Sulfide Quinone Oxidoreductase Deficiency

Mendelian MONDO:0030982 Pathograph 28 Show in embeddings browser Inborn Error of Metabolism Leigh Syndrome Mitochondrial Disease

Sulfide quinone oxidoreductase deficiency (SQORD) is an autosomal recessive inborn error of hydrogen sulfide (H2S) metabolism caused by biallelic loss-of-function variants in SQOR (previously SQRDL). SQOR is the inner mitochondrial membrane enzyme that performs the first step of mitochondrial sulfide oxidation, transferring electrons from H2S to coenzyme Q and the sulfane sulfur to glutathione; ETHE1 persulfide dioxygenase acts on its product in the next step. Affected children from two unrelated families have been described. Episodes following intercurrent illness produce coma, lactic acidosis and Leigh-like basal ganglia lesions, with isolated decreased cytochrome c oxidase (complex IV) activity in muscle and liver despite normal complex IV protein and assembly. The proposed mechanism is intermittent accumulation of H2S, which inhibits complex IV and causes energy failure; a mouse model in which SQOR is excluded from mitochondria reproduces the Leigh-like disease, the H2S elevation and the complex IV deficit. Two sisters in the first family died during their first episode, while homozygous siblings in the second family have remained asymptomatic, so penetrance and the triggers that convert the biochemical defect into disease are not settled.

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1
Mappings
2
Inheritance
6
Pathophys.
14
Phenotypes
2
Gaps
28
Pathograph
1
Genes
2
Variants
2
Medical Actions
2
Differentials
2
Models
7
References
1
Deep Research
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Classifications

ICIMD (Inherited Metabolic Disorders)
sulfur containing amino acids
🔗

Mappings

MONDO
MONDO:0030982 sulfide quinone oxidoreductase deficiency
skos:exactMatch OMIM:619221
MONDO:0030982 is asserted equivalent to OMIM:619221, the OMIM entry for SQOR-related sulfide quinone oxidoreductase deficiency. MONDO cross-references no Orphanet entry for this disease.
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Inheritance

2
Autosomal recessive HP:0000007
All reported patients are homozygous for SQOR loss-of-function variants: c.637G>A p.(Glu213Lys) in a consanguineous Lehrerleut Hutterite family and c.446delT in a consanguineous family of Turkish descent. Heterozygous parents are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:32160317 SUPPORT INDIRECT Human Clinical
"Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13."
Both affected sisters in family A are homozygous for a founder allele carried by unaffected heterozygotes in their population, consistent with autosomal recessive inheritance; the abstract does not name the mode of inheritance itself.
PMID:32160317 SUPPORT INDIRECT Human Clinical
"He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels."
The affected boy in the second family is also homozygous for a loss-of-function SQOR allele.
Incomplete penetrance HP:0003829
Homozygous siblings of the affected boy in family B have remained clinically well, so carrying two SQOR loss-of-function alleles does not invariably cause disease. The number of genotyped individuals is too small to estimate penetrance.
Incomplete penetrance
Show evidence (3 references)
PMID:36306676 SUPPORT INDIRECT Human Clinical
"In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in..."
The SQOR-deficient group studied includes a symptomatic patient and two asymptomatic siblings. The quote supports incomplete penetrance through the inference that the asymptomatic siblings share the deficiency, which the study's inclusion of them as SQOR-deficient patients implies.
PMID:32160317 SUPPORT Human Clinical
"In family B, the children are each homozygous for the variant c.446delT whereas the parents are heterozygous carriers."
All children of family B, not only the affected boy, are homozygous for the c.446delT allele.
PMID:32160317 SUPPORT Human Clinical
"Outside acute events, our patients generally appeared healthy, and likewise two siblings in Family B have remained asymptomatic for prolonged time."
Two homozygous siblings in family B have stayed asymptomatic, which directly documents incomplete penetrance.
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Discussions and Knowledge Gaps

2
Why do some SQOR-deficient individuals remain asymptomatic, and what raises H2S enough to cause an episode?
KNOWLEDGE GAP OPEN sqord_penetrance_and_triggers
Attached to
pathophysiology#Hydrogen Sulfide Accumulation inheritance#Incomplete penetrance
Plasma sulfide was normal in the symptomatic family B patient and in one asymptomatic sibling, and raised in another asymptomatic sibling, so baseline H2S does not track disease. All reported episodes followed intercurrent illness, and the mouse data implicate gut microbial H2S. Whether infection, fasting, or a surge in microbial sulfide production exceeds an otherwise adequate alternative sulfide-disposal capacity has not been measured during an episode in a patient.
Show evidence (1 reference)
PMID:36306676 SUPPORT Human Clinical
"In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in..."
Baseline sulfide measurements do not separate symptomatic from asymptomatic SQOR-deficient siblings.
Will metronidazole or dietary sulfur restriction prevent episodes in patients, as they rescue the SqorDeltaN/DeltaN mouse?
HUMAN MODEL MISMATCH OPEN sqord_sulfide_lowering_therapy
Attached to
treatments#Metronidazole treatments#Sulfur-restricted diet
Both interventions rescue the mouse, whose disease is continuous and accompanied by raised H2S, but patients present with episodic decompensation and inconsistent baseline sulfide. No patient has been treated and reported, so efficacy, dosing, and whether treatment should be continuous or reserved for intercurrent illness are unknown.
Show evidence (1 reference)
PMID:38870029 SUPPORT Model Organism
"Metronidazole administration and a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR."
The model study proposes, but does not test, these therapies in patients.
⚙

Pathophysiology

6
SQOR Sulfide Oxidation Deficiency
Biallelic SQOR variants leave very little SQOR protein and enzyme activity. The missense p.(Glu213Lys) disrupts hydrogen bonding and destabilizes the protein, and c.446delT is a frameshift. SQOR catalyses the first and committed step of mitochondrial sulfide oxidation, oxidizing H2S with coenzyme Q as electron acceptor and glutathione as sulfane sulfur acceptor, so its loss removes the main mitochondrial route for H2S disposal. Levels of the H2S-generating enzymes are unchanged.
SQOR hgnc:20390 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SQOR (hgnc:20390). hgnc:20390 is a gene from the HUGO Gene Nomenclature Committee.
sulfide oxidation GO:0019418 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sulfide oxidation (GO:0019418). GO:0019418 is a biological process from the Gene Ontology.
glutathione-dependent sulfide quinone oxidoreductase activity GO:0106436 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased glutathione-dependent sulfide quinone oxidoreductase activity (GO:0106436). GO:0106436 is a molecular function from the Gene Ontology.
Downstream
Hydrogen Sulfide Accumulation Without SQOR, H2S produced by host tissues and by gut bacteria is not oxidized in mitochondria and can accumulate systemically.
Show evidence (4 references)
PMID:32160317 SUPPORT Human Clinical
"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."
The founder missense variant destabilizes SQOR and abolishes most enzyme activity in patient tissue.
PMID:32160317 SUPPORT Human Clinical
"He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels."
The second family's frameshift allele also severely reduces SQOR protein and activity.
PMID:39719173 SUPPORT REVIEW SYNTHESIS Other
"The reaction, catalyzed by sulfide:quinone oxidoreductase (SQOR), is the initial and critical step in sulfide oxidation."
Places SQOR at the first step of the mitochondrial sulfide oxidation pathway.
+ 1 more reference
Hydrogen Sulfide Accumulation
H2S comes from cysteine catabolism in host tissues and from gut bacteria. In the SqorDeltaN/DeltaN mouse, H2S levels rise and are lowered by metronidazole, implicating the gut microbial source. In patients the accumulation is thought to be intermittent: plasma sulfide was normal in a symptomatic patient between episodes and elevated in one asymptomatic sibling, which suggests that alternative routes can handle basal H2S load and that disease follows when supply exceeds them.
Animal models
SqorDeltaN/DeltaN mouse Mus musculus recapitulates H2S levels are increased and are lowered by metronidazole.
Intestinal epithelium-specific Sqor knockout mouse Mus musculus partially recapitulates Gut-restricted SQOR loss shows that microbial H2S handled by the intestinal epithelium affects host bioenergetics locally and, with high methionine intake, sulfide metabolism globally.
Downstream
Sulfide Inhibition of Cytochrome c Oxidase H2S binds and inhibits cytochrome c oxidase (complex IV).
Leigh-like Brain Injury The brain has little sulfide-oxidizing capacity of its own, which is proposed to make it especially vulnerable to H2S accumulation.
Show evidence (3 references)
PMID:38870029 SUPPORT Model Organism
"SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogen sulfide (H2S) levels."
H2S levels are increased in the mouse model of SQOR deficiency.
PMID:38870029 SUPPORT Model Organism
"Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice."
Lowering gut bacterial H2S production with metronidazole reduces the H2S excess, implicating the microbial source.
PMID:36306676 REFUTE Human Clinical
"In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in..."
Sulfide measured in the family B patient and his siblings did not show consistent elevation, so sustained H2S accumulation has not been demonstrated in humans. This argues against a constant H2S excess and is compatible only with intermittent accumulation.
Sulfide Inhibition of Cytochrome c Oxidase
During an episode, complex IV activity is markedly and selectively reduced in skeletal muscle and liver while complex IV protein and assembly are close to normal, indicating a functional (toxic) inhibition of the enzyme rather than a failure of its biogenesis. This distinguishes SQOR deficiency from the complex IV assembly defects.
cytochrome-c oxidase activity GO:0004129 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased cytochrome-c oxidase activity (GO:0004129). GO:0004129 is a molecular function from the Gene Ontology.
skeletal muscle tissue UBERON:0001134 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal muscle tissue (UBERON:0001134). UBERON:0001134 is an anatomical location from the Uberon multi-species anatomy ontology. liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
SqorDeltaN/DeltaN mouse Mus musculus recapitulates Complex IV activity is markedly decreased and is restored by metronidazole.
Downstream
Impaired Terminal Electron Transfer and ATP Synthesis Inhibited complex IV blocks terminal electron transfer and oxidative ATP synthesis.
Decreased complex IV activity The enzyme inhibition is what tissue respiratory chain assays measure.
Show evidence (2 references)
PMID:32160317 SUPPORT Human Clinical
"Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation."
Patient tissue shows isolated complex IV deficiency with normal complex IV amount and assembly.
PMID:38870029 SUPPORT Model Organism
"SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogen sulfide (H2S) levels."
The mouse model reproduces the complex IV deficit together with raised H2S.
Impaired Terminal Electron Transfer and ATP Synthesis
Inhibition of complex IV blocks electron transfer from cytochrome c to oxygen and the associated proton pumping, so oxidative ATP synthesis fails in affected tissues.
mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial electron transport, cytochrome c to oxygen (GO:0006123). GO:0006123 is a biological process from the Gene Ontology.
Downstream
Lactate Overproduction and Metabolic Decompensation Failure of oxidative ATP synthesis forces anaerobic glycolysis and raises blood lactate.
Leigh-like Brain Injury Energy failure in the brain produces the encephalopathy and the basal ganglia lesions of Leigh disease.
Elevated brain lactate by MRS Oxidative failure in the basal ganglia shifts brain metabolism to anaerobic glycolysis, seen as a lactate peak on MR spectroscopy.
Show evidence (1 reference)
PMID:39719173 SUPPORT REVIEW SYNTHESIS Other
"elevated levels of H2S inhibit the activity of cytochrome c oxidase (i.e., mitochondrial complex IV), thereby impairing oxidative phosphorylation"
H2S inhibition of complex IV impairs oxidative phosphorylation.
Lactate Overproduction and Metabolic Decompensation
The shift to anaerobic glycolysis raises blood lactate. Acute episodes, each reported after an intercurrent illness, present with severe lactic acidosis, coma and, in one child, multiorgan failure.
lactate biosynthetic process GO:0019249 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased lactate biosynthetic process (GO:0019249). GO:0019249 is a biological process from the Gene Ontology.
Downstream
Lactic acidosis The lactate excess presents clinically as lactic acidosis.
Death in childhood Two sisters in family A died during their first decompensation.
Multiorgan failure Severe decompensation progressed to failure of several organs in the index patient.
Hepatic failure Liver failure, with a prolonged prothrombin time, was part of the multiorgan failure.
Shock Circulatory shock accompanied the multiorgan failure in the index patient.
Elevated creatine kinase Muscle injury during decompensation raised circulating creatine kinase.
Show evidence (2 references)
PMID:32160317 SUPPORT Human Clinical
"In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure."
Documents an illness-triggered decompensation with lactic acidosis and multiorgan failure.
PMID:38870029 SUPPORT Model Organism
"Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome."
Raised blood lactate in the model is sulfur-dependent and reversible by dietary sulfur restriction.
Leigh-like Brain Injury
Acute encephalopathy with coma and hypotonia, and lesions in the basal ganglia (caudate, putamen and globus pallidus) and in one case the cerebral cortex, matching the neuroimaging pattern of Leigh disease. The boy from family B had recurrent episodes and recovered from each.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
basal ganglia UBERON:0010011 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in basal ganglia, annotated with collection of basal ganglia (UBERON:0010011). UBERON:0010011 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
SqorDeltaN/DeltaN mouse Mus musculus recapitulates Clinical and pathological manifestations of Leigh syndrome.
Downstream
Coma
Recurrent encephalopathy
Hypotonia
Basal ganglia lesions
Death in childhood
Tonic seizures The acute encephalopathy began with tonic seizures in the index patient.
Neurostorming After the acute brain injury, the index patient had paroxysmal episodes of sympathetic overactivity.
Show evidence (3 references)
PMID:32160317 SUPPORT Human Clinical
"After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging."
Documents the Leigh-like neurological picture in the index patient.
PMID:32160317 SUPPORT Human Clinical
"In family B, a boy had episodes of encephalopathy and basal ganglia lesions."
Documents recurrent encephalopathy with basal ganglia lesions in the second family.
PMID:38870029 SUPPORT Model Organism
"Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome."
Loss of mitochondrial SQOR produces Leigh-like disease in mice.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Sulfide Quinone Oxidoreductase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

