Huntington Disease - HD

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Diagnostic confirmation in symptomatic individual (eg, chorea, cognitive defects, tremor)
  • Presymptomatic testing for adults with a family history of Huntington disease (HD)

Laboratory Testing

  • DNA testing of asymptomatic individuals should also involve neurological and psychological examination in addition to genetic counseling and proper informed consent

Differential Diagnosis

Huntington disease (HD) is a progressive, hereditary, neurodegenerative disorder.

Epidemiology

  • Incidence – 1/15,000 in Western Europe
    • Much lower prevalence in Japan
  • Age – typically onset is 35-44 years
    • Juvenile onset (<21 years) –  ~5% of cases

Inheritance

  • Autosomal dominant
  • >99% of cases result from an expanded number of cytosine-adenine-guanine (CAG) repeats in exon 1 of the Huntington gene (HD)
  • Encoded protein, huntingtin – expressed in neural and non-neural tissues
    • Mutant protein – suspected to cause neuronal loss in selective areas of the cortex, striatum and extrastriatal structures
  • Allele sizes are classified by the number of CAG repeats
    • Normal
      • ≤26 CAG repeats
      • Not at risk for developing or transmitting HD
    • Mutable normal
      • 27-35 CAG repeats
      • Unaffected; males have 2.5% risk for CAG expansion in offspring to disease-causing range
      • ~1-2% of the general population carry an allele of this size
    • Reduced penetrance
      • 36-39 CAG repeats
      • At risk for developing symptoms of HD
      • Offspring also at risk for HD
    • Full penetrance
      • ≥40 CAG repeats
      • Disease causing
      • Offspring at 50% risk for developing HD
  • Higher numbers of CAG repeat lengths are associated with earlier disease onset
    • Not possible to predict the specific age of onset, severity, symptoms, and rate of disease progression from number of CAG repeats
  • Most individuals with HD have an affected parent
    • Apparent de novo cases may be explained by the death of a parent before symptom onset, unrecognized diagnosis in family, intermediate or reduced penetrance allele resulting in absent or late-onset symptoms in a parent, or non-paternity
  • Allele sizes may increase during paternal transmission (genetic anticipation) – results in earlier onset in the offspring of an affected male

Clinical Presentation

  • Progressive neurodegenerative disorder
    • Motor symptoms
      • Tremor
      • Chorea/choreoathetosis
      • Slow ocular saccades
      • Akinesia, bradykinesia
      • Dystonia
    • Cognitive symptoms
      • Cognitive speed impaired first (executive function)
      • Mood disorders
      • Suicidal ideation
      • Dementia
    • Relentless progression of disease with death 15-20 years after onset
    • Successive generations tend to have earlier onset
  • Juvenile onset symptoms
    • Clumsiness
    • Hyperreflexia
    • Occulomotor disturbances
    • Physical instability/falls
    • Rigidity
    • Mental deterioration
    • Seizure disorder
    • Rapid decline
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Huntington Disease (HD) Mutation by PCR 0040018
Method: Polymerase Chain Reaction/Fragment Analysis

Limitations 

Test is NOT performed on minors <18 years 

Prenatal testing is NOT performed

HD mutations other than cytosine-adenine-guanine (CAG) expansions are not detected

Neurodegenerative conditions unrelated to HD are not detected

Follow-up 

If only one allele is detected by PCR, Southern blot is performed to determine if there is a second allele with an expanded CAG repeat

General References

Gövert F, Schneider SA. Huntington's disease and Huntington's disease-like syndromes: an overview. Curr Opin Neurol. 2013; 26(4): 420-7. PubMed

Huntington's Disease Society of America (HDSA). [Accessed: Nov 2015]

Imarisio S, Carmichael J, Korolchuk V, Chen C, Saiki S, Rose C, Krishna G, Davies JE, Ttofi E, Underwood BR, Rubinsztein DC. Huntington's disease: from pathology and genetics to potential therapies. Biochem J. 2008; 412(2): 191-209. PubMed

Novak MJ U, Tabrizi SJ. Huntington's disease: clinical presentation and treatment. Int Rev Neurobiol. 2011; 98: 297-323. PubMed

Roos RA C. Huntington's disease: a clinical review. Orphanet J Rare Dis. 2010; 5: 40. PubMed

Shannon KM. Huntington's disease - clinical signs, symptoms, presymptomatic diagnosis, and diagnosis. Handb Clin Neurol. 2011; 100: 3-13. PubMed

Tibben A. Predictive testing for Huntington's disease. Brain Res Bull. 2007; 72(2-3): 165-71. PubMed

Walker FO. Huntington's disease. Lancet. 2007; 369(9557): 218-28. PubMed

Medical Reviewers

Last Update: August 2016