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2. Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype

Author

Elsayed, Liena Elbaghir Omer, AlHarbi, Norah Ayed, Alqarni, Ashwaq Mohammed, Eltayeb, Huda Hussein Elwasila, Mostafa, Noura Mostafa Mohamed, Abdulrahim, Maha Mohammed, Zaid, Hadeel Ibrahim Bin, Alanzi, Latifah Mansour, Ababtain, Sarah Abdullah, Aldulaijan, Khawlah, Aloyouni, Sheka Yagub, Othman, Moneeb Abdullah Kassem, Alkheilewi, Mohammad Abdullah, Binduraihem, Adel Mohammed, Alrukban, Hadeel Abdollah, Ahmed, Hiba Yousif, AlRadini, Faten Abdullah, Alahdal, Hadil Mohammad, Mushiba, Aziza Mufareh, and Alzaher, Omaima Abdulazeem

Published
2024
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4. Awareness of consanguineous marriage burden and willingness towards premarital genetic testing in Sudan: a national cross-sectional study

Author

Elmugadam, Fatima M., primary, Ahmed, Haythem, additional, KARAMELGHANI, MOHAMMED, additional, Ali, Almigdad, additional, Ali, Israa, additional, Ahmed, Almegdad, additional, Salman, Mohammed, additional, Mohamed, Wadah, additional, Ahmed, Elhami A., additional, Abbasher Hussien Mohamed Ahmed, Khabab, additional, E. Mustafa Ahmed, Ghassan, additional, Elsayed, Liena, additional, and Musa, Ahmed, additional

Published
2024
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5. Novel variants causing megalencephalic leukodystrophy in Sudanese families

Author

Amin, Mutaz, Vignal, Cedric, Hamed, Ahlam A. A., Mohammed, Inaam N., Elseed, Maha A., Drunat, Severine, Babai, Arwa, Eltaraifee, Esraa, Elbadi, Iman, Abubaker, Rayan, Mustafa, Doaa, Yahia, Ashraf, Koko, Mahmoud, Osman, Melka, Bakhit, Yousuf, Elshafea, Azza, Alsiddig, Mohamed, Haroun, Sahwah, Lelay, Gurvan, Elsayed, Liena E. O., Ahmed, Ammar E., Boespflug-Tanguy, Odile, and Dorboz, Imen

Published
2022
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7. Bi-allelic PRRT2 variants may predispose to Self-limited Familial Infantile Epilepsy

Author

Koko, Mahmoud, primary, Elseed, Maha A., additional, Mohammed, Inaam N., additional, Hamed, Ahlam A., additional, Abd Allah, Amal S. I., additional, Yahia, Ashraf, additional, Siddig, Rayan A., additional, Altmüller, Janine, additional, Toliat, Mohammad Reza, additional, Elmahdi, Esra O., additional, Amin, Mutaz, additional, Ahmed, Elhami A., additional, Eltazi, Isra Z. M., additional, Elmugadam, Fatima A., additional, Abdelgadir, Wasma A., additional, Eltaraifee, Esraa, additional, Ibrahim, Mohamed O. M., additional, Ali, Nabila M. H., additional, Malik, Hiba M., additional, Babai, Arwa M., additional, Bakhit, Yousuf H., additional, Nürnberg, Peter, additional, Ibrahim, Muntaser E., additional, Salih, Mustafa A., additional, Schubert, Julian, additional, Elsayed, Liena E. O., additional, and Lerche, Holger, additional

Published
2024
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9. Machado-Joseph disease in a Sudanese family links East Africa to Portuguese families and allows reestimation of ancestral age of the Machado lineage

Author

Martins, Sandra, primary, Yahia, Ashraf, additional, Costa, Inês P. D., additional, Siddig, Hassab E., additional, Abubaker, Rayan, additional, Koko, Mahmoud, additional, Corral-Juan, Marc, additional, Matilla-Dueñas, Antoni, additional, Brice, Alexis, additional, Durr, Alexandra, additional, Leguern, Eric, additional, Ranum, Laura P. W., additional, Amorim, António, additional, Elsayed, Liena E. O., additional, Stevanin, Giovanni, additional, and Sequeiros, Jorge, additional

Published
2023
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10. Intrafamilial and interfamilial heterogeneity of PINK1-associated Parkinson's disease in Sudan

Author

Bakhit, Yousuf, primary, Ibrahim, Mohamed O., additional, Tesson, Christelle, additional, Elhassan, Ali A., additional, Ahmed, Mohamed Anwer, additional, Alebeed, Mohamed A., additional, Elrasheed, Salma M., additional, Omar, Mawia A., additional, Abubaker, Rayan, additional, Eltom, Khalid, additional, Shaheen, Mutaz T., additional, Ibrahim, Yousuf A., additional, Almak, Murad E., additional, Ali, Hiba A., additional, Abugrain, Ahmed A., additional, Almahal, Mohamed A., additional, MohamedSharif, Abubaker A., additional, Tahir, Mohamed Y., additional, Malik, Sawazen M., additional, Eldirdiri Abdelrahman, Hazim, additional, Khidir, Reem J., additional, Mohamed, Malaz T., additional, Abdalla, Abdelmohaymin, additional, Elsayed, Liena E.O., additional, Lesage, Suzanne, additional, Corvol, Jean-Christophe, additional, Seidi, Osheik, additional, and Wüllner, Ullrich, additional

Published
2023
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11. Bi-allelic PRRT2variants may predispose to Self-limited Familial Infantile Epilepsy

Author

Koko, Mahmoud, Elseed, Maha A., Mohammed, Inaam N., Hamed, Ahlam A., Abd Allah, Amal S. I., Yahia, Ashraf, Siddig, Rayan A., Altmüller, Janine, Toliat, Mohammad Reza, Elmahdi, Esra O., Amin, Mutaz, Ahmed, Elhami A., Eltazi, Isra Z. M., Elmugadam, Fatima A., Abdelgadir, Wasma A., Eltaraifee, Esraa, Ibrahim, Mohamed O. M., Ali, Nabila M. H., Malik, Hiba M., Babai, Arwa M., Bakhit, Yousuf H., Nürnberg, Peter, Ibrahim, Muntaser E., Salih, Mustafa A., Schubert, Julian, Elsayed, Liena E. O., and Lerche, Holger

Abstract

Heterozygous PRRT2variants are frequently implicated in Self-limited Infantile Epilepsy, whereas homozygous variants are so far linked to severe presentations including developmental and epileptic encephalopathy, movement disorders, and intellectual disability. In a study aiming to explore the genetics of epilepsy in the Sudanese population, we investigated several families including a consanguineous family with three siblings diagnosed with self-limited infantile epilepsy. We evaluated both dominant and recessive inheritance using whole exome sequencing and genomic arrays. We identified a pathogenic homozygous splice-site variant in the first intron of PRRT2[NC_000016.10(NM_145239.3):c.-65-1G > A] that segregated with the phenotype in this family. This work taps into the genetics of epilepsy in an underrepresented African population and suggests that the phenotypes of homozygous PRRT2variants may include milder epilepsy presentations without movement disorders.

