28 results on '"Sherbini O"'
Search Results
2. Classification of Mutations in TUBB4A: A New Spectrum of Disease
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Charsar, B., Cross, Z., Sherbini, O., Vanderver, A., Hamilton, E., van der Knapp, M., and Neurology
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- 2018
3. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females
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Gilles Morin, Krista Bluske, Nathaniel H. Robin, Laurence Faivre, Manuela Priolo, Dihong Zhou, Evangeline Kurtz-Nelson, Tianyun Wang, Omar Sherbini, Daryl A. Scott, Karen Stals, Fabíola Paoli Monteiro, Kaifang Pang, Sara Cabet, Francesca Clementina Radio, Bruno Dallapiccola, Marjon van Slegtenhorst, Rachel K. Earl, Katheryn Grand, Maria Iascone, Alice S. Brooks, Angelo Selicorni, July K. Jean Cuevas, Paolo Gasparini, Maria Lisa Dentici, Marialetizia Motta, Britt-Marie Anderlid, Kristin Lindstrom, Berrin Monteleone, Andrea Ciolfi, Karin Weiss, Katharina Steindl, Kirsty McWalter, Rosalba Carrozzo, Ruben Boers, Helen Kingston, Kym M. Boycott, Bekim Sadikovic, Laura Schultz-Rogers, Evan E. Eichler, Laura A Cross, Alison M R Castle, Louisa Kalsner, Lucia Pedace, Marijke R. Wevers, John M. Graham, Jessica Sebastian, Antonio Vitobello, Gaetan Lesca, Alexander P.A. Stegmann, Suneeta Madan-Khetarpal, Tahsin Stefan Barakat, Abdallah F. Elias, Teresa Robert Finestra, Adeline Vanderver, Peter D. Turnpenny, Bregje W.M. van Bon, Aida Telegrafi, David J. Amor, Deepali N. Shinde, Pedro A. Sanchez-Lara, Lisenka E.L.M. Vissers, Adam Jackson, Rolph Pfundt, Alessandro Bruselles, Andres Hernandez-Garcia, Karin E. M. Diderich, Flavio Faletra, Dana H. Goodloe, Joanne Baez, Sarit Ravid, Romano Tenconi, Sarah L. Sawyer, Lynn Pais, Bronwyn Kerr, Joost Gribnau, Lauren Carter, Melissa T. Carter, Zhandong Liu, Jennifer L. Kemppainen, Jennifer MacKenzie, Jimmy Holder, Elke de Boer, Margaret Au, Taila Hartley, Carol J Saunders, Luciana Musante, Bert B.A. de Vries, Tania Vertemati Secches, Haley McConkey, Willow Sheehan, Francesca Pantaleoni, Caterina Zanus, Christophe Philippe, Chelsea Roadhouse, Stefania Lo Cicero, Sian Ellard, R. Tanner Hagelstrom, Megha Desai, Fernando Kok, Joset Pascal, Marco Tartaglia, Eric W. Klee, Eva Morava, Michael A. Levy, Peggy Kulch, Lyndon Gallacher, Erica L. Macke, Emilia Stellacci, Siddharth Banka, Kristin G. Monaghan, Anita Rauch, Meghan C. Towne, Kate Chandler, Clinical Genetics, Developmental Biology, Radio, F. C., Pang, K., Ciolfi, A., Levy, M. A., Hernandez-Garcia, A., Pedace, L., Pantaleoni, F., Liu, Z., de Boer, E., Jackson, A., Bruselles, A., Mcconkey, H., Stellacci, E., Lo Cicero, S., Motta, M., Carrozzo, R., Dentici, M. L., Mcwalter, K., Desai, M., Monaghan, K. G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P. A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., Mackenzie, J. J., Monteleone, B., Saunders, C. J., Jean Cuevas, J. K., Cross, L., Zhou, D., Hartley, T., Sawyer, S. L., Monteiro, F. P., Secches, T. V., Kok, F., Schultz-Rogers, L. E., Macke, E. L., Morava, E., Klee, E. W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D. J., Pais, L., Gallacher, L., Turnpenny, P. D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A. M. R., Carter, M. T., Kalsner, L., de Vries, B. B. A., van Bon, B. W., Wevers, M. R., Pfundt, R., Stegmann, A. P. A., Kerr, B., Kingston, H. M., Chandler, K. E., Sheehan, W., Elias, A. F., Shinde, D. N., Towne, M. C., Robin, N. H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R. T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E. C., Earl, R. K., Anderlid, B. -M., Morin, G., van Slegtenhorst, M., Diderich, K. E. M., Brooks, A. S., Gribnau, J., Boers, R. G., Finestra, T. R., Carter, L. B., Rauch, A., Gasparini, P., Boycott, K. M., Barakat, T. S., Graham, J. M., Faivre, L., Banka, S., Wang, T., Eichler, E. E., Priolo, M., Dallapiccola, B., Vissers, L. E. L. M., Sadikovic, B., Scott, D. A., Holder, J. L., Tartaglia, M., MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output
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0301 basic medicine ,SHARP ,Male ,obesity ,genotype-phenotype correlations ,Autism Spectrum Disorder ,PROTEIN ,Chromosome Disorders ,Haploinsufficiency ,RNA-Binding Protein ,PHENOTYPE CORRELATIONS ,1p36 ,distal 1p36 deletion syndrome ,DNA methylome analysis ,episignature ,neurodevelopmental disorder ,proximal 1p36 deletion syndrome ,SPEN ,X chromosome ,Adolescent ,Child ,Child, Preschool ,Chromosome Deletion ,Chromosomes, Human, Pair 1 ,Chromosomes, Human, X ,DNA Methylation ,DNA-Binding Proteins ,Epigenesis, Genetic ,Female ,Humans ,Intellectual Disability ,Neurodevelopmental Disorders ,Phenotype ,RNA-Binding Proteins ,Young Adult ,0302 clinical medicine ,Neurodevelopmental disorder ,Neurodevelopmental Disorder ,Intellectual disability ,MOLECULAR CHARACTERIZATION ,Genetics (clinical) ,Genetics ,DNA methylome analysi ,SPLIT-ENDS ,Hypotonia ,Autism spectrum disorder ,MONOSOMY 1P36 ,Pair 1 ,medicine.symptom ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Human ,DNA-Binding Protein ,Biology ,genotype-phenotype correlation ,Chromosomes ,03 medical and health sciences ,Genetic ,SDG 3 - Good Health and Well-being ,Report ,REVEALS ,medicine ,Epigenetics ,Preschool ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,1p36 deletion syndrome ,IDENTIFICATION ,MUTATIONS ,medicine.disease ,GENE ,030104 developmental biology ,Chromosome Disorder ,030217 neurology & neurosurgery ,Epigenesis - Abstract
Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
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- 2021
4. De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features
