Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity

Abstract

We studied 20 Mediterranean families (40 patients) with autosomal recessive hereditary spastic paraplegia and thin corpus callosum (ARHSP-TCC, MIM 604360) to characterize their clinical and genetic features. In six families (17 patients) of Algerian Italian, Moroccan, and Portuguese ancestry, we found data consistent with linkage to the SPG11 locus on chromosome 15q13-15, whereas, in four families (nine patients of Italian, French, and Portuguese ancestry) linkage to the SPG11 locus could firmly be excluded, reinforcing the notion that ARHSP-TCC is genetically heterogeneous. Patients from linked and unlinked families could not be distinguished on the basis of clinical features alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal chromosomal interval, but analysis of two genes (MAP1A and SEMA6D) in this region did not identify causative mutations. Our findings suggest that ARHSP-TCC is the most frequent form of ARHSP in Mediterranean countries and that it is particularly frequent in Italy.

Screening of ARHSP-TCC patients expands the spectrum ofSPG11mutations and includes a large scale gene deletion

“…Since the initial reports linking Mediterranean and Asian ARHSP-TCC families to the SPG11 locus on chromosome 15q (Martinez-Murillo et al 1999;Shibasaki et al 2000), several groups, including our teams, proved that this phenotype has a worldwide distribution (Casali et al 2004;Lossos et al 2006;Olmez et al 2006;França et al 2007;Stevanin et al 2007Stevanin et al , 2008a and that it is particularly prevalent in the Mediterranean basin (Casali et al 2004;Stevanin et al 2006). More recently, we showed that ARHSP-TCC at this locus is associated with mutations in SPG11/KIAA1840 (MIM# 610844), a gene with an open reading frame of 7,787 nucleotides that comprises 40 exons and which spans a genomic region of approximately 100 Kb .…”

“…SPG11 mutation screening has been undertaken in at least one index case in 31 families with a neurological picture highly resembling the clinical features of ARHSP-TCC (Shibasaki et al 2000;Casali et al 2004;Lossos et al 2006;Stevanin et al 2006;Winner et al 2006) and in whom linkage to chromosome 15q had not been established a priori. We also included in the study a subset of isolated cases (n=20).…”

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

“…Sudanese families with AR HSP showed a high frequency of SPG11 variants (~13%) in conformity with other populations. 15 Other genes were identified in single families. Of note, SPG7 and SPG4 were not identified in this report.…”

“…Disease causing variants in SPG11 (KIAA1840) (OMIM phenotype #604360) constitute the most frequent cause of TCCassociated HSP (41-77%) and up to for 10-20% of all AR HSP, particularly in the Mediterranean basin. 6,10,[12][13][14][15][16] Next-generation sequencing aided in the identification of many rare HSP genes. 1,17 TFG/SPG57 stands as an example of this genetic surge.…”

SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia

“…The ARHSP-TCC was first linked to the SPG11 locus on chromosome 15q13-q15 in 7 spastic paraplegia families from North America and Europe, whose members showed pure and complicated HSP 2 , other HSP-TCC families from different ethnicities were also linked to the SPG11 locus ( [2][3][4][5] ). Refinement of the SPG11 locus to a region of 6 cM, which contained at least 70 genes, was described in 20 Mediterranean SPG11 families 3 and in a recent study of 20 Turkish families the SPG11 locus was narrowed to 2.93cM 4 .…”