SCO2-Related Fatal Infantile Cardioencephalomyopathy

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Discussions and Knowledge Gaps

1

Do the existing Sco2 mouse models reproduce the human hypertrophic cardiomyopathy and fatal infantile course, or does the model-human gap limit their use for preclinical testing of therapies such as copper-histidine?

HUMAN MODEL MISMATCH OPEN sco2_mouse_cardiac_phenotype_mismatch

Attached to

pathophysiology#SCO2 Loss and Defective Copper Delivery to COX pathophysiology#Impaired Terminal Electron Transfer and ATP Synthesis

The mouse models are allele-matched and biochemically faithful yet phenotypically divergent, which is exactly the situation HUMAN_MODEL_MISMATCH is for: the evidence exists, but its translational validity is the open question. Constitutive Sco2 knockout mice are embryonic lethal, while the E129K knock-in (orthologous to the recurrent human p.E140K allele) and the compound KI/KO animals are viable and show respiratory chain deficiency, Complex IV assembly defects across tissues, and reduced mitochondrial copper content — but muscle weakness rather than the hypertrophic cardiomyopathy and infantile lethality that define the human disorder. The most genetically faithful models therefore fail to express the defining cardiac endpoint, so a therapeutic effect measured in them cannot be read directly as a prediction of cardiac benefit in patients. This matters concretely for copper-histidine, whose human support is one case report and whose in vitro support is a myoblast rescue.

Proposed experiments

Copper-histidine rescue in SCO2 patient iPSC-derived cardiomyocytes

exp_sco2_ipsc_cardiomyocyte_copper_rescue

Use patient-derived and isogenic-corrected SCO2-mutant iPSC-derived cardiomyocytes to test whether copper-histidine restores oxidative ATP production, sarcoplasmic-reticulum calcium handling, and inotropic responsiveness in the human cardiac cell type the mouse models fail to model, with genotype stratification across p.E140K and p.G193S.

Supporting outcome

Genotype-dependent restoration of ATP production and calcium handling would support copper delivery as the rate-limiting, druggable step in human cardiomyocytes.

Refuting outcome

Failure to rescue human cardiomyocytes despite rescue of patient myoblasts would indicate a cardiomyocyte-specific block downstream of copper availability.

Cardiac stress phenotyping of viable Sco2 KI and KI/KO mice

exp_sco2_cardiac_stress_phenotyping_ki_mouse

Subject homozygous E129K knock-in and compound KI/KO animals to defined hemodynamic or adrenergic stress and assess left ventricular wall thickness, diastolic function, and survival, to test whether the absent cardiomyopathy reflects a genuine species difference or an unstressed baseline.

Supporting outcome

Emergence of hypertrophy under stress would restore the model's usefulness for cardiac preclinical work, with load as a required cofactor.

Refuting outcome

A persistently normal heart under stress would confirm a species-level divergence in cardiac vulnerability to Sco2 deficiency.

Show evidence (2 references)

PMID:19837698 SUPPORT Model Organism

"Whereas homozygous KO mice were embryonic lethals, homozygous KI and compound heterozygous KI/KO mice were viable, but had muscle weakness; biochemically, they had respiratory chain deficiencies as well as complex IV assembly defects in multiple tissues."

Documents that the allele-matched viable mouse genotypes show the biochemical lesion with myopathy rather than the human cardiomyopathy, defining the mismatch.

PMID:29193756 SUPPORT In Vitro

"To date, none of the recent pertaining reports provide deep understanding of the SCO2 disease pathophysiology."

Motivates the human iPSC-cardiomyocyte route as the proposed resolution to the model gap.

