SMPD4 encodes a neutral sphingomyelinase that catalyzes hydrolysis of sphingomyelin to phosphorylcholine and ceramide 1. This enzyme localizes to endoplasmic reticulum and nuclear envelope membranes, where it maintains sphingolipid homeostasis and membrane integrity 1. SMPD4 interacts with nuclear pore complex components, particularly nucleoporin NUP35, suggesting involvement in nuclear envelope dynamics and nuclear pore insertion 2. Biallelic loss-of-function variants in SMPD4 cause severe neurodevelopmental disorder characterized by progressive congenital microcephaly, arthrogryposis, and structural brain anomalies including hypomyelination and cerebellar hypoplasia 314. Mechanistically, SMPD4 deficiency impairs neural progenitor proliferation, causes prolonged mitosis, and abnormal nuclear envelope breakdown during cell division 1. In neural stem cells, SMPD4 loss results in reduced proliferation and shortened primary cilia, defects rescued by exogenous ceramide supplementation 5. Affected individuals surviving beyond infancy frequently develop insulin-dependent diabetes, making SMPD4-related disease a multisystem disorder 1. Conversely, elevated SMPD4 expression in hepatocellular carcinoma associates with poor prognosis and promotes tumor cell proliferation, invasion, and migration 6, indicating distinct roles in normal development versus pathological proliferation.