Published
2024
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12. PLA2G6-associated late-onset parkinsonism in a Sudanese family

Author

Bakhit, Yousuf, Tesson, Christelle, Group, Sudanese Parkinson's Disease Study, Ibrahim, Mohamed O, Eltom, Khalid, Eltazi, Isra, Elsayed, Liena E O, Lesage, Suzanne, Seidi, Osheik, Corvol, Jean-Christophe, and Wüllner, Ullrich

Subjects
Adult, genetics [Dystonic Disorders], Group VI Phospholipases A2, PLA2G6 protein, human, genetics [Parkinsonian Disorders], Mutation, Humans, genetics [Group VI Phospholipases A2], ddc:610, Genetic Testing, Middle Aged, genetics [Dystonia]
Abstract

The phospholipase A2 group VI gene (PLA2G6) encodes an enzyme that catalyzes the hydrolytic release of fatty acids from phospholipids. Four neurological disorders with infantile, juvenile, or early adult-onset are associated with PLA2G6 genetic alterations, namely infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia-parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP). Few studies in Africa reported PLA2G6-associated disorders and none with parkinsonism of late adult onset.The patients were clinically assessed following UK Brain Bank diagnostic criteria and International Parkinson and Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Brain MRI without contrast was performed. Genetic testing was done using a custom-made Twist panel, screening 34 known genes, 27 risk factors, and 8 candidate genes associated with parkinsonism. Filtered variants were PCR-amplified and validated using Sanger sequencing and also tested in additional family members to study their segregation.Two siblings born to consanguineous parents developed parkinsonism at the age of 58 and 60 years, respectively. MRI showed an enlarged right hippocampus in patient 2, but no overt abnormalities indicative of INAD or iron deposits. We found two heterozygous variants in PLA2G6, an in-frame deletion NM_003560:c.2070_2072del (p.Val691del) and a missense variant NM_003560:c.956C>T (p.Thr319Met). Both variants were classified as pathogenic.This is the first case in which PLA2G6 is associated with late-onset parkinsonism. Functional analysis is needed to confirm the dual effect of both variants on the structure and function of iPLA2β.

Published
2023

14. Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degeneration

Author

Stevanin, Giovanni, primary, Hamed, Ahlam, additional, Mohamed, Inaam, additional, Elseed, Maha, additional, Salih, Mustafa, additional, Elsadig, Sarah, additional, Siddig, Hassab Elrasoul, additional, Nasreldien, Ali, additional, Abdullah, Mohamed Ahmed, additional, Elzubair, Maha, additional, Omer, Farouk, additional, BAKHIET, Aisha, additional, Abubaker, Rayan, additional, Abozar, Fatima, additional, Adil, Rawaa, additional, Emad, Sara, additional, Musallam, Mhammed Alhassan, additional, Eltazi, Isra, additional, Omer, Zulfa, additional, Malik, Hiba, additional, Mohamed, Mayada, additional, Elhassan, Ali, additional, Mohamed, Eman, additional, Ahmed, Ahmed, additional, Ahmed, Elhami, additional, Eltaraifee, Esraa, additional, Hussein, Bidour, additional, Allah, Amal Abd, additional, Mohamed, Lina, additional, Nimir, Mohamed, additional, Elseed, Omnia Tag, additional, Elhassan, Tasneem, additional, Elbashier, Abubakr, additional, Alfadul, Esraa, additional, Fadul, Moneeb, additional, Ali, Khalil, additional, Taha, Shaimaa, additional, Bushara, Elfatih, additional, Amin, Mutaz, additional, koko, Mahmoud, additional, Ibrahim, Muntaser, additional, Ahmed, Ammar, additional, Elsayed, Liena, additional, and Yahia, Ashraf, additional

Published
2022
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15. Methylation of alpha-synuclein in a Sudanese cohort

Author

Bakhit, Yousuf, primary, Schmitt, Ina, additional, Hamed, Ahlam, additional, Ibrahim, Etedal Ahmed A., additional, Mohamed, Inaam N., additional, El-Sadig, Sarah M., additional, Elseed, Maha A., additional, Alebeed, Mohamed A., additional, Shaheen, Mutaz T., additional, Ibrahim, Mohamed O., additional, Elhassan, Ali A., additional, Eltom, Khalid, additional, Ali, Hiba A., additional, Ibrahim, Yousuf A., additional, Almak, Murad E., additional, Abubaker, Rayan, additional, Ahmed, Mohamed Anwer, additional, Abugrain, Ahmed A., additional, Elrasheed, Salma M., additional, Omar, Mawia A., additional, Almahal, Mohamed A., additional, MohamedSharif, Abubaker A., additional, Tahir, Mohamed Y., additional, Malik, Sawazen M., additional, Eldirdiri, Hazim S., additional, Khidir, Reem J., additional, Mohamed, Malaz T., additional, Abdalla, Abdelmohaymin, additional, Omer, Farouk Yassen, additional, Elsayed, Liena E.O., additional, Babikir, Haydar El Hadi, additional, Bukhari, Elfateh Abd-Allah, additional, Seidi, Osheik, additional, and Wüllner, Ullrich, additional

Published
2022
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17. Case Report: A New Family With Pontocerebellar Hypoplasia 10 From Sudan