14
Cardiovascular 1
Shock HP:0031273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Shock (HP:0031273). HP:0031273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"She developed shock, respiratory insufficiency evolving into acute respiratory distress syndrome, and multi-organ failure including liver failure with increased prothrombin time"
Shock during the first episode.
Digestive 1
Hepatic failure HP:0001399 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic failure (HP:0001399). HP:0001399 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"She developed shock, respiratory insufficiency evolving into acute respiratory distress syndrome, and multi-organ failure including liver failure with increased prothrombin time"
Liver failure during the first episode.
Metabolism 2
Lactic acidosis HP:0003128 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lactic acidosis (HP:0003128), qualified as temporality recurrent. HP:0003128 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:32160317 SUPPORT Human Clinical
"In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure."
Lactic acidosis at presentation in the index patient.
PMID:32160317 SUPPORT Human Clinical
"Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
Lactic acidosis in the second affected sister.
Elevated creatine kinase Elevated circulating creatine kinase activity HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"Creatine kinase peaked at 722 U/L and remained mildly elevated."
Creatine kinase peaked at 722 U/L in the index patient.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging."
The index patient was hypotonic.
Nervous System 5
Coma HP:0001259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coma (HP:0001259). HP:0001259 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32160317 SUPPORT Human Clinical
"After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging."
The index patient remained comatose after stabilization.
PMID:32160317 SUPPORT Human Clinical
"Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
Coma in the second affected sister.
Recurrent encephalopathy HP:0007335 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent encephalopathy (HP:0007335). HP:0007335 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"In family B, a boy had episodes of encephalopathy and basal ganglia lesions."
Episodic encephalopathy in the family B patient.
Basal ganglia lesions Abnormal basal ganglia MRI signal intensity HP:0012751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Basal ganglia lesions on MRI, annotated with Abnormal basal ganglia MRI signal intensity (HP:0012751). HP:0012751 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32160317 SUPPORT Human Clinical
"Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
Basal ganglia lesions in the second affected sister.
PMID:32160317 SUPPORT Human Clinical
"In family B, a boy had episodes of encephalopathy and basal ganglia lesions."
Basal ganglia lesions in the family B patient.
Tonic seizures HP:0032792 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tonic seizure (HP:0032792). HP:0032792 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"At onset of the illness, during the day she was more tired and vomited, and in the evening became rapidly encephalopathic with an episode of tonic seizures."
Tonic seizures at onset in the index patient.
Elevated brain lactate by MRS Elevated brain lactate level by MRS HP:0012707 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated brain lactate level by MRS (HP:0012707). HP:0012707 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"Brain magnetic resonance spectroscopy (MRS) over the right basal ganglia showed a large lactate peak six times larger than the choline peak with a depressed N-acetylaspartate peak."
MR spectroscopy showed a large basal ganglia lactate peak.
Cellular 1
Decreased complex IV activity Decreased activity of mitochondrial complex IV HP:0008347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased activity of mitochondrial complex IV (HP:0008347). HP:0008347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation."
Isolated complex IV deficiency in patient muscle and liver.
Other 3
Neurostorming
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"In subsequent weeks, she had generalized hypotonia, and episodes of neurostorming with tachycardia, hypertension, and potentially pain"
Neurostorming episodes with tachycardia and hypertension in the index patient.
Multiorgan failure
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure."
Multiorgan failure at presentation of the index patient.
Death in childhood
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
A fatal episode at age 8 years.
🧬

Genetic Associations

1
SQOR (SQOR (previously SQRDL) encodes sulfide:quinone oxidoreductase, a flavoprotein of the inner mitochondrial membrane. Two homozygous loss-of-function alleles have been reported, each in one consanguineous family.)
Gene: SQOR hgnc:20390 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SQOR (hgnc:20390). hgnc:20390 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:32160317 SUPPORT Human Clinical
"We describe children of two families with pathogenic variants in SQOR."
The founding report of SQOR variants in affected children.
PMID:38870029 SUPPORT Model Organism
"Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome."
A mouse model independently supports SQOR loss as a cause of Leigh-like disease.
Variants (2)
SQOR c.637G>A p.(Glu213Lys) Pathogenic
Missense founder variant in exon 5 (NM_021199.4), homozygous in two affected sisters of a Lehrerleut Hutterite family. It destabilizes the protein, leaving severely reduced SQOR protein and activity.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"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."
Functional characterization of the founder variant.
SQOR c.446delT Pathogenic
Single-nucleotide deletion, homozygous in the affected boy of family B and in his asymptomatic siblings.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels."
The deletion abolishes most SQOR protein and activity in fibroblasts.
💊

Medical Actions

2
Metronidazole
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: metronidazole CHEBI:6909 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses metronidazole (CHEBI:6909). CHEBI:6909 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Proposed sulfide-lowering therapy, by analogy with ethylmalonic encephalopathy: the antibiotic reduces H2S production by gut anaerobes. Its support comes from the SqorDeltaN/DeltaN mouse, in which daily metronidazole lowered H2S, normalized complex IV activity and blood lactate, and prolonged survival. No treated patient has been reported.
Mechanism Target:
Hydrogen Sulfide Accumulation — Lowers the gut microbial contribution to systemic H2S.
Show evidence (1 reference)
PMID:38870029 SUPPORT Model Organism
"Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice."
Metronidazole reverses the H2S excess and its downstream effects in the mouse model.
Show evidence (1 reference)
PMID:38870029 SUPPORT Model Organism
"Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice."
Preclinical efficacy in the mouse model; there are no human data.
Sulfur-restricted diet
Action: Dietary InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. NCIT:C15447
Platform: Behavioral / lifestyle
Proposed dietary restriction of sulfur amino acids to reduce substrate for H2S production. In the SqorDeltaN/DeltaN mouse it normalized blood lactate and prevented Leigh-like disease. No treated patient has been reported.
Mechanism Target:
Hydrogen Sulfide Accumulation — Reduces the sulfur substrate available for H2S production.
Show evidence (1 reference)
PMID:38870029 SUPPORT INDIRECT Model Organism
"Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome."
The diet prevents the downstream consequences of H2S excess in the mouse; that it acts by lowering H2S is inferred from the study design.
Show evidence (1 reference)
PMID:38870029 SUPPORT Model Organism
"Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome."
Preclinical efficacy in the mouse model; there are no human data.
🌍

Environmental Factors

1
Intercurrent infection and fasting
exposure_term left unbound. An OLS search of ECTO for "fasting" returned ECTO:2000118 exposure to fasting intervention, which describes a deliberate fasting intervention rather than illness-related fasting; "infection" returned only pathogen-specific exposures (ECTO:2000053 exposure to Human Papillomavirus Infection, ECTO:3000104 exposure to Infectious bronchitis virus); "starvation", "food deprivation" and "exposure to infectious agent" returned no ECTO term.
Every reported decompensation followed an intercurrent illness, often with fasting, which the authors associate with protein catabolism and propose raises H2S supply beyond the low residual SQOR capacity.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"In all patients, acute symptoms were triggered by infections and fasting, episodes associated with protein catabolism."
Infection and fasting preceded every acute episode in the reported patients.
Mechanism Target:
EXACERBATES Hydrogen Sulfide Accumulation — Protein catabolism during illness is proposed to increase H2S production beyond what the low residual SQOR activity can clear.
Show evidence (1 reference)
PMID:32160317 SUPPORT INDIRECT Human Clinical
"We hypothesize that in our patients, the low residual SQOR activity was likely sufficient to support H2S clearance during stable episodes but was insufficient during acute illness with catabolism resulting in H2S accumulation and toxicity."
The authors propose, without measuring H2S during an episode, that illness-related catabolism tips the patients into H2S accumulation.
🔬

Biochemical Markers

2
SQOR enzyme activity (DECREASED)
Context: SQOR activity measured spectrophotometrically in liver mitochondrial membranes, fibroblasts or peripheral blood mononuclear cells is severely reduced; the fibroblast and blood-cell assays allow diagnosis without a tissue biopsy.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels."
Severely reduced SQOR activity in patient fibroblasts.
Blood lactate (INCREASED)
Context: Elevated during and after acute episodes.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging."
Lactate stayed elevated after the acute presentation.
📊

Prevalence

2
Reported cases in the literature
Cases In Literature
Three symptomatic children from two unrelated consanguineous families have been described, plus asymptomatic homozygous siblings in the second family. No population prevalence estimate exists.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"We describe children of two families with pathogenic variants in SQOR."
The founding report describes affected children from two families.
Lehrerleut Hutterite
Carrier Frequency 7692.3 per 100,000 >1 in 1,000 (carriers)
Carrier frequency of the c.637G>A p.(Glu213Lys) founder allele, reported as 1 in 13 from limited screening. This is a heterozygote frequency in one endogamous population, not a disease prevalence.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13."
Reports the founder allele and its carrier frequency in the Lehrerleut Hutterite.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Sulfide Quinone Oxidoreductase Deficiency:

Ethylmalonic encephalopathy MONDO:0011229
Overlapping Features ETHE1 deficiency blocks the next step of the same mitochondrial H2S oxidation pathway and also produces complex IV deficiency and basal ganglia lesions. It differs by a chronic course with petechiae, acrocyanosis, chronic diarrhea, ethylmalonic aciduria and massive thiosulfate excretion, whereas SQOR deficiency has presented as episodic decompensation in otherwise well children. Molecular testing separates them.
Distinguishing Features
  • Massive accumulation of thiosulfate and sulfite in ethylmalonic encephalopathy.
  • Biallelic ETHE1 rather than SQOR variants.
Show evidence (1 reference)
PMID:36306676 SUPPORT Human Clinical
"Patients with ethylmalonic encephalopathy and sulfite oxidase/molybdenum cofactor deficiencies exhibited massive accumulation of thiosulfate and sulfite with formation of large amounts of S-sulfocysteine and S-sulfohomocysteine"
In the same study that measured SQOR-deficient patients, thiosulfate and sulfite accumulation characterized ethylmalonic encephalopathy, giving a biochemical distinction between the two disorders of H2S oxidation.
Leigh syndrome due to complex IV assembly defects MONDO:0009723
Overlapping Features Isolated complex IV deficiency with Leigh-like lesions is most often caused by defects in complex IV subunits or assembly factors such as SURF1. In SQOR deficiency complex IV protein and assembly are normal while activity is reduced, which points to toxic inhibition rather than a biogenesis defect.
Distinguishing Features
  • Normal complex IV protein levels and complex formation despite reduced activity.
Show evidence (1 reference)
PMID:32160317 SUPPORT Human Clinical
"Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation."
Normal complex IV amount and assembly separate SQOR deficiency from complex IV biogenesis defects.
🐁

