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Scala, M.* ; Wortmann, S.B.* ; Kaya, N.* ; Stellingwerff, M.D.* ; Pistorio, A.* ; Glamuzina, E.* ; van Karnebeek, C.D.M.* ; Skrypnyk, C.* ; Iwanicka-Pronicka, K.* ; Piekutowska-Abramczuk, D.* ; Ciara, E.* ; Tort, F.* ; Sheidley, B.R.* ; Poduri, A.* ; Jayakar, P.* ; Jayakar, A.* ; Upadia, J.* ; Walano, N.* ; Haack, T.B.* ; Prokisch, H. ; Aldhalaan, H.M.* ; Karimiani, E.G.* ; Yildiz, Y.* ; Ceylan, A.C.* ; 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.*

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

Hum. Mutat. 43, 403-419 (2022)

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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, analysing possible predictors for adverse clinical outcome. 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 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 2 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 outcome. 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, counselling, and follow-up of affected individuals. This article is protected by copyright. All rights reserved.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Itpa ; Itpase ; Congenital Microcephaly ; Developmental And Epileptic Encephalopathy 35 ; Heart Disease ; White Matter Abnormalities; Nucleotide Pools; Mutations; Retardation; Association; Growth

ISSN (print) / ISBN 1059-7794

e-ISSN 1098-1004

Journal Human Mutation

Quellenangaben Volume: 43, Issue: 3, Pages: 403-419

Publisher Wiley

Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Human Genetics (IHG)

Grants German Network for Mitochondrial Disorders (mitoNET)
Muscular Dystrophy Association (MDA USA)
Muscular Dystrophy UK (MDUK)
Sparks GOSH Charity
Brain Research UK
MSA Trust
Ataxia UK
Rosetree Trust
National Institute for Health Research University College London Hospitals Biomedical Research Centre
National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust
University of Oxford
Wellcome Trust
German Bundesministerium fur Bildung und Forschung (BMBF)
Erasmus MC Human Disease Model Award 2018
Erasmus MC Fellowship 2017
Netherlands Organization for Scientific Research (ZonMW Veni)
CERCA Programme
AGAUR 2017
Generalitat de Catalunya (URDCATproject )
Instituto de Salud Carlos III (Ministerio de Ciencia e Innovacion, Spain)
Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)
Instituto de Salud Carlos III (European Regional Development Fund "A way to make Europe")
MRC