Valente, Enza Maria; (2003) Clinical and molecular genetic study of movement disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes a molecular genetic study of three groups of inherited movement disorders: primary torsion dystonia (PTD), paroxysmal dyskinesias and autosomal recessive juvenile parkinsonism (ARJP). 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 or positional candidate strategy for disease gene identification. Primary Torsion Dystonia The prevalence of the DYTl gene in the British population was analysed and genotype phenotype correlations were drawn. Moreover, a detailed haplotype analysis in Ashkenazi Jewish and non-Jewish British dystonic patients carrying the GAG deletion in the DYTl gene and linkage disequilibrium analysis demonstrated a limited number of founder mutations in the United Kingdom. Three large PTD families were ascertained, and a detailed description of clinical features obtained. These families were analysed for linkage between the disease and all PTD loci (DYTl, DYT6 and DYT7). Exclusion of linkage with the known PTD loci in these three families indicated the existence of at least one more genetic locus for PTD. In family PTDOl a genome-wide search was performed, and a novel PTD locus (DYT13) was mapped to a 22 cM region on the short arm of chromosome 1. In families PTD02 and PTD03 linkage with this novel locus was also excluded, further supporting the wide genetic heterogeneity of primary torsion dystonia. Paroxysmal dyskinesias Three large families with paroxysmal kinesigenic dyskinesia were ascertained and clinical details were collected. A genome-wide analysis on the largest family mapped the disease on the pericentromeric region of chromosome 16, nearby but clearly separated from the only PKD locus so far identified and from the ICCA locus (another paroxysmal movement disorder associated with benign infantile convulsions). These data demonstrate the existence of a second PKD locus and are strongly suggestive of a cluster of genes for paroxysmal dyskinesias on human chromosome 16. One large British fannily with paroxysmal exercise-induced dyskinesia and migraine was tested for linkage with microsatellite markers spanning paroxysmal dyskinesia and hemiplegic migraine loci (PNKD on chromosome 2q, PKD and ICCA on chromosome 16, FHM on chromosome 19p). Exclusion of linkage with all tested loci indicates the existence of a novel PED locus in this and possibly in other families. Autosomal recessive juvenile parkinsonism A large consanguineous family from Italy was ascertained and detailed clinical analyses were performed. A novel locus for autosomal recessive juvenile parkinsonism (PARK6) was identified by means of homozygosity mapping on the short arm of chromosome 1, in a 12.5 cM region. Linkage with PARK6 was further confirmed in other eight European families, allowing preliminary genotype-phenotype correlates and the refinement of the linked interval to 7.4 cM (4.2 Mb on the physical map). These findings are discussed and future directions of study for identification of the disease genes involved are suggested.

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