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NEUROLOGY 2009;73:1111-1119
© 2009 American Academy of Neurology

SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum

C. Goizet, MD, PhD, A. Boukhris, MD, D. Maltete, MD, L. Guyant-Maréchal, MD, J. Truchetto, BS, E. Mundwiller, BS, S. Hanein, PhD, P. Jonveaux, MD, F. Roelens, MD, J. Loureiro, MD, E. Godet, MD, S. Forlani, PhD, J. Melki, MD, PhD, M. Auer-Grumbach, MD, J. C. Fernandez, BS, P. Martin-Hardy, BS, I. Sibon, MD, PhD, G. Sole, MD, I. Orignac, MD, C. Mhiri, MD, P. Coutinho, MD, PhD, A. Durr, MD, PhD, A. Brice, MD and G. Stevanin, PhD

From INSERM, U975 (C.G., A. Boukhris, J.T., E.M., S.H., S.F., J.C.F., P.M.-H., A.D., A. Brice, G.S.), Paris; Université Pierre et Marie Curie-Paris6 (C.G., A. Boukhris, J.T., E.M., S.H., S.F., J.C.F., P.M.-H., A.D., A. Brice, G.S.), UMR-S975, CNRS 7225, Centre de Recherche Institut du Cerveau et de la Moelle (CR-ICM), Groupe Hospitalier Pitié-Salpêtrière, Paris; Université Victor Segalen Bordeaux 2 (C.G.), Laboratoire de Génétique Humaine, and CHU Bordeaux, Service de Génétique Médicale, Hôpital Pellegrin, Bordeaux; AP-HP (A. Boukhris, A.D., A. Brice, G.S.), Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique et Cytogénétique, Paris, France; Service de Neurologie (A. Boukhris, C.M.), Hôpital Universitaire Habib Bourguiba, Sfax, Tunisia; Centre Hospitalier Universitaire de Rouen (D.M., L.G.-M.), Service de Neurologie, Rouen; Centre Hospitalier Universitaire de Nancy (P.J.), Service de Génétique, Nancy, France; H Hart Hospital (F.R.), Child Neurology, Roeselare, Belgium; Hosp. S. Sebastiao (J.L., P.C.), Santa Maria da Feira, Portugal; CHR Metz-Thionville (E.G.), Service de Neurologie, Hôpital Notre Dame de Bon Secours, Metz, France; Hadassah-Hebrew University Medical Center (J.M.), Jerusalem, Israel; Institute of Human Genetics and Department of Internal Medicine (M.A.-G.), Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Austria; CHU Bordeaux (I.S., G.S.), Fédération des Neurosciences Cliniques, Hôpital Pellegrin, Bordeaux; and CHU Nantes (I.O.), Service d'Ophtalmologie, Nantes, France.

Address correspondence and reprint requests to Dr. G. Stevanin, INSERM/UPMC UMR_S975 (formerly U679), Groupe Hospitalier Pitié-Salpêtrière, Bat. Pharmacie, 47 Bd de l'Hôpital, 75013 Paris, France giovanni.stevanin{at}upmc.fr

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.

Abbreviations: AR-HSP = autosomal recessive forms of HSP; HSP = hereditary spastic paraplegia; LL = lower limbs; MR = mental retardation; SSSC = Splice Site Score Calculation; SSPNN = Splice Site Prediction by Neural Network; TCC = thin corpus callosum; WMH = white matter hyperintensities.

Supplemental data at www.neurology.org

*These authors contributed equally.

Authors' affiliations are listed at the end of the article.

Supported by the French National Agency for Research (to A.D. and to G.S., France), the ANR-07-E-RARE-005-01/European & Mediterranean network on spastic paraplegias–EUROSPA (contract no. R07202DS, to A. Brice), INSERM (to A. Brice, France), and the VERUM foundation (to A. Brice, Germany). C.G. received grants from the Centre Hospitalier Universitaire de Bordeaux (France). A. Boukhris received a fellowship from the French Association Strümpell-Lorrain (ASL, France).

Disclosure: Author disclosures are provided at the end of the article.

Received February 16, 2009. Accepted in final form July 17, 2009.






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