A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia.

Mutations in the SPG7 gene, encoding the mitochondrial protein paraplegin, were the first to be identified in autosomal recessive hereditary spastic paraplegia (ARHSP). Four different SPG7 mutations have been described so far in association with both pure and complicated HSP phenotypes. Muscle biopsies from the most severely affected patients have shown histological evidence of an oxidative phosphorylation defect. We identified six ARHSP kindreds, in whom linkage to SPG7 could not be excluded, and 29 sporadic spastic paraplegia patients. The 17 exons and flanking regions of the SPG7 gene were screened for mutations using a combination of single-stranded conformation polymorphism (SSCP) analysis and sequencing. Three patients were found to carry compound heterozygous SPG7 mutations, comprising five novel and one previously described mutation. Muscle biopsies from two SPG7 mutation patients did not show any histological evidence of an oxidative phosphorylation defect. However, biochemical analysis revealed a reduction in citrate synthase-corrected complex I and complex II/III activities in muscle and complex I activity in mitochondrial-enriched fractions from cultured myoblasts, suggesting that either a primary or a secondary defect of respiratory chain function may play an important role in the pathogenesis of the disease.