Jarman, Paul Richard; (1998) A molecular genetic study of inherited movement disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes a molecular genetic study of four dominantly inherited movement disorders: paroxysmal dystonic choreoathetosis (PDC), hereditary geniospasm, primary torsion dystonia (PTD) and dopa-responsive dystonia (DRD). The principal methodology employed in the study of these disorders was genetic linkage analysis. Sets of highly polymorphic microsatellite markers were used to map the subchromosomal location of the disorders as the first step in a positional cloning strategy for disease gene identification. 1. Paroxysmal dystonic choreoathetosis. A large British family with PDC was ascertained, and a detailed description of clinical features obtained. A genome-wide search for genetic linkage was performed, and linkage of the PDC gene in this family to markers on the distal long arm of chromosome 2 was confirmed (maximum LOD score 8.7). Fine genetic mapping using closely spaced markers allowed refinement of the candidate region to a 3.8 cM interval. Two putative candidate genes mapping to this region were evaluated using intragenic polymorphisms for linkage analysis. 2. Hereditary geniospasm. Two large families with hereditary geniospasm were ascertained, and one family studied as described above. Linkage of a gene for geniospasm to genetic markers on the proximal long arm of chromosome 9 was found with a maximum LOD score of 5.24. The gene (GSMl) was mapped to a 2.1 cM interval. Geniospasm in a second family was excluded from this region, indicating genetic heterogeneity. 3. Primary torsion dystonia. A large Australian family with PTD was studied but genetic linkage was not observed with any of the markers analysed. Exclusion of dystonia in this family and two other families with PTD, from known PTD loci on chromosomes 8 and 18 indicates the existence of at least one more genetic locus for PTD. 4. Dopa-responsive dystonia. Mutation analysis of the GTP cyclohydrolase I gene (GCHl) was performed in seven patients diagnosed with anticholinergic-responsive PTD who were suspected of having DRD. Three novel GCHl mutations were identified in two patients, one of whom was a compound heterozygote. These findings are discussed and future directions of study for identification of the disease genes involved are suggested.

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