Expanding the Clinical and Genetic Spectrum of Mitochondrial Short‐Chain Enoyl‐CoA Hydratase 1 Deficiency: Insights From Two Unrelated Chinese Families

ABSTRACT Background Mitochondrial short‐chain enoyl‐CoA hydratase 1 deficiency (ECHS1D) is a rare autosomal recessive disorder affecting valine metabolism, with clinical severity ranging from neonatal death to survival into adulthood. Despite advances in understanding ECHS1D, the genetic basis remains underexplored, particularly in underrepresented populations. Methods This study aimed to investigate the clinical and genetic characteristics of ECHS1D in two unrelated Chinese families and identify novel pathogenic variants. Clinical and genetic data were collected, and whole‐genome sequencing was performed to identify pathogenic variants in the ECHS1 gene. Results The first proband, a 15‐month‐old girl, presented with developmental delays and metabolic acidosis, with an MRI revealing abnormal signals in the basal ganglia. The second proband, a 6.5‐year‐old girl with movement‐induced dystonia, exhibited lethargy following recurrent fever and vomiting, with similar MRI findings. Genetic testing identified novel compound heterozygous variants: c.759_762del (p.Gly255Valfs*21) and c.489G>A (p.Pro163=) in Proband 1 and c.518C>T (p.Ala173Val) and c.244G>A (p.Val82Met) in Proband 2. The c.759_762del (p.Gly255Valfs21) variant, identified for the first time, likely results in severe symptoms due to a loss of normal function. Conclusion These findings expand the ECHS1 mutational spectrum and emphasize the importance of genetic testing for early diagnosis and personalized management of ECHS1D. Interventions such as dietary valine restriction and the avoidance of triggering factors may improve clinical outcomes, while further research is needed to explore targeted therapeutic strategies.