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Pathophysiology

2

SCO2 Loss and Defective Copper Delivery to COX

Biallelic SCO2 variants impair copper delivery to the CuA center of COX2, preventing assembly of a catalytically competent Complex IV holoenzyme. Sco2 is a mitochondrial inner-membrane copper metallochaperone bearing a CxxxC metal-binding motif; loss of its chaperone function leaves the catalytic-core subunits unmetallated and destabilized, producing isolated COX deficiency that is most severe in striated muscle.

cardiac muscle cell CL:0000746

SCO2 hgnc:10604

copper ion transport GO:0006825 ↓ DECREASED mitochondrial respiratory chain complex IV assembly GO:0033617 ↓ DECREASED

Animal models

Sco2 E129K knock-in and knock-in/knock-out mouse Mouse partially recapitulates The viable KI and KI/KO genotypes reproduce the molecular lesion — Complex IV assembly failure with a selective reduction in mitochondrial copper content — in an allele-matched genetic background.

Downstream

Impaired Terminal Electron Transfer and ATP Synthesis Failure of CuA assembly yields a catalytically inactive enzyme.

Show evidence (3 references)

PMID:10545952 SUPPORT Human Clinical

"we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency."

Original identification of SCO2 mutations as the cause of fatal infantile cardioencephalomyopathy with COX deficiency.

PMID:11751685 SUPPORT In Vitro

"Studies on a yeast homolog have suggested that human Sco2 acts as a copper chaperone, transporting copper to the Cu(A) site on the Cox II subunit"

Localizes the SCO2 lesion to the copper-delivery sub-step of Complex IV assembly (metallation of the CuA site on COX2).

PMID:11751685 SUPPORT In Vitro

"Sco2 was severely reduced in patient fibroblasts and myoblasts by immunoblot analysis."

Documents loss of Sco2 protein in patient cells as the proximal molecular defect.

Impaired Terminal Electron Transfer and ATP Synthesis

Loss of functional COX blocks electron transfer from cytochrome c to oxygen and proton pumping, collapsing oxidative ATP synthesis, with greatest impact on cardiac and skeletal muscle.

cardiac muscle cell CL:0000746

mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED aerobic respiration GO:0009060 ↓ DECREASED

Experimental models

SCO2-mutant patient iPSC-derived cardiomyocytes IPSC DERIVED MODEL SCO2-mutant iPSC-derived cardiomyocytes show ultrastructural mitochondrial abnormalities and blunted inotropic responsiveness, with delayed afterdepolarizations and increased beat-rate variability attributed to impaired sarcoplasmic-reticulum calcium handling secondary to ATP shortage.

Downstream

Hypertrophic cardiomyopathy Energy failure in cardiomyocytes drives hypertrophic cardiomyopathy.

Encephalopathy Energy deficit in the CNS produces the encephalopathy component of SCO2 cardioencephalomyopathy.

Lactic acidosis Impaired oxidative phosphorylation shifts pyruvate metabolism toward lactate accumulation, producing lactic acidosis.

Muscular hypotonia Combined central and neuromuscular energy failure produces progressive muscular hypotonia.

Neurogenic muscular atrophy Anterior horn cell and motor neuron vulnerability produces a neurogenic, spinal-muscular-atrophy-like muscular atrophy.

Respiratory insufficiency Respiratory muscle involvement and brainstem dysfunction lead to ventilatory failure, the most common terminal event.

Show evidence (2 references)

PMID:10545952 SUPPORT Human Clinical

"Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane."

Defines the terminal electron-transfer and proton-pumping function lost in SCO2-related COX deficiency.

PMID:29193756 SUPPORT In Vitro

"Mutations in SCO2 are among the most common causes of COX deficiency, resulting in reduced mitochondrial oxidative ATP production capacity, often leading to hypertrophic cardiomyopathy (HCM)."

Patient iPSC-derived cardiomyocyte work links the SCO2 COX defect to reduced oxidative ATP production capacity and to the cardiac phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

7

Cardiovascular 1

Hypertrophic cardiomyopathy HP:0001639

Course: PROGRESSIVE

Show evidence (2 references)

PMID:10545952 SUPPORT Human Clinical

"we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency."

SCO2 mutations cause fatal infantile cardioencephalomyopathy, of which hypertrophic cardiomyopathy is the cardinal feature.

PMID:11673586 SUPPORT Human Clinical

"The clinical spectrum of SCO2 deficiency includes the delayed development of hypertrophic obstructive cardiomyopathy and severe neurogenic muscular atrophy."

