DOPA-RESPONSIVE DYSTONIA - A CLINICAL AND MOLECULAR-GENETIC STUDY

We have studied the GTP-cyclohydrolase 1 (GCH-1) gene in 30 patients w ith the diagnosis of clinically definite (n = 20) or possible (n = 10) dopa-responsive dystonia (DRD) as well as in a child with atypical ph enylketonuria due to complete GCH-1 deficiency. A large number of new heterozygote mutations (seven point mutations, two splice site mutatio ns, and one deletion) as well as a new homozygote mutation in the chil d with atypical phenylketonuria were detected. In addition, two previo usly described mutations were found in two other cases. We further ext ended our investigation of GCH-1 to the 5' and 3' regulatory regions a nd report the first detection of point mutations in the 5' untranslate d region. Demethylation of CpG islands does not appear to be an import ant causative factor for the GCH-1 mutations in DRD. In addition, we h ave extended the clinical phenotype of genetically proven DRD to focal dystonia, dystonia with relapsing and remitting course, and DRD with onset in the first week of life. None of our DRD patients without a mu tation in GCH-1 had the 3-bp deletion recently detected in DYT1, the c ausative gene for idiopathic torsion dystonia with linkage to 9q34.