ETHE1 – Ethylmalonic Encephalopathy

Ethylmalonic encephalopathy (EE) is a rare autosomal recessive mitochondrial disorder caused by biallelic pathogenic variants in the ETHE1 gene (Gene Symbol) and is cataloged as Ethylmalonic Encephalopathy (Disease Name). Patients typically present in infancy with chronic diarrhea, relapsing petechiae, orthostatic acrocyanosis and progressive neurodevelopmental impairment. In two multi-patient cohorts comprising 16 unrelated EE cases, homozygous or compound heterozygous ETHE1 variants were identified in all affected individuals ([PMID:16376514]; [PMID:18593870]).

Genetic evidence for ETHE1 involvement is robust: 37 distinct variants have been reported, including missense, nonsense, canonical splice-site, frameshift and exon deletion alleles ([PMID:32362910]). A recurrent start-codon variant c.3G>T (p.Met1Ile) was identified in a four-year-old patient with subtle acrocyanosis and delayed walking ([PMID:25878756]). Segregation analysis in monochorionic twins demonstrated concordant compound heterozygous mutations in both siblings, providing additional familial corroboration.

The phenotypic spectrum of EE encompasses chronic diarrhea (HP:0002028), global developmental delay (HP:0001263), orthostatic acrocyanosis (HP:0001063) and petechiae (HP:0000967), often accompanied by elevated plasma lactate and ethylmalonic acid excretion. Neuroimaging typically reveals basal ganglia and white matter abnormalities, while cytochrome c oxidase deficiency is observed in muscle and brain tissues.

Functional studies support a loss-of-function mechanism by haploinsufficiency of ETHE1. Ethe1–/– mice recapitulate diffuse endothelial lesions in brain and gut arterioles, mirroring human vascular pathology due to H₂S toxicity ([PMID:22020834]). Biochemical assays of patient-derived ETHE1 variants (p.Thr152Ile, p.Asp196Asn) demonstrate markedly reduced catalytic efficiency and protein stability compared to wild type ([PMID:23144459]; [PMID:25198162]).

Emerging therapeutic strategies highlight the translational impact of this genetic diagnosis. Liver-targeted interventions, including orthotopic liver transplantation and metronidazole plus N-acetylcysteine regimens, have shown clinical and biochemical amelioration, underscoring the benefit of early molecular confirmation for personalized management.

In conclusion, extensive genetic and experimental concordance establishes a Strong association between ETHE1 pathogenic variants and Ethylmalonic Encephalopathy. Early recognition of core clinical features with confirmatory ETHE1 sequencing enables accurate diagnosis, informed genetic counseling, and timely implementation of precision therapies.

References

• Brain & development • 2006 • Ethylmalonic encephalopathy-report of two cases. PMID:16376514
• Journal of medical genetics • 2008 • Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy. PMID:18593870
• Frontiers in genetics • 2020 • Novel Compound Heterozygous Variants of ETHE1 Causing Ethylmalonic Encephalopathy in a Chinese Patient: A Case Report. PMID:32362910
• Journal of pediatric neurosciences • 2015 • Importance of acrocyanosis in delayed walking. PMID:25878756
• Journal of inherited metabolic disease • 2012 • Morphologic evidence of diffuse vascular damage in human and in the experimental model of ethylmalonic encephalopathy. PMID:22020834
• The Journal of biological chemistry • 2012 • Characterization of patient mutations in human persulfide dioxygenase (ETHE1) involved in H2S catabolism. PMID:23144459
• PloS one • 2014 • Ethylmalonic encephalopathy ETHE1 R163W/R163Q mutations alter protein stability and redox properties of the iron centre. PMID:25198162

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