Hereditary spastic paraplegia: clinical genetic study of 15 families

摘要

Background: Autosomal dominant hereditary spastic paraplegia (ADHSP) is mainly caused by mutations in \udthe SPG4 gene, which encodes a new member of the AAA (adenosine triphosphatases associated with \uddiverse cellular activities) protein family (spastin). Accumulation of genotype-phenotype correlation is \udimportant for better understanding of SPG4-linked hereditary spastic paraplegia.\udObjectives: To perform a clinical and genetic study of families with ADHSP and to perform the functional\udanalysis of the founder mutation discovered in the SPG4 gene.\udDesign: Genetic and clinical study.\udPatients: Fifteen unrelated families with ADHSP originating from southern Scotland.\udMain Outcome Measures: Clinical assessment, linkage analysis, haplotype study, expression of mutant \udspastin protein in cultured cells.\udResults: Nine families with ADHSP were linked to the SPG4 locus at 2p21-p24. Sequence analysis of SPG4\udshowed a novel N386S mutation in all 9 of these families. Expression of mutant spastin showed aberrant\uddistribution in cultured cells. Haplotype analysis suggested the existence of a common founder. Clinical \udexamination of the affected members carrying the mutation showed phenotypic variations including \udbroad range of age at onset and disease duration and additional neurologic features such as mental \udretardation. Magnetic resonance imaging demonstrated unique features, including thin corpus callosum \udand atrophy of the cerebellum in 2 patients. Linkage and sequence analyses showed no evidence of linkage \udto the currently known ADHSP loci in the remaining 6 families.\udConclusions: A founder SPG4 mutation N386S was identified in the families with ADHSP originating from \udsouthern Scotland. Clinical investigation showed intrafamilial and interfamilial phenotypic variations. The \udgenetic study demonstrated evidence of further genetic heterogeneity in ADHSP.