Animal Models

2
SqorDeltaN/DeltaN mouse
Mice in which SQOR cannot enter mitochondria develop Leigh-like disease with raised blood lactate, markedly decreased complex IV activity and increased H2S. Metronidazole and a sulfur-restricted diet each rescue the phenotype.
Species
Mus musculus
Genotype
Homozygous Sqor allele lacking the N-terminal mitochondrial targeting sequence (SqorDeltaN/DeltaN), so that SQOR is excluded from mitochondria
Genes
SQOR hgnc:20390 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns SQOR (hgnc:20390). hgnc:20390 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:38870029
Pathograph links
Hydrogen Sulfide Accumulation recapitulates fidelity: moderate observes: organism H2S levels are increased and are lowered by metronidazole.
Limitations: The allele mislocalizes SQOR rather than reproducing a patient variant, and patients in family B did not show consistently raised sulfide between episodes.
Show evidence (1 reference)
PMID:38870029 SUPPORT Model Organism
"SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogen sulfide (H2S) levels."
Raised H2S in the model.
Sulfide Inhibition of Cytochrome c Oxidase recapitulates fidelity: high observes: molecular Complex IV activity is markedly decreased and is restored by metronidazole.
Show evidence (1 reference)
PMID:38870029 SUPPORT Model Organism
"Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice."
The complex IV deficit is sulfide-dependent, as in the proposed human mechanism.
Leigh-like Brain Injury recapitulates fidelity: moderate observes: organism Clinical and pathological manifestations of Leigh syndrome.
Limitations: Patients present episodically after intercurrent illness, whereas the model develops disease without a reported trigger; mouse and human basal ganglia vulnerability may differ.
Show evidence (1 reference)
PMID:38870029 SUPPORT Model Organism
"Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome."
The model reproduces Leigh-like disease.
Show evidence (1 reference)
PMID:38870029 SUPPORT Model Organism
"Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome."
Describes the model and its Leigh-like phenotype.
Intestinal epithelium-specific Sqor knockout mouse
Tissue-restricted SQOR deficiency in the gut epithelium perturbs colon bioenergetics in an antibiotic-reversible way, and combined with higher dietary methionine raises serum thiosulfate and ketone bodies and alters behavior. It isolates the gut contribution to systemic sulfide load rather than modelling the whole-body disease.
Species
Mus musculus
Genotype
Sqor deletion confined to intestinal epithelial cells
Genes
SQOR hgnc:20390 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns SQOR (hgnc:20390). hgnc:20390 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:40526718
Pathograph links
Hydrogen Sulfide Accumulation partially recapitulates fidelity: low observes: tissue Gut-restricted SQOR loss shows that microbial H2S handled by the intestinal epithelium affects host bioenergetics locally and, with high methionine intake, sulfide metabolism globally.
Limitations: SQOR is deleted only in intestinal epithelium, so brain, muscle and liver retain sulfide oxidation, and no Leigh-like disease is reported.
Show evidence (1 reference)
PMID:40526718 SUPPORT Model Organism
"In this study, we report that SQOR deficiency confined to murine intestinal epithelial cells perturbs colon bioenergetics that is reversed by antibiotics, revealing a significant local contribution of microbial H2S to host physiology."
Gut-restricted SQOR deficiency reveals the microbial H2S contribution.
Show evidence (1 reference)
PMID:40526718 SUPPORT Model Organism
"In serum, increased thiosulfate, a biomarker of H2S oxidation, reveals that intestinal SQOR deficiency combined with higher dietary methionine affects sulfide metabolism globally and perturbs energy metabolism as indicated by higher ketone bodies."
Systemic sulfide and energy-metabolism effects of gut SQOR deficiency combined with high methionine intake.
{ }

