Hereditary spastic paraplegia with mental impairment and thin corpus callosum in Tunisia - SPG11, SPG15, and further genetic heterogeneity

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.