Documents hypertrophic obstructive cardiomyopathy within the SCO2 deficiency spectrum, with delayed onset in p.E140K homozygotes.

Metabolism 1

Lactic acidosis HP:0003128

Show evidence (2 references)

PMID:19682572 SUPPORT Other

"Human diseases associated with COX deficiency including encephalomyopathies, Leigh syndrome, hypertrophic cardiomyopathies, and fatal lactic acidosis are caused by mutations in COX subunits or assembly factors."

Fatal lactic acidosis and hypertrophic cardiomyopathy are recognized manifestations of COX deficiency.

PMID:23407777 SUPPORT Human Clinical

"Routine blood tests showed lactic acidosis and mild elevation of the creatine kinase level."

Documents lactic acidosis in a genetically confirmed SCO2 compound heterozygote.

Musculoskeletal 1

Muscular hypotonia HP:0001252

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:23407777 SUPPORT Human Clinical

"She developed progressive muscular hypotonia and ventilatory failure."

Documents progressive muscular hypotonia in a genetically confirmed SCO2 patient.

Nervous System 1

Encephalopathy HP:0001298

Course: PROGRESSIVE

Show evidence (2 references)

PMID:10545952 SUPPORT Human Clinical

"we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency."

The cardioencephalomyopathy phenotype includes encephalopathy.

PMID:11673586 SUPPORT Human Clinical

"MRI and muscle morphology demonstrated an age-dependent progression of disease with predominant involvement of white matter, late appearance of basal ganglia lesions, and neurogenic muscular atrophy"

Characterizes the progressive, Leigh-like neuroimaging signature of the encephalopathy in SCO2 deficiency.

Respiratory 1

Respiratory insufficiency HP:0002093

Show evidence (1 reference)

PMID:23407777 SUPPORT Human Clinical

"She developed progressive muscular hypotonia and ventilatory failure."

Documents ventilatory (respiratory) failure in a genetically confirmed SCO2 patient.

Other 2

Neurogenic muscular atrophy Spinal muscular atrophy HP:0007269

Show evidence (2 references)

PMID:11673586 SUPPORT Human Clinical

"The clinical spectrum of SCO2 deficiency includes the delayed development of hypertrophic obstructive cardiomyopathy and severe neurogenic muscular atrophy."

Establishes severe neurogenic muscular atrophy as part of the SCO2 deficiency spectrum.

PMID:23719228 SUPPORT Human Clinical

"A search for SCO2 mutations in patients with histology resembling SMA appears to efficiently improve the detection rate."

The SMA-resembling muscle histology is characteristic enough of SCO2 deficiency to be a productive diagnostic screen.

Sensory axonal neuropathy HP:0003390

Show evidence (1 reference)

PMID:23407777 SUPPORT Human Clinical

"Nerve conduction studies showed severe axonal sensorimotor neuropathy."

Documents a severe axonal sensorimotor neuropathy in a genetically confirmed SCO2 patient.

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Genetic Associations

1

SCO2 pathogenic variants causing cardioencephalomyopathy

Gene: SCO2 hgnc:10604

Autosomal recessive

Show evidence (4 references)

PMID:10545952 SUPPORT Human Clinical

"The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome."

Establishes SCO2 as a distinct COX assembly gene with a cardioencephalomyopathy phenotype distinct from SURF1.

PMID:19353847 SUPPORT Human Clinical

"All patients reported to date with SCO2 deficiency share a common p.E140K mutation in at least 1 allele."

Documents p.E140K as the near-universal recurrent SCO2 allele, against which the homozygous p.G193S case is the reported exception.

PMID:23719228 SUPPORT Human Clinical

"A novel, milder phenotype (disease onset delayed until one year after birth, nonspecific encephalomyopathy, and 2-4 year survival period) associated with compound heterozygosity of the common p.E140K and a novel p.M177T mutations extends the range of symptoms of the SCO2 deficiency."

Establishes the SCO2 genotype-phenotype correlation and the mildest reported E140K/M177T combination.

