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

Marcello Scala; Saskia B Wortmann; Namik Kaya; Menno D Stellingwerff; Angela Pistorio; Emma Glamuzina; Clara D van Karnebeek; Cristina Skrypnyk; Katarzyna Iwanicka-Pronicka; Dorota Piekutowska-Abramczuk; Elżbieta Ciara; Frederic Tort; Beth Sheidley; Annapurna Poduri; Parul Jayakar; Anuj Jayakar; Jariya Upadia; Nicolette Walano; Tobias B Haack; Holger Prokisch; Hesham Aldhalaan; Ehsan G Karimiani; Yilmaz Yildiz; Ahmet C Ceylan; Teresa Santiago-Sim; Amy Dameron; Hui Yang; Mehran B Toosi; Farah Ashrafzadeh; Javad Akhondian; Shima Imannezhad; Hanieh S Mirzadeh; Shazia Maqbool; Aisha Farid; Mohamed A Al-Muhaizea; Meznah O Alshwameen; Lama Aldowsari; Maysoon Alsagob; Ashwaq Alyousef; Rawan AlMass; Aljouhra AlHargan; Ali H Alwadei; Maha M AlRasheed; Dilek Colak; Hanan Alqudairy; Sameena Khan; Matthew A Lines; M Ángeles García Cazorla; Antonia Ribes; Eva Morava; Farah Bibi; Shahzad Haider; Matteo P Ferla; Jenny C Taylor; Hessa S Alsaif; Abdulwahab Firdous; Mais Hashem; Chingiz Shashkin; Kairgali Koneev; Rauan Kaiyrzhanov; Stephanie Efthymiou; Queen Square Genomics; Thomas Schmitt-Mechelke; Andreas Ziegler; Mahmoud Y Issa; Hasnaa M Elbendary; Pasquale Striano; Fowzan S Alkuraya; Maha S Zaki; Joseph G Gleeson; Tahsin Stefan Barakat; Jorgen Bierau; Marjo S van der Knaap; Reza Maroofian; Henry Houlden

doi:10.1002/humu.24326

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

Journal article

Peer reviewed

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

Marcello Scala, Saskia B Wortmann, Namik Kaya, Menno D Stellingwerff, Angela Pistorio, Emma Glamuzina, Clara D van Karnebeek, Cristina Skrypnyk, Katarzyna Iwanicka-Pronicka, Dorota Piekutowska-Abramczuk, …

Human mutation, Vol.43(3), pp.403-419

03/2022

DOI: https://doi.org/10.1002/humu.24326

PMID: 34989426

Abstract

Epilepsy, Generalized

Humans

Inosine

Inosine Triphosphate

Microcephaly - pathology

Mutation

Prognosis

Pyrophosphatases - genetics

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.

