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

M. Scala, S.B. Wortmann, N. Kaya, M.D. Stellingwerff, A. Pistorio, E. Glamuzina, C.D. van Karnebeek, C. Skrypnyk, K. Iwanicka-Pronicka, D. Piekutowska-Abramczuk, E. Ciara, F. Tort, B. Sheidley, A. Poduri, P. Jayakar, A. Jayakar, J. Upadia, N. Walano, T.B. Haack, H. ProkischH. Aldhalaan, E.G. Karimiani, Y. Yildiz, A.C. Ceylan, T. Santiago-Sim, A. Dameron, H. Yang, M.B. Toosi, F. Ashrafzadeh, J. Akhondian, S. Imannezhad, H.S. Mirzadeh, S. Maqbool, A. Farid, M.A. Al-Muhaizea, M.O. Alshwameen, L. Aldowsari, M. Alsagob, A. Alyousef, R. AlMass, A. AlHargan, A.H. Alwadei, M.M. AlRasheed, D. Colak, H. Alqudairy, S. Khan, M.A. Lines, M.A.G. Cazorla, A. Ribes, E. Morava, J. Bierau, Marjo S. van der Knaap*, Reza Maroofian*, Henry H. Houlden*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Web of Science)


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
Early online date12 Jan 2022
Publication statusPublished - Mar 2022


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

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