+ 1 more reference

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Medical Actions

3

Supportive and Metabolic Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

No curative therapy; supportive management of cardiomyopathy, lactic acidosis, and metabolic decompensation, including ventilatory and nutritional support.

Copper-Histidine Supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: copper-histidine CHEBI:29036

Mechanism-based copper-histidine (Cu-his) supplementation, rationalized by the SCO2 copper-delivery defect. Addition of copper-histidine to the culture medium fully rescued COX activity in SCO2-deficient patient myoblasts, and subcutaneous Cu-his was the most likely explanation for resolution of severe hypertrophic cardiomyopathy in a single reported patient. Evidence remains in vitro plus a single case; benefit is presumed to require treatment before irreversible injury in post-mitotic tissue.

Mechanism Target:

BYPASSES SCO2 Loss and Defective Copper Delivery to COX — Exogenous copper-histidine bypasses or supplements the failing Sco2-dependent copper-delivery step, restoring COX activity in patient cells.

Show evidence (1 reference)

PMID:11751685 SUPPORT In Vitro

"COX activity in patient myoblasts was completely rescued by transduction with a retroviral vector expressing the human SCO2 coding sequence, and more interestingly by addition of copper-histidine (300 microM) to the culture medium."

Direct in vitro demonstration that copper-histidine acts on the SCO2 copper-delivery lesion.

Show evidence (2 references)

PMID:11751685 SUPPORT In Vitro

"Whatever the mechanism, this result suggests a possible therapy for the early treatment of this fatal infantile disease."

The authors propose early copper supplementation as a candidate therapy on the strength of the myoblast rescue.

PMID:14970747 SUPPORT Human Clinical

"Here, we report a patient with SCO 2 mutations and with resolution of severe hypertrophic cardiomyopathy."

Single-patient report of cardiomyopathy resolution attributed to subcutaneous copper-histidine; anecdotal, hence PARTIAL.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal recessive inheritance carries a 25% recurrence risk for carrier parents; molecular confirmation of the familial SCO2 variants enables prenatal and preimplantation genetic diagnosis.

Show evidence (1 reference)

PMID:23407777 SUPPORT Human Clinical

"the accurate diagnosis of SCO2 mutations is particularly important for genetic counseling."

Establishes molecular diagnosis of SCO2 as the basis for genetic counseling in affected families.

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Experimental Models

1

SCO2-mutant patient iPSC-derived cardiomyocytes IPSC_DERIVED_MODEL

Cardiomyocytes differentiated via embryoid bodies from induced pluripotent stem cells reprogrammed from skin fibroblasts of two SCO2 patients (one compound heterozygous for p.E140K, one homozygous for p.G193S) and healthy controls. The model captures the human cardiac arm of the disease that viable Sco2 mouse models do not reproduce.

Organism

human NCBITaxon:9606

Publication

PMID:29193756

Pathograph links

Impaired Terminal Electron Transfer and ATP Synthesis recapitulates fidelity: moderate SCO2-mutant iPSC-derived cardiomyocytes show ultrastructural mitochondrial abnormalities and blunted inotropic responsiveness, with delayed afterdepolarizations and increased beat-rate variability attributed to impaired sarcoplasmic-reticulum calcium handling secondary to ATP shortage.

Limitations: iPSC-derived cardiomyocytes are immature relative to adult myocardium and are studied in isolation from the hemodynamic load and neurohormonal context that shape hypertrophic remodeling in vivo; only two patient genotypes were assayed.

Show evidence (1 reference)

PMID:29193756 SUPPORT In Vitro

"we found in the mutated iPSC-CMs major ultrastructural abnormalities and markedly attenuated response to the inotropic interventions and caffeine, as well as delayed afterdepolarizations (DADs) and increased BRV, suggesting impaired SR Ca2+ handling due to attenuated SERCA activity caused by ATP..."

Establishes that the patient-derived cardiomyocyte model reproduces the bioenergetic-failure node with a measurable cardiac functional readout.