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Benjamin Navet, Renee Perrier, Kiyotaka Tomiwa, Alexander Pepler, Hui Xi, Adele Schneider, Xiao Mao, Ryan J. Taft, Paul Rollier, Alban Ziegler, Roberto Colombo, Noriko Miyake, Emmanuel Scalais, Katrien Stouffs, Estelle Colin, Denise L. Perry, Adeline Vanderver, Nobuhiko Okamoto, Magalie Barth, Li Shu, Elizabeth Wohler, Louise Amlie-Wolf, Hainan Zhang, Alessandro Serretti, Naomichi Matsumoto, Dominique Bonneau, Hua Wang, Omar Sherbini, Alka Malhotra, Nara Sobreira, Alessandra Ferrarini, Malhotra A., Ziegler A., Shu L., Perrier R., Amlie-Wolf L., Wohler E., Lygia De MacEna Sobreira N., Colin E., Vanderver A., Sherbini O., Stouffs K., Scalais E., Serretti A., Barth M., Navet B., Rollier P., Xi H., Wang H., Zhang H., Perry D.L., Ferrarini A., Colombo R., Pepler A., Schneider A., Tomiwa K., Okamoto N., Matsumoto N., Miyake N., Taft R., Mao X., Bonneau D., Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hunan Agricultural University [Changsha], Department of Neurology, Children's National Medical Center, Universitair Ziekenhuis Brussel, Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Institute of Psychiatry, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Réseau Maladies Métaboliques, Hôpitaux Universitaires du Grand Ouest, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), CHU Pontchaillou [Rennes], Shandong University, Nanjing University of Science and Technology (NJUST), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Università degli Studi di Brescia [Brescia], Genetics Division, Einstein Medical Center, Gifu University Graduate School of Medicine, Yokohama City University School of Medecine (YCUSM), Yokohama University School of Medecine, Institute for Molecular Bioscience, University of Queensland [Brisbane], Clinical sciences, Medical Genetics, Reproduction and Genetics, and Faculty of Law and Criminology
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0301 basic medicine ,gain of function mutation ,Microcephaly ,[SDV]Life Sciences [q-bio] ,Population ,Biology ,DNA sequencing ,03 medical and health sciences ,0302 clinical medicine ,Neurodevelopmental disorder ,Genetics ,medicine ,Missense mutation ,education ,Exome ,Allele frequency ,Genetics (clinical) ,Exome sequencing ,ComputingMilieux_MISCELLANEOUS ,education.field_of_study ,mutation, missense ,medicine.disease ,030104 developmental biology ,genetics, medical ,030217 neurology & neurosurgery - Abstract
ObjectiveTo determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes.MethodsHere we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher.ResultsLMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms.ConclusionThese findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.
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- 2021
5. Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy.
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Adang LA, Groeschel S, Grzyb C, D'Aiello R, Gavazzi F, Sherbini O, Bronner N, Patel A, Vincent A, Sevagamoorthy A, Mutua S, Muirhead K, Schmidt J, Pizzino A, Yu E, Jin D, Eichler F, Fraser JL, Emrick L, Van Haren K, Boulanger JM, Ruzhnikov M, Sylvain M, Nguyen CÉ, Potic A, Keller S, Fatemi A, Uebergang E, Poe M, Yazdani PA, Bernat J, Lindstrom K, Bonkowsky JL, Bernard G, Stutterd CA, Orchard P, Gupta AO, Ljungberg M, Groenborg S, Zambon A, Locatelli S, Fumagalli F, Elguen S, Kehrer C, Krägeloh-Mann I, Shults J, Vanderver A, and Escolar ML
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- Humans, Male, Female, Child, Preschool, Infant, Child, Adolescent, Cohort Studies, Disease Progression, Leukodystrophy, Metachromatic diagnosis, Leukodystrophy, Metachromatic pathology, Leukodystrophy, Metachromatic genetics, Developmental Disabilities diagnosis, Age of Onset
- Abstract
Objective: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease., Methods: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years., Results: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years)., Interpretation: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions., Competing Interests: Declaration of competing interest Dr. Adang is an advisor to Takeda Pharmaceuticals (enzyme replacement study for MLD), Orchard Therapeutics (gene therapy development for MLD), and is a site sub-investigator for the Takeda trial (enzyme replacement study); Dr. Gröschel is an advisor Takeda and Orchard Therapeutics; Dr. Bonkowsky is a site principal investigator for the Takeda trial; Dr. Bernard is a site principal investigator for the Takeda trial; Dr. Weller Grønborg is a consultant to Orchard Therapeutics; Dr. Orchard is a consultant to Orchard Therapeutics. Dr. Krägeloh-Mann is an advisor to Takeda, Orchard Therapeutics; Dr. Vanderver is an advisor to Takeda, Passagebio, Orchard; and is site PI Takeda trial; Dr. Escolar is an advisor to Takeda, Janssen; she is employed by Forge Biologics; Dr. Fumagalli is the license holder of OTL-200, I Orchard Therapeutics trial, advisor Orchard, Takeda, funding Telethon Foundation, GSK, Orchard. Dr. Eichler, Dr. Fatemi, Dr. Gavazzi, Dr. Sevagamoorthy, Ms. Mutua, Ms. Muirhead, Ms. Schmidt, Ms. Pizzino, Ms. Yu, Ms. Jin, Mr. Vincent, Ms. Grzyb, Mr. D'Aiello, Mr. Sherbini, Mr. Bronner, Mr. Patel, Dr. Fraser, Dr. Emrick, Dr. Van Haren, Dr. Ruzhnikov, Dr. Keller, Ms. Uebergang, Ms. Poe, Dr. Yazdani, Dr. Bernat, Dr. Lindstrom, Dr. Stutterd, Dr. Gupta, Dr. Boulanger, Dr. Sylvain, Dr. Nguyen, Dr. Potic, Dr. Ljungberg, Dr. Zambon, Ms. Locatelli, Ms. Elgün, Dr. Kehrer, and Dr. Shults have no relevant disclosures., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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6. The impact of clinical genome sequencing in a global population with suspected rare genetic disease.
