trinucleotide Repeats
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

Source: Caron, 2018 

ARUP Lab Tests

Diagnostic confirmation of HD in a symptomatic individual

Predictive testing for adults with a family history of HD

Test Fact Sheet(s)

Medical Experts

Contributor

Best

Hunter Best, PhD, FACMG
Associate Professor of Clinical Pathology, University of Utah
Scientific Director, NGS and Biocomputing; Medical Director, Molecular Genetics and Genomics, ARUP Laboratories
Contributor

References

Additional Resources