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Genetic diagnosis of Huntingtons disease
How is genetic diagnosis of Huntingtons disease confirmed?
The Huntingtons disease gene (designated IT15 ) has been identified near the tip of the short arm of chromosome 4 (4p16.3).
An unstable expansion of the CAG repeat sequence is present at the 5´ end of this large (210 kb) gene.
The Huntingtons disease gene encodes a 348-kDa protein called huntingtin.
Aggregation of mutant huntingtin may be part of the pathogenesis of Huntingtons disease.
With 40 or more repeats, a person develops Huntingtons disease with 100% certainty, but with repeats of 36 to 39, there is incomplete penetrance.
The intermediate range, from 27 to 35 repeats, does not cause Huntingtons disease, with a few reported exceptions.
All alleles of 27 repeats and higher are unstable and prone to expand in future generations, particularly when transmitted by a male parent.
Huntingtons disease families also display “anticipation,” or progressively earlier onset of disease in successive generations, typically with increasing CAG repeat size.
Such findings allow genetic testing of at-risk individuals before the onset of symptoms.
However, until effective treatment is available for Huntingtons disease, many ethical and legal dilemmas associated with genetic testing remain to be solved.
Sources
- Paulsen JS, Long JD, Ross CA, et al; PREDICT-HD Investigators and Coordinators of the Huntington Study Group: Prediction of manifest Huntington’s disease with clinical and imaging measures: a prospective observational study. Lancet Neurol 13(12):1193-1201, 2014.
- Reilmann R, Leavitt BR, Ross CA: Diagnostic criteria for Huntington’s disease based on natural history. Mov Disord 29(11):1335-1341, 2014.
- Ross CA, Aylward EH, Wild EJ, Langbehn DR, Long JD, Warner JH, et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 10(4):204-216, 2014.
- Baizabal-Carvallo JF, Jankovic J: Movement disorders in autoimmune diseases. Mov Disord 27(8):935-946, 2012.
- Baizabal-Carvallo JF, Bonnet C, Jankovic J: Movement disorders in systemic lupus erythematosus and the antiphospholipid syndrome. J Neural Transm 120(11):1579-1589, 2013.
