DYSTONIA IN ASHKENAZI JEWS - CLINICAL CHARACTERIZATION OF A FOUNDER MUTATION

A gene (DYT1) for idiopathic torsion dystonia maps to chromosome 9q34 in Ashkenazi Jewish families with early onset of symptoms. Further, th ere is linkage disequilibrium between DYT1 and a particular haplotype of alleles at 9q34 loci in this population. This implies that a large proportion of early-onset idiopathic torsion dystonia in Ashkenazi Jew s is due to a founder mutation in DYT1. To characterize the phenotypic range of this mutation, we studied 174 Ashkenazi Jewish individuals a ffected with idiopathic torsion dystonia. We used GT(n) markers on chr omosome 9q34 (D9S62, D9S63, and ASS) and classified individuals as hav ing (''carriers''), not having (''noncarriers''), or being ambiguous w ith respect to a DYT1-associated haplotype. We assessed clinical featu res and found marked clinical differences between haplotype carriers a nd noncarriers. There were 90 carriers, 70 noncarriers, and 14 ambiguo us individuals. The mean age at onset of symptoms was significantly lo wer in carriers than in noncarriers (12.5 +/- 8.2 vs 36.5 +/- 16.4 yea rs). In 94% of carriers, symptoms began in a limb (arm or leg equally) ; rarely the disorder started in the neck (3.3%) or larynx (2.2%). In contrast, the neck, larynx, and other cranial muscles were the sites o f onset in 79% of noncarriers; onset in the arms occurred in 21% and o nset in the legs never occurred. Limb onset, leg involvement in the co urse of disease, and age at onset distinguished haplotype carriers fro m noncarriers with 90% accuracy. In conclusion, there are clinical dif ferences between Ashkenazi Jewish individuals with idiopathic torsion dystonia who do or do not have a unique DYT1 mutation, as determined b y a DYT1-associated haplotype of 9q34 alleles. These differences sugge st that early, limb-onset idiopathic torsion dystonia and late, cervic al cranial-onset idiopathic torsion dystonia are genetically distinct entities.