Abstract
Short-chain enoyl-CoA hydratase 1 (SCEH) deficiency, caused by biallelic ECHS1 variants, is a rare inborn error of mitochondrial valine catabolism with poorly defined genotype-phenotype correlations and survival predictors. A systematic review was conducted using PubMed and Scopus with supplementary reference screening. Studies reporting molecularly confirmed ECHS1 deficiency with extractable individual patient data were eligible. Study quality was assessed using appropriate Joanna Briggs Institute (JBI) critical appraisal checklists. Survival analysis was performed using the Kaplan-Meier method with log-rank testing, and independent mortality predictors were identified using multivariate Cox proportional hazards regression. Forty-five studies encompassing 165 patients were included. Dystonia (67.27%) and developmental delay (60.61%) were the commonest features; globus pallidus involvement was the predominant neuroimaging finding (62.42%) and urinary 2,3-dihydroxy-2-methylbutyric acid the most frequent biomarker (41.82%). Neonatal-onset patients demonstrated the most adverse survival trajectory (median 28 months; log-rank p = 4.21 × 10⁻¹²), and neonatal onset was the sole independent mortality predictor on multivariate Cox regression (HR 7.41, 95% CI 3.02-18.14, p < 0.001). Neonatal onset is the strongest independent determinant of mortality in ECHS1 deficiency, underscoring the importance of early molecular diagnosis in unexplained metabolic encephalopathy with basal ganglia involvement. PROSPERO CRD420261376718; Registered on 22 April, 2026.