ECHS1 – Leigh Syndrome

ECHS1 encodes the mitochondrial short‐chain enoyl‐CoA hydratase, a key enzyme in fatty acid β‐oxidation and valine catabolism. Biallelic pathogenic variants in ECHS1 underlie an autosomal recessive form of Leigh syndrome, characterized by subacute necrotizing encephalomyelopathy with basal ganglia lesions, hypotonia, metabolic acidosis, and developmental delay. ECHS1 and Leigh syndrome should be considered in infants presenting with these features.

Genetic evidence supports a definitive gene–disease association: over 60 patients across >30 unrelated families with compound heterozygous or homozygous ECHS1 variants have been reported ([PMID:29882869]). Segregation analysis in sibships and pedigrees from diverse populations (European, Samoan, Japanese, Chinese) confirms recessive inheritance and cosegregation with disease.

The variant spectrum includes >40 distinct mutations, spanning missense (e.g., c.244G>A (p.Val82Met)), splice-site (c.414+3G>C), nonsense (c.232G>T (p.Glu78Ter)), frameshift, and hypomorphic alleles. A representative pathogenic variant is c.370dup (p.Thr124fs), recurrent in multiple families.

Functional studies demonstrate severely reduced ECHS1 protein levels and 2-enoyl-CoA hydratase activity in patient muscle and fibroblasts, with a combined OXPHOS and FAO defect. Exogenous expression of wild-type ECHS1 in patient‐derived myoblasts restores enzyme and respiratory chain activities, confirming loss-of-function pathogenicity. ([PMID:25393721]).

Mechanistically, ECHS1 deficiency leads to toxic accumulation of methacrylyl-CoA and acryloyl-CoA, contributing to neuronal injury. Early metabolic testing (urine acryloyl-CoA metabolites) and targeted exome sequencing facilitate diagnosis. Dietary interventions such as valine restriction and emergency regimens show promise in ameliorating symptoms.

Key take-home: ECHS1 deficiency is a definitive cause of autosomal recessive Leigh syndrome; integration of genetic, biochemical, and functional data enables accurate diagnosis and informs dietary management and genetic counseling in affected families.

References

• Human Mutation • 2015 • ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. PMID:25393721
• Brain | 2014 | ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. PMID:25125611
• Annals of Clinical and Translational Neurology • 2015 • Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. PMID:26000322
• Cells • 2018 • Mitochondrial Fatty Acid Oxidation Disorders Associated with Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency. PMID:29882869

Evidence Based Scoring (AI generated)