Paroxysmal dystonic choreoathetosis. Genetic linkage studies in a British family

Abstract

Paroxysmal dystonic choreoathetosis (PDC) is characterised by attacks of involuntary dystonic and choreoathetoid movements, typically several hours in duration with no sign of abnormality between attacks. Inheritance is autosomal dominant and the PDC locus has recently been assigned to the distal long arm of chromosome 2 in two families. We describe a six-generation British family with PDC and describe the results of fine genetic mapping and candidate gene linkage analysis. As part of the genome-wide search, linkage to chromosome 2q was confirmed in this family. Positive LOD scores were obtained for six markers on 2q. A LOD score of 5.08 at a recombination fraction of 0.0 was obtained for the marker D2S163. Construction of haplotypes allowed definition of a disease of 4 cM between the flanking markers D2S295 and D2S377. Polymorphic tandem repeats within the candidate genes CHRND (delta polypeptide of the nicotinic acetylcholine receptor) and SLC4A3 were examined yielding LOD scores of -7.68 and 6.08, respectively, at a recombination fraction of 0.0. This excludes CHRND as a candidate. Our data confirm the assignment of the locus for PDC to chromosome 2q and provide evidence for locus homogeneity in PDC. We have narrowed the disease interval to 4 cM and our findings provide support for the involvement of the gene for the chloride/bicarbonate exchanger as a candidate gene for PDC.