Autosomal dominant spastic paraplegia - Refined SPG8 locus and additional genetic heterogeneity

Objective: To map the gene responsible for autosomal dominant pure heredita ry spastic paraplegia (ADPHSP) in a large affected family. Background: Auto somal dominant pure hereditary spastic paraplegia (ADPHSP) is genetically h eterogeneous, and loci have been mapped at chromosomes 2p (SPG4), 14q (SPG3 ), 15q (SPG6), and recently, in a single family, at chromosome 8q24 (SPG8). Methods: The authors carried out a genomewide linkage screen on a large fa mily with ADPHSP, for which linkage to the chromosome 2, 14, and 15 loci wa s excluded. Results: Analysis of markers on chromosome 8q24 gave a peak two -point lod score of 4.49 at marker D8S1799. Analysis of recombination event s in this family and in the previously published SPG8-linked family narrowe d the SPG8 locus from 6.2 cM to a 3.4-cM region between markers D8S1804 and D8S1179. In another four families, linkage to all four known ADPHSP loci w as excluded. The SPG8-linked family had a significantly older mean age at o nset of symptoms and had significantly more wheelchair-using patients than the four linkage-excluded families. Conclusions: These results contain the presence of an autosomal dominant pure hereditary spastic paraplegia (ADPHS P) locus at chromosome 8q24 and strongly suggest that there are at least fi ve ADPHSP loci. The data provide additional evidence for locus-phenotype co rrelations in ADPHSP.