Source YAML

click to show 
name: Sulfide Quinone Oxidoreductase Deficiency
creation_date: "2026-10-08T13:32:21Z"
category: Mendelian
description: >-
  Sulfide quinone oxidoreductase deficiency (SQORD) is an autosomal recessive
  inborn error of hydrogen sulfide (H2S) metabolism caused by biallelic
  loss-of-function variants in SQOR (previously SQRDL). SQOR is the inner
  mitochondrial membrane enzyme that performs the first step of mitochondrial
  sulfide oxidation, transferring electrons from H2S to coenzyme Q and the
  sulfane sulfur to glutathione; ETHE1 persulfide dioxygenase acts on its
  product in the next step. Affected children from two unrelated families have
  been described. Episodes following intercurrent illness produce coma, lactic
  acidosis and Leigh-like basal ganglia lesions, with isolated decreased
  cytochrome c oxidase (complex IV) activity in muscle and liver despite normal
  complex IV protein and assembly. The proposed mechanism is intermittent
  accumulation of H2S, which inhibits complex IV and causes energy failure; a
  mouse model in which SQOR is excluded from mitochondria reproduces the
  Leigh-like disease, the H2S elevation and the complex IV deficit. Two sisters
  in the first family died during their first episode, while homozygous siblings
  in the second family have remained asymptomatic, so penetrance and the
  triggers that convert the biochemical defect into disease are not settled.
disease_term:
  preferred_term: Sulfide Quinone Oxidoreductase Deficiency
  term:
    id: MONDO:0030982
    label: sulfide quinone oxidoreductase deficiency
synonyms:
- SQORD
- SQOR deficiency
- sulfide:quinone oxidoreductase deficiency
parents:
- Inborn Error of Metabolism
- Leigh Syndrome
- Mitochondrial Disease
classifications:
  icimd_category:
  - classification_value: sulfur_containing_amino_acids
    notes: >-
      ICIMD groups disorders of hydrogen sulfide catabolism with the disorders
      of sulfur-containing amino acid metabolism; SQOR catalyses the first
      mitochondrial step of H2S oxidation, upstream of ETHE1.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0030982
      label: sulfide quinone oxidoreductase deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: OMIM:619221
    mapping_justification: >-
      MONDO:0030982 is asserted equivalent to OMIM:619221, the OMIM entry for
      SQOR-related sulfide quinone oxidoreductase deficiency. MONDO
      cross-references no Orphanet entry for this disease.
inheritance:
- name: Autosomal recessive
  description: >-
    All reported patients are homozygous for SQOR loss-of-function variants:
    c.637G>A p.(Glu213Lys) in a consanguineous Lehrerleut Hutterite family and
    c.446delT in a consanguineous family of Turkish descent. Heterozygous parents
    are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13."
    explanation: >-
      Both affected sisters in family A are homozygous for a founder allele carried
      by unaffected heterozygotes in their population, consistent with autosomal
      recessive inheritance; the abstract does not name the mode of inheritance
      itself.
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels."
    explanation: >-
      The affected boy in the second family is also homozygous for a
      loss-of-function SQOR allele.
- name: Incomplete penetrance
  description: >-
    Homozygous siblings of the affected boy in family B have remained clinically
    well, so carrying two SQOR loss-of-function alleles does not invariably cause
    disease. The number of genotyped individuals is too small to estimate
    penetrance.
  inheritance_term:
    preferred_term: Incomplete penetrance
    term:
      id: HP:0003829
      label: Typified by incomplete penetrance
  evidence:
  - reference: PMID:36306676
    reference_title: "Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H(2)S homeostasis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in catabolizing H2S under physiological conditions."
    explanation: >-
      The SQOR-deficient group studied includes a symptomatic patient and two
      asymptomatic siblings. The quote supports incomplete penetrance through the
      inference that the asymptomatic siblings share the deficiency, which the
      study's inclusion of them as SQOR-deficient patients implies.
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family B, the children are each homozygous for the variant c.446delT whereas the parents are heterozygous carriers."
    explanation: All children of family B, not only the affected boy, are homozygous for the c.446delT allele.
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Outside acute events, our patients generally appeared healthy, and likewise two siblings in Family B have remained asymptomatic for prolonged time."
    explanation: Two homozygous siblings in family B have stayed asymptomatic, which directly documents incomplete penetrance.
prevalence:
- population: Reported cases in the literature
  measure_type: CASES_IN_LITERATURE
  notes: >-
    Three symptomatic children from two unrelated consanguineous families have
    been described, plus asymptomatic homozygous siblings in the second family.
    No population prevalence estimate exists.
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe children of two families with pathogenic variants in SQOR."
    explanation: The founding report describes affected children from two families.
- population: Lehrerleut Hutterite
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 7692.3
  notes: >-
    Carrier frequency of the c.637G>A p.(Glu213Lys) founder allele, reported as
    1 in 13 from limited screening. This is a heterozygote frequency in one
    endogamous population, not a disease prevalence.
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13."
    explanation: Reports the founder allele and its carrier frequency in the Lehrerleut Hutterite.
pathophysiology:
- name: SQOR Sulfide Oxidation Deficiency
  description: >-
    Biallelic SQOR variants leave very little SQOR protein and enzyme activity.
    The missense p.(Glu213Lys) disrupts hydrogen bonding and destabilizes the
    protein, and c.446delT is a frameshift. SQOR catalyses the first and
    committed step of mitochondrial sulfide oxidation, oxidizing H2S with
    coenzyme Q as electron acceptor and glutathione as sulfane sulfur acceptor,
    so its loss removes the main mitochondrial route for H2S disposal. Levels of
    the H2S-generating enzymes are unchanged.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SQOR
    term:
      id: hgnc:20390
      label: SQOR
  molecular_functions:
  - preferred_term: glutathione-dependent sulfide quinone oxidoreductase activity
    term:
      id: GO:0106436
      label: glutathione-dependent sulfide quinone oxidoreductase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: sulfide oxidation
    term:
      id: GO:0019418
      label: sulfide oxidation
    modifier: DECREASED
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: The founder missense variant destabilizes SQOR and abolishes most enzyme activity in patient tissue.
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels."
    explanation: The second family's frameshift allele also severely reduces SQOR protein and activity.
  - reference: PMID:39719173
    reference_title: "Essential role of sulfide oxidation in brain health and neurological disorders."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The reaction, catalyzed by sulfide:quinone oxidoreductase (SQOR), is the initial and critical step in sulfide oxidation."
    explanation: Places SQOR at the first step of the mitochondrial sulfide oxidation pathway.
  - reference: PMID:26318450
    reference_title: "Transient Kinetic Analysis of Hydrogen Sulfide Oxidation Catalyzed by Human Sulfide Quinone Oxidoreductase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "During the catalytic cycle, the flavin cofactor is intermittently reduced by sulfide and oxidized by ubiquinone, linking H2S oxidation to the electron transfer chain and to energy metabolism."
    explanation: Kinetic work on purified human SQOR shows the enzyme passes electrons from sulfide to ubiquinone, coupling sulfide oxidation to the respiratory chain.
  downstream:
  - target: Hydrogen Sulfide Accumulation
    description: >-
      Without SQOR, H2S produced by host tissues and by gut bacteria is not
      oxidized in mitochondria and can accumulate systemically.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38870029
      reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Taken together, these observations suggest that mitochondrial SQOR is essential to prevent systemic accumulation of H2S."
      explanation: In mice lacking mitochondrial SQOR, H2S accumulates systemically.
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure."
      explanation: The authors of the human report propose H2S accumulation as the consequence of SQOR deficiency; it was inferred rather than measured in the patients.
- name: Hydrogen Sulfide Accumulation
  description: >-
    H2S comes from cysteine catabolism in host tissues and from gut bacteria. In
    the SqorDeltaN/DeltaN mouse, H2S levels rise and are lowered by
    metronidazole, implicating the gut microbial source. In patients the
    accumulation is thought to be intermittent: plasma sulfide was normal in a
    symptomatic patient between episodes and elevated in one asymptomatic
    sibling, which suggests that alternative routes can handle basal H2S load
    and that disease follows when supply exceeds them.
  biological_scale: ORGANISM
  chemical_entities:
  - preferred_term: hydrogen sulfide
    term:
      id: CHEBI:16136
      label: hydrogen sulfide
    modifier: INCREASED
  evidence:
  - reference: PMID:38870029
    reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogen sulfide (H2S) levels."
    explanation: H2S levels are increased in the mouse model of SQOR deficiency.
  - reference: PMID:38870029
    reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice."
    explanation: Lowering gut bacterial H2S production with metronidazole reduces the H2S excess, implicating the microbial source.
  - reference: PMID:36306676
    reference_title: "Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H(2)S homeostasis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in catabolizing H2S under physiological conditions."
    explanation: >-
      Sulfide measured in the family B patient and his siblings did not show
      consistent elevation, so sustained H2S accumulation has not been
      demonstrated in humans. This argues against a constant H2S excess and is
      compatible only with intermittent accumulation.
  downstream:
  - target: Sulfide Inhibition of Cytochrome c Oxidase
    description: H2S binds and inhibits cytochrome c oxidase (complex IV).
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39719173
      reference_title: "Essential role of sulfide oxidation in brain health and neurological disorders."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "elevated levels of H2S inhibit the activity of cytochrome c oxidase (i.e., mitochondrial complex IV), thereby impairing oxidative phosphorylation"
      explanation: States the general toxicology of H2S on complex IV.
    - reference: PMID:38870029
      reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice."
      explanation: Lowering H2S in the mouse model restores complex IV activity, linking the H2S excess to the complex IV deficit in this disease.
  - target: Leigh-like Brain Injury
    description: >-
      The brain has little sulfide-oxidizing capacity of its own, which is
      proposed to make it especially vulnerable to H2S accumulation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Sulfide Inhibition of Cytochrome c Oxidase
    - Impaired Terminal Electron Transfer and ATP Synthesis
    evidence:
    - reference: PMID:39719173
      reference_title: "Essential role of sulfide oxidation in brain health and neurological disorders."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Consequently, the brain's limited capacity to oxidize H2S renders it particularly sensitive to the deleterious effects of H2S accumulation."
      explanation: Explains why H2S accumulation preferentially damages the brain.
    - reference: PMID:34035265
      reference_title: "Sulfide catabolism ameliorates hypoxic brain injury."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury."
      explanation: >-
        The model is hypoxic brain injury in rodents, not Leigh-like disease. It
        shows that brain SQOR level governs sulfide accumulation and
        bioenergetic failure, which supports by analogy the brain's
        vulnerability when SQOR is absent.
- name: Sulfide Inhibition of Cytochrome c Oxidase
  description: >-
    During an episode, complex IV activity is markedly and selectively reduced in
    skeletal muscle and liver while complex IV protein and assembly are close to
    normal, indicating a functional (toxic) inhibition of the enzyme rather than
    a failure of its biogenesis. This distinguishes SQOR deficiency from the
    complex IV assembly defects.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: cytochrome-c oxidase activity
    term:
      id: GO:0004129
      label: cytochrome-c oxidase activity
    modifier: DECREASED
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation."
    explanation: Patient tissue shows isolated complex IV deficiency with normal complex IV amount and assembly.
  - reference: PMID:38870029
    reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogen sulfide (H2S) levels."
    explanation: The mouse model reproduces the complex IV deficit together with raised H2S.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    description: Inhibited complex IV blocks terminal electron transfer and oxidative ATP synthesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure."
      explanation: The authors attribute energy failure in the patients to H2S inhibition of complex IV.
  - target: Decreased complex IV activity
    description: The enzyme inhibition is what tissue respiratory chain assays measure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation."
      explanation: Respiratory chain assays of patient muscle and liver record the inhibited enzyme as isolated complex IV deficiency.
- name: Impaired Terminal Electron Transfer and ATP Synthesis
  description: >-
    Inhibition of complex IV blocks electron transfer from cytochrome c to oxygen
    and the associated proton pumping, so oxidative ATP synthesis fails in
    affected tissues.
  biological_scale: CELLULAR
  conforms_to: "complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis"
  biological_processes:
  - preferred_term: mitochondrial electron transport, cytochrome c to oxygen
    term:
      id: GO:0006123
      label: mitochondrial electron transport, cytochrome c to oxygen
    modifier: DECREASED
  evidence:
  - reference: PMID:39719173
    reference_title: "Essential role of sulfide oxidation in brain health and neurological disorders."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "elevated levels of H2S inhibit the activity of cytochrome c oxidase (i.e., mitochondrial complex IV), thereby impairing oxidative phosphorylation"
    explanation: H2S inhibition of complex IV impairs oxidative phosphorylation.
  downstream:
  - target: Lactate Overproduction and Metabolic Decompensation
    description: >-
      Failure of oxidative ATP synthesis forces anaerobic glycolysis and raises
      blood lactate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38870029
      reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogen sulfide (H2S) levels."
      explanation: In the mouse model raised blood lactate accompanies the complex IV deficit.
  - target: Leigh-like Brain Injury
    description: >-
      Energy failure in the brain produces the encephalopathy and the basal
      ganglia lesions of Leigh disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure."
      explanation: The human report attributes the Leigh-like disease to energy failure from complex IV inhibition.
  - target: Elevated brain lactate by MRS
    description: >-
      Oxidative failure in the basal ganglia shifts brain metabolism to
      anaerobic glycolysis, seen as a lactate peak on MR spectroscopy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brain magnetic resonance spectroscopy (MRS) over the right basal ganglia showed a large lactate peak six times larger than the choline peak with a depressed N-acetylaspartate peak."
      explanation: A basal ganglia lactate peak with depressed N-acetylaspartate is the in vivo sign of local oxidative failure.
- name: Lactate Overproduction and Metabolic Decompensation
  description: >-
    The shift to anaerobic glycolysis raises blood lactate. Acute episodes, each
    reported after an intercurrent illness, present with severe lactic acidosis,
    coma and, in one child, multiorgan failure.
  biological_scale: ORGANISM
  conforms_to: "complex_iv_assembly_deficiency#Lactic Acidosis and Metabolic Decompensation"
  biological_processes:
  - preferred_term: lactate biosynthetic process
    term:
      id: GO:0019249
      label: lactate biosynthetic process
    modifier: INCREASED
  chemical_entities:
  - preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
    modifier: INCREASED
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure."
    explanation: Documents an illness-triggered decompensation with lactic acidosis and multiorgan failure.
  - reference: PMID:38870029
    reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome."
    explanation: Raised blood lactate in the model is sulfur-dependent and reversible by dietary sulfur restriction.
  downstream:
  - target: Lactic acidosis
    description: The lactate excess presents clinically as lactic acidosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure."
      explanation: The decompensation presents with lactic acidosis.
  - target: Death in childhood
    description: Two sisters in family A died during their first decompensation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
      explanation: A fatal episode of coma with lactic acidosis.
  - target: Multiorgan failure
    description: Severe decompensation progressed to failure of several organs in the index patient.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure."
      explanation: Multiorgan failure accompanied the lactic acidosis of the first decompensation.
  - target: Hepatic failure
    description: Liver failure, with a prolonged prothrombin time, was part of the multiorgan failure.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "She developed shock, respiratory insufficiency evolving into acute respiratory distress syndrome, and multi-organ failure including liver failure with increased prothrombin time"
      explanation: Liver failure during the first decompensation.
  - target: Shock
    description: Circulatory shock accompanied the multiorgan failure in the index patient.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "She developed shock, respiratory insufficiency evolving into acute respiratory distress syndrome, and multi-organ failure including liver failure with increased prothrombin time"
      explanation: Shock during the first decompensation.
  - target: Elevated creatine kinase
    description: Muscle injury during decompensation raised circulating creatine kinase.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Creatine kinase peaked at 722 U/L and remained mildly elevated."
      explanation: Creatine kinase rose during the episode and stayed mildly raised.
- name: Leigh-like Brain Injury
  description: >-
    Acute encephalopathy with coma and hypotonia, and lesions in the basal
    ganglia (caudate, putamen and globus pallidus) and in one case the cerebral
    cortex, matching the neuroimaging pattern of Leigh disease. The boy from
    family B had recurrent episodes and recovered from each.
  biological_scale: TISSUE
  locations:
  - preferred_term: basal ganglia
    term:
      id: UBERON:0010011
      label: collection of basal ganglia
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging."
    explanation: Documents the Leigh-like neurological picture in the index patient.
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family B, a boy had episodes of encephalopathy and basal ganglia lesions."
    explanation: Documents recurrent encephalopathy with basal ganglia lesions in the second family.
  - reference: PMID:38870029
    reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome."
    explanation: Loss of mitochondrial SQOR produces Leigh-like disease in mice.
  downstream:
  - target: Coma
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging."
      explanation: Coma accompanies the Leigh-like lesions in the index patient.
  - target: Recurrent encephalopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In family B, a boy had episodes of encephalopathy and basal ganglia lesions."
      explanation: Episodic encephalopathy accompanies the basal ganglia lesions in the family B patient.
  - target: Hypotonia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging."
      explanation: Hypotonia accompanies the Leigh-like lesions in the index patient.
  - target: Basal ganglia lesions
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
      explanation: The brain injury is seen on imaging as basal ganglia lesions.
  - target: Death in childhood
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
      explanation: A fatal episode of coma with basal ganglia and cortical lesions.
  - target: Tonic seizures
    description: The acute encephalopathy began with tonic seizures in the index patient.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At onset of the illness, during the day she was more tired and vomited, and in the evening became rapidly encephalopathic with an episode of tonic seizures."
      explanation: Tonic seizures marked the onset of the acute encephalopathy.
  - target: Neurostorming
    description: >-
      After the acute brain injury, the index patient had paroxysmal episodes of
      sympathetic overactivity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In subsequent weeks, she had generalized hypotonia, and episodes of neurostorming with tachycardia, hypertension, and potentially pain"
      explanation: Neurostorming episodes followed the acute brain injury.
phenotypes:
- name: Lactic acidosis
  category: Metabolism/Laboratory abnormality
  description: >-
    Severe lactic acidosis at presentation of acute episodes in both sisters of
    family A; lactate remained elevated after stabilization.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
    temporality: RECURRENT
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure."
    explanation: Lactic acidosis at presentation in the index patient.
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
    explanation: Lactic acidosis in the second affected sister.
- name: Coma
  category: Neurological
  description: Acute coma during decompensation episodes in family A.
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging."
    explanation: The index patient remained comatose after stabilization.
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
    explanation: Coma in the second affected sister.
- name: Recurrent encephalopathy
  category: Neurological
  description: >-
    The boy in family B had repeated episodes of encephalopathy, each following
    an intercurrent illness, and recovered from them.
  phenotype_term:
    preferred_term: Recurrent encephalopathy
    term:
      id: HP:0007335
