title: Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia.
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.
authors.affiliation: Service de Neurologie, Hôpital Universitaire Habib Bourguiba, 3029 Sfax, Tunisia.
authors.forename: Amir
authors.initials: A
authors.lastname: Boukhris
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schule
authors.forename: José L
authors.initials: JL
authors.lastname: Loureiro
authors.forename: Charles Marques
authors.initials: CM
authors.lastname: Lourenço
authors.forename: Emeline
authors.initials: E
authors.lastname: Mundwiller
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.forename: Imen
authors.initials: I
authors.lastname: Rekik
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Acosta Lebrigio
authors.forename: Marion
authors.initials: M
authors.lastname: Gaussen
authors.forename: Fiorella
authors.initials: F
authors.lastname: Speziani
authors.forename: Andreas
authors.initials: A
authors.lastname: Ferbert
authors.forename: Imed
authors.initials: I
authors.lastname: Feki
authors.forename: Andrés
authors.initials: A
authors.lastname: Caballero-Oteyza
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dionne-Laporte
authors.forename: Mohamed
authors.initials: M
authors.lastname: Amri
authors.forename: Anne
authors.initials: A
authors.lastname: Noreau
authors.forename: Sylvie
authors.initials: S
authors.lastname: Forlani
authors.forename: Vitor T
authors.initials: VT
authors.lastname: Cruz
authors.forename: Fanny
authors.initials: F
authors.lastname: Mochel
authors.forename: Paula
authors.initials: P
authors.lastname: Coutinho
authors.forename: Patrick
authors.initials: P
authors.lastname: Dion
authors.forename: Chokri
authors.initials: C
authors.lastname: Mhiri
authors.forename: Ludger
authors.initials: L
authors.lastname: Schols
authors.forename: Jean
authors.initials: J
authors.lastname: Pouget
authors.forename: Frédéric
authors.initials: F
authors.lastname: Darios
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Wilson
authors.initials: W
authors.lastname: Marques
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001938:Brazil; D002524:Cerebellar Ataxia / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping / Q000379:methods; D060825:Cognitive Dysfunction / Q000235:genetics*; D059472:Exome; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism; D005732:Gangliosides / Q000096:biosynthesis* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005858:Germany; D006720:Homozygote; D006801:Humans; D007223:Infant; D050356:Lipid Metabolism; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011174:Portugal; D013030:Spain; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism; D014416:Tunisia; D055815:Young Adult
chemical_list: D005732:Gangliosides; D005700:Galactosyltransferases; C119701:beta-1,4-galactosyltransferase I