Clinical Genetic Spectrum of Primary Dystonia

DESCRIPTION (Investigator's abstract): Primary torsion dystonia (PTD) and the "dystonia-plus" syndromes comprise a group of disorders that share dystonia, or twisting movements, as their primary abnormality. They have no identified neuronal degeneration or exogenous cause and are often disabling. Despite this commonality, PTD and "dystonia plus" are phenotypically and genetically heterogeneous with at least seven mapped loci. Two loci, DYT1 and DYT5, have identified genes and contribute significantly to their respective phenotypes: a GAG deletion in the DYT1 gene, TOR1A, encodes torsinA, and is a common cause of early-onset Pm; different mutations in DYT 5, which encodes GTP cyclohydrolasel, account for most dopa-responsive dystonia. The contributions of the other PTD loci are not clear, although recent studies indicate that DYF1 I on chromosome 7q21 is responsible for myoclonus-dystonia (M-D) in most families. The primary aim of this competitive renewal is to further localize and identify genes for the mapped loci including: DYT1 1, the major M-D locus; DYT 6, identified in Swiss Mennonite families with a "mixed" limb and cervical-cranial phenotype; DYT 13, a recently identified locus producing cervical-cranial dystonia in an Italian family; and a locus for cervical dystonia, "ru," for which we have preliminary evidence. We also aim to map PTD loci in families excluded from linkage to these known loci, and to define the phenotypic range of dystonia loci/gene mutations and the extent to which they account for dystonia in examined families. Forty families with three or more affected will be examined, targeting large multigenerational pedigrees with phenotypes consistent with mapped loci. Families, grouped by phenotype, will be screened for linkage with the DYT1 1, DYT6, DYT13 and DYT "ru." Linkage disequilibrium will be investigated, especially for DYF6 among Swiss Mennonite families. Using recombination's and haplotype information the obligate genetic region will be determined, and candidate genes within the region will be screened for mutations. Any families excluded from linkage with identified PTD loci will be analyzed by linkage analysis in a genome search and other PTD identified loci will be localized, as above. Clinical features of dystonia due to identified PTD loci and mutations will be characterized, including clinicalgenetic differences among families that correspond to allelic and locus heterogeneity. The phenotypic spectrum of identified loci and mutations, including non-dystonic features such as tremor, will be determined.