ISOLATION OF GENE CAUSING DOPA-RESPONSIVE DYSTONIA

Dystonia is a disorder causing involuntary muscle contractions. Dopa- responsive dystonia (DRD) is a form of childhood-onset idiopathic dystonia with significant clinical differences from other dystonias. The most significant feature is the "curative" effect of levodopa therapy. DRD is inherited as an autosomal dominant condition with reduced penetrance. Some children with infantile-onset of DRD present clinical features suggestive of "cerebral palsy." The gene for DRD also appears to be responsible for a benign form of late adult onset parkinsonism in some at risk individuals without prior dystonia. Recent work in one DRD family has excluded the 9q32-q34 region implicated in idiopathic torsion dystonia, thus proving that DRD is genetically distinct from this disease. Other candidate loci for DRD have also been excluded. The single pathological analysis of DRD brain suggests that the disorder is due to an abnormal development of striatal dopaminergic connections; no degenerative changes were found. Lacking other clues, we propose to use positional cloning to identify the gene causing DRD. We are performing linkage analysis with two large families with DRD utilizing highly informative simple sequence repeat polymorphisms (mono-, di, tri- and tetranucleotide repeat polymorphisms). Using linkage analysis, we have excluded 65% of the genome as harboring the mutation causing DRD. Finding a linked marker will be the first step towards identifying the gene for DRD. Following linkages we will create a high resolution genetic map of the region. This will allow restriction of the area that we will ultimately explore by physical mapping and cloning techniques. We will then apply methods to identify the DRD gene from among candidates from this region. Identification of this gene should allow better diagnosis in children with dystonia and may spare some children from a misguided diagnosis of "cerebral palsy." Ultimately, an understanding of the mutation causing DRD may provide important insights into normal development of the neural dopaminergic system.