DEGS1 encodes delta 4-desaturase, sphingolipid 1, a key enzyme in sphingolipid biosynthesis that catalyzes the conversion of dihydroceramide to ceramide by introducing a double bond at the C4-C5 position 1. The enzyme is localized to mitochondria-associated endoplasmic reticulum membranes (MAM) where it plays essential roles in maintaining MAM integrity and function 1. DEGS1 deficiency disrupts multiple MAM functions including mitochondrial dynamics, cholesterol metabolism, phospholipid metabolism, and lipid droplet biogenesis, while also impairing mitochondrial respiration 1. Biallelic pathogenic variants in DEGS1 cause hypomyelinating leukodystrophy-18 (HLD18), a rare neurodevelopmental disorder characterized by severe developmental delay, failure to thrive, dystonia, seizures, and brain hypomyelination 2. Functional assessment shows significantly elevated dihydroceramide/ceramide ratios in patient samples, confirming enzyme dysfunction 2. Beyond its role in disease, DEGS1 has broader physiological significance, with genetic variants associated with fitness outcomes in aging populations 3 and the enzyme playing regulatory roles in hematopoietic stem cell self-renewal through sphingolipid modulation 4. The enzyme is also responsive to inflammatory cytokines in keratinocytes, suggesting involvement in skin barrier function 5.