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SPG11, SPG15, and Further Genetic Heterogeneity

Amir Boukhris, MD; Giovanni Stevanin, PhD; Imed Feki, MD; Elodie Denis, BS; Nizar Elleuch, MD; Mohamed Imed Miladi, MD; Jérémy Truchetto, BS; Paola Denora, PhD; Samir Belal, MD; Chokri Mhiri, MD; Alexis Brice, MD

Arch Neurol. 2008;65(3):393-402.

Objective  To perform a clinical and genetic study of Tunisian families with autosomal recessive (AR) hereditary spastic paraplegia with thin corpus callosum (HSP-TCC).

Design  Linkage studies and mutation screening.

Setting  Reference Center for Neurogenetics in South and Center Tunisia.

Participants  Seventy-three subjects from 33 "apparently" unrelated Tunisian families with AR HSP.

Main Outcome Measures  Families with AR HSP-TCC were subsequently tested for linkage to the corresponding loci using microsatellite markers from the candidate intervals, followed by direct sequencing of the KIAA1840 gene in families linked to SPG11.

Results  We identified 8 Tunisian families (8 of 33 [24%]), including 19 affected patients, fulfilling the clinical criteria for HSP-TCC. In 7 families, linkage to either SPG11 (62.5%) or SPG15 (25%) was suggested by haplotype reconstruction and positive logarithm of odds score values for microsatellite markers. The identification of 2 recurrent mutations (R2034X and M245VfsX) in the SPG11 gene in 5 families validated the linkage results. The neurological and radiological findings in SPG11 and SPG15 patients were relatively similar. The remaining family, characterized by an earlier age at onset and the presence of cataracts, was excluded for linkage to the 6 known loci, suggesting further genetic heterogeneity.

Conclusions  Autosomal recessive HSP-TCC is a frequent subtype of complicated HSP in Tunisia and is clinically and genetically heterogeneous. SPG11 and SPG15 are the major loci for this entity, but at least another genetic form with unique clinical features exists.

Author Affiliations: Department of Neurology, Habib Bourguiba University Hospital (Drs Boukhris, Feki, Elleuch, Miladi, and Mhiri), and the Faculté de Médecine de Sfax (Drs Boukhris, Feki, Elleuch, Miladi, and Mhiri), Sfax, and Department of Neurology, National Institute of Neurology, Tunis (Dr Belal), Tunisia; and Institut national de la santé et de la recherche médicale (INSERM) U679 (Drs Boukhris, Stevanin, Denora, and Brice and Mr Truchetto), and the Pierre and Marie Curie–Paris 6 University, UMR S679, Federative Institute for Neuroscience Research (IFR70) (Drs Boukhris, Stevanin, Denora, and Brice and Mr Truchetto), and Department of Genetics and Cytogenetics (Drs Stevanin and Brice and Ms Denis), Assistance Publique–Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.