Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood. Symptoms are believed to result from altered neuronal communication in the basal ganglia. This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease. Almost all cases of early-onset dystonia have a unique 3-bp deletion that appears to have arisen idependently in different ethnic populations. This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA. This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases.

We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (> 90%) of early-onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.

Diagnostic DYT1 testing in conjunction with genetic counseling is recommended for patients with PTD with onset before age 26 years, as this single criterion detected 100% of clinically ascertained carriers, with specificities of 43% to 63%. Testing patients with onset after age 26 years also may be warranted in those having an affected relative with early onset, as the only carriers we observed with onset at age 26 or later were genetically ascertained relatives of individuals whose symptoms started before age 26 years.

A gene (DYT1) for idiopathic torsion dystonia maps to chromosome 9q34 in Ashkenazi Jewish families with early onset of symptoms. Further, there 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 Jews is due to a founder mutation in DYT1. To characterize the phenotypic range of this mutation, we studied 174 Ashkenazi Jewish individuals affected with idiopathic torsion dystonia. We used GT(n) markers on chromosome 9q34 (D9S62, D9S63, and ASS) and classified individuals as having ("carriers"), not having ("noncarriers"), or being ambiguous with respect to a DYT1-associated haplotype. We assessed clinical features and found marked clinical differences between haplotype carriers and noncarriers. There were 90 carriers, 70 noncarriers, and 14 ambiguous individuals. The mean age at onset of symptoms was significantly lower in carriers than in noncarriers (12.5 +/- 8.2 vs 36.5 +/- 16.4 years). 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 of onset in 79% of noncarriers; onset in the arms occurred in 21% and onset in the legs never occurred. Limb onset, leg involvement in the course of disease, and age at onset distinguished haplotype carriers from noncarriers with 90% accuracy. In conclusion, there are clinical differences between Ashkenazi Jewish individuals with idiopathic torsion dystonia who do or do not have a unique DYT1 mutation, as determined by a DYT1-associated haplotype of 9q34 alleles.(ABSTRACT TRUNCATED AT 250 WORDS)

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