Frontiers in Neurology (Aug 2021)
Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia
- Ashraf Yahia,
- Ashraf Yahia,
- Ashraf Yahia,
- Ashraf Yahia,
- Liena E. O. Elsayed,
- Liena E. O. Elsayed,
- Remi Valter,
- Remi Valter,
- Ahlam A. A. Hamed,
- Inaam N. Mohammed,
- Maha A. Elseed,
- Mustafa A. Salih,
- Typhaine Esteves,
- Typhaine Esteves,
- Nicolas Auger,
- Nicolas Auger,
- Rayan Abubaker,
- Mahmoud Koko,
- Fatima Abozar,
- Hiba Malik,
- Rawaa Adil,
- Sara Emad,
- Mhammed Alhassan Musallam,
- Razaz Idris,
- Isra Z. M. Eltazi,
- Arwa Babai,
- Elhami A. A. Ahmed,
- Amal S. I. Abd Allah,
- Mathilde Mairey,
- Ahmed K. M. A. Ahmed,
- Ahmed K. M. A. Ahmed,
- Ahmed K. M. A. Ahmed,
- Mustafa I. Elbashir,
- Alexis Brice,
- Muntaser E. Ibrahim,
- Ammar E. Ahmed,
- Foudil Lamari,
- Giovanni Stevanin,
- Giovanni Stevanin
Affiliations
- Ashraf Yahia
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Ashraf Yahia
- Department of Biochemistry, Faculty of Medicine, National University, Khartoum, Sudan
- Ashraf Yahia
- Sorbonne Université, Institut du Cerveau–Paris Brain Institute, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
- Ashraf Yahia
- Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris, France
- Liena E. O. Elsayed
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Liena E. O. Elsayed
- College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
- Remi Valter
- Sorbonne Université, Institut du Cerveau–Paris Brain Institute, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
- Remi Valter
- Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris, France
- Ahlam A. A. Hamed
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Inaam N. Mohammed
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Maha A. Elseed
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Mustafa A. Salih
- Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Typhaine Esteves
- Sorbonne Université, Institut du Cerveau–Paris Brain Institute, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
- Typhaine Esteves
- Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris, France
- Nicolas Auger
- Sorbonne Université, Institut du Cerveau–Paris Brain Institute, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
- Nicolas Auger
- Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris, France
- Rayan Abubaker
- Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan
- Mahmoud Koko
- Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tubingen, Germany
- Fatima Abozar
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Hiba Malik
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Rawaa Adil
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Sara Emad
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Mhammed Alhassan Musallam
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Razaz Idris
- Letterkenny University Hospital, Letterkenny, Ireland
- Isra Z. M. Eltazi
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Arwa Babai
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Elhami A. A. Ahmed
- 0UNESCO Chair on Bioethics, University of Khartoum, Khartoum, Sudan
- Amal S. I. Abd Allah
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Mathilde Mairey
- Sorbonne Université, Institut du Cerveau–Paris Brain Institute, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
- Ahmed K. M. A. Ahmed
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Ahmed K. M. A. Ahmed
- 1Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan
- Ahmed K. M. A. Ahmed
- 2Immunology Frontier Research Center, Osaka University, Suita, Japan
- Mustafa I. Elbashir
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Alexis Brice
- Sorbonne Université, Institut du Cerveau–Paris Brain Institute, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
- Muntaser E. Ibrahim
- Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan
- Ammar E. Ahmed
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Foudil Lamari
- 3APHP, Pitié-Salpêtrière Hospital, Metabolic Biochemistry unit, Department of Biochemistry of Neurometabolic Diseases, Paris, France
- Giovanni Stevanin
- Sorbonne Université, Institut du Cerveau–Paris Brain Institute, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
- Giovanni Stevanin
- Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris, France
- DOI
- https://doi.org/10.3389/fneur.2021.720201
- Journal volume & issue
-
Vol. 12
Abstract
Introduction: 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.Methods: 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.Results and Discussion: Two homozygous variants in ABHD16A segregated with the disease in the two studied families. ABHD16A encodes the main brain phosphatidylserine hydrolase. In vitro, we confirmed that ABHD16A loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts.Conclusion:ABHD16A loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.
Keywords
- ABHD16A
- hereditary spastic paraplegia
- next-generation sequencing
- targeted-metabolomics
- lipid metabolism
- phosphatidylserine
