O7 Biallelic variants in the Kennedy pathway gene CEPT1 disrupt phospholipid synthesis and cause a complex neurological disorder with epilepsy, ataxia and developmental delay

The Kennedy pathways control the de novo synthesis of phosphatidylcholine (PC) and phospha-tidylethanolamine (PE), which are the most abundant phospholipids in mammalian membranes and are enriched in the brain. Recently, variants in genes encoding Kennedy pathway enzymes have been associated with rare monogenic disorders exhibiting a wide range of clinical manifestations. Here we describe biallelic variants in the choline/ethanolamine phosphotransferase 1 (CEPT1) gene which encodes a Kennedy pathway enzyme responsible for the final step of both PC and PE biosynthesis. Patients with CEPT1 variants have early-onset ataxia, spasticity, motor/speech delay and epilepsy. Our studies confirm that pathogenic CEPT1 variants dramatically impair enzymatic activity for the synthesis of both PC and PE. SH-SY5Y neuroblastoma CEPT1 knockout cells and CEPT1 patient-derived fibroblasts both exhibit altered lipidomic profiles and ER stress responses. Similar to other Kennedy pathway disorders, substantive mitochondrial defects are also present including inefficient respiration coupled with increased reactive oxygen species production. Together these findings corroborate the importance of Kennedy pathway function for neuronal development, survival and function, and expand the neurodevelopmental and neurodegenerative clinical outcomes associated with the Kennedy pathway disorders.