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Reduction of the SPG11 Interval and Evidence for Further Genetic Heterogeneity

Alexander Lossos, MD; Giovanni Stevanin, PhD; Vardiella Meiner, MD; Zohar Argov, MD; Naima Bouslam, MS; J. P. Newman, PhD; John M. Gomori, MD; Stephan Klebe, MD; Israela Lerer, MSc; Nizar Elleuch, MD; Shira Silverstein, MSc; Alexandra Durr, MD; Oded Abramsky, MD, PhD; Ziva Ben-Nariah, MD; Alexis Brice, MD

Arch Neurol. 2006;63:756-760.

Background  Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) is an autosomal recessive form of complicated HSP mainly characterized by slowly progressive spastic paraparesis and mental deterioration beginning in the second decade of life. The locus for HSP-TCC, designated SPG11, was mapped to chromosome 15q13-15 in some of the affected families from Japan, Europe, and North America, spanning an interval of 17.5 megabases (Mb).

Objective  To perform a clinical and genetic study of HSP-TCC.

Design and Setting  Case series; multi-institutional study.

Patients  Seven patients with HSP-TCC who belong to 3 consanguineous families of Arab origin residing in Israel.

Results  The 7 patients manifested a relatively similar combination of adolescence-onset cognitive decline and spastic paraparesis with TCC on brain magnetic resonance imaging. After excluding the SPG7 locus, we tested the 3 families for linkage to the SPG11, SPG21/MAST, and ACCPN loci associated with autosomal recessive disorders with TCC. Two families showed evidence for linkage to SPG11 (Z_max = 5.55) and reduced the candidate region to 13 Mb.

Conclusions  Our findings in HSP-TCC further confirm its worldwide distribution and genetic heterogeneity, and they significantly reduce the candidate SPG11 interval.

Author Affiliations: Department of Neurology, Agnes Ginges Center for Human Neurogenetics (Drs Lossos, Argov, Newman, and Abramsky), and Departments of Human Genetics (Drs Meiner and Ben-Nariah and Mss Lerer and Silverstein) and Radiology (Dr Gomori), Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and Institut National de la Santé et de la Recherche Médicale Unit 679 (formerly Unit 289), Federative Institute for Neuroscience Research (IFR70) (Drs Stevanin, Klebe, Elleuch, Durr, and Brice and Ms Bouslam), Department of Genetics, Cytogenetics, and Embryology, AP-HP (Drs Stevanin, Durr, and Brice), Federation of Neurology, AP-HP (Dr Brice), and Pitié-Salpêtrière Medical School, Pierre and Marie Curie University (Dr Brice), Salpêtrière Hospital, Paris, France.

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