Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency
Por:
Scala M, Wortmann SB, Kaya N, Stellingwerff MD, Pistorio A, Glamuzina E, van Karnebeek CD, Skrypnyk C, Iwanicka-Pronicka K, Piekutowska-Abramczuk D, Ciara E, Tort F, Sheidley B, Poduri A, Jayakar P, Jayakar A, Upadia J, Walano N, Haack TB, Prokisch H, Aldhalaan H, Karimiani EG, Yildiz Y, Ceylan AC, Santiago-Sim T, Dameron A, Yang H, Toosi MB, Ashrafzadeh F, Akhondian J, Imannezhad S, Mirzadeh HS, Maqbool S, Farid A, Al-Muhaizea MA, Alshwameen MO, Aldowsari L, Alsagob M, Alyousef A, AlMass R, AlHargan A, Alwadei AH, AlRasheed MM, Colak D, Alqudairy H, Khan S, Lines MA, Garcia-Cazorla A, Ribes A, Morava E, Bibi F, Haider S, Ferla MP, Taylor JC, Alsaif HS, Firdous A, Hashem M, Shashkin C, Koneev K, Kaiyrzhanov R, Efthymiou S, Genomics QS, Schmitt-Mechelke T, Ziegler A, Issa MY, Elbendary HM, Striano P, Alkuraya FS, Zaki MS, Gleeson JG, Barakat TS, Bierau J, van der Knaap MS, Maroofian R and Houlden H
Publicada:
1 mar 2022
Ahead of Print:
1 ene 2022
Resumen:
Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.
Filiaciones:
Scala M:
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
UCL Queen Square Institute of Neurology, University College London, London, UK
Wortmann SB:
Amalia Children's Hospital, Radboud University Nijmegen, Nijmegen, The Netherlands
University Children's Hospital, Paracelsus Medical University, Salzburg, Austria
Kaya N:
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Stellingwerff MD:
Department of Child Neurology, Emma Children's Hospital, Amsterdam Leukodystrophy Center, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience, Amsterdam, The Netherlands
Pistorio A:
Clinical Epidemiology and Biostatistics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
Glamuzina E:
Adult and Paediatric National Metabolic Service, Starship Children's Hospital, Auckland, New Zealand
van Karnebeek CD:
Departments of Pediatrics and Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands
Skrypnyk C:
Department of Molecular Medicine, Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain
Iwanicka-Pronicka K:
Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland
Department of Audiology and Phoniatrics, The Children's Memorial Health Institute, Warsaw, Poland
Piekutowska-Abramczuk D:
Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland
Ciara E:
Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland
Tort F:
Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica iGenètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain
Sheidley B:
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusettes, USA
Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Children's Hospital, Boston, Massachusettes, USA
Poduri A:
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusettes, USA
Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Children's Hospital, Boston, Massachusettes, USA
Department of Neurology, Harvard Medical School, Boston, Massachusettes, USA
Jayakar P:
Nicklaus Children's Hospital, Miami, Florida, USA
Jayakar A:
Nicklaus Children's Hospital, Miami, Florida, USA
Upadia J:
Tulane University School of Medicine, New Orleans, Louisiana, USA
Walano N:
Tulane University School of Medicine, New Orleans, Louisiana, USA
Haack TB:
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
Prokisch H:
Institute of Human Genetics, Technische Universität München, Munich, Germany
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
Aldhalaan H:
Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Karimiani EG:
Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Molecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London, UK
Innovative Medical Research Center, Islamic Azad University, Mashhad Branch, Mashhad, Iran
Yildiz Y:
Pediatric Metabolic Diseases Clinic, Dr. Sami Ulus Training and Research Hospital for Maternity and Children, Ankara, Turkey
Ceylan AC:
Department of Medical Genetics, Ankara City Hospital, Ankara, Turkey
Santiago-Sim T:
GeneDx, Gaithersburg, Maryland, USA
Dameron A:
GeneDx, Gaithersburg, Maryland, USA
Yang H:
GeneDx, Gaithersburg, Maryland, USA
Toosi MB:
Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
Ashrafzadeh F:
Department of Pediatrics, Mashhad University of Medical Sciences, Mashhad, Iran
Akhondian J:
Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
Imannezhad S:
Department of Pediatric Diseases, Mashhad University of Medical Sciences, Mashhad, Iran
Mirzadeh HS:
Department of Pediatric Diseases, Mashhad University of Medical Sciences, Mashhad, Iran
Maqbool S:
Development and Behavioral Pediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan
Farid A:
Development and Behavioral Pediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan
Al-Muhaizea MA:
Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Alshwameen MO:
Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Aldowsari L:
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Alsagob M:
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Alyousef A:
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
AlMass R:
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
AlHargan A:
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Alwadei AH:
Neurosciences Department, King Fahad Medical City, Riyadh, Saudi Arabia
AlRasheed MM:
Department of Clinical Pharmacy, King Saud University, Riyadh, Saudi Arabia
Colak D:
Department of Biostatistics, Epidemiology and Scientific Computing, KFSHRC, Riyadh, Kingdom of Saudi Arabia
Alqudairy H:
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Khan S:
Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Lines MA:
Medical Genetics, Department of Pediatrics, Alberta Children's Hospital, Calgary, Canada
Garcia-Cazorla A:
Inborn Errors of Metabolism Unit, Hospital Sant Joan de Déu, Barcelona, Spain
Ribes A:
Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica iGenètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain
Morava E:
Department of Clinical Genomics, Laboratory of Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
Bibi F:
Institute of Biochemistry and Biotechnology, Pir Mehar Ali Shah Arid Agriculture University, Rawalpindi, Pakistan
Haider S:
Izzat Ali Shah Hospital, Lalarukh Wah Cantt, Rawalpindi, Pakistan
Ferla MP:
NIHR Oxford BRC Genomic Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
Taylor JC:
NIHR Oxford BRC Genomic Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
Alsaif HS:
Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Firdous A:
Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Hashem M:
Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Shashkin C:
International University of Postgraduate Education, Almaty, Kazakhstan
Koneev K:
Department of Neurology and Neurosurgery, Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan
Kaiyrzhanov R:
UCL Queen Square Institute of Neurology, University College London, London, UK
Efthymiou S:
UCL Queen Square Institute of Neurology, University College London, London, UK
Genomics QS:
UCL Queen Square Institute of Neurology, University College London, London, UK
Schmitt-Mechelke T:
Department of Neuropaediatrics, Children's Hospital, Cantonal Hospital, Lucerne, Switzerland
Ziegler A:
Zentrum für Kinder und Jugendmedizin Heidelberg, Sektion Neuropädiatrie und Stoffwechselmedizin, Universitätsklinikum Heidelberg, Heidelberg, Germany
Issa MY:
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
Elbendary HM:
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
Striano P:
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
Alkuraya FS:
Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Department of Anatomy and Cell Biology, Alfaisal University, Riyadh, Saudi Arabia
Zaki MS:
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
Gleeson JG:
Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, California, USA
Barakat TS:
Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
Bierau J:
Laboratory of Biochemical Genetics, Department of Clinical Genetics, Maastricht University Hospital, Maastricht, The Netherlands
van der Knaap MS:
Department of Child Neurology, Emma Children's Hospital, Amsterdam Leukodystrophy Center, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience, Amsterdam, The Netherlands
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands
Maroofian R:
UCL Queen Square Institute of Neurology, University College London, London, UK
Houlden H:
UCL Queen Square Institute of Neurology, University College London, London, UK
Green Submitted, hybrid
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