title: 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.
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.
authors.affiliation: Department of Neurology, Habib Bourguiba University Hospital, Sfax, Tunisia. boukhris_amir@yahoo.fr
authors.forename: Amir
authors.initials: A
authors.lastname: Boukhris
authors.forename: Imed
authors.initials: I
authors.lastname: Feki
authors.forename: Nizar
authors.initials: N
authors.lastname: Elleuch
authors.forename: Mohamed Imed
authors.initials: MI
authors.lastname: Miladi
authors.forename: Anne
authors.initials: A
authors.lastname: Boland-Augé
authors.forename: Jérémy
authors.initials: J
authors.lastname: Truchetto
authors.forename: Emeline
authors.initials: E
authors.lastname: Mundwiller
authors.forename: Nadia
authors.initials: N
authors.lastname: Jezequel
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.forename: Chokri
authors.initials: C
authors.lastname: Mhiri
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
mesh_terms: D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D003337:Corpus Callosum / Q000473:pathology*; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D014416:Tunisia