Huntington Disease - HD

Diagnosis

Indications for Testing

  • Family history of Huntington disease (HD)
  • Neurologic symptoms consistent with the disease
  • Laboratory test showing presence of an expanded HD allele
  • Neurological examination showing symptoms consistent with HD in individual with confirmed family history

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

Clinical Background

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

Epidemiology

  • Incidence – 1/15,000 in Western Europe
    • Much lower prevalence in Japan
  • Age – onset is usually 35-45 years

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)
  • The encoded protein, huntingtin, is expressed in neural and non-neural tissues; the mutant protein is suspected to cause neuronal loss in selective areas of the cortex, striatum and extra-striatal 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
  • Longer CAG repeat lengths are associated with earlier disease onset; however, it is not possible to predict the specific age of onset, severity, symptoms, and rate of disease progression from CAG repeat length
  • 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 (anticipation), resulting in earlier age of onset in the offspring of an affected male

Clinical Presentation

  • Motor symptoms
    • Tremor
    • Chorea/choreoathetosis
    • Slow ocular saccades
    • Akinesia, bradykinesia
    • Dystonia
  • Cognitive symptoms
    • Cognitive speed impaired initially (executive function)
    • Mood disorders
    • Suicidal ideation
    • Dementia
  • Relentless progression of disease with death 15-20 years after onset
  • Juvenile onset symptoms (<21 years in 5% of patients)
    • Clumsiness
    • Hyperreflexia
    • Occulomotor disturbances
    • Physical instability
    • Rigidity
    • Mental deterioration
    • Seizure disorder
    • Rapid decline

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Huntington Disease (HD) Mutation with Reflex to Southern Blot 0040018
Method: Polymerase Chain Reaction/Fragment Analysis

Confirm diagnosis in a symptomatic adult

Presymptomatic testing for adults with a family history of HD

99% clinical sensitivity and specificity

All samples must be accompanied by completed HD-specific informed consent

Test is NOT performed on minors <18 years 

Prenatal testing is NOT performed

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

Sizing by Southern blot is not precise, varying up to +/-15 repeats

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