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Thorpe E, Williams T, Shaw C, Chekalin E, Ortega J, Robinson K, Button J, Jones MC, Campo MD, Basel D, McCarrier J, Keppen LD, Royer E, Foster-Bonds R, Duenas-Roque MM, Urraca N, Bosfield K, Brown CW, Lydigsen H, Mroczkowski HJ, Ward J, Sirchia F, Giorgio E, Vaux K, Salguero HP, Lumaka A, Mubungu G, Makay P, Ngole M, Lukusa PT, Vanderver A, Muirhead K, Sherbini O, Lah MD, Anderson K, Bazalar-Montoya J, Rodriguez RS, Cornejo-Olivas M, Milla-Neyra K, Shinawi M, Magoulas P, Henry D, Gibson K, Wiafe S, Jayakar P, Salyakina D, Masser-Frye D, Serize A, Perez JE, Taylor A, Shenbagam S, Abou Tayoun A, Malhotra A, Bennett M, Rajan V, Avecilla J, Warren A, Arseneault M, Kalista T, Crawford A, Ajay SS, Perry DL, Belmont J, and Taft RJ
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- Humans, Male, Female, Child, Child, Preschool, Adolescent, Adult, Infant, Genetic Diseases, Inborn genetics, Genetic Diseases, Inborn diagnosis, Rare Diseases genetics, Rare Diseases diagnosis, Genetic Testing methods, Whole Genome Sequencing
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There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities., Competing Interests: Declaration of interests E.T., E.C., K.R., J. Button, A.M., M.B., J.A., A.W., M.A., T.K., A.C., S.S.A., D.L.P., and R.J.T. were employees of and stockholders in Illumina, Inc. at the time of this investigation. V.R. is a stockholder in Illumina, Inc. J.O. is a stockholder in Illumina, Inc. and employee of C2N Diagnostics. J. Belmont and T.W. are stockholders in Illumina, Inc. and were compensated as research advisors through Genetics & Genomics Services Inc. C.S. was compensated as a consultant through Genetics & Genomics Services Inc. for statistical analysis. K.M. is an employee of Ambry Genetics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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7. Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach.
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Adang LA, Sevagamoorthy A, Sherbini O, Fraser JL, Bonkowsky JL, Gavazzi F, D'Aiello R, Modesti NB, Yu E, Mutua S, Kotes E, Shults J, Vincent A, Emrick LT, Keller S, Van Haren KP, Woidill S, Barcelos I, Pizzino A, Schmidt JL, Eichler F, Fatemi A, and Vanderver A
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- Humans, Longitudinal Studies, United States, Prospective Studies, Rare Diseases diagnosis, Rare Diseases therapy, Rare Diseases epidemiology
- Abstract
Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts., Competing Interests: Declaration of competing interest Adeline Vanderver and Laura Adang have received research support from IONIS pharmaceuticals, Takeda, Sanofi, Eli Lilly, Boehringer Ingelheim, Affinia and Orchard Therapeutics. In addition, Dr. Vanderver has received research support from Illumina, Sana, Passage Bio, Homology and PMD foundation. Dr. Adang from Biogen, MSD Foundation, Don't Forget Morgan, Legacy of Angels and Orphan Disease Center. Dr. Vanderver and Dr. Adang hold the license for the AGS Severity Scale and Dr. Vanderver the patent of ASO in TUBB4A. Dr. Vanderver participates on the advisory board of ELA and United Leukodystrophy Foundation. Dr. Adang is the scientific advisor for CureMLD, MLD Foundation, Don't Forget Morgan, Yaya Foundation and MLDi. Dr. Vanderver is a site Principal Investigator (PI) for Takeda Pharmaceutical's clinical trial for Metachromatic Leukodystrophy NCT03771898 and is an advisor to Passagebio. Dr. Adang also serves as an advisor to Biogen. Dr. Vanderver, Dr. Adang, Dr. Fatemi, Dr. Eichler, Dr. Bonkowsky, Dr. Fraser, Dr. Keller, Dr. Emrick and Dr. Van Haren are recipients of NIH funding through the NINDS (National Institute of Neurological Disorders and Stroke) and/or NCATS (National Center for Advancing Translational Sciences). Dr. Eichler is a recipient of grants through Kennedy Krieger Institute Inc. and Children's Hospital Corporation dba Boston Children's Hospital, and has <1% equity in Swan Bio, and royalties from AAV9 license for AMN. Dr. Eichler receives consulting fees from Leal Therapeutics, Swan Bio, Ionis, Minoryx, UptoDate, Origen, Takeda Therapeutics and Third Rock Ventures. Dr. Eichler is the founder and consultant of Swan Bio, is the ALD connect chair, and serves on the chair on the advisory board of European Leukodystrophy Association, board member at United Leukodystrophy Foundation, and as a scientific advisor for National Tay Sachs and Allied Diseases Association. Dr. Fatemi is a PI for Viking Therapeutics and Minoryx Therapeutics and receives research support from CureLBSL, Brian's Hope Foundation, SwanBio, Autobahn Therapeutics, Poxel Therapeutics, Vertex Pharmaceuticals, and Maryland Stem Cell Research Fund. Also, Dr. Fatemi was former Data and Safety Monitoring Board (DSMB) member for BlueBird Bio, and serves as the ALD Connect Board member. Dr. Fatemi co-invented a patent currently licensed to Ashvattha. All other authors have no conflicts of interest. Dr. Bonkowsky receives research support through grant from European Leukodystrophy Association, and consults for Ionis, Sanofi, Autobahn, Denali, Passage Bio, Bluebird, Calico. He also serves on the ALD connect board. Dr. Keller is the site PI for Ionis Pharmaceuticals Alexander Disease trial and Biomarin Pharmaceuticals Brineura extension study. Dr. Keller consults for Veristat and serves on United Leukodystrophy Foundation and Leukodystrophy Care Network Certified Center. Dr. Emrick serves on the advisory board for Ionis pharmaceuticals. Dr. Van Haren receives research support from United Leukodystrophy Foundation and Stanford MCHRI. He consults for Bluebird Bio, Poxel, Autobahn Therapeutics and Viking, and has participated in the Calico Board. He also serves in the leadership capacity at ALD connect, United Leukodystrophy Foundation and Global Leukodystrophy Alliance. All other authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)
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- 2024
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8. Exploration of Gross Motor Function in Aicardi-Goutières Syndrome.