Show evidence (1 reference)

PMID:29193756 SUPPORT In Vitro

"Our novel results show that iPSC-CMs are useful for investigating the pathophysiological mechanisms underlying the SCO2 mutation syndrome."

The authors' own assessment that this model is informative for SCO2 disease mechanism.

🐁

Animal Models

1

Sco2 E129K knock-in and knock-in/knock-out mouse

Allele-matched mouse models of the recurrent human SCO2 variant. Homozygous KO animals are embryonic lethal; homozygous KI and KI/KO animals are viable with muscle weakness, respiratory chain deficiency, Complex IV assembly defects across tissues, and reduced mitochondrial copper content.

Species

Mouse

Genotype

Sco2 knock-out (KO) allele and Sco2 E129K knock-in (KI) allele (orthologous to the human p.E140K); homozygous KI and compound heterozygous KI/KO animals

Publication

PMID:19837698

Pathograph links

SCO2 Loss and Defective Copper Delivery to COX partially recapitulates fidelity: moderate The viable KI and KI/KO genotypes reproduce the molecular lesion — Complex IV assembly failure with a selective reduction in mitochondrial copper content — in an allele-matched genetic background.

Limitations: The null allele is embryonic lethal, so the human genotype range cannot be modeled across its full severity, and the viable allele-matched genotypes develop muscle weakness without the hypertrophic cardiomyopathy and fatal infantile course that define the human disease. See the HUMAN_MODEL_MISMATCH discussion.

Readouts

Mitochondrial copper content

Direction: DECREASED

Interpretation: Selective mitochondrial copper depletion without a fall in total tissue copper is the direct correlate of failed Sco2-mediated copper delivery.

Show evidence (1 reference)

PMID:19837698 SUPPORT Model Organism

"There was a concomitant reduction in mitochondrial copper content, but the total amount of copper in examined tissues was not reduced."

Reports the mitochondrial-copper measurement behind this readout.

Show evidence (1 reference)

PMID:19837698 SUPPORT Model Organism

"Whereas homozygous KO mice were embryonic lethals, homozygous KI and compound heterozygous KI/KO mice were viable, but had muscle weakness; biochemically, they had respiratory chain deficiencies as well as complex IV assembly defects in multiple tissues."

Establishes that the allele-matched mouse reproduces the Complex IV assembly defect while diverging from the human phenotype.

