ECHS1 – Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency

Short-chain enoyl-CoA hydratase 1 (ECHS1; HGNC:3151) deficiency is an autosomal recessive mitochondrial disorder (MONDO:0014563) first described in 2014. Patients typically present with psychomotor delay, lactic acidosis, basal ganglia lesions resembling Leigh syndrome, and systemic metabolic derangements ([PMID:35206276]). Early recognition is critical for dietary interventions.

Over 63 unrelated probands with biallelic ECHS1 variants have been reported to date ([PMID:35206276]). Cohorts include five Chinese patients from unrelated families ([PMID:32677908]) and two additional probands in Chinese pedigrees ([PMID:40192239]). Segregation in multiple consanguineous and nonconsanguineous families confirms autosomal recessive inheritance with complete penetrance.

The mutation spectrum encompasses >34 missense, frameshift, splice-site, and synonymous hypomorphic alleles ([PMID:32677908]). A recurrent founder missense variant c.463G>A (p.Gly155Ser) appears in three unrelated families ([PMID:32677908]). Other recurrent changes include c.476A>G (p.Gln159Arg) identified across ethnicities ([PMID:35206276]). Loss-of-function mutations and splice variants such as p.Pro163= reduce normal splicing.

Functional assays in patient-derived fibroblasts demonstrate markedly reduced ECHS1 protein and hydratase activity, accumulation of valine catabolites, and rescue of enzyme function with wild-type cDNA ([PMID:26000322]). High-throughput validation of variants of uncertain significance confirmed loss of function for novel alleles, including cryptic splice mutations ([PMID:37055166]).

CRISPR/Cas9 ECHS1 knockout human cells recapitulate complex I and IV assembly defects, reduced oxygen consumption, and impaired tricarboxylic acid cycle transcription ([PMID:35962613]). Echs1+/- mice develop myocardial fibrosis and cardiomyopathy via p300-mediated H3K9 acetylation, which is ameliorated by nicotinamide mononucleotide treatment ([PMID:35540099]).

Pathogenic loss of hydratase activity leads to accumulation of toxic methacrylyl-CoA and acryloyl-CoA, resulting in neurotoxicity and energy failure consistent with Leigh neuropathology ([PMID:25125611]). Dietary valine restriction and avoidance of catabolic stressors may improve outcomes, though no curative therapy exists.

No significant conflicting evidence has been reported. The collective data support a definitive gene–disease association, with robust genetic segregation, recurrent and founder variants, and concordant functional and animal model studies.

Key Take-home: Biallelic ECHS1 variants cause a definitive autosomal recessive mitochondrial disorder amenable to early metabolic interventions.

References

• International journal of environmental research and public health • 2022 • Pathogenic Biallelic Mutations in ECHS1 in a Case with Short-Chain Enoyl-CoA Hydratase (SCEH) Deficiency-Case Report and Literature Review. PMID:35206276
• BMC medical genetics • 2020 • Novel ECHS1 mutations in Leigh syndrome identified by whole-exome sequencing in five Chinese families: case report. PMID:32677908
• Molecular genetics & genomic medicine • 2025 • Expanding the Clinical and Genetic Spectrum of Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency: Insights From Two Unrelated Chinese Families. PMID:40192239
• Annals of clinical and translational neurology • 2015 • Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. PMID:26000322
• Journal of medical genetics • 2023 • Strategic validation of variants of uncertain significance in ECHS1 genetic testing. PMID:37055166
• The FEBS journal • 2023 • Loss of mitochondrial fatty acid β-oxidation protein short-chain Enoyl-CoA hydratase disrupts oxidative phosphorylation protein complex stability and function. PMID:35962613
• JACC. Basic to translational science • 2022 • Nicotinamide Mononucleotide Alleviates Cardiomyopathy Phenotypes Caused by Short-Chain Enoyl-Coa Hydratase 1 Deficiency. PMID:35540099
• Brain : a journal of neurology • 2014 • ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. PMID:25125611

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