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Gavazzi F, Glanzman AM, Woidill S, Formanowski B, Dixit A, Isaacs D, Kornafel T, Ballance E, Pierce SR, Modesti N, Barcelos I, Cusack SV, Jan AK, Flores Z, Sherbini O, Vincent A, D'Aiello R, Lorch SA, DeMauro SB, Jawad A, Vanderver A, and Adang L
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- Humans, Genotype, Mutation, Nervous System Malformations genetics, Autoimmune Diseases of the Nervous System genetics
- Abstract
Background: Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by a spectrum of motor abilities. While the Aicardi-Goutières syndrome severity score favors severely impacted individuals, there is an unmet need to define tools measuring function across the Aicardi-Goutières syndrome spectrum as potential outcome assessments for future clinical trials. Methods: Gross Motor Function Measure-88 (GMFM-88) and AGS Severity Scale were administered in individuals affected by Aicardi-Goutières syndrome (n = 71). We characterized the performance variability by genotype. Derived versions of the GMFM-88, including the GMFM-66, GMFM-66 item set (GMFM-66IS), and GMFM-66 Basal&Ceiling (GMFM-66BC) were calculated. The Aicardi-Goutières syndrome cohort was divided into severe (AGS Severity Scale score <4) or attenuated (≥4). Performance on the AGS Severity Scale highly correlated with total GMFM-88 scores (Spearman Correlation: R = 0.91). To assess variability of the GMFM-88 within genotypic subcohorts, interquartile ranges (IQRs) were compared. Results : GMFM-88 performance in the TREX1 cohort had least variability while the SAMHD1 cohort had the largest IQR (4.23 vs 81.8). Floor effect was prominent, with most evaluations scoring below 20% (n = 46, 64.79%), particularly in TREX1 - and RNASEH2- cohorts. Performance by the GMFM-66, GMFM-66IS, and GMFM-66BC highly correlated with the full GMFM-88. The Aicardi-Goutières syndrome population represents a broad range of gross motor skills. Conclusions: This work identified the GMFM-88 as a potential clinical outcome assessment in subsets of the Aicardi-Goutières syndrome population but underscores the need for additional validation of outcome measures reflective of the diverse gross motor function observed in this population, including low motor function. When time is limited by resources or patient endurance, shorter versions of the GMFM-88 may be a reasonable alternative.
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- 2023
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9. Identification of PMD subgroups using a myelination score for PMD.
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Harting I, Garbade SF, Rosendaal SD, Mohr A, Sherbini O, Vanderver A, and Wolf NI
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- Infant, Newborn, Humans, Female, Myelin Proteolipid Protein genetics, Mutation, Magnetic Resonance Imaging, Corpus Callosum diagnostic imaging, Pelizaeus-Merzbacher Disease
- Abstract
Background: The clinical spectrum of Pelizaeus-Merzbacher disease (PMD), a common hypomyelinating leukodystrophy, ranges between severe neonatal onset and a relatively stable presentation with later onset and mainly lower limb spasticity. In view of emerging treatment options and in order to grade severity and progression, we developed a PMD myelination score., Methods: Myelination was scored in 15 anatomic sites (items) on conventional T2-and T1w images in controls (n = 328) and 28 PMD patients (53 MRI; n = 5 connatal, n = 3 transitional, n = 10 classic, n = 3 intermediate, n = 2 PLP0, n = 3 SPG2, n = 2 female). Items included in the score were selected based on interrater variability, practicability of scoring and importance of scoring items for discrimination between patients and controls and between patient subgroups. Bicaudate ratio, maximal sagittal pons diameter, and visual assessment of midsagittal corpus callosum were separately recorded., Results: The resulting myelination score consisting of 8 T2-and 5 T1-items differentiates patients and controls as well as patient subgroups at first MRI. There was very little myelin and early loss in severely affected connatal and transitional patients, more, though still severely deficient myelin in classic PMD, ongoing myelination during childhood in classic and intermediate PMD. Atrophy, present in 50% of patients, increased with age at imaging., Conclusions: The proposed myelination score allows stratification of PMD patients and standardized assessment of follow-up. Loss of myelin in severely affected and PLP0 patients and progressing myelination in classic and intermediate PMD must be considered when evaluating treatment efficacy., Competing Interests: Declaration of competing interest IH, SFG, SDR, AM, OS: none. AV is an investigator in clinical trials, mechanistic studies, and natural history studies for leukodystrophies (Ionis, Takeda, Homology, Passage Bio, Biogen, Eli-Lilly, Illumina, SynaptixBio) without personal payment. NIW is advisor and/or co-investigator for trials in Pelizaeus-Merzbacher disease and other leukodystrophies (Shire/Takeda, Orchard, Ionis, PassageBio, VigilNeuro, Sana Biotech), without personal payment., (© 2022 The Author(s). Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)
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- 2022
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10. Psychometric outcome measures in beta-propeller protein-associated neurodegeneration (BPAN).
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Gavazzi F, Pierce SR, Vithayathil J, Cunningham K, Anderson K, McCann J, Moll A, Muirhead K, Sherbini O, Prange E, Dubbs H, Tochen L, Fraser J, Helbig I, Lewin N, Thakur N, and Adang LA
- Subjects
- Humans, Psychometrics, Prospective Studies, Retrospective Studies, Carrier Proteins genetics, Iron metabolism, Outcome Assessment, Health Care, Iron Metabolism Disorders diagnosis, Iron Metabolism Disorders genetics
- Abstract
Background: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes., Methods: A total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2., Results: Overall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests., Conclusion: Our data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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11. Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform.
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Helman G, Takanohashi A, Hagemann TL, Perng MD, Walkiewicz M, Woidill S, Sase S, Cross Z, Du Y, Zhao L, Waldman A, Haake BC, Fatemi A, Brenner M, Sherbini O, Messing A, Vanderver A, and Simons C
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- 2022
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12. Hematologic abnormalities in Aicardi Goutières Syndrome.