{ }

Source YAML

click to show

name: SCO2-Related Fatal Infantile Cardioencephalomyopathy
category: Mendelian
creation_date: "2026-05-30T00:00:00Z"
synonyms:
- SCO2 deficiency
- Fatal infantile cardioencephalomyopathy due to cytochrome c oxidase deficiency 1
- Cardioencephalomyopathy, fatal infantile, due to COX deficiency, SCO2-related
description: >
  SCO2-related fatal infantile cardioencephalomyopathy is a nuclear form of
  isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic
  variants in SCO2, a copper-delivery metallochaperone required to assemble the
  CuA center of COX. Affected infants present with hypertrophic cardiomyopathy,
  encephalopathy, hypotonia, and lactic acidosis, and typically die in infancy.
  The recurrent p.E140K (c.1541G>A) allele is carried on at least one allele by
  nearly all reported patients, and genotype predicts course: compound
  heterozygosity for E140K with a null or truncating allele gives the severe
  neonatal cardioencephalomyopathic form, E140K homozygosity gives a
  delayed-onset Leigh-like course with prominent neurogenic (SMA-like) muscular
  atrophy, and E140K/p.M177T gives the mildest reported phenotype with survival
  to 2-4 years. The disorder conforms to the conserved Complex IV assembly
  deficiency mechanism, with the assembly defect localized to copper delivery
  and the dominant tissue involvement being cardiac.
disease_term:
  preferred_term: SCO2-related fatal infantile cardioencephalomyopathy
  term:
    id: MONDO:0011451
    label: cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
pathophysiology:
- name: SCO2 Loss and Defective Copper Delivery to COX
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  biological_scale: MOLECULAR
  description: >
    Biallelic SCO2 variants impair copper delivery to the CuA center of COX2,
    preventing assembly of a catalytically competent Complex IV holoenzyme.
    Sco2 is a mitochondrial inner-membrane copper metallochaperone bearing a
    CxxxC metal-binding motif; loss of its chaperone function leaves the
    catalytic-core subunits unmetallated and destabilized, producing isolated
    COX deficiency that is most severe in striated muscle.
  genes:
  - preferred_term: SCO2
    term:
      id: hgnc:10604
      label: SCO2
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: copper ion transport
    term:
      id: GO:0006825
      label: copper ion transport
    modifier: DECREASED
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:10545952
    reference_title: "Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency.
    explanation: Original identification of SCO2 mutations as the cause of fatal infantile cardioencephalomyopathy with COX deficiency.
  - reference: PMID:11751685
    reference_title: "Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Studies on a yeast homolog have suggested that human Sco2 acts as a copper chaperone, transporting copper to the Cu(A) site on the Cox II subunit"
    explanation: Localizes the SCO2 lesion to the copper-delivery sub-step of Complex IV assembly (metallation of the CuA site on COX2).
  - reference: PMID:11751685
    reference_title: "Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Sco2 was severely reduced in patient fibroblasts and myoblasts by immunoblot analysis."
    explanation: Documents loss of Sco2 protein in patient cells as the proximal molecular defect.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    causal_link_type: DIRECT
    description: Failure of CuA assembly yields a catalytically inactive enzyme.
- name: Impaired Terminal Electron Transfer and ATP Synthesis
  conforms_to: "complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis"
  biological_scale: CELLULAR
  description: >
    Loss of functional COX blocks electron transfer from cytochrome c to oxygen
    and proton pumping, collapsing oxidative ATP synthesis, with greatest impact
    on cardiac and skeletal muscle.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  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
  - preferred_term: ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  evidence:
  - reference: PMID:10545952
    reference_title: "Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane.
    explanation: Defines the terminal electron-transfer and proton-pumping function lost in SCO2-related COX deficiency.
  - reference: PMID:29193756
    reference_title: "Investigating the cardiac pathology of SCO2-mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell-derived cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutations in SCO2 are among the most common causes of COX deficiency, resulting in reduced mitochondrial oxidative ATP production capacity, often leading to hypertrophic cardiomyopathy (HCM)."
    explanation: Patient iPSC-derived cardiomyocyte work links the SCO2 COX defect to reduced oxidative ATP production capacity and to the cardiac phenotype.
  downstream:
  - target: Hypertrophic cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy failure in cardiomyocytes drives hypertrophic cardiomyopathy.
  - target: Encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy deficit in the CNS produces the encephalopathy component of SCO2 cardioencephalomyopathy.
  - target: Lactic acidosis
    causal_link_type: DIRECT
    description: Impaired oxidative phosphorylation shifts pyruvate metabolism toward lactate accumulation, producing lactic acidosis.