Author

Amin, Mutaz, primary, Vignal, Cedric, additional, Hamed, Ahlam A. A., additional, Mohammed, Inaam N., additional, Elseed, Maha A., additional, Abubaker, Rayan, additional, Bakhit, Yousuf, additional, Babai, Arwa, additional, Elbadi, Eman, additional, Eltaraifee, Esraa, additional, Mustafa, Doua, additional, Yahia, Ashraf, additional, Osman, Melka, additional, Koko, Mahmoud, additional, Mustafa, Mohamed, additional, Alsiddig, Mohamed, additional, Haroun, Sahwah, additional, Elshafea, Azza, additional, Drunat, Severine, additional, Elsayed, Liena E. O., additional, Ahmed, Ammar E., additional, Boespflug-Tanguy, Odile, additional, and Dorboz, Imen, additional

Published
2022
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18. Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Author

Elsayed, Liena, Eltazi, Isra Zuhair, Ahmed, Ammar, Stevanin, Giovanni, University of Khartoum, Princess Nourah Bint Abdulrahman University, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), HAL-SU, Gestionnaire, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS)

Subjects
genetic heterogeneity, spastic paraplegia, allelic variants, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, diagnostic yield, molecular mechanisms, phenotype-genotype correlation, diagnostic gap, clinical spectrum, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype ("SPGn" designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

Published
2021

19. Involvement of ADGRV1 Gene in Familial Forms of Genetic Generalized Epilepsy

Author

Dahawi, Maha, primary, Elmagzoub, Mohamed S., additional, A. Ahmed, Elhami, additional, Baldassari, Sara, additional, Achaz, Guillaume, additional, Elmugadam, Fatima A., additional, Abdelgadir, Wasma A., additional, Baulac, Stéphanie, additional, Buratti, Julien, additional, Abdalla, Omer, additional, Gamil, Sahar, additional, Alzubeir, Maha, additional, Abubaker, Rayan, additional, Noé, Eric, additional, Elsayed, Liena, additional, Ahmed, Ammar E., additional, and Leguern, Eric, additional

Published
2021
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20. Correction: Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, primary, Barbier, Mathieu, additional, Papin, Mélanie, additional, Davoine, Claire-Sophie, additional, Sayah, Sabrina, additional, Coarelli, Giulia, additional, Charles, Perrine, additional, Marelli, Cecilia, additional, Parodi, Livia, additional, Tranchant, Christine, additional, Goizet, Cyril, additional, Klebe, Stephan, additional, Lohmann, Ebba, additional, Van Maldergem, Lionel, additional, van Broeckhoven, Christine, additional, Coutelier, Marie, additional, Tesson, Christelle, additional, Stevanin, Giovanni, additional, Duyckaerts, Charles, additional, Brice, Alexis, additional, Durr, Alexandra, additional, Darios, Frédéric, additional, Forlani, Sylvie, additional, Site, Pitié-Salpêtrière, additional, Banneau, Guillaume, additional, Cazeneuve, Cécile, additional, Fontaine, Bertrand, additional, Azulay, Jean-Philippe, additional, Boesfplug-Tanguy, Odile, additional, Hannequin, Didier, additional, Hazan, Jamilé, additional, Burgo, Andrea, additional, Verny, Christophe, additional, Koenig, Michel, additional, Labauge, Pierre, additional, N’guyen, Karine, additional, Rodriguez, Diana, additional, Belarbi, Soraya, additional, Hamri, Abdelmadjid, additional, Tazir, Meriem, additional, Boesch, Sylvia, additional, Pandolfo, Massimo, additional, Laura, Jardim, additional, Guergueltcheva, Velina, additional, Tournev, Ivalo, additional, Pedraza Linarès, Olga Lucia, additional, Nielsen, Jørgen E., additional, Svenstrup, Kirsten, additional, Zaki, Maha, additional, Bauer, Peter, additional, Schöls, Lüdger, additional, Schüle, Rebecca, additional, Lossos, Alexander, additional, Bassi, Maria-Teresa, additional, Basso, Manuela, additional, Bertini, Enrico, additional, Brusco, Alfredo, additional, Casali, Carlo, additional, Casari, Giorgio, additional, Criscuolo, Chiara, additional, Filla, Alessandro, additional, Orsi, Laura, additional, Santorelli, Filippo M., additional, Valente, Enza Maria, additional, Vavla, Marinela, additional, Vazza, Giovanni, additional, Megarbane, André, additional, Benomar, Ali, additional, Kremer, Berry, additional, Van Roon-Mom, Willeke, additional, Roxburgh, Richard, additional, Erichsen, Anne Kjersti, additional, Tallaksen, Chantal, additional, Alonso, Isabel, additional, Coutinho, Paula, additional, Loureiro, José Léal, additional, Sequeiros, Jorge, additional, Salih, Mustapha, additional, Kostic, Vladimir S, additional, Rouco Axpe, Idoia, additional, Elsayed, Liena, additional, Paucar, Martin Arce, additional, Roumani, Samir, additional, Bing-Wen, Soong, additional, Reid, Evan, additional, Suran, Nethisinghe, additional, Warner, Thomas, additional, and Wood, Nicholas, additional

Published
2021
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21. Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia

Author

Yahia, Ashraf, Elsayed, Liena, Valter, Remi, Hamed, Ahlam, Mohammed, Inaam, Elseed, Maha, Salih, Mustafa, Esteves, Typhaine, Auger, Nicolas, Abubaker, Rayan, Koko, Mahmoud, Abozar, Fatima, Malik, Hiba, Adil, Rawaa, Emad, Sara, Musallam, Mhammed Alhassan, Idris, Razaz, Eltazi, Isra, Babai, Arwa, Ahmed, Elhami, Abd Allah, Amal, Mairey, Mathilde, Ahmed, Ahmed, Elbashir, Mustafa, Brice, Alexis, Ibrahim, Muntaser, Ahmed, Ammar, Lamari, Foudil, Stevanin, Giovanni, University of Khartoum, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Princess Nourah Bint Abdulrahman University, King Saud University [Riyadh] (KSU), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, Letterkenny Institute of Technology (LYIT), Osaka University [Osaka], Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), HAL-SU, Gestionnaire, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Letterkenny Institute of Technology

Subjects
phosphatidylserine, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Neurology, targeted-metabolomics, lipid metabolism, next-generation sequencing, ABHD16A, hereditary spastic paraplegia, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Original Research
Abstract

International audience; 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.

