Mitochondrial Morpho-Functional Dysfunction in SPG31 Patients (IN7-1.007)

Abstract

Objective: To decipher the pathophysiological mechanisms involved in SPG31 determinism. Background Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized at least by slowly progressive spasticity of the lower limbs. Mutations in REEP1 were recently associated with SPG31, a pure dominant HSP. We recently identified 12 different heterozygous mutations in REEP1 by screening 175 unrelated HSP index patients from kindreds with dominant inheritance (AD-HSP), associated with either a pure or a complex phenotype. The overall mutation rate in our clinically heterogeneous sample was 4.5% in French families with AD-HSP. The phenotype was restricted to pyramidal signs in the lower limbs in most patients but 9 had a complex phenotype. Design/Methods: We performed analyses on primary cultures of fibroblasts in 5 patients from 2 unrelated SPG31 families. In family 1 (one patient), the mutation c.103delG, p.Val36SerfsX4 was identified in exon 3 of REEP1. In family 2 (4 patients), the mutation c.124T>C, p.Trp42Arg was identified in exon 3 of REEP1. Results: We evidenced abnormal mitochondrial network organization in fibroblasts of all patients from two SPG31 families in addition to defective mitochondrial energy production in both fibroblasts and muscle. The localization of some mitochondrial proteins appeared dramatically impaired in all the fibroblasts studied. Conclusions: The alteration of mitochondrial morphogenesis seems correlated to the type of mutation. Studies of potential partners of REEP1 highlight the crucial role of mitochondrial fusion-fission balance in the pathogenesis of SPG31 and suggest a direct involvement of mitochondrial dysfunction in this neurodegenerative condition. Supported by: Association contre les maladies mitochondriales (AMMi), Association Strumpell-Lorrain (ASL). Disclosure: Dr. Goizet has received research support from Genzyme Corporation. Dr. Benard has nothing to disclose. Dr. Depienne has nothing to disclose. Dr. Boukhris has nothing to disclose. Dr. Sole has nothing to disclose. Dr. Coupry has nothing to disclose. Dr. Pilliod has nothing to disclose. Dr. Martin-Negrier has nothing to disclose. Dr. Forlani has nothing to disclose. Dr. Durr has nothing to disclose. Dr. Brice has nothing to disclose. Dr. Lacombe has received personal compensation for activities with Genzyme as a consultant. Dr. Rossignol has nothing to disclose. Dr. Stevanin has nothing to disclose.