Expansion of a (CAG)n repeat region in a sporadic case of HD

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Abstract
The genetic mutation underlying Huntington's disease (HD) has been identified as an expansion and instability of a specific CAG repeat sequence in a gene on chromosome 4. A simple polymerase chain reaction assay has been used for the assessment of the (CAG)n expansion in a 72-year-old woman with typical HD symptoms, but no family history of the disorder. The DNA analysis showed that the patient had an allele with 41 repeat units, in the size range seen in HD chromosomes. Therefore, HD diagnosis is confirmed in this seemingly sporadic case and the disease is newly diagnosed in a large family. The risk of inheriting this unstable expanded allele is discussed. INTRODUCTION--The discovery of an expansion of a trinucleotide (CAG) repeat region in the IT15 gene on the short arm of chromosome 4 has identified the mutational mechanism causing Huntington's disease (HD) and enables the direct diagnosis of affected subjects based on DNA analysis alone. Here a 72-year-old woman with typical HD symptoms, but no family history of the disorder, has been unambiguously diagnosed by using a quick DNA analysis. This is relevant because the disease is newly diagnosed in a large family. MATERIAL AND METHODS--A labelled polymerase chain reaction (PCR) test has been used to amplify the repeat region of the IT15 gene and DNA fragments were analyzed by Polyacrylamide gel electrophoresis. RESULTS--The number the CAG repeats in the proband displayed two alleles of 23 and 41 repeats, respectively. Since normal chromosomes are reported to contain 11-34 repeats, the clinical appearance of HD in the proband is explained by the presence of the repeat expansion. DISCUSSION--The parents of the proposita both died aged over 80 y apparently without neurological signs referable to HD. Hence, this is presumably a sporadic case of the disease. Because of the length of 41 repeats of this HD chromosome, offspring of this proband could inherit the expanded allele with 37 repeats, as expected for the reversal of the trinucleotide expansion. A subject with this intermediate allele could be affected, but would not be affected if the HD IT gene with reduced triplets had recovered its normal function. Thus, in a seemingly sporadic case like the one reported here, despite the PCR analysis, the risk of transmission of HD to her offspring may remain uncertain.