Novel SPG10 Mutation Associated with Hereditary Spastic Paraplegia and Dysautonomia (P05.194)

Abstract

Objective: We report the characteristics of a French family with a novel missense mutation c.580 G>C in exon 7 of the KIF5A/SPG10 gene. Background Hereditary spastic paraplegias (HSP) are a group of clinically and genetically heterogeneous neurodegenerative disorders. Design/Methods: Patients were identified in the Department of Neurology at the Strasbourg University Hospital. Clinical (including the spastic paraplegia rating scale), biological (including blood inflammatory indexes, CSF analysis, long chain fatty acids, folic acid, vitamin B12 and E levels), neurophysiological (evoked potentials, electromyography, nerve conduction velocities) and morphological (brain and spinal cord MRI) exams were performed in the patients and their siblings. The coding regions including the flanking intronic sequences of SPAST (SPG4 RefSeq NM_014946.3), REEP1 (RefSeq NM_022912.2 SPG31) and KIF5A (SPG10, RefSeq NM_004984.2) genes were amplified using standard procedures. We performed a skin biopsy to analyse the axonal network using PGP 9.5, synaptophysin and electron microscopy. Results: We have identified a novel mutation in KIF5A/SPG10 gene associated with 1) late-onset HSP; 2) autonomic dysfunction; 3) rapid progression followed by a mild recovery in the sister and a progressive/continuous accumulation of disability in the brother; 4) central demyelination and spinal cord atrophy on MRI scans in the proband; and 5) loss of vesicles at the presynaptic membrane in the proband on skin biopsy. Conclusions: This study extends the range of neurological impairment associated with SPG10 HSP. For patients who accumulate progressive neurological disability without typical demyelinating lesions on brain MRI and with normal CSF, screening of the KIF5A gene could be envisaged if there is a family history of HSP. Furthermore, skin biopsy could be used to evidence abnormality in vesicles axonal transport in patients with HSP. Disclosure: Dr. Collongues has received personal compensation for activities with Biogen Idec, Bayer Schering Pharma, Teva Neuroscience, Merck-Serono, Sanofi-Aventis Pharmaceuticals, Inc., and Novartis. Dr. Depienne has nothing to disclose. Dr. Boehm has nothing to disclose. Dr. Echaniz-Laguna has nothing to disclose. Dr. Samama has nothing to disclose. Dr. Durr has nothing to disclose. Dr. Stevanin has nothing to disclose. Dr. Leguern has nothing to disclose. Dr. Brice has nothing to disclose. Dr. Labauge has nothing to disclose. Dr. De Seze has received personal compensation for activities with Bayer Schering, Biogen Idec, LFB, Merck Serono, Novartis, Sanofi-Aventis, and Teva Neuroscience.Dr. De Seze has received personal compensation in an editorial capacity for Elsevier.