No evidence of allelic heterogeneity in the DYT1 gene of European patients with early onset torsion dystonia.

EDITOR—Torsion dystonia is a movement disorder characterised by sustained involuntary muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. Primary torsion dystonia (PTD) occurs either in a familial or sporadic pattern with dystonia as the sole phenotypic manifestation with the exception that tremor can be present as well. Early onset, generalised torsion dystonia is the most severe form of hereditary dystonia, and the most prevalent form is the result of mutation in the DYT1 (TOR1A) gene on chromosome 9q34. Inheritance follows an autosomal dominant mode of transmission with reduced penetrance (30-40%), and there is a particularly high prevalence in Ashkenazi Jews (AJ) as a result of a founder eVect and genetic drift. Early onset primary dystonia resulting from DYT1 usually starts in an arm or a leg at a mean age of 12.5 years (this can range, however, from 4 to 44 years). More than 60-70% of cases have progression to generalised dystonia involving limb and axial muscles, but the cranial muscles are only involved in 11-18% of cases. The causative mutation has been identified as a 3 bp deletion (946delGAG) in the coding sequence of the DYT1 gene, resulting in loss of one of a pair of glutamic acid residues near the C-terminus of the encoded protein, torsinA. Presumably, deletion of this amino acid results in a critical change in the function of the gene product that leads to clinical signs of dystonia. Currently, this mutation is the only sequence change found to be associated with the disease state, regardless of ethnic origin, both as an inherited or a de novo deletion. The ÄGAG in the heterozygous state accounts for 50-60% of non-Jewish (NJ) subjects and over 90% of AJ subjects with early, limb onset generalised dystonia. In contrast to the AJ population, analysis of haplotypes in the NJ population suggests no founder eVect but multiple events resulting in independent occurrences of the same recurrent mutation, a situation which is highly unusual in clinical genetics. The high proportion of European PTD patients with early limb onset phenotype who do not carry the mutation (40%) may represent either allelic or locus heterogeneity in dystonia. Whether other changes within the DYT1 gene lead to dystonia or some other phenotype still remains unknown, as patients with early onset PTD have been tested only for the 946delGAG mutation in recent studies. Only one previous study reported screening for new DYT1 mutations using a genomic DNA approach in American dystonic patients. The main purpose of this study was to assess if non-Jewish European patients with early onset torsion dystonia without the deletion had other mutations in the DYT1 gene or anomalies in other genes. Additional mutations in the DYT1 gene were screened by transcript analysis to allow detection of base substitutions as well as rearrangements resulting from splicing defects, or heterozygous exon deletion (or duplication) not detected by simple PCR amplification.