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Adang LA, Gavazzi F, D'Aiello R, Isaacs D, Bronner N, Arici ZS, Flores Z, Jan A, Scher C, Sherbini O, Behrens EM, Goldbach-Mansky R, Olson TS, Lambert MP, Sullivan KE, Teachey DT, Witmer C, Vanderver A, and Shults J
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- Autoimmune Diseases of the Nervous System, Child, Humans, Infant, Newborn, Inflammation, Nervous System Malformations, Anemia, Neutropenia, Thrombocytopenia
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Background: Because of the broad clinical spectrum, heritable autoinflammatory diseases present a management and therapeutic challenge. The most common genetic interferonopathy, Aicardi Goutières Syndrome (AGS), is associated with early onset neurologic disability and systemic inflammation. The chronic inflammation of AGS is the result of dysregulation of interferon (IFN) expression by one of nine genes within converging pathways. While each AGS subtype shares common features, distinct patterns of severity and potential for systemic complications amongst the genotypes are emerging. Multilineage cytopenias are a potentially serious, but poorly understood, complication of AGS. As immunomodulatory treatment options are developed, it is important to characterize the role of the disease versus treatment in hematologic abnormalities. This will allow for better understanding and management of cytopenia., Methods: In total, 142 individuals with molecularly-confirmed AGS were included. Information on genotype, demographics, and all available hematologic laboratory values were collected from existing medical records. As part of a clinical trial, a subset of this cohort (n = 52) were treated with a janus kinase inhibitor (baricitinib), and both pre- and post-treatment values were included. Abnormal values were graded based on Common Terminology Criteria for Adverse Events (CTCAE v5.0), supplemented with grading definitions for thrombocytosis, and were compared across genotypes and baricitinib exposure., Results: In total, 11,184 laboratory values were collected over a median of 2.54 years per subject (range 0-22.68 years). To reduce bias from repeated sampling within a limited timeframe, laboratory results were restricted to the most abnormal value within a month (n = 8485). The most common abnormalities were anemia (noted in 24% of subjects prior to baricitinib exposure), thrombocytopenia (9%), and neutropenia (30%). Neutropenia was most common in the SAMHD1 cohort and increased with baricitinib exposure (38/69 measurements on baricitinib versus 14/121 while not on baricitinib). Having an abnormality prior to treatment was associated with having an abnormality on treatment for neutropenia and thrombocytopenia., Conclusion: By collecting available laboratory data throughout the lifespan, we were able to identify novel patterns of hematologic abnormalities in AGS. We found that AGS results in multilineage cytopenias not limited to the neonatal period. Neutropenia, anemia, and thrombocytopenia were common. Moderate-severe graded events of neutropenia, anemia, and leukopenia were more common on baricitinib, but rarely of clinical consequence. Based on these results, we would recommend careful monitoring of hematologic parameters of children affected by AGS throughout the lifespan, especially while on therapy, and consideration of AGS as a potential differential diagnosis in children with neurologic impairment of unclear etiology with hematologic abnormalities. Trial registration ClinicalTrials.gov Identifier: NCT01724580 ClinicalTrials.gov Identifier: NCT03921554., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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13. Brain Abnormalities in Patients with Germline Variants in H3F3 : Novel Imaging Findings and Neurologic Symptoms Beyond Somatic Variants and Brain Tumors.
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Alves CAPF, Sherbini O, D'Arco F, Steel D, Kurian MA, Radio FC, Ferrero GB, Carli D, Tartaglia M, Balci TB, Powell-Hamilton NN, Schrier Vergano SA, Reutter H, Hoefele J, Günthner R, Roeder ER, Littlejohn RO, Lessel D, Lüttgen S, Kentros C, Anyane-Yeboa K, Catarino CB, Mercimek-Andrews S, Denecke J, Lyons MJ, Klopstock T, Bhoj EJ, Bryant L, and Vanderver A
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- Brain diagnostic imaging, Brain pathology, Child, Germ Cells pathology, Humans, Male, Retrospective Studies, Brain Neoplasms diagnostic imaging, Brain Neoplasms genetics, Brain Neoplasms pathology, Histones genetics, Malformations of Cortical Development pathology, Neurodevelopmental Disorders pathology
- Abstract
Background and Purpose: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B ( H3F3 ) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants., Materials and Methods: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range., Results: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation., Conclusions: Imaging phenotypes in germline H3F3- affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles., (© 2022 by American Journal of Neuroradiology.)
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- 2022
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14. Expanded phenotype of AARS1-related white matter disease.
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Helman G, Mendes MI, Nicita F, Darbelli L, Sherbini O, Moore T, Derksen A, Amy Pizzino, Carrozzo R, Torraco A, Catteruccia M, Aiello C, Goffrini P, Figuccia S, Smith DEC, Hadzsiev K, Hahn A, Biskup S, Brösse I, Kotzaeridou U, Gauck D, Grebe TA, Elmslie F, Stals K, Gupta R, Bertini E, Thiffault I, Taft RJ, Schiffmann R, Brandl U, Haack TB, Salomons GS, Simons C, Bernard G, van der Knaap MS, Vanderver A, and Husain RA
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- Cross-Sectional Studies, Disease Progression, Humans, Phenotype, Leukoencephalopathies diagnostic imaging, Leukoencephalopathies genetics
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Purpose: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease., Methods: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts., Results: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes., Conclusion: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)
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- 2021
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15. De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.
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Malhotra A, Ziegler A, Shu L, Perrier R, Amlie-Wolf L, Wohler E, Lygia de Macena Sobreira N, Colin E, Vanderver A, Sherbini O, Stouffs K, Scalais E, Serretti A, Barth M, Navet B, Rollier P, Xi H, Wang H, Zhang H, Perry DL, Ferrarini A, Colombo R, Pepler A, Schneider A, Tomiwa K, Okamoto N, Matsumoto N, Miyake N, Taft R, Mao X, and Bonneau D
- Subjects
- Alleles, Amino Acid Substitution, Cohort Studies, Genetic Predisposition to Disease, Genotype, Humans, Phenotype, Developmental Disabilities diagnosis, Developmental Disabilities genetics, Motor Skills Disorders diagnosis, Motor Skills Disorders genetics, Mutation, Missense, Nervous System Malformations diagnosis, Nervous System Malformations genetics, Nucleocytoplasmic Transport Proteins genetics
- Abstract
Objective: To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes., Methods: Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher., Results: LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms., Conclusion: These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene., Competing Interests: Competing interests: AM, DLP and RT are full-time employees of Illumina, Inc. AP is an employee of CeGaT GmbH, Germany., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2021
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16. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.
