ECHS1

ECHS1 is a gene that encodes the enzyme enoyl-CoA hydratase, short chain, mitochondrial (ECHS1). This mitochondrial matrix enzyme participates in the beta-oxidation of fatty acids, hydrating enoyl-CoA substrates to form 3-hydroxyacyl-CoA. It contributes to the degradation of short-chain fatty acids and also plays a role in the catabolism of certain branched-chain amino acids, including valine, within mitochondria. The protein is widely expressed, with notable levels in metabolically active tissues such as liver and muscle.

Functionally, ECHS1 acts within the mitochondrial fatty acid oxidation pathway and related metabolic processes that manage energy production from lipids and amino acids. By processing specific enoyl-CoA intermediates, it helps maintain efficient energy metabolism, particularly under metabolic stress or fasting conditions where beta-oxidation is upregulated.

Clinical significance arises from pathogenic variants in ECHS1, which cause ECHS1 deficiency, a rare autosomal recessive metabolic disorder. The condition is characterized by early-onset neurological involvement, developmental delay or hypotonia, lactic acidosis, and episodes of metabolic decompensation. Biochemical findings may include accumulation of valine-derived metabolites and intermediates such as methacrylyl-CoA–related compounds, contributing to mitochondrial dysfunction. Phenotypes are variable, ranging from severe neonatal presentations to later-onset neurodevelopmental disorders. Diagnosis typically relies on genetic testing demonstrating biallelic pathogenic variants in ECHS1, supported by clinical features and biochemical or neuroimaging data. Management is primarily supportive, emphasizing metabolic stabilization, avoidance of prolonged fasting, control of seizures where present, and rehabilitation therapies. Ongoing research seeks to clarify the precise metabolic consequences of ECHS1 deficiency and to explore targeted therapeutic approaches.