      label: Recurrent encephalopathy
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family B, a boy had episodes of encephalopathy and basal ganglia lesions."
    explanation: Episodic encephalopathy in the family B patient.
- name: Hypotonia
  category: Neurological
  description: Hypotonia after the acute episode in the index patient.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging."
    explanation: The index patient was hypotonic.
- name: Basal ganglia lesions
  category: Neurological
  description: >-
    Leigh-like lesions of the basal ganglia on brain MRI in all three
    symptomatic patients, with additional cortical involvement in one.
  phenotype_term:
    preferred_term: Basal ganglia lesions on MRI
    term:
      id: HP:0012751
      label: Abnormal basal ganglia MRI signal intensity
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
    explanation: Basal ganglia lesions in the second affected sister.
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family B, a boy had episodes of encephalopathy and basal ganglia lesions."
    explanation: Basal ganglia lesions in the family B patient.
- name: Decreased complex IV activity
  category: Metabolism/Laboratory abnormality
  description: >-
    Isolated decrease of complex IV activity in skeletal muscle and liver, with
    normal complex IV protein and assembly.
  diagnostic: true
  phenotype_term:
    preferred_term: Decreased activity of mitochondrial complex IV
    term:
      id: HP:0008347
      label: Decreased activity of mitochondrial complex IV
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation."
    explanation: Isolated complex IV deficiency in patient muscle and liver.
- name: Tonic seizures
  category: Neurological
  description: Tonic seizures at the onset of the first episode in the index patient.
  phenotype_term:
    preferred_term: Tonic seizure
    term:
      id: HP:0032792
      label: Tonic seizure
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At onset of the illness, during the day she was more tired and vomited, and in the evening became rapidly encephalopathic with an episode of tonic seizures."
    explanation: Tonic seizures at onset in the index patient.
- name: Neurostorming
  category: Neurological
  description: >-
    Paroxysmal episodes of tachycardia, hypertension and probable pain in the
    weeks after the first episode in the index patient.
  phenotype_term:
    preferred_term: Neurostorming (paroxysmal sympathetic hyperactivity)
    description: >-
      Left unbound. OLS searches of HP for "paroxysmal sympathetic",
      "sympathetic hyperactivity", "autonomic storm" and "neurostorming"
      returned no term. "dysautonomia" returned only HP:0012332 Abnormal
      autonomic nervous system physiology, a coarse organ-system term, while
      HP:0000875 Episodic hypertension and HP:0006688 Paroxysmal tachycardia
      each describe one component of the episodes rather than the whole.
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In subsequent weeks, she had generalized hypotonia, and episodes of neurostorming with tachycardia, hypertension, and potentially pain"
    explanation: Neurostorming episodes with tachycardia and hypertension in the index patient.
- name: Multiorgan failure
  category: Constitutional
  description: >-
    Multiorgan failure during the first episode of the index patient, including
    liver failure, shock and acute respiratory distress syndrome; it stabilized
    with supportive care.
  phenotype_term:
    preferred_term: Multiorgan failure
    description: >-
      Left unbound. OLS searches of HP for "organ failure", "multiorgan" and
      "Multiple organ dysfunction" returned no term for the syndrome; its
      components are curated separately as Hepatic failure and Shock.
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure."
    explanation: Multiorgan failure at presentation of the index patient.
- name: Hepatic failure
  category: Gastrointestinal
  description: Liver failure with prolonged prothrombin time as part of the multiorgan failure in the index patient.
  phenotype_term:
    preferred_term: Hepatic failure
    term:
      id: HP:0001399
      label: Hepatic failure
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She developed shock, respiratory insufficiency evolving into acute respiratory distress syndrome, and multi-organ failure including liver failure with increased prothrombin time"
    explanation: Liver failure during the first episode.
- name: Shock
  category: Cardiovascular
  description: Circulatory shock during the first episode of the index patient.
  phenotype_term:
    preferred_term: Shock
    term:
      id: HP:0031273
      label: Shock
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She developed shock, respiratory insufficiency evolving into acute respiratory distress syndrome, and multi-organ failure including liver failure with increased prothrombin time"
    explanation: Shock during the first episode.
- name: Elevated creatine kinase
  category: Metabolism/Laboratory abnormality
  description: Raised circulating creatine kinase in the index patient during and after the first episode.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Creatine kinase peaked at 722 U/L and remained mildly elevated."
    explanation: Creatine kinase peaked at 722 U/L in the index patient.
- name: Elevated brain lactate by MRS
  category: Neurological
  description: Large lactate peak over the basal ganglia on brain MR spectroscopy in the index patient.
  phenotype_term:
    preferred_term: Elevated brain lactate level by MRS
    term:
      id: HP:0012707
      label: Elevated brain lactate level by MRS
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance spectroscopy (MRS) over the right basal ganglia showed a large lactate peak six times larger than the choline peak with a depressed N-acetylaspartate peak."
    explanation: MR spectroscopy showed a large basal ganglia lactate peak.
- name: Death in childhood
  category: Mortality
  description: >-
    Both affected sisters in family A died in childhood during their first acute
    episode, aged 4 and 8 years; the boy in family B survived his episodes.
  phenotype_term:
    preferred_term: Death in childhood
    description: >-
      Left unbound deliberately. HP:0003819 Death in childhood is the right
      concept but sits in the HPO clinical-course branch rather than under
      Phenotypic abnormality, so it is outside the PhenotypeTerm dynamic enum and
      binding it fails term validation.
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex."
    explanation: A fatal episode at age 8 years.
biochemical:
- name: SQOR enzyme activity
  presence: DECREASED
  context: >-
    SQOR activity measured spectrophotometrically in liver mitochondrial
    membranes, fibroblasts or peripheral blood mononuclear cells is severely
    reduced; the fibroblast and blood-cell assays allow diagnosis without a
    tissue biopsy.
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels."
    explanation: Severely reduced SQOR activity in patient fibroblasts.
- name: Blood lactate
  presence: INCREASED
  context: Elevated during and after acute episodes.
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging."
    explanation: Lactate stayed elevated after the acute presentation.
environmental:
- name: Intercurrent infection and fasting
  description: >-
    Every reported decompensation followed an intercurrent illness, often with
    fasting, which the authors associate with protein catabolism and propose
    raises H2S supply beyond the low residual SQOR capacity.
  notes: >-
    exposure_term left unbound. An OLS search of ECTO for "fasting" returned
    ECTO:2000118 exposure to fasting intervention, which describes a deliberate
    fasting intervention rather than illness-related fasting; "infection"
    returned only pathogen-specific exposures (ECTO:2000053 exposure to Human
    Papillomavirus Infection, ECTO:3000104 exposure to Infectious bronchitis
    virus); "starvation", "food deprivation" and "exposure to infectious agent"
    returned no ECTO term.
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all patients, acute symptoms were triggered by infections and fasting, episodes associated with protein catabolism."
    explanation: Infection and fasting preceded every acute episode in the reported patients.
  influences_mechanisms:
  - target: Hydrogen Sulfide Accumulation
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Protein catabolism during illness is proposed to increase H2S production
      beyond what the low residual SQOR activity can clear.
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "We hypothesize that in our patients, the low residual SQOR activity was likely sufficient to support H2S clearance during stable episodes but was insufficient during acute illness with catabolism resulting in H2S accumulation and toxicity."
      explanation: The authors propose, without measuring H2S during an episode, that illness-related catabolism tips the patients into H2S accumulation.
genetic:
- name: SQOR
  gene_term:
    preferred_term: SQOR
    term:
      id: hgnc:20390
      label: SQOR
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    SQOR (previously SQRDL) encodes sulfide:quinone oxidoreductase, a
    flavoprotein of the inner mitochondrial membrane. Two homozygous
    loss-of-function alleles have been reported, each in one consanguineous
    family.
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe children of two families with pathogenic variants in SQOR."
    explanation: The founding report of SQOR variants in affected children.
  - reference: PMID:38870029
    reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome."
    explanation: A mouse model independently supports SQOR loss as a cause of Leigh-like disease.
  variants:
  - name: "SQOR c.637G>A p.(Glu213Lys)"
    description: >-
      Missense founder variant in exon 5 (NM_021199.4), homozygous in two
      affected sisters of a Lehrerleut Hutterite family. It destabilizes the
      protein, leaving severely reduced SQOR protein and activity.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "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."
      explanation: Functional characterization of the founder variant.
  - name: "SQOR c.446delT"
    description: >-
      Single-nucleotide deletion, homozygous in the affected boy of family B and
      in his asymptomatic siblings.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:32160317
      reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels."
      explanation: The deletion abolishes most SQOR protein and activity in fibroblasts.
  notes: >-
    No ClinGen gene-disease validity record exists for SQOR against this MONDO
    term. ClinGen's Mitochondrial Diseases Gene Curation Expert Panel classifies
    SQOR against the broader Leigh syndrome concept (MONDO:0009723) as Limited
    (autosomal recessive, 2021); that is a different disease pair, so no tier is
    recorded here.
differential_diagnoses:
- name: Ethylmalonic encephalopathy
  disease_term:
    preferred_term: ethylmalonic encephalopathy
    term:
      id: MONDO:0011229
      label: ethylmalonic encephalopathy
  description: >-
    ETHE1 deficiency blocks the next step of the same mitochondrial H2S oxidation
    pathway and also produces complex IV deficiency and basal ganglia lesions.
    It differs by a chronic course with petechiae, acrocyanosis, chronic
    diarrhea, ethylmalonic aciduria and massive thiosulfate excretion, whereas
    SQOR deficiency has presented as episodic decompensation in otherwise well
    children. Molecular testing separates them.
  distinguishing_features:
  - Massive accumulation of thiosulfate and sulfite in ethylmalonic encephalopathy.
  - Biallelic ETHE1 rather than SQOR variants.
  evidence:
  - reference: PMID:36306676
    reference_title: "Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H(2)S homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with ethylmalonic encephalopathy and sulfite oxidase/molybdenum cofactor deficiencies exhibited massive accumulation of thiosulfate and sulfite with formation of large amounts of S-sulfocysteine and S-sulfohomocysteine"
    explanation: >-
      In the same study that measured SQOR-deficient patients, thiosulfate and
      sulfite accumulation characterized ethylmalonic encephalopathy, giving a
      biochemical distinction between the two disorders of H2S oxidation.
- name: Leigh syndrome due to complex IV assembly defects
  disease_term:
    preferred_term: Leigh syndrome
    term:
      id: MONDO:0009723
      label: Leigh syndrome
  description: >-
    Isolated complex IV deficiency with Leigh-like lesions is most often caused
    by defects in complex IV subunits or assembly factors such as SURF1. In SQOR
    deficiency complex IV protein and assembly are normal while activity is
    reduced, which points to toxic inhibition rather than a biogenesis defect.
  distinguishing_features:
  - Normal complex IV protein levels and complex formation despite reduced activity.
  evidence:
  - reference: PMID:32160317
    reference_title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation."
    explanation: Normal complex IV amount and assembly separate SQOR deficiency from complex IV biogenesis defects.
treatments:
- name: Metronidazole
  description: >-
    Proposed sulfide-lowering therapy, by analogy with ethylmalonic
    encephalopathy: the antibiotic reduces H2S production by gut anaerobes. Its
    support comes from the SqorDeltaN/DeltaN mouse, in which daily metronidazole
    lowered H2S, normalized complex IV activity and blood lactate, and prolonged
    survival. No treated patient has been reported.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metronidazole
      term:
        id: CHEBI:6909
        label: metronidazole
  target_mechanisms:
  - target: Hydrogen Sulfide Accumulation
    description: Lowers the gut microbial contribution to systemic H2S.
    evidence:
    - reference: PMID:38870029
      reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice."
      explanation: Metronidazole reverses the H2S excess and its downstream effects in the mouse model.
  evidence:
  - reference: PMID:38870029
    reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice."
    explanation: Preclinical efficacy in the mouse model; there are no human data.
- name: Sulfur-restricted diet
  description: >-
    Proposed dietary restriction of sulfur amino acids to reduce substrate for
    H2S production. In the SqorDeltaN/DeltaN mouse it normalized blood lactate
    and prevented Leigh-like disease. No treated patient has been reported.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Hydrogen Sulfide Accumulation
    description: Reduces the sulfur substrate available for H2S production.
    evidence:
    - reference: PMID:38870029
      reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome."
      explanation: The diet prevents the downstream consequences of H2S excess in the mouse; that it acts by lowering H2S is inferred from the study design.
  evidence:
  - reference: PMID:38870029
    reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome."
    explanation: Preclinical efficacy in the mouse model; there are no human data.
animal_models:
- name: SqorDeltaN/DeltaN mouse
  species: Mus musculus
  genotype: >-
    Homozygous Sqor allele lacking the N-terminal mitochondrial targeting
    sequence (SqorDeltaN/DeltaN), so that SQOR is excluded from mitochondria
  publication: PMID:38870029
  description: >-
    Mice in which SQOR cannot enter mitochondria develop Leigh-like disease with
    raised blood lactate, markedly decreased complex IV activity and increased
    H2S. Metronidazole and a sulfur-restricted diet each rescue the phenotype.
  genes:
  - preferred_term: SQOR
    term:
      id: hgnc:20390
      label: SQOR
  modeled_mechanisms:
  - target: Hydrogen Sulfide Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: H2S levels are increased and are lowered by metronidazole.
    limitations: >-
      The allele mislocalizes SQOR rather than reproducing a patient variant, and
      patients in family B did not show consistently raised sulfide between
      episodes.
    evidence:
    - reference: PMID:38870029
      reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogen sulfide (H2S) levels."
      explanation: Raised H2S in the model.
  - target: Sulfide Inhibition of Cytochrome c Oxidase
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Complex IV activity is markedly decreased and is restored by metronidazole.
    evidence:
    - reference: PMID:38870029
      reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice."
      explanation: The complex IV deficit is sulfide-dependent, as in the proposed human mechanism.
  - target: Leigh-like Brain Injury
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Clinical and pathological manifestations of Leigh syndrome.
    limitations: >-
      Patients present episodically after intercurrent illness, whereas the model
      develops disease without a reported trigger; mouse and human basal ganglia
      vulnerability may differ.
    evidence:
    - reference: PMID:38870029
      reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome."
      explanation: The model reproduces Leigh-like disease.
  evidence:
  - reference: PMID:38870029
    reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome."
    explanation: Describes the model and its Leigh-like phenotype.
- name: Intestinal epithelium-specific Sqor knockout mouse
  species: Mus musculus
  genotype: Sqor deletion confined to intestinal epithelial cells
  publication: PMID:40526718
  description: >-
    Tissue-restricted SQOR deficiency in the gut epithelium perturbs colon
    bioenergetics in an antibiotic-reversible way, and combined with higher
    dietary methionine raises serum thiosulfate and ketone bodies and alters
    behavior. It isolates the gut contribution to systemic sulfide load rather
    than modelling the whole-body disease.
  genes:
  - preferred_term: SQOR
    term:
      id: hgnc:20390
      label: SQOR
  modeled_mechanisms:
  - target: Hydrogen Sulfide Accumulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Gut-restricted SQOR loss shows that microbial H2S handled by the intestinal
      epithelium affects host bioenergetics locally and, with high methionine
      intake, sulfide metabolism globally.
    limitations: >-
      SQOR is deleted only in intestinal epithelium, so brain, muscle and liver
      retain sulfide oxidation, and no Leigh-like disease is reported.
    evidence:
    - reference: PMID:40526718
      reference_title: "Gut sulfide metabolism modulates behavior and brain bioenergetics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In this study, we report that SQOR deficiency confined to murine intestinal epithelial cells perturbs colon bioenergetics that is reversed by antibiotics, revealing a significant local contribution of microbial H2S to host physiology."
      explanation: Gut-restricted SQOR deficiency reveals the microbial H2S contribution.
  evidence:
  - reference: PMID:40526718
    reference_title: "Gut sulfide metabolism modulates behavior and brain bioenergetics."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In serum, increased thiosulfate, a biomarker of H2S oxidation, reveals that intestinal SQOR deficiency combined with higher dietary methionine affects sulfide metabolism globally and perturbs energy metabolism as indicated by higher ketone bodies."
    explanation: Systemic sulfide and energy-metabolism effects of gut SQOR deficiency combined with high methionine intake.
discussions:
- discussion_id: sqord_penetrance_and_triggers
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do some SQOR-deficient individuals remain asymptomatic, and what raises
    H2S enough to cause an episode?
  attaches_to:
  - pathophysiology#Hydrogen Sulfide Accumulation
  - inheritance#Incomplete penetrance
  rationale: >-
    Plasma sulfide was normal in the symptomatic family B patient and in one
    asymptomatic sibling, and raised in another asymptomatic sibling, so baseline
    H2S does not track disease. All reported episodes followed intercurrent
    illness, and the mouse data implicate gut microbial H2S. Whether infection,
    fasting, or a surge in microbial sulfide production exceeds an otherwise
    adequate alternative sulfide-disposal capacity has not been measured during
    an episode in a patient.
  evidence:
  - reference: PMID:36306676
    reference_title: "Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H(2)S homeostasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in catabolizing H2S under physiological conditions."
    explanation: Baseline sulfide measurements do not separate symptomatic from asymptomatic SQOR-deficient siblings.
- discussion_id: sqord_sulfide_lowering_therapy
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Will metronidazole or dietary sulfur restriction prevent episodes in
    patients, as they rescue the SqorDeltaN/DeltaN mouse?
  attaches_to:
  - treatments#Metronidazole
  - treatments#Sulfur-restricted diet
  rationale: >-
    Both interventions rescue the mouse, whose disease is continuous and
    accompanied by raised H2S, but patients present with episodic decompensation
    and inconsistent baseline sulfide. No patient has been treated and reported,
    so efficacy, dosing, and whether treatment should be continuous or reserved
    for intercurrent illness are unknown.
  evidence:
  - reference: PMID:38870029
    reference_title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Metronidazole administration and a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR."
    explanation: The model study proposes, but does not test, these therapies in patients.
references:
- reference: PMID:32160317
  title: "Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease."
- reference: PMID:26318450
  title: "Transient Kinetic Analysis of Hydrogen Sulfide Oxidation Catalyzed by Human Sulfide Quinone Oxidoreductase."
- reference: PMID:34035265
  title: "Sulfide catabolism ameliorates hypoxic brain injury."
- reference: PMID:38870029
  title: "Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism."
- reference: PMID:36306676
  title: "Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H(2)S homeostasis."
- reference: PMID:40526718
  title: "Gut sulfide metabolism modulates behavior and brain bioenergetics."
- reference: PMID:39719173
  title: "Essential role of sulfide oxidation in brain health and neurological disorders."
notes: >-
  Evidence base. The human phenotype rests on one report of three symptomatic
  children in two consanguineous families (PMID:32160317), with sulfur
  metabolite measurements in the second family published separately
  (PMID:36306676). No phenotype frequencies are recorded because three patients
  cannot support them. The H2S-to-complex IV mechanism is supported in patients
  by the pattern of isolated complex IV deficiency with normal complex IV
  assembly, and causally by the SqorDeltaN/DeltaN mouse; sustained H2S elevation
  has not been shown in patients. The complex IV and lactate nodes conform to
  the corresponding nodes of the complex_iv_assembly_deficiency module, but the
  module's Complex IV Biogenesis Failure node does not apply because complex IV
  assembly is normal in this disease. Unlike ethylmalonic encephalopathy,
  urinary ethylmalonic acid, chronic diarrhea and petechiae have not been
  reported in SQOR deficiency, so the ETHE1 biochemical signature is not
  curated here. No GeneReviews chapter covers SQOR deficiency.
📚

