GENETIC POLYMORPHISMS ADJACENT TO THE CAG REPEAT INFLUENCE CLINICAL-FEATURES AT ONSET IN HUNTINGTONS-DISEASE

Objectives-To evaluate possible influences of CCG and Delta 2642 gluta mic acid polymorphisms adjacent to the (CAG)n trinucleotide repeat in Huntington's disease gene IT15 on some clinical features (age and symp toms) at onset. Methods-84 patients and a control group of 68 unaffect ed relatives were studied. Patients all belonged to a group of affecte d persons tested for molecular confirmation of Huntington's disease. T he length of the CAG repeat sequence in the IT15 gene and the adjacent CCG and Delta 2642 polymorphisms were determined by quantitative poly merase chain reaction. Results-Two intragenic polymorphisms were studi ed: (CCG)n and Delta 2642 glutamic acid. Patients were classified firs tly according to the size of the CCG rich segment adjacent to the CAG repeat into genotype groups CCG 7/7, 7/8, 7/9, 7/10, and 10/10 and the n according to Delta 2642 polymorphism into genotype groups AIA (absen ce of the Delta 2642 deletion), A/B, and B/B (presence of the Delta 26 32 deletion in respectively one and two alleles). The presence of Delt a 2642 mutation was associated with a significant decrease in age at o nset, although there was no significant increase in CAG size. A good c orrelation was found between the (CAG), trinucleotide repeat size and the age at onset in patients with genotype AA (r(2)=0.72). Within pati ents of the A/B genotype group however, a significant correlation was found but with a drop of the r(2) value to 0.44. No association was fo und between age at onset and the CCG polymorphism. Although an increas ed percentage of patients within the AIA genotype group had a neurolog ical onset, we found no overall significant association between CCG or Delta 2642 polymorphisms and the nature of symptoms at onset. Conclus ions-The Delta 2642 glutamic acid polymorphism did not affect CAG repe at size nor the nature of symptoms at onset but seems to influence the age at onset in patients with Huntington's disease.