ORIGINAL ARTICLE New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP) Channa Hewamadduma & Christopher McDermott & Janine Kirby & Andrew Grierson & Maria Panayi & Ann Dalton & Yusuuf Rajabally & Pamela Shaw Received: 7 September 2008 / Accepted: 4 November 2008 / Published online: 26 November 2008 # Springer-Verlag 2008 Abstract 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 sequenc- ing. 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, amyo- trophy 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. Keywords Hereditary spastic paraparesis . REEP1 . Genetic screening . Secretory pathway . Mitochondrial function . Dying back axonopathy Abbreviations HSP Hereditary spastic paraparesis REEP1 Receptor expression enhancing protein 1 ADHSP Autosomal dominant HSP SSP Sporadic spastic paraparesis MLPA Multiplex Ligation-dependent Probe Amplification miRNA microRNA Introduction Hereditary spastic paraparesis (HSP) represents a heteroge- neous group of conditions in which the main feature is progressive spasticity predominantly affecting the lower limbs. Pure and complicated forms of the disease have been described [1]. The pure form is characterised by a Neurogenetics (2009) 10:105–110 DOI 10.1007/s10048-008-0163-z C. Hewamadduma : C. McDermott : J. Kirby : A. Grierson : P. Shaw The Academic Neurology Unit, Section of Neuroscience, Medical School, University of Sheffield, Sheffield, UK M. Panayi : A. Dalton The Department of Molecular Genetics, Sheffield Children’ s Hospital, Sheffield, UK Y. Rajabally Department of Neurology, University Hospitals of Leicester, Leicester, UK C. Hewamadduma (*) Medical Research Council (MRC) Clinical Training Fellow, Academic Neurology Unit, Section of Neuroscience, Medical School, University of Sheffield, E floor, Beech Hill Road, S10 2RX Sheffield, UK e-mail: channa.hewamadduma@sth.nhs.uk