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Scala M, Wortmann SB, Kaya N, et al. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency. Hum Mutat. 2022;doi: 10.1002/humu.24326.
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. �. �., 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. (2022). Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency. Human mutation, . https://doi.org/10.1002/humu.24326
Scala, Marcello, et al. "Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency." Human mutation vol. (2022). doi: https://doi.org/10.1002/humu.24326
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, García Cazorla MÁ, 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, Houlden H. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency. Hum Mutat. 2022 Jan 06; doi: 10.1002/humu.24326. Epub 2022 Jan 06. PMID: 34989426.
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Hum Mutat. 2022 Jan 06; doi: 10.1002/humu.24326. Epub 2022 Jan 06.

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

Human mutation

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

Affiliations

  1. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy.
  2. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  3. UCL Queen Square Institute of Neurology, University College London, London, UK.
  4. Amalia Children's Hospital, Radboud University Nijmegen, Nijmegen, The Netherlands.
  5. University Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
  6. Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
  7. Department of Translational Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
  8. Department of Child Neurology, Emma Children's Hospital, Amsterdam Leukodystrophy Center, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience, Amsterdam, The Netherlands.
  9. Clinical Epidemiology and Biostatistics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  10. Adult and Paediatric National Metabolic Service, Starship Children's Hospital, Auckland, New Zealand.
  11. Departments of Pediatrics and Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
  12. Department of Molecular Medicine, Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain.
  13. Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
  14. Department of Audiology and Phoniatrics, The Children's Memorial Health Institute, Warsaw, Poland.
  15. Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica iGenètica Molecular, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain.
  16. Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusettes, USA.
  17. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Children's Hospital, Boston, Massachusettes, USA.
  18. Department of Neurology, Harvard Medical School, Boston, Massachusettes, USA.
  19. Nicklaus Children's Hospital, Miami, Florida, USA.
  20. Tulane University School of Medicine, New Orleans, Louisiana, USA.
  21. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
  22. Institute of Human Genetics, Technische Universität München, Munich, Germany.
  23. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
  24. Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
  25. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
  26. Molecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London, UK.
  27. Innovative Medical Research Center, Islamic Azad University, Mashhad Branch, Mashhad, Iran.
  28. Pediatric Metabolic Diseases Clinic, Dr. Sami Ulus Training and Research Hospital for Maternity and Children, Ankara, Turkey.
  29. Department of Medical Genetics, Ankara City Hospital, Ankara, Turkey.
  30. GeneDx, Gaithersburg, Maryland, USA.
  31. Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.
  32. Department of Pediatrics, Mashhad University of Medical Sciences, Mashhad, Iran.
  33. Department of Pediatric Diseases, Mashhad University of Medical Sciences, Mashhad, Iran.
  34. Development and Behavioral Pediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan.
  35. Neurosciences Department, King Fahad Medical City, Riyadh, Saudi Arabia.
  36. Department of Clinical Pharmacy, King Saud University, Riyadh, Saudi Arabia.
  37. Department of Biostatistics, Epidemiology and Scientific Computing, KFSHRC, Riyadh, Kingdom of Saudi Arabia.
  38. Medical Genetics, Department of Pediatrics, Alberta Children's Hospital, Calgary, Canada.
  39. Inborn Errors of Metabolism Unit, Hospital Sant Joan de Déu, Barcelona, Spain.
  40. Department of Clinical Genomics, Laboratory of Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.
  41. Institute of Biochemistry and Biotechnology, Pir Mehar Ali Shah Arid Agriculture University, Rawalpindi, Pakistan.
  42. Izzat Ali Shah Hospital, Lalarukh Wah Cantt, Rawalpindi, Pakistan.
  43. NIHR Oxford BRC Genomic Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  44. International University of Postgraduate Education, Almaty, Kazakhstan.
  45. Department of Neurology and Neurosurgery, Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan.
  46. Department of Neuropaediatrics, Children's Hospital, Cantonal Hospital, Lucerne, Switzerland.
  47. Zentrum für Kinder und Jugendmedizin Heidelberg, Sektion Neuropädiatrie und Stoffwechselmedizin, Universitätsklinikum Heidelberg, Heidelberg, Germany.
  48. Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
  49. Department of Anatomy and Cell Biology, Alfaisal University, Riyadh, Saudi Arabia.
  50. Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, California, USA.
  51. Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
  52. Laboratory of Biochemical Genetics, Department of Clinical Genetics, Maastricht University Hospital, Maastricht, The Netherlands.
  53. Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.

PMID: 34989426 DOI: 10.1002/humu.24326

Abstract

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.

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

Keywords: ITPA; ITPase; congenital microcephaly; developmental and epileptic encephalopathy 35; heart disease; white matter abnormalities

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