Further delineation of the phenotypic and metabolomic profile of ALDH1L2‐related neurodevelopmental disorder

Abstract ALDH1L2, a mitochondrial enzyme in folate metabolism, converts 10‐formyl‐THF (10‐formyltetrahydrofolate) to THF (tetrahydrofolate) and CO 2 . At the cellular level, deficiency of this NADP + ‐dependent reaction results in marked reduction in NADPH/NADP + ratio and reduced mitochondrial ATP. Thus far, a single patient with biallelic ALDH1L2 variants and the phenotype of a neurodevelopmental disorder has been reported. Here, we describe another patient with a neurodevelopmental disorder associated with a novel homozygous missense variant in ALDH1L2 , Pro133His. The variant caused marked reduction in the ALDH1L2 enzyme activity in skin fibroblasts derived from the patient as probed by 10‐FDDF, a stable synthetic analog of 10‐formyl‐THF. Additional associated abnormalities in these fibroblasts include reduced NADPH/NADP + ratio and pool of mitochondrial ATP, upregulated autophagy and dramatically altered metabolomic profile. Overall, our study further supports a link between ALDH1L2 deficiency and abnormal neurodevelopment in humans.