Published
2021

22. A Novel Nonsense Mutation in DNAJC6 Expands the Phenotype of Autosomal-Recessive Juvenile-Onset Parkinsonʼs Disease

Author

Elsayed, Liena Elbaghir Omer, Drouet, Valérie, Usenko, Tatiana, Mohammed, Inaam N., Hamed, Ahlam AbdAlrahman Ahmed, Elseed, Maha Abdelmoneim, Salih, Mustafa A.M., Koko, Mahmoud Eltayeb, Mohamed, Ashraf Yahia Osman, Siddig, Rayan Abubaker, Elbashir, Mustafa Idris, Ibrahim, Muntaser Eltayeb, Durr, Alexandra, Stevanin, Giovanni, Lesage, Suzanne, Ahmed, Ammar Eltahir, and Brice, Alexis

Published
2016
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23. Novel variants causing megalencephalic leukodystrophy in Sudanese families

Author

Amin, Mutaz, primary, Vignal, Cedric, additional, Hamed, Ahlam A. A., additional, Mohammed, Inaam N., additional, Elseed, Maha A., additional, Drunat, Severine, additional, Babai, Arwa, additional, Eltaraifee, Esraa, additional, Elbadi, Iman, additional, Abubaker, Rayan, additional, Mustafa, Doaa, additional, Yahia, Ashraf, additional, Koko, Mahmoud, additional, Osman, Melka, additional, Bakhit, Yousuf, additional, Elshafea, Azza, additional, Alsiddig, Mohamed, additional, Haroun, Sahwah, additional, Lelay, Gurvan, additional, Elsayed, Liena E. O., additional, Ahmed, Ammar E., additional, Boespflug-Tanguy, Odile, additional, and Dorboz, Imen, additional

Published
2021
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24. Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations

Author

Yahia, Ashraf, Hamed, Ahlam A. A., Mohamed, Inaam N., Elseed, Maha A., Salih, Mustafa A., El-sadig, Sarah M., Siddig, Hassab Elrasoul, Nasreldien, Ali Elsir Musa, Abdullah, Mohamed Ahmed, Elzubair, Maha, Omer, Farouk Yassen, Bakhiet, Aisha Motwakil, Abubaker, Rayan, Abozar, Fatima, Adil, Rawaa, Emad, Sara, Musallam, Mhammed Alhassan, Eltazi, Isra Z. M., Omer, Zulfa, Malik, Hiba, Mohamed, Mayada O. E., Elhassan, Ali A., Mohamed, Eman O. E., Ahmed, Ahmed K. M. A., Ahmed, Elhami A. A., Eltaraifee, Esraa, Hussein, Bidour K., Abd Allah, Amal S. I., Salah, Lina, Nimir, Mohamed, Tag Elseed, Omnia M., Elhassan, Tasneem E. A., Elbashier, Abubakr, Alfadul, Esraa S. A., Fadul, Moneeb, Ali, Khalil F., Taha, Shaimaa Omer M. A., Bushara, Elfatih E., Amin, Mutaz, Koko, Mahmoud, Ibrahim, Muntaser E., Ahmed, Ammar E., Elsayed, Liena E. O., and Stevanin, Giovanni

Abstract

Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively). We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52–59% (31–35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population.

Published
2023
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26. An identical‐by‐descent novel splice‐donor variant in PRUNE1 causes a neurodevelopmental syndrome with prominent dystonia in two consanguineous Sudanese families

Author

Koko, Mahmoud, primary, Yahia, Ashraf, additional, Elsayed, Liena E., additional, Hamed, Ahlam A., additional, Mohammed, Inaam N., additional, Elseed, Maha A., additional, Hamad, Muddathir H. A., additional, Babai, Arwa M., additional, Siddig, Rayan A., additional, Abd Allah, Amal S. I., additional, Mohamed, Mayada, additional, EL‐Amin, Melka, additional, Esteves, Typhaine, additional, Altmüller, Janine, additional, Toliat, Mohammad Reza, additional, Thiele, Holger, additional, Nürnberg, Peter, additional, Salih, Mustafa A., additional, Ahmed, Ammar E., additional, Lerche, Holger, additional, and Stevanin, Giovanni, additional

Published
2021
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27. supplementary file - A heterozygous mutation in CCDC88C gene causes early onset pure hereditary spastic paraplegia

Author

Yahia, Ashraf, Zhefan Stephen Chen, Ahmed, Ammar E., Emad, Sara, Rawaa Adil, Rayan Abubaker, Taha, Shaimaa Omer M.A., Salih, Mustafa A., Elsayed, Liena, Chan, Ho Yin Edwin, and Stevanin, Giovanni

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, nervous system diseases
Abstract

Supplementary material for "A heterozygous mutation in in CCDC88C gene causes early onset pure hereditary spastic paraplegia".

