Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in nineteen patients from thirteen unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity and profound failure to thrive. MRI showed hypomyelination, thinning of corpus callosum and progressive thalami and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patient's fibroblasts and muscle. Further, we used a knockdown approach for disease modelling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of ceramide synthase, one step prior to DEGS1 in the pathway, by fingolimod, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in the zebrafish model. These proof-of-concept results pave the way to clinical translation.