Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia

Abstract

<b>Introduction:</b> Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity. <b>Methods:</b> We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies. <b>Results and Discussion:</b> Two homozygous variants in <i>ABHD16A</i> segregated with the disease in the two studied families. <i>ABHD16A</i> encodes the main brain phosphatidylserine hydrolase. <i>In vitro</i>, we confirmed that <i>ABHD16A</i> loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts. <b>Conclusion:</b> <i>ABHD16A</i> loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.