Published
2020
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28. Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, primary, Barbier, Mathieu, additional, Papin, Mélanie, additional, Davoine, Claire-Sophie, additional, Sayah, Sabrina, additional, Coarelli, Giulia, additional, Charles, Perrine, additional, Marelli, Cecilia, additional, Parodi, Livia, additional, Tranchant, Christine, additional, Goizet, Cyril, additional, Klebe, Stephan, additional, Lohmann, Ebba, additional, Van Maldergem, Lionel, additional, van Broeckhoven, Christine, additional, Coutelier, Marie, additional, Tesson, Christelle, additional, Stevanin, Giovanni, additional, Duyckaerts, Charles, additional, Brice, Alexis, additional, Durr, Alexandra, additional, Darios, Frédéric, additional, Forlani, Sylvie, additional, Site, Pitié-Salpêtrière, additional, Banneau, Guillaume, additional, Cazeneuve, Cécile, additional, Fontaine, Bertrand, additional, Azulay, Jean-Philippe, additional, Boesfplug-Tanguy, Odile, additional, Hannequin, Didier, additional, Hazan, Jamilé, additional, Burgo, Andrea, additional, Verny, Christophe, additional, Koenig, Michel, additional, Labauge, Pierre, additional, N’guyen, Karine, additional, Rodriguez, Diana, additional, Belarbi, Soraya, additional, Hamri, Abdelmadjid, additional, Tazir, Meriem, additional, Boesch, Sylvia, additional, Pandolfo, Massimo, additional, Laura, Jardim, additional, Guergueltcheva, Velina, additional, Tournev, Ivalo, additional, Pedraza Linarès, Olga Lucia, additional, Nielsen, Jørgen E., additional, Svenstrup, Kirsten, additional, Zaki, Maha, additional, Bauer, Peter, additional, Schöls, Lüdger, additional, Schüle, Rebecca, additional, Lossos, Alexander, additional, Bassi, Maria-Teresa, additional, Basso, Manuela, additional, Bertini, Enrico, additional, Brusco, Alfredo, additional, Casali, Carlo, additional, Casari, Giorgio, additional, Criscuolo, Chiara, additional, Filla, Alessandro, additional, Orsi, Laura, additional, Santorelli, Filippo M., additional, Valente, Enza Maria, additional, Vavla, Marinela, additional, Vazza, Giovanni, additional, Megarbane, André, additional, Benomar, Ali, additional, Kremer, Berry, additional, Van Roon-Mom, Willeke, additional, Roxburgh, Richard, additional, Erichsen, Anne Kjersti, additional, Tallaksen, Chantal, additional, Alonso, Isabel, additional, Coutinho, Paula, additional, Loureiro, José Léal, additional, Sequeiros, Jorge, additional, Salih, Mustapha, additional, Kostic, Vladimir S., additional, Rouco Axpe, Idoia, additional, Elsayed, Liena, additional, Paucar, Martin Arce, additional, Roumani, Samir, additional, Bing-Wen, Soong, additional, Reid, Evan, additional, Suran, Nethisinghe, additional, Warner, Thomas, additional, and Wood, Nicholas, additional

Published
2020
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29. Novel Homozygous Missense Mutation in the ARG1 Gene in a Large Sudanese Family

Author

Elsayed, Liena E. O., primary, Mohammed, Inaam N., additional, Hamed, Ahlam A. A., additional, Elseed, Maha A., additional, Salih, Mustafa A. M., additional, Yahia, Ashraf, additional, Abubaker, Rayan, additional, Koko, Mahmoud, additional, Abd Allah, Amal S. I., additional, Elbashir, Mustafa I., additional, Ibrahim, Muntaser E., additional, Brice, Alexis, additional, Ahmed, Ammar E., additional, and Stevanin, Giovanni, additional

Published
2020
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30. Exome Sequencing Revealed Mutations in ADAT3 and HERC2 Genes in two Sudanese Families with Syndromic Mental Retardation

Author

Yahia, Ashraf, primary, Bakhiet, Aisha M., additional, Hamed, Ahlam A., additional, Abozar, Fatima, additional, Adil, Rawaa, additional, Emad, Sara, additional, Musallam, Mhammed Alhassan, additional, Eltazi, Isra Z. M., additional, Maaroof, Omer M., additional, Ahmed, Ammar E., additional, Elsayed, Liena E., additional, and Stevanin, Giovanni, additional

Published
2020
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32. Overlap of polymicrogyria, hydrocephalus, and Joubert syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556

Author

Cauley, Edmund S., primary, Hamed, Ahlam, additional, Mohamed, Inaam N., additional, Elseed, Maha, additional, Martinez, Samantha, additional, Yahia, Ashraf, additional, Abozar, Fatima, additional, Abubakr, Rayan, additional, Koko, Mahmoud, additional, Elsayed, Liena, additional, Piao, Xianhua, additional, Salih, Mustafa A., additional, and Manzini, M. Chiara, additional

Published
2019
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33. Paraplégies spastiques héréditaires : exploration clinique au Soudan, études des origines moléculaires des formes autosomiques récessives et identification de nouveaux gènes en cause

Author

Elbaghir Omer Elsayed, Liena, STAR, ABES, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris VI, University of Khartoum, Ammar Ahmed, and Giovanni Stevanin

Subjects
Sudanese families, Séquençage de nouvelle génération, Consanguinité, Paraplégies spastiques héréditaires, Famille soudanaise, Neurodegenerative disorders, Hereditary spastic paraplegias, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Nouveaux gènes, Le séquençage de l'exome
Abstract

Hereditary spastic paraplegias (HSP), a heterogeneous group of spastic neurodegenerative disorders which impose diagnostic challenges. I explored the clinical varieties and genetic pathways of spastic neurodegeneration in a familial Sudanese cohort. We recruited 41 Sudanese families [337 individuals/106 HSP patients]. I have established a genomic DNA bank and when necessary, skin biopsies and fibroblasts were also obtained. A phenotype-based candidate gene approach was followed in 4 families. A targeted next generation sequencing (NGS) for 74 HSP-related genes was the main screening strategy in all-remaining 37 families. Whole exome sequencing (WES) was done in search for novel mutations in new genes in families with negative screening results. Occasionally, functional studies were conducted when feasible and relevant. I identified the genetic cause in 17/41 families. In 12 families, the mutated genes were known HSP genes. In 3 families, novel genes were identified mutated. 5 candidate genes segregated with disease in 2 other families with more experiments needed to conclude. Analysis of the NGS screening panel and of WES data imposed certain challenges as multiple genetic disorders were sometimes found running in parallel in the same/different branches of highly inbred families. We could expand the phenotypic heterogeneity of these disorders due to clinical differences observed between Sudanese patients and patients of other origins even when caused by mutations by the same gene/variant. This is the first genetic screening in a large set of HSP families in Sudan. It describes new causative genes, paving the way for further deciphering of the underlying mechanisms., Les paraplégies spastiques héréditaires (PSH) font partie d’un groupe plus large de pathologies neurodégénératives associant une spasticité. J’ai exploré la variabilité clinique et moléculaire de ces pathologies à l’aide d’une cohorte de familles soudanaises. Nous avons recruté 41 familles soudanaises [337 individus/106 atteints de PSH]. J’ai extrait l’ADN génomique et constitué une banque. Le criblage de gènes candidats a été réalisé dans 4 familles en fonction du phénotype des patients. La technologie de séquençage de nouvelle génération (SNG) appliquée à 74 gènes de PSH a ensuite été appliquée aux 37 cas restants. Enfin, le séquençage de l’exome a permis de rechercher les gènes en cause dans les cas négatifs. Dans certains cas, des études fonctionnelles ont été utilisées afin de valider l’effet biologique des mutations. J’ai pu identifier la cause génétique dans 17 familles. Dans 12 familles, la mutation concernait un gène de PSH connu. Dans 3 familles, un nouveau gène a été identifié. 5 gènes candidats restent à départager dans 2 familles. Il est à noter que parfois, de multiple mutations ou maladies génétiques ségrégaient dans nos familles, dans la même branche ou dans des branches séparées. La complexité de ces familles fortement consanguines a rendu l’analyse des données du SNG difficile. Une autre particularité a été l’hétérogénéité clinique associée à des mutations du même gène entre patients de la même famille ou en comparaison avec la littérature. Ce travail est la première étude à grande échelle de patients soudanais avec PSH et rapporte de nouveaux gènes en cause, prérequis pour mieux comprendre dans le futur les mécanismes sous-jacents.