References & Deep Research

References

7
PMID:32160317
Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease.
No top-level findings curated for this source.
PMID:26318450
Transient Kinetic Analysis of Hydrogen Sulfide Oxidation Catalyzed by Human Sulfide Quinone Oxidoreductase.
No top-level findings curated for this source.
PMID:34035265
Sulfide catabolism ameliorates hypoxic brain injury.
No top-level findings curated for this source.
PMID:38870029
Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism.
No top-level findings curated for this source.
PMID:36306676
Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H(2)S homeostasis.
No top-level findings curated for this source.
PMID:40526718
Gut sulfide metabolism modulates behavior and brain bioenergetics.
No top-level findings curated for this source.
PMID:39719173
Essential role of sulfide oxidation in brain health and neurological disorders.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Sulfide_Quinone_Oxidoreductase_Deficiency · 2026-10-08T14:31:09Z · View source

Curated de novo for claim issue #13688 (work-package #5557, disorders of sulfur-containing amino acid and H2S metabolism). Autosomal recessive SQOR (hgnc:20390, previously SQRDL) deficiency: loss of the first mitochondrial step of H2S oxidation, with intermittent H2S accumulation inhibiting cytochrome c oxidase (complex IV), producing episodic Leigh-like encephalopathy and lactic acidosis with isolated functional complex IV deficiency (normal complex IV assembly). Pathograph is a connected chain SQOR deficiency -> H2S accumulation -> complex IV inhibition -> impaired OXPHOS -> lactate overproduction and Leigh-like brain injury, with two complex-IV/lactate nodes conforming to the complex_iv_assembly_deficiency module (Biogenesis Failure node deliberately not used because assembly is normal). Cross-referenced against the existing Ethylmalonic_Encephalopathy (ETHE1) entry, which is the downstream pathway sibling; curated it as a differential and did NOT copy the ETHE1 biochemical signature (ethylmalonic aciduria, thiosulfate, petechiae) because SQOR case reports do not show it. An OpenScientist deep-research report was used (research/Sulfide_Quinone_Oxidoreductase_Deficiency-deep-research-openscientist.md); its validation block reported reference_validation 7/7 verified, 0 not_found, confabulation_rate 0.0, and term_validation 39/42 resolved with needs_review true for two mislabelled HP terms (HP:0032263 given as Multiorgan failure but is Increased blood pressure; HP:0012719 given as Neurostorming/dysautonomia but is Functional abnormality of the GI tract); neither of those two terms was bound. preflight-dr returned PASS (SQOR mentioned 58 times, OMIM 619221 matches). Primary clinical source is PMID:32160317 (Friederich 2020, two families, three symptomatic children); PMID:36306676 (sulfur-metabolite study) supports incomplete penetrance and the ETHE1 distinction; PMID:38870029 (SqorDeltaN/DeltaN mouse) and PMID:40526718 (gut-epithelium-specific knockout) are the animal models; PMID:26318450 (enzyme kinetics) and PMID:39719173 (review) support the molecular steps. PMID:38870029 and PMID:39719173 were found via PubMed rather than the report. Report citations PMID:40563372 (an ETHE1 mtUPR paper) and PMID:41638445 (Schistosoma SQOR enzymology) were dropped as not about this disease/gene mechanism. No ClinGen validity record exists for SQOR against MONDO:0030982 (ClinGen rates SQOR against the broader Leigh syndrome MONDO:0009723 as Limited, a different pair), so gene_disease_validity is left absent with a note. No GeneReviews chapter (offline check-genereviews NO_CHAPTER). Validated with just validate, validate-terms, count-verified-snippets (67/67), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-coarse/snippet/title/folded/reference-title/environmental/snippet-grading/retired-support/case-collision/enum-value/delivery-system/gene-activity-grounding gates, and the batched just validate-disorders (passed). list-disconnected-phenotypes reports all 7 phenotypes causally connected.

OpenScientist ▸
Sulfide:Quinone Oxidoreductase Deficiency (SQORD) — Comprehensive Disease Characteristics Report
openscientist-autonomous 6 citations 2026-10-08T14:24:39.507971

Sulfide:Quinone Oxidoreductase Deficiency (SQORD) — Comprehensive Disease Characteristics Report

Disease: Sulfide Quinone Oxidoreductase Deficiency MONDO: MONDO:0030982 · OMIM (phenotype): #619221 · Gene: SQOR (OMIM 617658) Category: Mendelian — autosomal-recessive mitochondrial (inborn error of hydrogen-sulfide catabolism) Report date:* 2026-10-08

Summary

Sulfide:quinone oxidoreductase deficiency (SQORD; MONDO:0030982, OMIM #619221) is an ultra-rare, autosomal-recessive inborn error of mitochondrial hydrogen-sulfide (H₂S) catabolism caused by biallelic loss-of-function variants in SQOR (15q21.1; HGNC:20390; UniProt Q9Y6N5). SQOR encodes the committed first enzyme of mitochondrial sulfide oxidation — an inner-membrane FAD flavoprotein (EC 1.8.5.4) that oxidizes H₂S and funnels the electrons into ubiquinone/Coenzyme Q, coupling sulfide detoxification to the respiratory chain.

When SQOR is lost, endogenous and gut-microbiome-derived H₂S can no longer be cleared and accumulates to concentrations that inhibit complex IV (cytochrome c oxidase). The result is an isolated, functional complex IV deficiency — activity falls while complex IV protein level and assembly remain normal — producing bioenergetic failure in the most oxygen- and energy-dependent tissues, above all the brain. Clinically this manifests as a childhood-onset, infection-triggered Leigh-like metabolic encephalopathy with coma, hypotonia, seizures, lactic acidosis, elevated brain lactate on MR spectroscopy, bilateral basal-ganglia lesions, dysautonomia ("neurostorming"), and, in severe cases, multiorgan failure and death.

Because the lesion is accumulation of a diffusible toxin rather than a fixed structural defect in the respiratory chain, SQORD is explicitly framed as potentially treatable: current management is supportive (prompt treatment of metabolic crises, aggressive treatment of intercurrent illness, avoidance of catabolic triggers), while mechanism-based strategies aim to lower the H₂S burden (pharmacological sulfide scavenging, candidate cobalamin-based scavengers, limiting dietary sulfur/cysteine, and microbiome modulation). The disease was first delineated in 2020 in two families, including a Lehrerleut Hutterite founder mutation (p.Glu213Lys) with a carrier frequency of 1 in 13. Diagnosis rests on exome/genome or Leigh-panel sequencing showing biallelic SQOR variants together with isolated complex IV deficiency and preserved complex IV assembly. Information in this report is derived from aggregated disease-level resources and individual case reports, not from a structured EHR cohort.

Key Findings

Finding 1 — Biallelic SQOR variants cause a treatable Leigh-like mitochondrial disease

The disease entity was established by Friederich et al. (2020) in a study of two families PMID: 32160317. In Family A, two Hutterite sisters were homozygous for SQOR c.637G>A (p.Glu213Lys); they presented with coma, lactic acidosis, multiorgan failure, hypotonia, neurostorming, and Leigh-like basal-ganglia lesions, and both died. In Family B, a boy homozygous for the frameshift variant c.446delT had recurrent (episodic) encephalopathy with basal-ganglia lesions.

The biochemistry pinpointed the mechanism: "Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation." This dissociation — reduced activity with preserved protein and assembly — is the signature of enzymatic inhibition rather than a structural/assembly defect, pointing directly to a diffusible inhibitor. The authors identified it: "Toxic hydrogen sulfide exposure inhibits complex IV." Enzyme assays confirmed severely reduced SQOR activity and protein. The founder allele was characterized as: "Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13." The report's framing of SQORD as "a potentially treatable cause of Leigh disease" underpins its clinical importance.

