New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP)

The hereditary spastic paraplegias (HSP) are a heterogeneous group of conditions in which the main feature is a progressive spastic paraparesis. Mutations in the receptor expression enhancing protein 1 (REEP1) gene have recently been reported to be associated with an autosomal dominant HSP phenotype (SPG31). The objective of this study was to identify the frequency of REEP1 mutations in both autosomal dominant HSP (ADHSP) and sporadic spastic paraparesis (SSP) cases and to analyse the genotype/phenotype correlation of mutations so far described in REEP1. One hundred thirty-three index cases from large ADHSP pedigrees and 80 SSP cases were screened for mutation in REEP1 by direct sequencing. Three mutations were identified in REEP1 in the ADHSP group. A novel nonsense mutation in exon 5, c.[337C>T] (p.[Arg113X]), was associated with spastic paraparesis, amyotrophy and mitochondrial dysfunction. A second previously reported mutation, c.[606+43G>T], was identified in two pedigrees. The index case of one of these pedigrees had a peripheral neuropathy in association with spastic paraparesis, and the proband of the second pedigree had a severe spastic tetraparesis and bulbar dysfunction. No mutations were detected in the SSP cases. We report a mutation frequency of 2.3% in REEP1 in ADHSP, suggesting REEP1 mutation is a relatively uncommon cause of ADHSP in a population of patients drawn from the UK. The phenotype of ADHSP associated with REEP1 mutation is broader than initially reported. The spastic paraparesis in SPG31 may be complicated by the presence of amyotrophy, bulbar palsy and/or peripheral neuropathy.