Aberrant DEGS1 sphingolipid metabolism impairs central and peripheral nervous system function in humans

Sphingolipids including ceramides are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids are associated with various neurological pathologies, however, the entire spectrum of disorders affecting sphingolipid metabolism remains elusive. By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous system, we identified a homozygous variant p.(Ala280Val) in DEGS1, encoding an enzyme of the ceramide synthesis pathway. The blood sphingolipid profile and patient-derived fibroblasts both showed a significant shift from the unsaturated to the dihydro-forms of sphingolipids. Moreover, an atypical and potentially toxic sphingolipid metabolite is formed as consequence of the altered synthesis pathway. The changes in the sphingolipid profile were recapitulated in a CRISPR/Cas-based DEGS1 knockout HAP1-cell model and by chemical inhibition of DEGS1, suggesting a loss of DEGS1 function in the disease. DEGS1 insufficiency is thus a novel cause for a multisystem neurological disorder. A sphingolipid-rich diet may correct the metabolic profile and improve the clinical outcome of affected individuals and suggests that this heritable condition might be treatable.