Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Scala M. Wortmann S.B. Kaya N. Stellingwerff M.D. Pistorio A. Glamuzina E. van Karnebeek C.D. 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 T.B. Prokisch H. Aldhalaan H. Karimiani E.G. Yildiz Y. Ceylan A.C. Santiago-Sim T. Dameron A. Yang H. Toosi M.B. Ashrafzadeh F. Akhondian J. Imannezhad S. Mirzadeh H.S. Maqbool S. Farid A. Al-Muhaizea M.A. Alshwameen M.O. Aldowsari L. Alsagob M. Alyousef A. AlMass R. AlHargan A. Alwadei A.H. AlRasheed M.M. Colak D. Alqudairy H. Khan S. Lines M.A. García Cazorla M.Á. Ribes A. Morava E. Bibi F. Haider S. Ferla M.P. Taylor J.C. Alsaif H.S. Firdous A. Hashem M. Shashkin C. Koneev K. Kaiyrzhanov R. Efthymiou S. Genomics Q.S. Schmitt-Mechelke T. Ziegler A. Issa M.Y. Elbendary H.M. Striano P. Alkuraya F.S. Zaki M.S. Gleeson J.G. Barakat T.S. Bierau J. van der Knaap M.S. Maroofian R. Houlden H.
March 2022 John Wiley and Sons Inc

Human Mutation
2022 #43 Issue 3 403 - 419 pp.

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.

congenital microcephaly , developmental and epileptic encephalopathy 35 , heart disease , ITPA , ITPase , white matter abnormalities

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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, United Kingdom
Amalia Childrens Hospital, Radboud University Nijmegen, Nijmegen, Netherlands
University Childrens Hospital, Paracelsus Medical University, Salzburg, Austria
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
Department of Child Neurology, Emma Childrens Hospital, Amsterdam Leukodystrophy Center, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience, Amsterdam, Netherlands
Clinical Epidemiology and Biostatistics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
Adult and Paediatric National Metabolic Service, Starship Childrens Hospital, Auckland, New Zealand
Departments of Pediatrics and Clinical Genetics, Academic Medical Centre, Amsterdam, Netherlands
Department of Molecular Medicine, Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Bahrain
Department of Medical Genetics, The Childrens Memorial Health Institute, Warsaw, Poland
Department of Audiology and Phoniatrics, The Childrens Memorial Health Institute, Warsaw, Poland
Secció dErrors Congènits del Metabolisme-IBC, Servei de Bioquímica iGenètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Childrens Hospital, Boston, MA, United States
Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Childrens Hospital, Boston, MA, United States
Department of Neurology, Harvard Medical School, Boston, MA, United States
Nicklaus Childrens Hospital, Miami, FL, United States
Tulane University School of Medicine, New Orleans, LA, United States
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
Institute of Human Genetics, Technische Universität München, Munich, Germany
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Molecular and Clinical Sciences Institute, St. Georges University of London, Cranmer Terrace, London, United Kingdom
Innovative Medical Research Center, Islamic Azad University, Mashhad Branch, Mashhad, Iran
Pediatric Metabolic Diseases Clinic, Dr. Sami Ulus Training and Research Hospital for Maternity and Children, Ankara, Turkey
Department of Medical Genetics, Ankara City Hospital, Ankara, Turkey
GeneDx, Gaithersburg, MD, United States
Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
Department of Pediatrics, Mashhad University of Medical Sciences, Mashhad, Iran
Department of Pediatric Diseases, Mashhad University of Medical Sciences, Mashhad, Iran
Development and Behavioral Pediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan
Neurosciences Department, King Fahad Medical City, Riyadh, Saudi Arabia
Department of Clinical Pharmacy, King Saud University, Riyadh, Saudi Arabia
Department of Biostatistics, Epidemiology and Scientific Computing, KFSHRC, Riyadh, Saudi Arabia
Medical Genetics, Department of Pediatrics, Alberta Childrens Hospital, Calgary, Canada
Inborn Errors of Metabolism Unit, Hospital Sant Joan de Déu, Barcelona, Spain
Department of Clinical Genomics, Laboratory of Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
Institute of Biochemistry and Biotechnology, Pir Mehar Ali Shah Arid Agriculture University, Rawalpindi, Pakistan
Izzat Ali Shah Hospital, Lalarukh Wah Cantt, Rawalpindi, Pakistan
NIHR Oxford BRC Genomic Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
International University of Postgraduate Education, Almaty, Kazakhstan
Department of Neurology and Neurosurgery, Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan
Department of Neuropaediatrics, Childrens Hospital, Cantonal Hospital, Lucerne, Switzerland
Zentrum für Kinder und Jugendmedizin Heidelberg, Sektion Neuropädiatrie und Stoffwechselmedizin, Universitätsklinikum Heidelberg, Heidelberg, Germany
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
Department of Anatomy and Cell Biology, Alfaisal University, Riyadh, Saudi Arabia
Department of Neuroscience, Rady Childrens Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, CA, United States
Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, Netherlands
Laboratory of Biochemical Genetics, Department of Clinical Genetics, Maastricht University Hospital, Maastricht, Netherlands
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, Netherlands

Department of Neurosciences
Pediatric Neurology and Muscular Diseases Unit
UCL Queen Square Institute of Neurology
Amalia Childrens Hospital
University Childrens Hospital
Department of Genetics
Department of Translational Genomics
Department of Child Neurology
Clinical Epidemiology and Biostatistics Unit
Adult and Paediatric National Metabolic Service
Departments of Pediatrics and Clinical Genetics
Department of Molecular Medicine
Department of Medical Genetics
Department of Audiology and Phoniatrics
Secció dErrors Congènits del Metabolisme-IBC
Department of Neurology
Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program
Department of Neurology
Nicklaus Childrens Hospital
Tulane University School of Medicine
Institute of Medical Genetics and Applied Genomics
Institute of Human Genetics
Institute of Human Genetics
Department of Neurosciences
Department of Medical Genetics
Molecular and Clinical Sciences Institute
Innovative Medical Research Center
Pediatric Metabolic Diseases Clinic
Department of Medical Genetics
GeneDx
Pediatric Neurology Department
Department of Pediatrics
Department of Pediatric Diseases
Development and Behavioral Pediatrics Department
Neurosciences Department
Department of Clinical Pharmacy
Department of Biostatistics
Medical Genetics
Inborn Errors of Metabolism Unit
Department of Clinical Genomics
Institute of Biochemistry and Biotechnology
Izzat Ali Shah Hospital
NIHR Oxford BRC Genomic Medicine
International University of Postgraduate Education
Department of Neurology and Neurosurgery
Department of Neuropaediatrics
Zentrum für Kinder und Jugendmedizin Heidelberg
Clinical Genetics Department
Department of Anatomy and Cell Biology
Department of Neuroscience
Department of Clinical Genetics
Laboratory of Biochemical Genetics
Department of Functional Genomics

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