Published
2016

35. Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

Author

Elsayed, Liena E O, primary, Mohammed, Inaam N, additional, Hamed, Ahlam A A, additional, Elseed, Maha A, additional, Johnson, Adam, additional, Mairey, Mathilde, additional, Mohamed, Hassab Elrasoul S A, additional, Idris, Mohamed N, additional, Salih, Mustafa A M, additional, El-sadig, Sarah M, additional, Koko, Mahmoud E, additional, Mohamed, Ashraf Y O, additional, Raymond, Laure, additional, Coutelier, Marie, additional, Darios, Frédéric, additional, Siddig, Rayan A, additional, Ahmed, Ahmed K M A, additional, Babai, Arwa M A, additional, Malik, Hiba M O, additional, Omer, Zulfa M B M, additional, Mohamed, Eman O E, additional, Eltahir, Hanan B, additional, Magboul, Nasr Aldin A, additional, Bushara, Elfatih E, additional, Elnour, Abdelrahman, additional, Rahim, Salah M Abdel, additional, Alattaya, Abdelmoneim, additional, Elbashir, Mustafa I, additional, Ibrahim, Muntaser E, additional, Durr, Alexandra, additional, Audhya, Anjon, additional, Brice, Alexis, additional, Ahmed, Ammar E, additional, and Stevanin, Giovanni, additional

Published
2016
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36. A Novel Nonsense Mutation in DNAJC 6 Expands the Phenotype of Autosomal-Recessive Juvenile-Onset Parkinson's Disease

Author

Elsayed, Liena Elbaghir Omer, primary, Drouet, Valérie, additional, Usenko, Tatiana, additional, Mohammed, Inaam N., additional, Hamed, Ahlam AbdAlrahman Ahmed, additional, Elseed, Maha Abdelmoneim, additional, Salih, Mustafa A.M., additional, Koko, Mahmoud Eltayeb, additional, Mohamed, Ashraf Yahia Osman, additional, Siddig, Rayan Abubaker, additional, Elbashir, Mustafa Idris, additional, Ibrahim, Muntaser Eltayeb, additional, Durr, Alexandra, additional, Stevanin, Giovanni, additional, Lesage, Suzanne, additional, Ahmed, Ammar Eltahir, additional, and Brice, Alexis, additional

Published
2016
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37. Correction: Clinical, neuropathological, and genetic characterization of STUB1variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, Barbier, Mathieu, Papin, Mélanie, Davoine, Claire-Sophie, Sayah, Sabrina, Coarelli, Giulia, Charles, Perrine, Marelli, Cecilia, Parodi, Livia, Tranchant, Christine, Goizet, Cyril, Klebe, Stephan, Lohmann, Ebba, Van Maldergem, Lionel, van Broeckhoven, Christine, Coutelier, Marie, Tesson, Christelle, Stevanin, Giovanni, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Durr, Alexandra, Stevanin, Giovanni, Brice, Alexis, Darios, Frédéric, Forlani, Sylvie, Site, Pitié-Salpêtrière, Banneau, Guillaume, Cazeneuve, Cécile, Charles, Perrine, Duyckaerts, Charles, Fontaine, Bertrand, Azulay, Jean-Philippe, Boesfplug-Tanguy, Odile, Goizet, Cyril, Hannequin, Didier, Hazan, Jamilé, Burgo, Andrea, Verny, Christophe, Koenig, Michel, Labauge, Pierre, Marelli, Cecilia, N’guyen, Karine, Rodriguez, Diana, Belarbi, Soraya, Hamri, Abdelmadjid, Tazir, Meriem, Boesch, Sylvia, Pandolfo, Massimo, Laura, Jardim, Guergueltcheva, Velina, Tournev, Ivalo, Pedraza Linarès, Olga Lucia, Nielsen, Jørgen E., Svenstrup, Kirsten, Zaki, Maha, Bauer, Peter, Schöls, Lüdger, Schüle, Rebecca, Lossos, Alexander, Bassi, Maria-Teresa, Basso, Manuela, Bertini, Enrico, Brusco, Alfredo, Casali, Carlo, Casari, Giorgio, Criscuolo, Chiara, Filla, Alessandro, Orsi, Laura, Santorelli, Filippo M., Valente, Enza Maria, Vavla, Marinela, Vazza, Giovanni, Megarbane, André, Benomar, Ali, Kremer, Berry, Van Roon-Mom, Willeke, Roxburgh, Richard, Erichsen, Anne Kjersti, Tallaksen, Chantal, Alonso, Isabel, Coutinho, Paula, Loureiro, José Léal, Sequeiros, Jorge, Salih, Mustapha, Kostic, Vladimir S, Rouco Axpe, Idoia, Elsayed, Liena, Paucar, Martin Arce, Roumani, Samir, Bing-Wen, Soong, Reid, Evan, Suran, Nethisinghe, Warner, Thomas, and Wood, Nicholas

Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41436-020-01064-y

Published
2021
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38. Novel Homozygous Missense Mutation in the ARG1 Gene in a Large Sudanese Family

