Majority of cases of Hereditary spastic paraplegias (HSPs) are due to genes involved in axonal growth or vesicular trafficking, there is an overlooked group of HSPs that can be caused by inborn errors of metabolism (IEMs) . Adrenomyeloneuropathy, late-onset biotinidase deficiency, cerebrotendineous xanthomatosis are among relatively known metabolic causes of HSPs.

Objective: To report a new hereditary metabolic cause of HSP in a Brazilian family caused by enzyme deficiency of beta-1,4-N-acetyl-galactosaminyl transferase 1 (B4GALNT1), involved in ganglioside biosynthesis.

Methodology: After excluding the traditional IEMs associated with HSPs and molecular analysis of SPG11 and SPG15 genes, whole exome sequencing (WES) effort was performed . All sequencing results were imported and analyzed by the GEnomes Management Application (GEM.app).

Results: Mutations in the B4GALNT1 gene (in the SPG26 locus) were identified in all affected patients in the family; parents were heterozygous carriers of the mutation. Patients affected by this disease have early onset spastic paresis, mild intellectual disability, cerebellar ataxia, strabismus and some can develop psychiatric disturbance. Male hypogonadism was also noticed. Brain MRI showed non especif white matter changes in older patients.

Conclusions: Although there are many IEMs involved in ganglioside catabolism presenting as neurodegenerative disorders, this enzyme deficiency is the second human disorder identified in the pathway of ganglioside biosynthesis, suggesting that other human diseases can be caused by metabolic errors in this biochemical pathway.