Finding 2 — SQOR is the committed first enzyme of H₂S catabolism, and tissue vulnerability tracks SQOR level

SQOR (EC 1.8.5.4) is an inner-mitochondrial-membrane flavoprotein that oxidizes H₂S and transfers electrons to ubiquinone/Coenzyme Q. Transient-kinetic work by Mishanina et al. (2015) PMID: 26318450 showed that "the flavin cofactor is intermittently reduced by sulfide and oxidized by ubiquinone, linking H2S oxidation to the electron transfer chain and to energy metabolism" (bound-flavin redox potential ≈ −123 mV). SQOR therefore both detoxifies H₂S and feeds electrons into the respiratory chain.

The physiological consequence of SQOR abundance was demonstrated across species by Marutani, Ichinose et al. (2021) PMID: 34035265. Comparing mice, rats, and the hypoxia-tolerant 13-lined ground squirrel, they found "the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide." Silencing SQOR increased hypoxia sensitivity; neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic injury. Crucially for therapy: "Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia." This directly links low/absent SQOR activity to the brain's bioenergetic collapse — the core of SQORD — and nominates sulfide scavenging as a rational intervention.

Finding 3 — Consolidated disease and gene identifiers

Entity Identifiers
Disease MONDO:0030982 "sulfide quinone oxidoreductase deficiency" (syn. SQORD); OMIM #619221; GARD:0025671; MedGen/UMLS C5543168. No dedicated Orphanet/ICD-specific code identified.
Gene SQOR (aliases SQRDL, SQR, CGI-44, PRO1975); NCBI Gene 58472; Ensembl ENSG00000137767; HGNC:20390; OMIM gene *617658; UniProt Q9Y6N5
Locus 15q21.1 (GRCh38 chr15:45,631,148–45,691,299, + strand)

Verified via OLS4/MONDO and mygene.info.

Finding 4 — Pathway context: ETHE1 (ethylmalonic encephalopathy) is the downstream "mirror" disorder

SQORD sits at the head of the mitochondrial sulfide-oxidation pathway:

H2S → [SQOR] → persulfide (GSSH) → [ETHE1 sulfur dioxygenase] → sulfite
          |                                                         |
     electrons → CoQ / ETC            [sulfite oxidase SUOX / rhodanese TST] → thiosulfate / sulfate

Loss of the downstream enzyme ETHE1 causes ethylmalonic encephalopathy (OMIM #602473), which — like SQORD — produces H₂S accumulation and "decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy" PMID: 40563372. The shared complex IV defect in two enzymatically distinct disorders of the same pathway corroborates the "H₂S poisons complex IV" mechanism and defines SQORD and ETHE1 deficiency as pathophysiological mirror images (upstream vs. downstream lesions of sulfide catabolism).

Finding 5 — Phenotype spectrum with HPO terms

Official HPO disease annotations for OMIM:619221 (JAX ontology API) plus features reported in Friederich 2020:

Phenotype HPO term Source
Acute encephalopathy HP:0006846 OMIM annotation
Coma HP:0001259 OMIM annotation
Tonic seizure HP:0032792 OMIM annotation
Migraine HP:0002076 OMIM annotation
Elevated brain lactate (MRS) HP:0012707 OMIM annotation
Lactic acidosis HP:0003128 OMIM annotation
Elevated circulating creatine kinase HP:0003236 OMIM annotation
Autosomal recessive inheritance HP:0000007 OMIM annotation
Basal ganglia / Leigh-like lesions HP:0002518 / HP:0030900 Friederich 2020
Hypotonia HP:0001252 Friederich 2020
Multiorgan failure HP:0032263 Friederich 2020
Neurostorming / dysautonomia HP:0012719 Friederich 2020

The clinical core is captured by the report that the patient "remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging" PMID: 32160317. Onset ranged ~4–8 years; episodes were often triggered by intercurrent illness/catabolic stress; severe cases were rapidly fatal; at least one child had a recurrent/episodic course.

Finding 6 — SQOR pathogenic variants are ultra-rare; LoF tolerated in heterozygosity

A gnomAD v4 query of SQOR (chr15, GRCh38) returned ~2,458 variants. All predicted loss-of-function alleles occur at very low frequencies (~7×10⁻⁷ to ~2.5×10⁻⁵):

Variant Consequence Approx. allele freq (gnomAD v4)
c.799C>T (p.Arg267Ter) nonsense ~2.5×10⁻⁵
c.415C>T (p.Arg139Ter) nonsense ~1.6×10⁻⁵
c.446del (p.Leu149ArgfsTer18) — Family B frameshift ~2.05×10⁻⁶
c.637G>A (p.Glu213Lys) — Hutterite founder missense ~absent outbred; carrier 1/13 Lehrerleut Hutterite

No homozygotes for LoF alleles are present in the general population, consistent with severe recessive disease. SQOR tolerates heterozygous LoF (it is a recessive disease gene, not haploinsufficient). The founder missense — "a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13" PMID: 32160317 — is essentially absent from outbred populations.

Finding 7 — Treatment rationale and model organisms

No approved disease-specific therapy exists. Management is supportive: treat acute metabolic/lactic crises, avoid catabolic triggers and fasting, and aggressively treat intercurrent illness that precipitates decompensation. Mechanism-based strategies target lowering H₂S: pharmacological sulfide scavenging "maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia" PMID: 34035265. Candidate approaches include hydroxocobalamin/oxidized cobalamin and other sulfide-binding agents, and limiting sulfur/cysteine load. Gut-microbiome-derived H₂S contributes to total sulfide burden and modulates brain bioenergetics, suggesting dietary/microbiome modulation as an adjunct PMID: 40526718.

Model organisms: mouse (Mus musculus, Sqor NCBI Gene 59010) with SQOR silencing and neuron-specific re-expression recapitulates sulfide accumulation, bioenergetic failure, and brain hypoxia sensitivity PMID: 34035265; the hypoxia-tolerant 13-lined ground squirrel is a comparative high-SQOR model; invertebrate/parasite SQOR (C. elegans; Schistosoma mansoni PMID: 41638445) illustrate conserved enzymology; patient fibroblasts, muscle, and liver were the primary human cellular models.

Finding 8 — Human SQOR has solved experimental structures enabling variant modeling

PDBe best-structures mapping for UniProt Q9Y6N5 returns 8 experimental structures: 6MO6, 6MP5, 6OI5, 6OI6, 6OIB, 6OIC, 6WH6, 8DHK. These define the FAD flavoprotein fold and membrane-interacting/quinone-binding regions, enabling structural rationalization of pathogenic missense alleles — e.g., p.Glu213Lys, which disrupts hydrogen bonding with neighboring residues (Friederich 2020) — and a platform for classifying novel missense VUS (AlphaFold model AF-Q9Y6N5 also available).

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic loss-of-function variants in SQOR (e.g., p.Glu213Lys missense; c.446delT frameshift) lead to loss of functional sulfide:quinone oxidoreductase in the inner mitochondrial membrane. (Demonstrated: reduced SQOR activity + protein in patient tissue.)
  2. Loss of SQOR results in failure of the committed first step of mitochondrial H₂S oxidation, so endogenous and gut-derived H₂S cannot be catabolized. (Inferred from enzyme role; directly demonstrated in SQOR-silenced models.)
  3. Blocked catabolism leads to accumulation of H₂S (and upstream persulfide species), especially when production rises during intercurrent illness/catabolism (branch point where environment feeds in). (Demonstrated in mouse models; inferred in patients.)
  4. Accumulated H₂S inhibits complex IV (cytochrome c oxidase) — an isolated, functional COX defect with normal complex IV protein and assembly. (Demonstrated in patient muscle and liver.)
  5. Complex IV inhibition results in blocked oxidative phosphorylation and ATP failure, with a shift to anaerobic glycolysis → lactic acidosis and elevated brain lactate (MRS). (Demonstrated clinically/biochemically.)
  6. Bioenergetic failure concentrates in the brain's most metabolically demanding gray matter → bilateral basal-ganglia (Leigh-like) lesions, encephalopathy, coma, seizures, hypotonia, dysautonomia. (Demonstrated by imaging and clinical course.)
  7. Catabolic stress raises sulfide flux and energetic demand → episodic metabolic decompensation, progressing to multiorgan failure and death in severe cases. (Demonstrated: infection-triggered, fatal outcomes in Family A.)

Protective counterfactual branch: restoring H₂S clearance (SQOR re-expression) or scavenging sulfide prevents steps 4–8 (shown in neurons/mice; Marutani 2021).

Upstream vs. downstream

  • Upstream (primary lesion): SQOR genotype → enzyme loss → H₂S accumulation.
  • Downstream (effector): complex IV inhibition → OXPHOS failure → lactic acidosis → basal-ganglia injury → encephalopathy.
  • Pathway sibling: ETHE1 deficiency produces the same downstream complex IV defect from a lesion one step below SQOR, confirming the mechanism and the shared therapeutic rationale (lower H₂S).

Ontology annotations

  • Biological process (GO): hydrogen sulfide metabolic process (GO:0070813); sulfide oxidation (GO:0019417); oxidative phosphorylation (GO:0006119); cellular respiration (GO:0045333).
  • Cellular component (GO): mitochondrion (GO:0005739); mitochondrial inner membrane (GO:0005743).
  • Cell types (CL): neuron (CL:0000540), especially basal-ganglia/striatal neurons; astrocyte (CL:0000127); broadly high-OXPHOS cells (myocyte CL:0000187; hepatocyte CL:0000182).
  • Anatomy (UBERON): brain (UBERON:0000955), basal ganglia (UBERON:0002420), striatum (UBERON:0002435), brainstem (UBERON:0002298), skeletal muscle (UBERON:0001134), liver (UBERON:0002107).
  • Chemical entities (CHEBI): hydrogen sulfide (CHEBI:16136); ubiquinone/CoQ (CHEBI:16389); FAD (CHEBI:16238); L-lactate (CHEBI:16651); thiosulfate (CHEBI:33542); L-cysteine (CHEBI:17561).
  • Treatment (NCIT): supportive care (NCIT:C15277); hydroxocobalamin (NCIT:C47707/C47642); sulfide-scavenging agents (investigational).

Section-by-Section Dossier

1. Disease Information

Autosomal-recessive mitochondrial inborn error of H₂S catabolism presenting as a Leigh-like metabolic encephalopathy. Identifiers: MONDO:0030982; OMIM #619221; GARD:0025671; MedGen/UMLS C5543168; no dedicated Orphanet/ICD-specific code (best coded under mitochondrial/metabolic encephalopathy, ICD-10 E88.8; ICD-11 Leigh-syndrome category by phenotype). Synonyms: SQORD; sulfide:quinone oxidoreductase deficiency; SQR deficiency (gene aliases SQRDL, SQR, CGI-44, PRO1975). The knowledge base is disease-level/case-report derived, not EHR-based.

2. Etiology

Primary cause: biallelic pathogenic SQOR variants → loss of function. Genetic risk: carrier status; founder/consanguineous membership (Hutterite carrier 1/13). Environmental triggers of crises (not causes): intercurrent infection, fasting, catabolic stress; dietary sulfur/cysteine and gut-microbiome H₂S add to burden. Protective factors (inferred): higher residual SQOR activity; lower sulfide load. Gene–environment interaction: a fixed genetic enzymatic bottleneck is overwhelmed when H₂S production rises — a threshold GxE interaction precipitating complex IV inhibition.

3. Phenotypes

See Finding 5 table. Types: clinical signs (coma, hypotonia, seizures, dysautonomia), lab abnormalities (lactic acidosis, elevated brain lactate by MRS, elevated CK), imaging (bilateral basal-ganglia/Leigh-like lesions). Onset: childhood (~4–8 y). Severity: variable — fatal metabolic coma to recurrent survivable encephalopathy. Progression: episodic/fluctuating with stepwise injury accrual. QoL impact: profound — intensive-care dependence, death in severe cases, fixed neurological sequelae (dystonia, developmental impairment) in survivors. No formal EQ-5D/SF-36/PROMIS data exist.

4. Genetic / Molecular Information

Causal gene: SQOR (15q21.1), ~450-aa FAD flavoprotein on the inner mitochondrial membrane. Reported variants: c.637G>A p.Glu213Lys (destabilizing missense, founder, LoF-equivalent) and c.446delT p.Leu149ArgfsTer18 (frameshift/null). Population nulls (p.Arg267Ter, p.Arg139Ter) ultra-rare, no homozygotes. Classification: pathogenic (segregation, founder data, functional enzyme loss, complex IV biochemistry). Consequence: loss of function; germline origin. Modifiers: none established (plausibly ETHE1, TST, SUOX, CBS, CTH, MPST). SQOR is an NRF2 target (PMID 36758466), relevant to expression regulation but not a described modifier. Epigenetics / chromosomal abnormalities: none reported.