  - target: Muscular hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Combined central and neuromuscular energy failure produces progressive muscular hypotonia.
  - target: Neurogenic muscular atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Anterior horn cell and motor neuron vulnerability produces a neurogenic, spinal-muscular-atrophy-like muscular atrophy.
  - target: Respiratory insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Respiratory muscle involvement and brainstem dysfunction lead to ventilatory failure, the most common terminal event.
phenotypes:
- name: Hypertrophic cardiomyopathy
  description: >
    Cardiac hypertrophy, the hallmark feature of SCO2-related disease.
    Obstructive forms are reported, and onset is later in p.E140K homozygotes
    than in compound heterozygotes.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:10545952
    reference_title: "Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency.
    explanation: SCO2 mutations cause fatal infantile cardioencephalomyopathy, of which hypertrophic cardiomyopathy is the cardinal feature.
  - reference: PMID:11673586
    reference_title: "Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical spectrum of SCO2 deficiency includes the delayed development of hypertrophic obstructive cardiomyopathy and severe neurogenic muscular atrophy."
    explanation: Documents hypertrophic obstructive cardiomyopathy within the SCO2 deficiency spectrum, with delayed onset in p.E140K homozygotes.
- name: Encephalopathy
  description: >
    Encephalopathy as part of the cardioencephalomyopathy phenotype, with a
    Leigh-like neuroimaging pattern: predominant white matter involvement and
    later-appearing basal ganglia lesions.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:10545952
    reference_title: "Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency.
    explanation: The cardioencephalomyopathy phenotype includes encephalopathy.
  - reference: PMID:11673586
    reference_title: "Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI and muscle morphology demonstrated an age-dependent progression of disease with predominant involvement of white matter, late appearance of basal ganglia lesions, and neurogenic muscular atrophy"
    explanation: Characterizes the progressive, Leigh-like neuroimaging signature of the encephalopathy in SCO2 deficiency.
- name: Lactic acidosis
  description: Elevated lactate from impaired oxidative metabolism.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:19682572
    reference_title: "Cytochrome c oxidase deficiency: patients and animal models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Human diseases associated with COX deficiency including encephalomyopathies, Leigh syndrome, hypertrophic cardiomyopathies, and fatal lactic acidosis are caused by mutations in COX subunits or assembly factors.
    explanation: Fatal lactic acidosis and hypertrophic cardiomyopathy are recognized manifestations of COX deficiency.
  - reference: PMID:23407777
    reference_title: "Mitochondrial cardioencephalomyopathy due to a novel SCO2 mutation in a Brazilian patient: case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Routine blood tests showed lactic acidosis and mild elevation of the creatine kinase level."
    explanation: Documents lactic acidosis in a genetically confirmed SCO2 compound heterozygote.
- name: Muscular hypotonia
  description: >
    Profound, progressive muscular hypotonia, frequently present from the
    neonatal period in the severe compound-heterozygous form.
  phenotype_term:
    preferred_term: Muscular hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23407777
    reference_title: "Mitochondrial cardioencephalomyopathy due to a novel SCO2 mutation in a Brazilian patient: case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She developed progressive muscular hypotonia and ventilatory failure."
    explanation: Documents progressive muscular hypotonia in a genetically confirmed SCO2 patient.
- name: Respiratory insufficiency
  description: >
    Ventilatory failure requiring intensive-care support; cardiopulmonary
    failure is the usual terminal event.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:23407777
    reference_title: "Mitochondrial cardioencephalomyopathy due to a novel SCO2 mutation in a Brazilian patient: case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She developed progressive muscular hypotonia and ventilatory failure."
    explanation: Documents ventilatory (respiratory) failure in a genetically confirmed SCO2 patient.
- name: Neurogenic muscular atrophy
  description: >
    Severe neurogenic muscular atrophy with a muscle histology resembling
    spinal muscular atrophy. The SMA-like biopsy pattern is characteristic
    enough that screening SMA-like histology improves the SCO2 detection rate.
  phenotype_term:
    preferred_term: Spinal muscular atrophy-like neurogenic muscular atrophy
    term:
      id: HP:0007269
      label: Spinal muscular atrophy
  evidence:
  - reference: PMID:11673586
    reference_title: "Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical spectrum of SCO2 deficiency includes the delayed development of hypertrophic obstructive cardiomyopathy and severe neurogenic muscular atrophy."
    explanation: Establishes severe neurogenic muscular atrophy as part of the SCO2 deficiency spectrum.
  - reference: PMID:23719228
