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

Abstract

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.

Clinical Spectrum of Hereditary Spastic Paraplegia in Children : A Study of 74 Cases = الطيف السريري للشلل السفلي التشنجي الوراثي في الأطفال : دراسة 74 حالة

“…5 Mental retardation in HSP has been reported in several previous studies. 5,7,[15][16][17][18][19] Some of our patients experienced a worsening of cognitive functions with disease progression, as noted previously. 19,20 However, in this cohort, this observation could not be substantiated by an appropriate IQ assessment.…”

SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

“…5,7 In patient 9, we found a novel intronic variant c.988-1G4A located one base pair before exon 8. This variant was absent from the 1000 Genomes and EVS databases and present at a frequency of 1.66e-05 in the Exome Aggregation Consortium (ExAC).…”

“…This study, as well as more recent publications on SPG7 mutation carriers, supports that cerebellar ataxia is a very frequent feature. [5][6][7]9,15 When present in milder adult-onset cases with spasticity, it suggests this diagnosis if not associated with cognitive deficit or peripheral neuropathy. In fact, cerebellar features, including ataxia, are more pronounced than spasticity in our cohort.…”

“…In parallel, we also identified variants in SPG7 in subject 22 using a Sanger sequencing HSP panel. This included five missense variants that were previously reported to affect the protein function, 5,7,10,15,22 and two novel variants (Table 1). In fact, five families (eight individuals) carried the novel splice site variant c.988-1G4A described above, making it the second most common variant in our cohort.…”

“…4 Since then, a significant number of causative mutations were found in several HSP cohorts from different populations. [5][6][7][8][9][10][11][12][13][14] SPG7 can be characterized by a pure or complex HSP phenotype. Increasingly, reports documented that cerebellar ataxia and cerebellar atrophy on magnetic resonance imaging (MRI) are the most frequent additional features in complex SPG7 cases.…”