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Title: Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency
Creators - without role: Marcello Scala - University College London
Saskia B Wortmann - Radboud University Nijmegen
Namik Kaya - King Faisal Specialist Hospital & Research Centre
Menno D Stellingwerff - Amsterdam Neuroscience
Angela Pistorio - Istituto Giannina Gaslini
Emma Glamuzina - Starship Children's Health
Clara D van Karnebeek - Departments of Pediatrics and Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands
Cristina Skrypnyk - Arabian Gulf University
Katarzyna Iwanicka-Pronicka - Children's Memorial Health Institute
Dorota Piekutowska-Abramczuk - Children's Memorial Health Institute
Elżbieta Ciara - Children's Memorial Health Institute
Frederic Tort - Consorci Institut D'Investigacions Biomediques August Pi I Sunyer
Beth Sheidley - Boston Children's Hospital
Annapurna Poduri - Harvard University
Parul Jayakar - Miami Children's Hospital
Anuj Jayakar - Miami Children's Hospital
Jariya Upadia - Tulane University
Nicolette Walano - Tulane University
Tobias B Haack - University of Tübingen
Holger Prokisch - Helmholtz Zentrum München
Hesham Aldhalaan - King Faisal Specialist Hospital & Research Centre
Ehsan G Karimiani - St George's, University of London
Yilmaz Yildiz - Ankara
Ahmet C Ceylan - Memorial Ankara Hospital
Teresa Santiago-Sim - GeneDx, Gaithersburg, Maryland, USA
Amy Dameron - GeneDx Gaithersburg MD 20877 USA
Hui Yang - GeneDx Gaithersburg MD 20877 USA
Mehran B Toosi - Mashhad University of Medical Sciences
Farah Ashrafzadeh - Mashhad University of Medical Sciences
Javad Akhondian - Mashhad University of Medical Sciences
Shima Imannezhad - Mashhad University of Medical Sciences
Hanieh S Mirzadeh - Mashhad University of Medical Sciences
Shazia Maqbool - Development and Behavioral Pediatrics Department, Institute of Child Health and The Children Hospital Lahore 54000 Pakistan
Aisha Farid - Development and Behavioral Pediatrics Department, Institute of Child Health and The Children Hospital Lahore 54000 Pakistan
Mohamed A Al-Muhaizea - Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Meznah O Alshwameen - King Faisal Specialist Hospital & Research Centre
Lama Aldowsari - King Faisal Specialist Hospital & Research Centre
Maysoon Alsagob - King Faisal Specialist Hospital & Research Centre
Ashwaq Alyousef - King Faisal Specialist Hospital & Research Centre
Rawan AlMass - King Faisal Specialist Hospital & Research Centre
Aljouhra AlHargan - King Faisal Specialist Hospital & Research Centre
Ali H Alwadei - King Fahd Medical City
Maha M AlRasheed - King Saud University
Dilek Colak - King Faisal Specialist Hospital & Research Centre
Hanan Alqudairy - King Faisal Specialist Hospital & Research Centre
Sameena Khan - King Faisal Specialist Hospital & Research Centre
Matthew A Lines - Alberta Children's Hospital
M Ángeles García Cazorla - Hospital Sant Joan de Déu Barcelona
Antonia Ribes - Consorci Institut D'Investigacions Biomediques August Pi I Sunyer
Eva Morava - Mayo Clinic
Farah Bibi - Pir Mehr Ali Shah Arid Agriculture University
Shahzad Haider - Benazir Bhutto Hospital
Matteo P Ferla - Wellcome Centre for Human Genetics
Jenny C Taylor - Wellcome Centre for Human Genetics
Hessa S Alsaif - King Faisal Specialist Hospital & Research Centre
Abdulwahab Firdous - King Faisal Specialist Hospital & Research Centre
Mais Hashem - Genomics Medicine
Chingiz Shashkin - University of International Business
Kairgali Koneev - Kazakh National Medical University
Rauan Kaiyrzhanov - University College London
Stephanie Efthymiou - University College London
Queen Square Genomics - University College London
Thomas Schmitt-Mechelke - Department of Neuropaediatrics, Children's Hospital, Cantonal Hospital, Lucerne, Switzerland
Andreas Ziegler - University Hospital Heidelberg
Mahmoud Y Issa - National Research Centre
Hasnaa M Elbendary - National Research Centre
Pasquale Striano - University of Genoa
Fowzan S Alkuraya - King Faisal Specialist Hospital & Research Centre
Maha S Zaki - National Research Centre
Joseph G Gleeson - Howard Hughes Medical Institute
Tahsin Stefan Barakat - Erasmus MC
Jorgen Bierau - Maastricht University
Marjo S van der Knaap - Amsterdam Neuroscience
Reza Maroofian - National Hospital for Neurology and Neurosurgery
Henry Houlden - National Hospital for Neurology and Neurosurgery
Publication Details: Human mutation, Vol.43(3), pp.403-419
Grant note: G0601943 / Medical Research Council MR/S005021/1 / Medical Research Council Department of Health 203141/Z/16/Z / Wellcome Trust MR/S01165X/1 / Medical Research Council
Identifiers: 9918629208331
Academic Unit: King Faisal University; King Abdulaziz City for Science & Technology; King Saud University
Language: English
Resource Type: Journal article