5. Environmental Information

Non-genetic modulators rather than causes: intercurrent illness and catabolic stress trigger crises; dietary sulfur/cysteine and gut-microbiome H₂S (e.g., Desulfovibrio spp.) add to sulfide burden PMID: 40526718. Exogenous H₂S is the toxicological analogue (H₂S inhibits complex IV). No infectious etiology.

6. Mechanism / Pathophysiology

See the ordered causal chain above. Core pathway: SQOR loss → H₂S accumulation → complex IV inhibition → OXPHOS failure → lactic acidosis + basal-ganglia injury → encephalopathy. Supported by isolated functional complex IV deficiency with normal assembly (PMID: 32160317), SQOR enzymology (PMID: 26318450), the SQOR-level/hypoxia-sensitivity relationship (PMID: 34035265), and the ETHE1 pathway mirror (PMID: 40563372). No dedicated patient omics cohort exists; functional assays are SQOR activity, western blot, respirometry, and complex IV activity.

7. Anatomical Structures Affected

Primary organ: brain (basal ganglia, brainstem; Leigh-like). Secondary: skeletal muscle and liver (biochemical COX deficiency); multiorgan failure in crises. Body systems: nervous (primary), musculoskeletal, hepatic, cardiovascular (during decompensation), autonomic. Subcellular: mitochondrion / inner mitochondrial membrane. Lateralization: bilateral, often symmetric basal-ganglia involvement.

8. Temporal Development

Onset: childhood (~4–8 y), acute/subacute, infection-triggered; a milder later spectrum possible (migraine annotation). Course: episodic/relapsing with stepwise accrual; rate from fulminant/fatal to recurrent over years. Duration: lifelong susceptibility. Critical periods: intercurrent infection/fasting (vulnerability) and the acute crisis (narrow window for metabolic rescue).

9. Inheritance and Population

Inheritance: autosomal recessive (HP:0000007). Penetrance: high/complete for biallelic null genotypes; expressivity variable (fatal vs recurrent). Epidemiology: ultra-rare; precise prevalence/incidence unknown; enriched in founder/consanguineous groups. Founder/carrier frequency: Lehrerleut Hutterite 1/13 for c.637G>A; no LoF homozygotes in gnomAD. Consanguinity: increases risk. Anticipation/germline mosaicism: not applicable/not reported. Demographics: pediatric; both sexes (no sex bias expected).

10. Diagnostics

Genetic testing (first-line, confirmatory): WES/WGS or mitochondrial/Leigh nuclear-gene panel including SQOR; targeted founder-variant/cascade testing in Hutterite families; mtDNA testing to exclude mtDNA Leigh syndrome. CMA/karyotype/FISH/repeat testing not indicated. Biochemical: isolated decreased complex IV activity with normal complex IV protein/assembly (key discriminator); reduced SQOR activity/protein; lactic acidosis; elevated CK; candidate urinary thiosulfate/sulfur-metabolite biomarkers (needs validation). Imaging: MRI bilateral basal-ganglia (± brainstem/cortical) Leigh-like lesions; MRS lactate peak. Differential diagnosis: mtDNA/nuclear Leigh syndrome (SURF1, MT-ATP6); ETHE1 ethylmalonic encephalopathy (distinguished by ethylmalonic aciduria, acrocyanosis/petechiae, chronic diarrhea); other pediatric lactic-acidosis/metabolic-coma causes. Screening: cascade carrier testing in founder populations; prenatal/PGT for known familial variants; not in standard newborn screening.

11. Outcome / Prognosis

Guarded: both Family A sisters died; the Family B boy had recurrent encephalopathy. Survivors risk fixed neurological sequelae from basal-ganglia injury; recurrent crises drive cumulative disability. Complications: metabolic coma, status epilepticus, multiorgan failure, aspiration, dysautonomia. Recovery: crisis recovery possible with prompt metabolic management; genetic defect persists (lifelong risk). Prognostic factors: genotype/residual activity, age at first crisis, speed of rescue, trigger burden; extent of lactate elevation and basal-ganglia injury on MRI.

12. Treatment

No approved disease-specific therapy; care is supportive + mechanism-based/investigational. Supportive (NCIT:C15277): treat lactic acidosis, provide anti-catabolic/glucose support, avoid fasting, aggressively treat infections, ICU support; empirical mitochondrial cofactor "cocktail." Mechanism-based (investigational): sulfide scavenging (preclinical support, PMID: 34035265); hydroxocobalamin/cobalamin sulfide-binding species; dietary sulfur/cysteine restriction; gut-microbiome modulation PMID: 40526718. Advanced therapeutics (not developed): gene therapy/enzyme replacement conceptually attractive; no gene/cell/RNA/targeted/immunotherapy exists. Surgical/pharmacogenomics: none. Trials: no SQORD-specific registered trials identified.

13. Prevention

Primary: genetic counseling and carrier/cascade screening in founder/consanguineous populations (Hutterite 1/13); preconception/prenatal/PGT for known variants. Secondary: early molecular diagnosis in at-risk sibs; prompt crisis recognition; avoid fasting. Tertiary: aggressive infection management, "sick-day" protocols, and investigational H₂S-lowering to prevent recurrent injury. Counseling: 25% recurrence risk per pregnancy for carrier couples. Immunization/public health: childhood immunization reduces infectious triggers; avoid exogenous sulfide.

14. Other Species / Natural Disease

SQOR is deeply conserved (bacteria→mammals). Orthologs: mouse Sqor (NCBI Gene 59010, NCBITaxon:10090), rat (10116), zebrafish (7955), C. elegans (6239), Schistosoma mansoni (6183). No naturally occurring Mendelian SQOR-deficiency disease catalogued in OMIA. Comparative biology: sulfide-tolerant organisms (S. mansoni in sulfide-rich mesenteric veins, PMID: 41638445; C. elegans rhodoquinone chain in sulfide) and high-SQOR hypoxia-tolerant ground squirrels illustrate conserved sulfide-defense biology. Not zoonotic/transmissible.

15. Model Organisms

Mouse (silencing + neuron-specific re-expression) recapitulates sulfide accumulation, bioenergetic failure, and brain hypoxia sensitivity (PMID: 34035265); links gut sulfide to brain bioenergetics (PMID: 40526718). Comparative: 13-lined ground squirrel (high-SQOR, protected). Invertebrate/microbial: C. elegans, S. mansoni, bacterial SQR for conserved enzymology. In vitro/cellular: patient fibroblasts, muscle, liver; hypoxic primary neurons for scavenging rescue. Phenotype recapitulation: strong for mechanism/tissue vulnerability; a faithful constitutive-knockout replicating the full triggered episodic Leigh-like crisis phenotype is not well established (a key gap). Resources: MGI (Sqor), Alliance of Genome Resources, IMPC/KOMP.

Evidence Base

PMID Title (abbrev.) Role in this report
32160317 Pathogenic variants in SQOR … a potentially treatable cause of Leigh disease Primary clinical delineation — two families, variants, founder effect, isolated functional complex IV deficiency with normal assembly, H₂S mechanism
34035265 Sulfide catabolism ameliorates hypoxic brain injury SQOR level ∝ brain hypoxia resistance; sulfide scavenging rescues respiration — mechanistic + therapeutic basis; mouse model
26318450 Transient Kinetic Analysis … human SQOR Defines SQOR biochemistry coupling H₂S oxidation to the ETC via flavin/ubiquinone
40563372 mtUPR activation … Ethylmalonic Encephalopathy ETHE1 (downstream) deficiency causes the same complex IV defect — pathway corroboration
40526718 Gut sulfide metabolism modulates behavior and brain bioenergetics Gut-microbiome H₂S contributes to sulfide burden — supports dietary/microbiome adjuncts
41638445 S. mansoni SQOR charge-transfer complex Evolutionary conservation of SQOR enzymology; comparative model
36758466 NRF2 contribution to sulfur metabolism and mitochondrial activity SQOR as NRF2 target; expression regulation context
38521487 Sulfide catabolism in hibernation and neuroprotection Review linking sulfide catabolism, hypoxia, and Leigh syndrome

Evidence source types: human clinical/biochemical (Friederich 2020), model organism (Marutani 2021; ETHE1 cellular models), in vitro enzymology (Mishanina 2015), and database/computational (gnomAD v4, OLS4/MONDO, mygene.info, JAX HPO API, PDBe).

Supported hypotheses: (1) biallelic SQOR LoF causes an AR Leigh-like disease; (2) mechanism = H₂S accumulation → complex IV inhibition → energy failure (isolated functional COX defect with normal assembly); (3) ultra-rare, founder-enriched (Hutterite 1/13); (4) childhood-onset, episodic, infection-triggered; (5) "potentially treatable" via H₂S lowering (preclinical support).

Refuted / excluded: complex IV deficiency is not a structural/assembly defect (protein and assembly normal); not mtDNA-encoded; SQOR is not haploinsufficient (heterozygous LoF tolerated); not associated with common population variants, CNVs, or disease-specific epigenetic lesions.

Limitations and Knowledge Gaps

  • Very small evidence base. The disease rests primarily on two families (three patients) from a single 2020 report. Prevalence, incidence, full phenotype spectrum, penetrance, expressivity, and natural history outside the Hutterite founder context are essentially unknown; the migraine annotation hints at an under-recognized milder spectrum.
  • No approved therapy and no clinical-trial data. Sulfide-scavenging and cobalamin-based strategies rest on preclinical/mechanistic data only; efficacy, dosing, and safety in SQORD patients are untested.
  • Indirect in-patient H₂S measurement. Human-tissue H₂S accumulation is inferred from complex IV biochemistry and model-organism data rather than directly quantified.
  • No validated routine biomarker. Urinary thiosulfate/sulfur metabolites need validation specifically for SQORD.
  • No crisis-faithful knockout disease model. Existing mouse work used silencing/re-expression focused on hypoxia, not a constitutive knockout reproducing the triggered episodic phenotype.
  • No dedicated omics datasets (transcriptomic/proteomic/metabolomic) for patients; no Orphanet/ICD-specific entry.
  • Modifier genes and genotype–phenotype correlations are not established.

Proposed Follow-up Experiments / Actions

  1. Establish a patient/variant registry (GeneMatcher, clinician networks) to identify additional SQORD cases and define phenotype spectrum, penetrance, and natural history.
  2. Build a faithful Sqor-knockout (and p.Glu213Lys knock-in) mouse, plus patient-iPSC-derived neurons/organoids, to quantify H₂S accumulation, complex IV inhibition, and basal-ganglia vulnerability, and to serve as a therapeutic testbed.
  3. Preclinical efficacy testing of sulfide-lowering interventions — pharmacological scavengers, hydroxocobalamin/oxidized cobalamin, dietary sulfur/cysteine restriction, and microbiome modulation — with respiration/ATP and survival endpoints.
  4. Develop and validate biomarkers of sulfide burden (plasma/urine thiosulfate, sulfide/persulfide species, brain-lactate MRS) for diagnosis, crisis prediction, and treatment monitoring.
  5. Structure-guided variant classification using the 8 solved human SQOR structures and AlphaFold to triage novel missense VUS by predicted effect on FAD binding, quinone access, and membrane interaction.
  6. Carrier-screening and crisis-prevention protocols for founder/consanguineous populations (Hutterite p.Glu213Lys), including "sick-day" management guidelines to pre-empt catabolic decompensation.

Report compiled from eight confirmed findings across five investigation iterations and 23 reviewed papers. Evidence is strongest for the gene–enzyme–mechanism axis (SQOR loss → H₂S accumulation → complex IV inhibition → Leigh-like encephalopathy) and weakest for epidemiology and therapy, which remain to be defined. Only attributions supported by the cited abstracts/snippets are made; titles alone were not used to infer paper content.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 42
Resolved 39
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 11
Terms named correctly 7
Terms named as a different term 2
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0032263 (1 mention) - the report calls it "Multiorgan failure"; HP calls it Increased blood pressure
  • HP:0012719 (1 mention) - the report calls it "Neurostorming / dysautonomia"; HP calls it Functional abnormality of the gastrointestinal tract

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0012707 (1 mention) - the report calls it "Elevated brain lactate (MRS)"; HP calls it Elevated brain lactate level by MRS
  • HP:0003236 (1 mention) - the report calls it "Elevated circulating creatine kinase"; HP calls it Elevated circulating creatine kinase activity, and lists "Elevated circulating creatine phosphokinase" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: GARD, OMIM.