Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital

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.9176T>C), MT‐ND5 , PDHA1 , SUCLG1 , and SURF1 . Poorest survival was associated with MT‐ND5 , MT‐ATP6 (m.8993T>C and m.9176T>C), SURF1 , and ALDH5A1 (≤50% 3 year's survival), in contrast to milder defects with specific treatment ( ECHS1 and SLC19A3 , 100% 3 year's 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 counseling, and to the design and monitoring of future clinical trials, the next frontier of LS research. ANN NEUROL 2022;91:466–482