Author

Elsayed, Liena, Mohammed, Inaam, Hamed, Ahlam, Elseed, Maha, Salih, Mustafa, Yahia, Ashraf, Abubaker, Rayan, Koko, Mahmoud, Abd Allah, Amal, Elbashir, Mustafa, Ibrahim, Muntaser, Brice, Alexis, Ahmed, Ammar, Stevanin, Giovanni, University of Khartoum, Princess Nourah Bint Abdulrahman University, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), King Saud University [Riyadh] (KSU), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université

Subjects
[SDV] Life Sciences [q-bio], Sudan, spastic quadriplegia, Neurology, [SDV]Life Sciences [q-bio], hyperargininemia, Case Report, ARG1 gene, whole exome sequencing
Abstract

International audience; Background: Arginases catalyze the last step in the urea cycle. Hyperargininemia, a rare autosomal-recessive disorder of the urea cycle, presents after the first year of age with regression of milestones and evolves gradually into progressive spastic quadriplegia and cognitive dysfunction. Genetic studies reported various mutations in the ARG1 gene that resulted in hyperargininemia due to a complete or partial loss of arginase activity. Case Presentation: Five patients from an extended highly consanguineous Sudanese family presented with regression of the acquired milestones, spastic quadriplegia, and mental retardation. The disease onset ranged from 1 to 3 years of age. Two patients had epileptic seizures and one patient had stereotypic clapping. Genetic testing using whole-exome sequencing, done for the patients and a healthy parent, confirmed the presence of a homozygous novel missense variant in the ARG1 gene [GRCh37 (NM_001244438.1): exon 4: g.131902487T>A, c.458T>A, p.(Val153Glu)]. The variant was predicted pathogenic by five algorithms and affected a highly conserved amino acid located in the protein domain ureohydrolase, arginase subgroup. Sanger sequencing of 13 sampled family members revealed complete co-segregation between the variant and the disease distribution in the family in line with an autosomal-recessive mode of inheritance. Biochemical analysis confirmed hyperargininemia in five patients. Conclusion: This study reports the first Sudanese family with ARG1 mutation. The reported variant is a loss-of-function missense mutation. Its pathogenicity is strongly supported by the clinical phenotype, the computational functional impact prediction, the complete co-segregation with the disease, and the biochemical assessment.

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39. Case report of a novel homozygous splice site mutation in <italic>PLA2G6</italic> gene causing infantile neuroaxonal dystrophy in a Sudanese family.

Author

Elsayed, Liena E. O., Mohammed, Inaam N., Hamed, Ahlam A. A., Elseed, Maha A., Salih, Mustafa A. M., Yahia, Ashraf, Siddig, Rayan A., Amin, Mutaz, Koko, Mahmoud, Elbashir, Mustafa I., Ibrahim, Muntaser E., Brice, Alexis, Ahmed, Ammar E., and Stevanin, Giovanni

Subjects
GENETIC mutation, DYSTROPHY, PHENOTYPES
Abstract

Background: Infantile neuroaxonal dystrophy (INAD) is a rare hereditary neurological disorder caused by mutations in PLA2G6. The disease commonly affects children below 3 years of age and presents with delay in motor skills, optic atrophy and progressive spastic tetraparesis. Studies of INAD in Africa are extremely rare, and genetic studies from Sub Saharan Africa are almost non-existent. Case presentation: Two Sudanese siblings presented, at ages 18 and 24 months, with regression in both motor milestones and speech development and hyper-reflexia. Brain MRI showed bilateral and symmetrical T2/FLAIR hyperintense signal changes in periventricular areas and basal ganglia and mild cerebellar atrophy. Whole exome sequencing with confirmatory Sanger sequencing were performed for the two patients and healthy family members. A novel variant (NM_003560.2 c.1427 + 2 T > C) acting on a splice donor site and predicted to lead to skipping of exon 10 was found in PLA2G6. It was found in a homozygous state in the two patients and homozygous reference or heterozygous in five healthy family members. Conclusion: This variant has one very strong (loss of function mutation) and three supporting evidences for its pathogenicity (segregation with the disease, multiple computational evidence and specific patients' phenotype). Therefore this variant can be currently annotated as "pathogenic". This is the first study to report mutations in PLA2G6 gene in patients from Sudan. [ABSTRACT FROM AUTHOR]

Published
2018
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40. Standards of NGS Data Sharing and Analysis in Ataxias: Recommendations by the NGS Working Group of the Ataxia Global Initiative

Author

Beijer, Danique, Fogel, Brent L, Beltran, Sergi, Danzi, Matt C, Németh, Andrea H, Züchner, Stephan, Synofzik, Matthis, AGI Ataxia NGS genomics, platforms Working Group, Ashrafi, Mahmoud Reza, Bataller, Luis, Bertini, Enrico, Boesch, Sylvia, Buijsen, Ronald, Cassou, Emanuel, Chan, Edwin, Damásio, Joana, Donis, Karina, Elert-Dobkowska, Ewelina, Elsayed, Liena, Espinos, Carmen, Hanağasi, Haşmet, Heidari, Morteza, Nachbauer, Wolfgang, Oliveira, Jorge, Opal, Puneet, Paisan-Ruiz, Coro, Puccio, Hélène, Saccà, Francesco, Saraiva-Pereira, Maria Luiza, Schmidt, Thorsten, Schüle-Freyer, Rebecca, Stevanin, Giovanni, Wilke, Carlo, Yoon, Grace, Zach, Neta, Zanni, Ginevra, Adarmes, Astrid, and Alhusaini, Saud

Subjects
Consensus, Neurology, Information dissemination, ddc:610, Genomics, Neurology (clinical), High-throughput nucleotide sequencing, Cerebellar ataxia
Abstract

