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Original Contribution
May 2006

Eight Novel Mutations in SPG4 in a Large Sample of Patients With Hereditary Spastic Paraplegia

Author Affiliations

Author Affiliations: IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy (Drs Crippa, Panzeri, Arnoldi, Redaelli, Tonelli, D’Angelo, Galbiati, Bresolin, and Bassi and Ms Baschirotto), Conegliano Research Center, Conegliano, Italy (Dr Martinuzzi), and Ostuni Center, Ostuni, Italy (Drs Profice and Trabacca); Department of Biology (Drs Vazza and Mostacciuolo), Dulbecco Telethon Institute, Department of Pharmacology (Drs Daga and Orso), and Department of Neurological Sciences (Dr Trevisan), University of Padua, Padua, Italy; Centro Dino Ferrari, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Department of Neurological Sciences (Drs Comi, Galbiati, Lamperti, Bonato, and Bresolin), and Policlinico San Donato (Dr Meola), University of Milan, Milan, Italy; Department of Neurology, Université Libre de Bruxelles, Hôpital Erasme, Brussels, Belgium (Dr Pandolfo); Department of Neurosciences, Psychiatry, and Anaesthesiology, University of Messina, Messina, Italy (Drs Musumeci and Toscano).

Arch Neurol. 2006;63(5):750-755. doi:10.1001/archneur.63.5.750

Background  Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous disorders characterized by progressive spasticity of the lower limbs. Mutations in the SPG4 gene, which encodes spastin protein, are responsible for up to 45% of autosomal dominant cases.

Objective  To search for disease-causing mutations in a large series of Italian patients with HSP.

Design  Samples of DNA were analyzed by direct sequencing of all exons in SPG4. Samples from a subset of patients were also analyzed by direct sequencing of all exons in SPG3A, SPG6, SPG10, and SPG13.

Setting  Molecular testing facility in Italy.

Patients  Sixty unrelated Italian patients with pure (n = 50) and complicated (n = 10) HSP.

Main Outcome Measures  Mutations in SPG4, SPG3A, SPG6, SPG10, and SPG13.

Results  We identified 12 different mutations, 8 of which were novel, in 13 patients. No mutations of any of the other HSP genes tested were found in 15 patients with sporadic pure HSP who did not have mutations in the SPG4 gene.

Conclusions  The overall rate of mutation in the SPG4 gene within our sample was 22%, rising to 26% when only patients with pure HSP were considered. The negative result obtained in 15 patients without mutations in SPG4 in whom 4 other genes were analyzed (SPG3A, SPG6, SPG10, and SPG13) indicate that these genes are not frequently mutated in sporadic pure HSP.