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Stenton, S. ; Zou, Y.* ; Cheng, H.* ; Liu, Z.* ; Wang, J.* ; Shen, D.* ; Jin, H.* ; Ding, C.* ; Tang, X.* ; Sun, S.* ; Han, H.* ; Ma, Y.* ; Zhang, W.* ; Jin, R.* ; Wang, H.* ; Sun, D.* ; Lv, J.L.* ; Prokisch, H. ; Fang, F.*

Leigh syndrome: A study of 209 patients at the Beijing Children's Hospital.

Ann. Neurol. 91, 466-482 (2022)
DOI
Open Access Green: Postprint online available 04/2023
OBJECTIVE: Leigh syndrome (LS) is a heterogeneous neurodegenerative disease and the most frequent pediatric manifestation of mitochondrial disease. In the largest patient collection to date, this study aimed to provide new insights into the clinical and genetic spectrum of LS, defect-specific associations, and predictors of disease course and survival. METHODS: Clinical, metabolic, neuroimaging, onset, and survival data were collected from the medical records of 209 patients referred to the Beijing Children's Hospital with symmetrical basal ganglia and/or brainstem neuroimaging changes indicative of LS by 30 centers from the Chinese network of mitochondrial disease (mitoC-NET) between January 2013 and July 2021 for exploratory analysis. RESULTS: Pathogenic variants were identified in 52 genes, most frequently MT-ATP6, SURF1, and PDHA1. Maternally inherited variants accounted for 42% (heteroplasmy level ≥ 90% in 64%). Phenotypes spanned 92 Human Phenotype Ontology terms. Elevated serum lactate (144/195), global developmental delay (142/209), and developmental regression (103/209) were most frequent. Discriminating neuroimaging and/or clinical features were identified for MT-ATP6 (m.9176 T > C), MT-ND5, PDHA1, SUCLG1, and SURF1. Poorest survival was associated with MT-ND5, MT-ATP6 (m.8993 T > C and m.9176 T > C), SURF1, and ALDH5A1 (≤50% 3 year survival), in contrast to milder defects with specific treatment (ECHS1 and SLC19A3, 100% 3 year survival). INTERPRETATION: Our data define phenotype, onset, and survival of LS in a defect-specific manner, identifying features discriminating between genetic defects and predictive of disease outcome. These findings are essential to early diagnosis, in optimizing family counselling, and to the design and monitoring of future clinical trials, the next frontier of LS research. This article is protected by copyright. All rights reserved.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genotype Correlations; Clinical-features; Mitochondrial; Deficiency; Mutations; Phenotype; Disease; Sucla2
ISSN (print) / ISBN 0364-5134
e-ISSN 1531-8249
Quellenangaben Volume: 91, Issue: 4, Pages: 466-482 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Grants National Natural Science Foundation of China
Capital Health Development Research Foundation Project
European Joint Programme on Rare Diseases project GENOMIT
Horizon2020 through the ERA PerMed project PerMiM
German BMBF