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Radio FC, Pang K, Ciolfi A, Levy MA, Hernández-García A, Pedace L, Pantaleoni F, Liu Z, de Boer E, Jackson A, Bruselles A, McConkey H, Stellacci E, Lo Cicero S, Motta M, Carrozzo R, Dentici ML, McWalter K, Desai M, Monaghan KG, Telegrafi A, Philippe C, Vitobello A, Au M, Grand K, Sanchez-Lara PA, Baez J, Lindstrom K, Kulch P, Sebastian J, Madan-Khetarpal S, Roadhouse C, MacKenzie JJ, Monteleone B, Saunders CJ, Jean Cuevas JK, Cross L, Zhou D, Hartley T, Sawyer SL, Monteiro FP, Secches TV, Kok F, Schultz-Rogers LE, Macke EL, Morava E, Klee EW, Kemppainen J, Iascone M, Selicorni A, Tenconi R, Amor DJ, Pais L, Gallacher L, Turnpenny PD, Stals K, Ellard S, Cabet S, Lesca G, Pascal J, Steindl K, Ravid S, Weiss K, Castle AMR, Carter MT, Kalsner L, de Vries BBA, van Bon BW, Wevers MR, Pfundt R, Stegmann APA, Kerr B, Kingston HM, Chandler KE, Sheehan W, Elias AF, Shinde DN, Towne MC, Robin NH, Goodloe D, Vanderver A, Sherbini O, Bluske K, Hagelstrom RT, Zanus C, Faletra F, Musante L, Kurtz-Nelson EC, Earl RK, Anderlid BM, Morin G, van Slegtenhorst M, Diderich KEM, Brooks AS, Gribnau J, Boers RG, Finestra TR, Carter LB, Rauch A, Gasparini P, Boycott KM, Barakat TS, Graham JM Jr, Faivre L, Banka S, Wang T, Eichler EE, Priolo M, Dallapiccola B, Vissers LELM, Sadikovic B, Scott DA, Holder JL Jr, and Tartaglia M
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- Adolescent, Autism Spectrum Disorder genetics, Autism Spectrum Disorder pathology, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders physiopathology, DNA Methylation genetics, Epigenesis, Genetic genetics, Female, Haploinsufficiency genetics, Humans, Intellectual Disability genetics, Intellectual Disability physiopathology, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders physiopathology, Phenotype, Young Adult, Chromosome Disorders genetics, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, X genetics, DNA-Binding Proteins genetics, RNA-Binding Proteins genetics
- Abstract
Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2021
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17. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.
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Bryant L, Li D, Cox SG, Marchione D, Joiner EF, Wilson K, Janssen K, Lee P, March ME, Nair D, Sherr E, Fregeau B, Wierenga KJ, Wadley A, Mancini GMS, Powell-Hamilton N, van de Kamp J, Grebe T, Dean J, Ross A, Crawford HP, Powis Z, Cho MT, Willing MC, Manwaring L, Schot R, Nava C, Afenjar A, Lessel D, Wagner M, Klopstock T, Winkelmann J, Catarino CB, Retterer K, Schuette JL, Innis JW, Pizzino A, Lüttgen S, Denecke J, Strom TM, Monaghan KG, Yuan ZF, Dubbs H, Bend R, Lee JA, Lyons MJ, Hoefele J, Günthner R, Reutter H, Keren B, Radtke K, Sherbini O, Mrokse C, Helbig KL, Odent S, Cogne B, Mercier S, Bezieau S, Besnard T, Kury S, Redon R, Reinson K, Wojcik MH, Õunap K, Ilves P, Innes AM, Kernohan KD, Costain G, Meyn MS, Chitayat D, Zackai E, Lehman A, Kitson H, Martin MG, Martinez-Agosto JA, Nelson SF, Palmer CGS, Papp JC, Parker NH, Sinsheimer JS, Vilain E, Wan J, Yoon AJ, Zheng A, Brimble E, Ferrero GB, Radio FC, Carli D, Barresi S, Brusco A, Tartaglia M, Thomas JM, Umana L, Weiss MM, Gotway G, Stuurman KE, Thompson ML, McWalter K, Stumpel CTRM, Stevens SJC, Stegmann APA, Tveten K, Vøllo A, Prescott T, Fagerberg C, Laulund LW, Larsen MJ, Byler M, Lebel RR, Hurst AC, Dean J, Schrier Vergano SA, Norman J, Mercimek-Andrews S, Neira J, Van Allen MI, Longo N, Sellars E, Louie RJ, Cathey SS, Brokamp E, Heron D, Snyder M, Vanderver A, Simon C, de la Cruz X, Padilla N, Crump JG, Chung W, Garcia B, Hakonarson HH, and Bhoj EJ
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- Animals, Forkhead Transcription Factors genetics, Germ-Line Mutation, Humans, Zebrafish genetics, Zebrafish metabolism, Zebrafish Proteins metabolism, Histones genetics, Histones metabolism, Neurodegenerative Diseases genetics
- Abstract
Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A ( H3F3A ) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
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- 2020
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18. Janus Kinase Inhibition in the Aicardi-Goutières Syndrome.
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Vanderver A, Adang L, Gavazzi F, McDonald K, Helman G, Frank DB, Jaffe N, Yum SW, Collins A, Keller SR, Lebon P, Meritet JF, Rhee J, Takanohashi A, Armangue T, Ulrick N, Sherbini O, Koh J, Peer K, Besnier C, Scher C, Boyle K, Dubbs H, Kramer-Golinkoff J, Pizzino A, Woidill S, and Shults J
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- Adolescent, Age of Onset, Azetidines adverse effects, Biomarkers, Child, Child Development drug effects, Child, Preschool, Dose-Response Relationship, Drug, Female, Gene Expression drug effects, Humans, Infant, Interferons genetics, Interferons metabolism, Janus Kinase Inhibitors adverse effects, Least-Squares Analysis, Male, Purines, Pyrazoles, Sulfonamides adverse effects, Young Adult, Autoimmune Diseases of the Nervous System drug therapy, Azetidines therapeutic use, Janus Kinase Inhibitors therapeutic use, Nervous System Malformations drug therapy, Sulfonamides therapeutic use
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- 2020
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19. Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders.
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Vanderver A, Bernard G, Helman G, Sherbini O, Boeck R, Cohn J, Collins A, Demarest S, Dobbins K, Emrick L, Fraser JL, Masser-Frye D, Hayward J, Karmarkar S, Keller S, Mirrop S, Mitchell W, Pathak S, Sherr E, van Haren K, Waters E, Wilson JL, Zhorne L, Schiffmann R, van der Knaap MS, Pizzino A, Dubbs H, Shults J, Simons C, and Taft RJ
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- Child, Child, Preschool, Cross-Over Studies, Female, Humans, Infant, Male, Prospective Studies, White Matter pathology, Leukoencephalopathies diagnosis, Leukoencephalopathies genetics, Sequence Analysis, DNA methods
- Abstract
Objective: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied., Methods: A prospective time-delayed crossover design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS., Results: Thirty-four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild-Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild-Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log-rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8-89.3%) in <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single-arm observational study., Interpretation: In this study, first-line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence-based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020;88:264-273., (© 2020 American Neurological Association.)
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- 2020
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20. Phenotypic and Imaging Spectrum Associated With WDR45.