Data de publicació electrònica: 04-03-2023 The Ataxia Global Initiative (AGI) is a worldwide multi-stakeholder research platform to systematically enhance trial-readiness in degenerative ataxias. The next-generation sequencing (NGS) working group of the AGI aims to improve methods, platforms, and international standards for ataxia NGS analysis and data sharing, ultimately allowing to increase the number of genetically ataxia patients amenable for natural history and treatment trials. Despite extensive implementation of NGS for ataxia patients in clinical and research settings, the diagnostic gap remains sizeable, as approximately 50% of patients with hereditary ataxia remain genetically undiagnosed. One current shortcoming is the fragmentation of patients and NGS datasets on different analysis platforms and databases around the world. The AGI NGS working group in collaboration with the AGI associated research platforms—CAGC, GENESIS, and RD-Connect GPAP—provides clinicians and scientists access to user-friendly and adaptable interfaces to analyze genome-scale patient data. These platforms also foster collaboration within the ataxia community. These efforts and tools have led to the diagnosis of > 500 ataxia patients and the discovery of > 30 novel ataxia genes. Here, the AGI NGS working group presents their consensus recommendations for NGS data sharing initiatives in the ataxia field, focusing on harmonized NGS variant analysis and standardized clinical and metadata collection, combined with collaborative data and analysis tool sharing across platforms. Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Horizon 2020 research and innovation programme (grant 779257 Solve-RD to MS and SB), and the European Joint Programme on Rare Diseases (grant 825575 EJP RD to SB) under the EJP RD COFUND-EJP No. 825575 (PROSPAX consortium, to MS and—as an associated partner—SZ). DB is supported by a Postdoctoral Fellowship from the Alexander von Humboldt Foundation.

Published
2023

41. A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2 -related disorders caused by missense changes.

Author

Flannery KP, Safwat S, Matsell E, Battula N, Hamed AAA, Mohamed IN, Elseed MA, Koko M, Abubaker R, Abozar F, Elsayed LEO, Bhise V, Molday RS, Salih MA, Yahia A, and Manzini MC

Abstract

ATPase, class 1, type 8A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals., Competing Interests: Conflict of Interest The authors declare no conflicts of interest.

Published
2024
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42. PLA2G6-associated late-onset parkinsonism in a Sudanese family.

Author

Bakhit Y, Tesson C, Ibrahim MO, Eltom K, Eltazi I, Elsayed LEO, Lesage S, Seidi O, Corvol JC, and Wüllner U

Subjects
Adult, Humans, Middle Aged, Genetic Testing, Group VI Phospholipases A2 genetics, Mutation, Dystonia genetics, Dystonic Disorders genetics, Parkinsonian Disorders genetics
Abstract

Introduction: The phospholipase A2 group VI gene (PLA2G6) encodes an enzyme that catalyzes the hydrolytic release of fatty acids from phospholipids. Four neurological disorders with infantile, juvenile, or early adult-onset are associated with PLA2G6 genetic alterations, namely infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia-parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP). Few studies in Africa reported PLA2G6-associated disorders and none with parkinsonism of late adult onset., Material and Methods: The patients were clinically assessed following UK Brain Bank diagnostic criteria and International Parkinson and Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Brain MRI without contrast was performed. Genetic testing was done using a custom-made Twist panel, screening 34 known genes, 27 risk factors, and 8 candidate genes associated with parkinsonism. Filtered variants were PCR-amplified and validated using Sanger sequencing and also tested in additional family members to study their segregation., Result: Two siblings born to consanguineous parents developed parkinsonism at the age of 58 and 60 years, respectively. MRI showed an enlarged right hippocampus in patient 2, but no overt abnormalities indicative of INAD or iron deposits. We found two heterozygous variants in PLA2G6, an in-frame deletion NM&#95;003560:c.2070&#95;2072del (p.Val691del) and a missense variant NM&#95;003560:c.956C>T (p.Thr319Met). Both variants were classified as pathogenic., Conclusion: This is the first case in which PLA2G6 is associated with late-onset parkinsonism. Functional analysis is needed to confirm the dual effect of both variants on the structure and function of iPLA2β., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Published
2023
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43. Genetic diagnosis in Sudanese and Tunisian families with syndromic intellectual disability through exome sequencing.

Author

Yahia A, Ayed IB, Hamed AA, Mohammed IN, Elseed MA, Bakhiet AM, Guillot-Noel L, Abozar F, Adil R, Emad S, Abubaker R, Musallam MA, Eltazi IZM, Omer Z, Maaroof OM, Soussi A, Bouzid A, Kmiha S, Kamoun H, Salih MA, Ahmed AE, Elsayed L, Masmoudi S, and Stevanin G

Subjects
Exome, Humans, Microcephaly genetics, Mutation, Paraplegia genetics, Pedigree, Phenotype, Sudan, Tunisia, Exome Sequencing, Adenosine Deaminase genetics, Intellectual Disability diagnosis, RNA-Binding Proteins genetics, Tumor Suppressor Proteins genetics, Ubiquitin-Protein Ligases genetics
Abstract

Background: Intellectual disability is a form of neurodevelopmental disorders that begin in childhood and is characterized by substantial intellectual difficulties as well as difficulties in conceptual, social, and practical areas of living. Several genetic and nongenetic factors contribute to its development; however, its most severe forms are generally attributed to single-gene defects. High-throughput technologies and data sharing contributed to the diagnosis of hundreds of single-gene intellectual disability subtypes., Method: We applied exome sequencing to identify potential variants causing syndromic intellectual disability in six Sudanese patients from four unrelated families. Data sharing through the Varsome portal corroborated the diagnosis of one of these patients and a Tunisian patient investigated through exome sequencing. Sanger sequencing validated the identified variants and their segregation with the phenotypes in the five studied families., Result: We identified three pathogenic/likely pathogenic variants in CCDC82, ADAT3, and HUWE1 and variants of uncertain significance in HERC2 and ATP2B3. The patients with the CCDC82 variants had microcephaly and spasticity, two signs absent in the two previously reported families with CCDC82-related intellectual disability., Conclusion: In conclusion, we report new patients with pathogenic mutations in the genes CCDC82, ADAT3, and HUWE1. We also highlight the possibility of extending the CCDC82-linked phenotype to include spastic paraplegia and microcephaly., (© 2022 John Wiley & Sons Ltd/University College London.)

Published
2022
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44. Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview.

Author

Elsayed LEO, Eltazi IZ, Ahmed AE, and Stevanin G

Abstract

Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype ("SPGn" designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, except a grant received by GS from Biogen, but unrelated to this work., (Copyright © 2021 Elsayed, Eltazi, Ahmed and Stevanin.)

Published
2021
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