Original Article

neurogenetics

, Volume 11, Issue 4, pp 441-448

First online:

A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum

  • Amir BoukhrisAffiliated withDepartment of Neurology, Habib Bourguiba University HospitalFaculté de Médecine de SfaxINSERM, U975 (formerly U679)Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S975, CNRS 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, Groupe Hospitalier Universitaire Pitié-SalpêtrièreAP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and CytogeneticsService de Neurologie, Hôpital Habib Bourguiba Email author 
  • , Imed FekiAffiliated withDepartment of Neurology, Habib Bourguiba University HospitalFaculté de Médecine de Sfax
  • , Nizar ElleuchAffiliated withDepartment of Neurology, Habib Bourguiba University HospitalFaculté de Médecine de Sfax
  • , Mohamed Imed MiladiAffiliated withDepartment of Neurology, Habib Bourguiba University HospitalFaculté de Médecine de Sfax
  • , Anne Boland-AugéAffiliated withCentre National de Génotypage
  • , Jérémy TruchettoAffiliated withINSERM, U975 (formerly U679)Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S975, CNRS 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, Groupe Hospitalier Universitaire Pitié-Salpêtrière
  • , Emeline MundwillerAffiliated withINSERM, U975 (formerly U679)Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S975, CNRS 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, Groupe Hospitalier Universitaire Pitié-Salpêtrière
  • , Nadia JezequelAffiliated withINSERM, U975 (formerly U679)Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S975, CNRS 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, Groupe Hospitalier Universitaire Pitié-Salpêtrière
  • , Diana ZelenikaAffiliated withCentre National de Génotypage
    • , Chokri MhiriAffiliated withDepartment of Neurology, Habib Bourguiba University HospitalFaculté de Médecine de Sfax
    • , Alexis BriceAffiliated withINSERM, U975 (formerly U679)Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S975, CNRS 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, Groupe Hospitalier Universitaire Pitié-SalpêtrièreAP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics
    • , Giovanni StevaninAffiliated withINSERM, U975 (formerly U679)Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S975, CNRS 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, Groupe Hospitalier Universitaire Pitié-SalpêtrièreAP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and CytogeneticsEcole Pratique des Hautes Etudes

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Abstract

Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) and mental impairment is a frequent subtype of complicated HSP, often inherited as an autosomal recessive (AR) trait. It is clear from molecular genetic analyses that there are several underlying causes of this syndrome, with at least six genetic loci identified to date. However, SPG11 and SPG15 are the two major genes for this entity. To map the responsible gene in a large AR-HSP-TCC family of Tunisian origin, we investigated a consanguineous family with a diagnosis of AR-HSP-TCC excluded for linkage to the SPG7, SPG11, SPG15, SPG18, SPG21, and SPG32 loci. A genome-wide scan was undertaken using 6,090 SNP markers covering all chromosomes. The phenotypic presentation in five patients was suggestive of a complex HSP that associated an early-onset spastic paraplegia with mild handicap, mental deterioration, congenital cataract, cerebellar signs, and TCC. The genome-wide search identified a single candidate region on chromosome 9, exceeding the LOD score threshold of +3. Fine mapping using additional markers narrowed the candidate region to a 45.1-Mb interval (15.4 cM). Mutations in three candidate genes were excluded. The mapping of a novel AR-HSP-TCC locus further demonstrates the extensive genetic heterogeneity of this condition. We propose that testing for this locus should be performed, after exclusion of mutations in SPG11 and SPG15 genes, in AR-HSP-TCC families, especially when cerebellar ataxia and cataract are present.

Keywords

Hereditary spastic paraplegia Autosomal recessive Thin corpus callosum Linkage SPG46