Diagnosis:
Triplet repeat expansion: Huntington’s disease
• Huntington disease (HD) is a progressive neurodegenerative disorder with midlife onset, characterized by involuntary choreic movements and psychiatric disorders. It affects about 1 in 10,000 individuals. The symptoms result from the selective loss of neurons in the caudate nucleus and putamen.
• A rapid progressive variant of HD, which presents with rigidity and intellectual decline before the age of 20 years, occurs in about 5% of affected patients.
• The HD gene is large (11 kb), contains 67 exons, and is on the short arm of chromosome 4 (4p16.3). The encoded protein, huntingtin (htt), consists of 3136 amino acid residues with a molecular weight of 350 kDa. The mutation associated with clinical manifestations of the disease is expansion of an unstable CAG repeat encoding a polyglutamine tract in the first exon of the htt gene.
• The range of repeat length in the unaffected population varies from 6 to 35 repeats.
• Normal alleles are defined as alleles with no more than 26 CAG repeats.
• Alleles with 27 to 35 repeats are defined as mutable normal. These alleles have not been convincingly associated with the HD phenotype, but they can be meiotically unstable in sperm, and pathologic expansion of the paternally derived allele in this size range has been described.
• HD alleles with reduced penetrance are defined as alleles with 36 to 39 CAG repeats.
• HD alleles with full penetrance are defined as alleles with at least 40 CAG repeats.
• CAG-repeat expansion mutations account for more than 99% of cases of HD. Therefore, tests that effectively detect and measure the CAG repeat in the htt gene have more than 99% sensitivity.
• With regard to specificity, the absence of HD pathology has not been documented in any individual with an HD allele size of at least 40 repeats who died, disease-free, after living up to or past the normal life expectancy. Therefore, positive results are 100% specific.
