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 ProkischHesham 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)403-419
Number of pages17
JournalHuman Mutation
Issue number3
Publication statusPublished - Mar 2022

Bibliographical note

Funding Information:
We thank the patients and their families for their collaboration and consent to the publication of this paper. This study was funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), and also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, the Wellcome Trust Core award (203141/Z/16/Z), the Instituto de Salud Carlos III (PI19/01310) (Co‐funded by European Regional Development Fund "A way to make Europe"), the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovación, Spain), Generalitat de Catalunya (URDCAT project, SLT002/16/00174; (AGAUR 2017: SGR 1428), and the CERCA Programme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. TSB's lab is supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021), an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by German Bundesministerium für Bildung und Forschung (BMBF) through the ERA PerMed project PerMiM (01KU2016A) and the German Network for Mitochondrial Disorders (mitoNET; 01GM1113C)

Publisher Copyright:
© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC


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