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Objective: Hereditary spastic paraplegias (HSPs) are very heterogeneous inherited neurodegenerative disorders. Our group recently identified ZFYVE26 as the gene responsible for one of the clinical and genetic entities, SPG15. Our aim was to describe its clinical and mutational spectra. Methods: We analyzed all exons of SPG15 / ZFYVE26 gene by direct sequencing in a series of 60 non-SPG11 HSP subjects with associated mental or MRI abnormalities, including 30 isolated cases. The clinical data were collected through the SPATAX network. Results: We identified 13 novel truncating mutations in ZFYVE26 , 12 of which segregated at the homozygous or compound heterozygous states in 8 new SPG15 families while 1 was found at the heterozygous state in a single family. Two of 3 splice site mutations were validated on mRNA of 2 patients. The SPG15 phenotype in 11 affected individuals was characterized by early onset HSP, severe progression of the disease, and mental impairment dominated by cognitive decline. Thin corpus callosum and white matter hyperintensities were MRI hallmarks of the disease in this series. Conclusions: The mutations are truncating, private, and distributed along the entire coding sequence of ZFYVE26 , which complicates the analysis of this gene in clinical practice. In our series of patients with hereditary spastic paraplegia–thin corpus callosum, the largest analyzed so far, SPG15 was the second most frequent form (11.5%) after SPG11. Both forms share similar clinical and imaging presentations with very few distinctions, which are, however, insufficient to infer the molecular diagnosis when faced with a single patient.

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.