DEGS1 Mutation Causes a Sphingolipidosis neurological syndrome

Mutations in enzymes of lipid synthesis and metabolism have been demonstrated to cause sphingolipidoses. We describe an autosomal recessive neurological disorder affecting consanguineous kindred. All four affected individuals, born at term following normal pregnancies, had mild to severe intellectual disability, spastic quadriplegia, scoliosis and epilepsy in most, with no dysmorphic features. Brain MRI demonstrated leukodystrophy with abnormal hyperintense signal in the periventricular perioccipital region and thinning of corpus callosum. Notably, affected individuals were asymptomatic at early infancy and developed normally until the age of 8-18 months, when deterioration ensued. Homozygosity mapping identified a single 8.7 Mb disease-associated locus on chromosome 1q41-1q42.13 between rs1511695 and rs537250 (two-point LOD score 2.1). Whole exome sequencing identified within this locus a single disease-associated homozygous mutation in DEGS1, encoding C4-dihydroceramide desaturase, an enzyme of the ceramide synthesis pathway. The missense mutation, segregating within the family as expected for recessive heredity, affects an evolutionary-conserved amino acid of both isoforms of DEGS1 and was not found in a homozygous state in ExAC and gnomAD databases or in 300 ethnically matched individuals. Analysis of whole blood of affected individuals demonstrated augmented levels of dihydroceramides, dihydrosphingosine, dihydrosphingosine-1-phosphate and dihydrosphingomyelins with reduced levels of ceramide, sphingosine, sphingosine-1-phosphate and monohexosylceramides, as expected in malfunction of C4-dihydroceramide desaturase. Thus, we demonstrate that a mutation in DEGS1 causes a sphingolipidosis presenting at age 8-18 months with severe leukodystrophy.