Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia

Background: Hereditary spastic paraplegia (HSP), a genetically and clinically heterogeneous group of neurodegenerative disorders, is characterized by progressive lower limb weakness and spasticity. Among the 8 loci associated with the autosomal dominant uncomplicated HSP (AD-HSP), the spastin (SPG4) and atlastin (SPG3A) genes have been known to account for approximately 40% and 10% of all cases, respectively. Objective: To investigate the contribution of these 2 genes in the occurrence of HSP in Korean patients. Design: Clinical and genetic study. Setting: Tertiary care center. Patients: Eighteen patients with uncomplicated HSP (11 AD and 7 sporadic) underwent screening for gene mutation. Main Outcome Measures: Mutations in the SPG4 and SPG3A genes as detected by direct sequencing of all coding exons and flanking intronic sequences. Results: We identified 8 different SPG4 mutations, 7 of which have not been reported elsewhere. Among the detected mutations were 3 missense mutations, 2 in-frame deletions, 2 frameshift mutations, and 1 splice-site mutation. No mutation was found in the SPG3A gene. Conclusion: Compared with previous studies, a higher frequency of SPG4 gene mutations in AD-HSP (7/11; 64%) was observed, suggesting that a mutation analysis for the SPG4 gene might be helpful for molecular diagnosis of AD-HSP in Korean patients.