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Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in <jats:italic>SQOR<\/jats:italic>. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4\u2010year\u2010old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh\u2010like lesions on brain imaging. She died shortly after. Her 8\u2010year\u2010old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G\u2009&gt;\u2009A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.<\/jats:p>","DOI":"10.1002\/jimd.12232","type":"journal-article","created":{"date-parts":[[2020,3,11]],"date-time":"2020-03-11T16:15:23Z","timestamp":1583943323000},"page":"1024-1036","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Pathogenic variants in <scp><i>SQOR<\/i><\/scp> encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease"],"prefix":"10.1002","volume":"43","author":[{"given":"Marisa W.","family":"Friederich","sequence":"first","affiliation":[{"name":"Section of Clinical Genetics and Metabolism, Department of Pediatrics University of Colorado  Aurora Colorado"},{"name":"Department of Pathology and Laboratory Medicine Children's Hospital Colorado  Aurora Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdallah F.","family":"Elias","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Shodair Children's Hospital  Helena Montana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Kuster","sequence":"additional","affiliation":[{"name":"Department of Neurometabolism University Hospital of Nantes  Nantes France"},{"name":"INRAE, UMR1280, PhAN, Nantes Universit\u00e9  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Laugwitz","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Genetik und Angewandte Genomik Universit\u00e4tsklinikum, University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin A.","family":"Larson","sequence":"additional","affiliation":[{"name":"Section of Clinical Genetics and Metabolism, Department of Pediatrics University of Colorado  Aurora 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Montana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Schoof","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Shodair Children's Hospital  Helena Montana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Goujon","sequence":"additional","affiliation":[{"name":"Department of Neurometabolism University Hospital of Nantes  Nantes France"},{"name":"Service de G\u00e9n\u00e9tique Clinique University Hospital of Rennes  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Lefrancois","sequence":"additional","affiliation":[{"name":"Pediatric Radiology University Hospital of Nantes  Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Friederich","sequence":"additional","affiliation":[{"name":"Section of Clinical Genetics and Metabolism, Department of Pediatrics University of Colorado  Aurora 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