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Adang LA, Pizzino A, Malhotra A, Dubbs H, Williams C, Sherbini O, Anttonen AK, Lesca G, Linnankivi T, Laurencin C, Milh M, Perrine C, Schaaf CP, Poulat AL, Ville D, Hagelstrom T, Perry DL, Taft RJ, Goldstein A, Vossough A, Helbig I, and Vanderver A
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- Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Male, Middle Aged, Phenotype, Exome Sequencing, Young Adult, Carrier Proteins genetics, Demyelinating Diseases diagnosis, Demyelinating Diseases etiology, Demyelinating Diseases genetics, Demyelinating Diseases physiopathology, Developmental Disabilities diagnosis, Developmental Disabilities etiology, Developmental Disabilities genetics, Developmental Disabilities physiopathology, Epilepsy diagnosis, Epilepsy etiology, Epilepsy genetics, Epilepsy physiopathology, Iron Metabolism Disorders complications, Iron Metabolism Disorders diagnosis, Iron Metabolism Disorders genetics, Iron Metabolism Disorders physiopathology, Neuroaxonal Dystrophies complications, Neuroaxonal Dystrophies diagnosis, Neuroaxonal Dystrophies genetics, Neuroaxonal Dystrophies physiopathology
- Abstract
Background: Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain., Methods: We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected., Results: Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age., Conclusions: WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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21. Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform.
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Helman G, Takanohashi A, Hagemann TL, Perng MD, Walkiewicz M, Woidill S, Sase S, Cross Z, Du Y, Zhao L, Waldman A, Haake BC, Fatemi A, Brenner M, Sherbini O, Messing A, Vanderver A, and Simons C
- Subjects
- Adult, Aged, Child, Female, Humans, Male, Middle Aged, Mutation, Missense, Pedigree, Protein Isoforms genetics, Young Adult, Alexander Disease genetics, Glial Fibrillary Acidic Protein genetics, RNA Splicing
- Abstract
Alexander disease results from gain-of-function mutations in the gene encoding glial fibrillary acidic protein (GFAP). At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for ∼90% of GFAP protein. We describe exonic variants identified in three unrelated families with Type II Alexander disease that alter the splicing of GFAP pre-messenger RNA (mRNA) and result in the upregulation of a previously uncharacterized GFAP lambda isoform (NM_001363846.1). Affected members of Family 1 and Family 2 shared the same missense variant, NM_001363846.1:c.1289G>A;p.(Arg430His) while in Family 3 we identified a synonymous variant in the adjacent nucleotide, NM_001363846.1:c.1290C>A;p.(Arg430Arg). Using RNA and protein analysis of brain autopsy samples, and a mini-gene splicing reporter assay, we demonstrate both variants result in the upregulation of the lambda isoform. Our approach demonstrates the importance of characterizing the effect of GFAP variants on mRNA splicing to inform future pathophysiologic and therapeutic study for Alexander disease., (© 2020 Wiley Periodicals, Inc.)
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- 2020
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22. Leukocyte and Dried Blood Spot Arylsulfatase A Assay by Tandem Mass Spectrometry.
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Hong X, Kumar AB, Daiker J, Yi F, Sadilek M, De Mattia F, Fumagalli F, Calbi V, Damiano R, Della Bona M, la Marca G, Vanderver AL, Waldman AT, Adang L, Sherbini O, Woidill S, Suhr T, Kurtzberg J, Beltran-Quintero ML, Escolar M, Aiuti A, Finglas A, Olsen A, and Gelb MH
- Subjects
- Cerebroside-Sulfatase metabolism, Chromatography, Liquid, Humans, Leukodystrophy, Metachromatic diagnosis, Leukodystrophy, Metachromatic enzymology, Molecular Structure, Multiple Sulfatase Deficiency Disease diagnosis, Multiple Sulfatase Deficiency Disease enzymology, Sulfoglycosphingolipids chemistry, Tandem Mass Spectrometry, Cerebroside-Sulfatase analysis, Dried Blood Spot Testing, Leukocytes enzymology, Leukodystrophy, Metachromatic blood, Multiple Sulfatase Deficiency Disease blood
- Abstract
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays were developed to measure arylsulfatase A (ARSA) activity in leukocytes and dried blood spots (DBS) using deuterated natural sulfatide substrate. These new assays were highly specific and sensitive. Patients with metachromatic leukodystrophy (MLD) and multiple sulfatase deficiency (MSD) displayed a clear deficit in the enzymatic activity and could be completely distinguished from normal controls. The leukocyte assay reported here will be important for diagnosing MLD and MSD patients and for monitoring the efficacy of therapeutic treatments. ARSA activity was measured in DBS for the first time without an antibody. This new ARSA DBS assay can serve as a second-tier test following the sulfatide measurement in DBS for newborn screening of MLD. This leads to an elimination of most of the false positives identified by the sulfatide assay.
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- 2020
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23. The AAA + ATPase Thorase is neuroprotective against ischemic injury.
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Zhang J, Yang J, Wang H, Sherbini O, Keuss MJ, Umanah GK, Pai EL, Chi Z, Paldanius KM, He W, Wang H, Andrabi SA, Dawson TM, and Dawson VL
- Subjects
- ATPases Associated with Diverse Cellular Activities genetics, Adenosine Triphosphatases, Animals, Brain Ischemia genetics, Brain Ischemia metabolism, Brain Ischemia pathology, Cells, Cultured, Female, Gene Deletion, Glucose metabolism, Infarction, Middle Cerebral Artery genetics, Infarction, Middle Cerebral Artery pathology, Ischemic Preconditioning, Male, Mice, Neurons metabolism, Neuroprotection, Oxygen metabolism, Stroke genetics, Stroke metabolism, Stroke pathology, Up-Regulation, ATPases Associated with Diverse Cellular Activities metabolism, Infarction, Middle Cerebral Artery metabolism
- Abstract
Neuronal preconditioning in vitro or in vivo with a stressful but non-lethal stimulus leads to new protein expression that mediates a profound neuroprotection against glutamate excitotoxicity and experimental stroke. The proteins that mediate neuroprotection are relatively unknown and under discovery. Here we find that the expression of the AAA + ATPase Thorase is induced by preconditioning stimulation both in vitro and in vivo. Thorase provides neuroprotection in an ATP-dependent manner against oxygen-glucose deprivation (OGD) neurotoxicity or glutamate N-Methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity in vitro. Knock-down of Thorase prevents the establishment of preconditioning induced neuroprotection against OGD or NMDA neurotoxicity. Transgenic overexpression of Thorase provides neuroprotection in vivo against middle cerebral artery occlusion (MCAO)-induced stroke in mice, while genetic deletion of Thorase results in increased injury in vivo following stroke. These results define Thorase as a neuroprotective protein and understanding Thorase signaling could offer a new therapeutic strategy for the treatment of neurologic disorders.
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- 2019
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24. Aicardi goutières syndrome is associated with pulmonary hypertension.
