AUTHOR=Yahia Ashraf , Elsayed Liena E. O. , Valter Remi , Hamed Ahlam A. A. , Mohammed Inaam N. , Elseed Maha A. , Salih Mustafa A. , Esteves Typhaine , Auger Nicolas , Abubaker Rayan , Koko Mahmoud , Abozar Fatima , Malik Hiba , Adil Rawaa , Emad Sara , Musallam Mhammed Alhassan , Idris Razaz , Eltazi Isra Z. M. , Babai Arwa , Ahmed Elhami A. A. , Abd Allah Amal S. I. , Mairey Mathilde , Ahmed Ahmed K. M. A. , Elbashir Mustafa I. , Brice Alexis , Ibrahim Muntaser E. , Ahmed Ammar E. , Lamari Foudil , Stevanin Giovanni 

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

JOURNAL=Frontiers in Neurology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.720201

DOI=10.3389/fneur.2021.720201

ISSN=1664-2295

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results and Discussion:</bold> Two homozygous variants in <italic>ABHD16A</italic> segregated with the disease in the two studied families. <italic>ABHD16A</italic> encodes the main brain phosphatidylserine hydrolase. <italic>In vitro</italic>, we confirmed that <italic>ABHD16A</italic> loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts.</p><p><bold>Conclusion:</bold><italic>ABHD16A</italic> loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.</p>