1. Alteration of Ganglioside Biosynthesis Responsible for Complex Hereditary Spastic Paraplegia
- Author
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Rafael F. Acosta Lebrigio, Alexandre Dionne-Laporte, Patrick A. Dion, Julie Gauthier, Andrés Caballero-Oteyza, Chokri Mhiri, Wilson Marques, Anne Noreau, Imed Feki, Mohamed Amri, Rebecca Schüle, Stephan Züchner, Alexis Brice, Fanny Mochel, Perrine Charles, Amir Boukhris, Guy A. Rouleau, Alexandra Durr, Emeline Mundwiller, Michael A. Gonzalez, José Leal Loureiro, Vítor Tedim Cruz, Ludger Schöls, Marion Gaussen, Sylvie Forlani, Jean Pouget, Giovanni Stevanin, Andreas Ferbert, Frédéric Darios, Fiorella Speziani, Paula Coutinho, Charles Marques Lourenço, and Imen Rekik
- Subjects
Male ,biosynthesis [Gangliosides] ,0302 clinical medicine ,Gangliosides ,Germany ,Spastic ,Missense mutation ,Genetics(clinical) ,Exome ,Age of Onset ,Child ,Genetics (clinical) ,Genetics ,0303 health sciences ,genetics [Cerebellar Ataxia] ,Homozygote ,Chromosome Mapping ,methods [Chromosome Mapping] ,Galactosyltransferases ,3. Good health ,Pedigree ,Child, Preschool ,Female ,medicine.symptom ,Brazil ,Adult ,Tunisia ,Adolescent ,Cerebellar Ataxia ,Hereditary spastic paraplegia ,Mutation, Missense ,Locus (genetics) ,Biology ,genetics [Gangliosides] ,genetics [Galactosyltransferases] ,03 medical and health sciences ,Young Adult ,Genetic linkage ,ddc:570 ,genetics [Spastic Paraplegia, Hereditary] ,Report ,medicine ,Humans ,Cognitive Dysfunction ,Genetic Predisposition to Disease ,030304 developmental biology ,Cerebellar ataxia ,Portugal ,Spastic Paraplegia, Hereditary ,genetics [Cognitive Dysfunction] ,Infant ,medicine.disease ,beta-1,4-galactosyltransferase I ,Lipid Metabolism ,Hyperintensity ,Spain ,metabolism [Spastic Paraplegia, Hereditary] ,metabolism [Galactosyltransferases] ,030217 neurology & neurosurgery - Abstract
Hereditary spastic paraplegias (HSPs) form a heterogeneous group of neurological disorders. A whole-genome linkage mapping effort was made with three HSP-affected families from Spain, Portugal, and Tunisia and it allowed us to reduce the SPG26 locus interval from 34 to 9 Mb. Subsequently, a targeted capture was made to sequence the entire exome of affected individuals from these three families, as well as from two additional autosomal-recessive HSP-affected families of German and Brazilian origins. Five homozygous truncating (n = 3) and missense (n = 2) mutations were identified in B4GALNT1. After this finding, we analyzed the entire coding region of this gene in 65 additional cases, and three mutations were identified in two subjects. All mutated cases presented an early-onset spastic paraplegia, with frequent intellectual disability, cerebellar ataxia, and peripheral neuropathy as well as cortical atrophy and white matter hyperintensities on brain imaging. B4GALNT1 encodes β-1,4-N-acetyl-galactosaminyl transferase 1 (B4GALNT1), involved in ganglioside biosynthesis. These findings confirm the increasing interest of lipid metabolism in HSPs. Interestingly, although the catabolism of gangliosides is implicated in a variety of neurological diseases, SPG26 is only the second human disease involving defects of their biosynthesis.
- Published
- 2013