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Adang LA, Frank DB, Gilani A, Takanohashi A, Ulrick N, Collins A, Cross Z, Galambos C, Helman G, Kanaan U, Keller S, Simon D, Sherbini O, Hanna BD, and Vanderver AL
- Subjects
- Adolescent, Child, Humans, Infant, Infant, Newborn, Male, Prognosis, Prospective Studies, Retrospective Studies, Autoimmune Diseases of the Nervous System complications, Exodeoxyribonucleases genetics, Hypertension, Pulmonary etiology, Hypertension, Pulmonary pathology, Interferon-Induced Helicase, IFIH1 genetics, Mutation, Nervous System Malformations complications, Phosphoproteins genetics
- Abstract
While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney p < .001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney p < .0001). We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH., (Copyright © 2018. Published by Elsevier Inc.)
- Published
- 2018
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25. Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.
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Adang LA, Sherbini O, Ball L, Bloom M, Darbari A, Amartino H, DiVito D, Eichler F, Escolar M, Evans SH, Fatemi A, Fraser J, Hollowell L, Jaffe N, Joseph C, Karpinski M, Keller S, Maddock R, Mancilla E, McClary B, Mertz J, Morgart K, Langan T, Leventer R, Parikh S, Pizzino A, Prange E, Renaud DL, Rizzo W, Shapiro J, Suhr D, Suhr T, Tonduti D, Waggoner J, Waldman A, Wolf NI, Zerem A, Bonkowsky JL, Bernard G, van Haren K, and Vanderver A
- Subjects
- Adrenal Insufficiency therapy, Adult, Child, Demyelinating Diseases congenital, Female, Gallbladder pathology, Genetic Predisposition to Disease, Humans, Leukoencephalopathies congenital, Male, Quality of Life, Demyelinating Diseases therapy, Hereditary Central Nervous System Demyelinating Diseases therapy, Leukoencephalopathies therapy, Lysosomal Storage Diseases prevention & control, Lysosomal Storage Diseases therapy
- Abstract
Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2017
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26. High-Content Genome-Wide RNAi Screen Reveals CCR3 as a Key Mediator of Neuronal Cell Death.
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Zhang J, Wang H, Sherbini O, Ling-Lin Pai E, Kang SU, Kwon JS, Yang J, He W, Wang H, Eacker SM, Chi Z, Mao X, Xu J, Jiang H, Andrabi SA, Dawson TM, and Dawson VL
- Subjects
- Animals, Brain metabolism, Brain pathology, Cell Death drug effects, Cell Hypoxia physiology, Cells, Cultured, Computational Biology, Disease Models, Animal, Glucose deficiency, Infarction, Middle Cerebral Artery, Male, Methylnitronitrosoguanidine toxicity, Mice, Knockout, Motor Activity physiology, Neural Stem Cells drug effects, Neural Stem Cells metabolism, Neurons drug effects, Neurons pathology, RNA Interference, Receptors, CCR3 antagonists & inhibitors, Receptors, CCR3 genetics, Stroke metabolism, Stroke pathology, Cell Death physiology, Neurons metabolism, Receptors, CCR3 metabolism
- Abstract
Neuronal loss caused by ischemic injury, trauma, or disease can lead to devastating consequences for the individual. With the goal of limiting neuronal loss, a number of cell death pathways have been studied, but there may be additional contributors to neuronal death that are yet unknown. To identify previously unknown cell death mediators, we performed a high-content genome-wide screening of short, interfering RNA (siRNA) with an siRNA library in murine neural stem cells after exposure to N -methyl- N -nitroso- N '-nitroguanidine (MNNG), which leads to DNA damage and cell death. Eighty genes were identified as key mediators for cell death. Among them, 14 are known cell death mediators and 66 have not previously been linked to cell death pathways. Using an integrated approach with functional and bioinformatics analysis, we provide possible molecular networks, interconnected pathways, and/or protein complexes that may participate in cell death. Of the 66 genes, we selected CCR3 for further evaluation and found that CCR3 is a mediator of neuronal injury. CCR3 inhibition or deletion protects murine cortical cultures from oxygen-glucose deprivation-induced cell death, and CCR3 deletion in mice provides protection from ischemia in vivo. Taken together, our findings suggest that CCR3 is a previously unknown mediator of cell death. Future identification of the neural cell death network in which CCR3 participates will enhance our understanding of the molecular mechanisms of neural cell death., Competing Interests: Authors report no conflict of interest.
- Published
- 2016
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27. Impotence in diabetics: organic versus psychogenic factors.
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el-Bayoumi M, el-Sherbini O, and Mostafa M
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- Adult, Age Factors, Aged, Diabetes Mellitus physiopathology, Erectile Dysfunction physiopathology, Erectile Dysfunction psychology, Humans, Libido, Male, Middle Aged, Psychophysiologic Disorders physiopathology, Time Factors, Diabetes Complications, Erectile Dysfunction etiology
- Abstract
Four types of impotence were diagnosed in 75 consecutive impotent diabetic patients: chronic persistent organic type due to vascular and/or neurologic factors (44%), temporary organic types due to medical illness other than diabetes (10.6%) or uncontrolled metabolic state (6.6%), and psychogenic impotence (38.6%). Despite higher incidence of organic etiology (61.3%) the incidence of psychogenic impotence was significant. None of the methods used to diagnose the type of impotence in the present study proved 100 per cent accurate, and we advise a combination of history-taking including the wife's history, physical examination including vascular and neurologic tests, nocturnal penile tumescence studies, and therapeutic trials with sex therapy to differentiate between true organic, temporary organic, and psychogenic types of impotence in diabetic patients. This differentiation is mandatory since the latter two types may have a better prognosis.
- Published
- 1984
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28. Experience with the classification, diagnosis, and therapy of nonejaculatory intercourse.
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El-Bayoumi M, El-Mokaddem H, El-Sherbini O, Amer M, and Mahmoud KZ
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- Adolescent, Adult, Genital Diseases, Male etiology, Genital Diseases, Male therapy, Humans, Male, Middle Aged, Patient Education as Topic, Psychotherapy, Coitus, Ejaculation, Genital Diseases, Male physiopathology
- Abstract
Twenty-one consecutive patients complaining of nonejaculatory intercourse were studied. Fifteen patients had anejaculation of various types, and sex therapy succeeded in 4 of 7 cases. Three patients had retrograde ejaculation that could be corrected by ephedrine sulfate in two cases having a neurologic cause. In one of three patients having nonemission, ejaculation was restored after stopping the drug thioridazine. A juvenile diabetic patient was discovered to have nonemission and not retrograde ejaculation. A classification of the disorders leading to nonejaculatory intercourse based on pathogenetic and clinical data is presented, including anejaculation, retrograde ejaculation, nonemission, and aspermia.
- Published
- 1983
- Full Text
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