Huntington Disease

Indications for Testing

Family history of 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
- HD-approved testing centers can be identified through the Huntington Disease Society of America website
- Not recommended in asymptomatic minors
- Not for prenatal testing

Differential Diagnosis

Neuroacanthocytosis
Slow virus prion disease
Sydenham chorea
Tardive dyskinesias
Parkinson disease
Amyotrophic lateral sclerosis
Wilson disease
Drug induced (phenytoin, L-dopa, cocaine, oral contraceptives)
HIV/AIDS
Paraneoplastic syndrome
Thyrotoxicosis
Dentato-rubro-pallido-luysian atrophy

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

Tests generally appear in the order most useful for common clinical situations

Test name: Huntington Disease (HD) Mutation with Reflex to Southern Blot

ARUP #: 0040018

Methodology: Polymerase Chain Reaction/Fragment Analysis

Use:

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

Limitations:

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

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

Comprehensive Review: September 2011
Last Update: September 2011

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