Stability of the Huntington disease (CAG)n repeat in a late onset form occuring on the Island of Crete.

Huntington disease (HD) is an autosomal-dominant disorder of mid-life onset characterized by chorea, dementia, and oculomotor disturbances. Anticipation is commonly seen in HD families, particularly when the disease is inherited through the father. The disorder is associated with an expanded (CAG)n repeat in the IT15 gene that is unstable and tends to increase in size during meiotic transmissions, particularly of paternal origin. We have detected an unusual form of HD on the island of Crete which has distinctly different characteristics. Data from eight families encompassing 48 HD patients, showed a median age at onset 15-20 years later than that for HD occurring worldwide. There is no juvenile cases and no anticipation. DNA analysis in 12 HD patients showed expansion of the (CAG)n repeat the size of which was identical among members of each family or varied by only one unit. The elongated DNA segment was passed stably or contracted during both paternal and maternal transmissions thus indicating that unique molecular mechanisms may be operational in this form of HD.

Linkage disequilibrium between the expanded (CAG)n repeat and an allele of the adjacent (CCG)n repeat in Huntington's disease patients of Greek origin.

Huntington's disease (HD) is associated with an expanded unstable (CAG)n repeat in the IT15 gene. This repeat was investigated in 44 HD patients and 59 of their relatives at risk who were members of 29 unrelated families from various parts of Greece. Abnormal elongation of the (CAG)n repeat ranging from 39 to 95 trinucleotide units was found in all but one of the 44 HD patients tested with 70% of these patients showing 42-47 repeats. The size of the expanded sequence correlated inversely with the age at disease onset (r = 0.77, p < 0.00001, n = 43). In a single sporadic case, de novo expansion of the (CAG)n repeat was detected. Twenty-four of 59 asymptomatic family members at risk showed expansion of the (CAG)n repeat in the HD range (39-56 trinucleotide units) while three had intermediate alleles (36-37 repeats). Evaluation of the adjacent polymorphic (CCG)n repeat showed a strong linkage disequilibrium between the 7-unit (CCG)n repeat allele and the HD mutation, with 51% of normal and 93% of HD chromosomes showing this allele (chi 2 = 15.55, p < 0.0001, n - 260). These data on HD patients of Greek origin are consistent with the thesis that the (CAG)n expansion is the primary gene defect of the disease and that this mutation occurred primarily on chromosomes with the (CCG)7 repeat haplotype.