ETHE1 – Leigh Syndrome

ETHE1 encodes mitochondrial persulfide dioxygenase, critical for hydrogen sulfide catabolism. In a cohort of six Tunisian patients with clinical and imaging features of Leigh syndrome, targeted sequencing identified a single homozygous ETHE1 c.122G>A (p.Gly41Asp) variant in one child, consistent with autosomal recessive inheritance and absent segregation data (PMID:36093993). This finding illustrates the utility of genomic testing in consanguineous populations for precise diagnosis of Leigh syndrome subtypes.

Although c.122G>A (p.Gly41Asp) has not been biochemically characterized, extensive functional studies of other ETHE1 missense variants establish a loss-of-function mechanism. Steady-state kinetics show that p.Thr152Ile and p.Asp196Asn reduce enzyme activity by three- and two-fold, respectively, and decrease iron incorporation (PMID:23144459). Variants p.Arg163Gln and p.Arg163Trp compromise protein stability and catalytic efficiency to ~10% of wild-type levels (PMID:25198162). In ETHE1-knockout mice, quantitative proteomics reveals metabolic reprogramming and redox imbalance, supporting pathogenicity of loss-of--function alleles (PMID:26867521).

These data support a limited genetic association between ETHE1 and Leigh syndrome under an autosomal recessive model, driven by a single proband with a homozygous variant and bolstered by functional concordance of other pathogenic alleles. Additional unrelated cases and direct functional assays of p.Gly41Asp are needed to strengthen clinical validity.

Key Take-home: Screening ETHE1 in unexplained Leigh syndrome may uncover rare autosomal recessive cases amenable to targeted metabolic intervention.

References

• Bioscience Reports • 2022 • Next-generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment. PMID:36093993
• 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
• Proteomics • 2016 • Quantitative proteomics suggests metabolic reprogramming during ETHE1 deficiency. PMID:26867521

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