期刊
HUMAN MUTATION
卷 43, 期 3, 页码 403-419出版社
WILEY-HINDAWI
DOI: 10.1002/humu.24326
关键词
congenital microcephaly; developmental and epileptic encephalopathy 35; heart disease; ITPA; ITPase; white matter abnormalities
资金
- MRC [MR/S01165X/1, MR/S005021/1, G0601943]
- 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)
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust
- University of Oxford
- Wellcome Trust [203141/Z/16/Z]
- Instituto de Salud Carlos III (European Regional Development Fund A way to make Europe) [PI19/01310]
- Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER)
- Instituto de Salud Carlos III (Ministerio de Ciencia e Innovacion, Spain)
- Generalitat de Catalunya (URDCATproject ) [SLT002/16/00174]
- AGAUR 2017 [SGR 1428]
- CERCA Programme
- Netherlands Organization for Scientific Research (ZonMW Veni) [91617021]
- Erasmus MC Fellowship 2017
- Erasmus MC Human Disease Model Award 2018
- German Bundesministerium fur Bildung und Forschung (BMBF) [01KU2016A]
- German Network for Mitochondrial Disorders (mitoNET) [01GM1113C]
- Medical Research Council [G0601943, MR/S005021/1, MR/S01165X/1] Funding Source: researchfish
- Rosetrees Trust [PGL19-2 10118] Funding Source: researchfish
This study elucidates the genotypic and phenotypic spectrum of developmental and epileptic encephalopathy 35 (DEE 35) and analyzes predictors for adverse clinical outcomes. It identifies biallelic variants in the ITPA gene as the cause of severe neurological condition and highlights developmental delay, microcephaly, and refractory epilepsy as common symptoms. Additionally, congenital microcephaly and cardiac involvement are identified as potential predictors of adverse outcomes.
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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