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Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia

From INSERM U679, Neurology and Experimental Therapeutics, Département de Génétique, Cytogénétique, et Embryologie, Hôpital de la Pitié-Salpêtrière, and Université Pierre et Marie Curie, Faculté de Médecine, Paris (N.E., C.D., C.M.E.T., G.S., A.D., A.B.), Department of Neurology (A.M.O.H.), Centre Hospitalier Universitaire, Grenoble, Department of Neurology (X.F.), Centre Hospitalier Universitaire, Bordeaux, INSERM U546 (B.F.), Hôpital de la Pitié-Salpêtrière, Paris, and Généthon III (D.G.), Evry, France; Laboratory of Neurogenetics and Department of Neurology (A.B.), Hôpital des Spécialités, Rabat, Morocco; and Department of Neurology (R.Z.), Centre Hospitalier Universitaire Mustapha Bacha, Alger, Algeria.

Address correspondence and reprint requests to Dr. A. Brice, INSERM U679, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l’hôpital, 75013 Paris, France; e-mail: brice{at}ccr.jussieu.fr

Background: Mutations in the SPG7 gene, which encodes paraplegin, are responsible for an autosomal recessive hereditary spastic paraplegia (HSP).

Objective: To screen the SPG7 gene in a large population of HSP families compatible with autosomal recessive transmission.

Methods: The authors analyzed 136 probands with pure or complex HSP for mutations in the SPG7 using denaturation high-performance liquid chromatography and direct sequencing.

Results: The authors identified 47 variants including 6 mutations, 27 polymorphisms, and 14 changes with unknown effects. In one family from Morocco, compound c.850_851delTTinsC and c.1742_1744delTGG heterozygous mutations were shown to be causative. This family had complex HSP with cerebellar impairment. Progression of the disease was rapid, resulting in a severe disease after 8 years of duration. Also detected were 20 families with one heterozygous mutation that was not found in a large control population. The mutations produced highly defective proteins in four of these families, suggesting that they were probably causative. Direct sequencing of all exons and reverse transcription PCR experiments demonstrated the absence of a second mutation. However, the p.Ala510Val missense substitution previously described as a polymorphism was shown to be significantly associated with HSP, suggesting that it had a functional effect.

Conclusion: SPG7 mutations account for less than 5% of hereditary spastic paraplegia (HSP) families compatible with autosomal recessive inheritance. Cerebellar signs or cerebellar atrophy on brain imaging were the most frequent additional features in patients with SPG7 HSP. Rare nucleotide variants in SPG7 are frequent, complicating routine diagnosis.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the March 14 issue to find the title link for this article.

Supported by the Verum Foundation (to A.B.), the GIS/maladies rares (A02191OJ-SPATAX, to A.D.), and the Foundation "Connaître les syndromes cerebelleux" (to N.E.).

Disclosure: The authors report no conflicts of interest.

Received June 2, 2005. Accepted in final form November 4, 2005.

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