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.
Amir Boukhris, Rebecca Schule, José L. Loureiro, Charles Marques Lourenço, Emeline Mundwille, Michael A. Gonzalez, Perrine Charles, Julie Gauthier, Imen Rekik, Rafael F. Acosta Lebrigio, Marion Gaussen, Fiorella Speziani, Andreas Ferbert, Imed Feki, Andrés Caballero-Oteyza, Alexandre Dionne-Laporte, Mohamed Amri, Anne Noreau, Sylvie Forlani, Vitor T. Cruz, Fanny Mochel, Paula Coutinho, Patrick Dion, Chokri Mhiri, Ludger Schols, Jean Pouget, Frédéric Darios, Guy A. Rouleau, Wilson Marques, Alexis Brice, Alexandra Durr, Stephan Zuchner and Giovanni Stevanin