    reference_title: "The natural history of SCO2 deficiency in 36 Polish children confirmed the genotype-phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A search for SCO2 mutations in patients with histology resembling SMA appears to efficiently improve the detection rate."
    explanation: The SMA-resembling muscle histology is characteristic enough of SCO2 deficiency to be a productive diagnostic screen.
- name: Sensory axonal neuropathy
  description: >
    Severe axonal sensorimotor peripheral neuropathy on nerve conduction
    studies; rarely documented electrophysiologically because of the early
    fatal course.
  phenotype_term:
    preferred_term: Axonal sensorimotor neuropathy
    term:
      id: HP:0003390
      label: Sensory axonal neuropathy
  evidence:
  - reference: PMID:23407777
    reference_title: "Mitochondrial cardioencephalomyopathy due to a novel SCO2 mutation in a Brazilian patient: case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction studies showed severe axonal sensorimotor neuropathy."
    explanation: Documents a severe axonal sensorimotor neuropathy in a genetically confirmed SCO2 patient.
genetic:
- name: SCO2 pathogenic variants causing cardioencephalomyopathy
  gene_term:
    preferred_term: SCO2
    term:
      id: hgnc:10604
      label: SCO2
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:10749987
      reference_title: "Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: compound heterozygotes for the G1541A mutation
      explanation: Patients are compound heterozygous for SCO2 variants, indicating autosomal recessive inheritance.
    - reference: PMID:11673586
      reference_title: "Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The patients all had a homozygous missense mutation in SCO2."
      explanation: Homozygous SCO2 missense variants in affected infants confirm autosomal recessive inheritance.
  features: >
    Biallelic SCO2 variants impair copper delivery to the COX CuA center,
    causing fatal infantile cardioencephalomyopathy. The clinical phenotype
    differs from that caused by SURF1. The recurrent p.E140K (c.1541G>A /
    G1541A) missense allele, adjacent to the CxxxC copper-binding motif, is
    present on at least one allele in nearly all reported patients and behaves
    as a founder/hotspot allele in Central European (notably Polish and other
    Slavic) populations; the single reported homozygous p.G193S patient is the
    documented exception. Genotype predicts course: E140K in trans with a null
    or truncating allele gives the severe neonatal cardioencephalomyopathic
    form, E140K homozygosity gives delayed onset with a Leigh-like,
    SMA-like-atrophy course, and E140K/p.M177T gives the mildest reported
    phenotype (onset after one year, nonspecific encephalomyopathy, 2-4 year
    survival).
  evidence:
  - reference: PMID:10545952
    reference_title: "Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome.
    explanation: Establishes SCO2 as a distinct COX assembly gene with a cardioencephalomyopathy phenotype distinct from SURF1.
  - reference: PMID:19353847
    reference_title: "A novel homozygous SCO2 mutation, p.G193S, causing fatal infantile cardioencephalomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients reported to date with SCO2 deficiency share a common p.E140K mutation in at least 1 allele."
    explanation: Documents p.E140K as the near-universal recurrent SCO2 allele, against which the homozygous p.G193S case is the reported exception.
  - reference: PMID:23719228
    reference_title: "The natural history of SCO2 deficiency in 36 Polish children confirmed the genotype-phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel, milder phenotype (disease onset delayed until one year after birth, nonspecific encephalomyopathy, and 2-4 year survival period) associated with compound heterozygosity of the common p.E140K and a novel p.M177T mutations extends the range of symptoms of the SCO2 deficiency."
    explanation: Establishes the SCO2 genotype-phenotype correlation and the mildest reported E140K/M177T combination.
  - reference: PMID:23719228
    reference_title: "The natural history of SCO2 deficiency in 36 Polish children confirmed the genotype-phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of SCO2 deficiency in Poland is relatively high."
    explanation: Supports the founder-allele enrichment of SCO2 deficiency in a Central European population.
experimental_models:
- name: SCO2-mutant patient iPSC-derived cardiomyocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >
    Cardiomyocytes differentiated via embryoid bodies from induced pluripotent
    stem cells reprogrammed from skin fibroblasts of two SCO2 patients (one
    compound heterozygous for p.E140K, one homozygous for p.G193S) and healthy
    controls. The model captures the human cardiac arm of the disease that
    viable Sco2 mouse models do not reproduce.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  publication: PMID:29193756
  modeled_mechanisms:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >
      SCO2-mutant iPSC-derived cardiomyocytes show ultrastructural
      mitochondrial abnormalities and blunted inotropic responsiveness, with
      delayed afterdepolarizations and increased beat-rate variability
      attributed to impaired sarcoplasmic-reticulum calcium handling secondary
      to ATP shortage.
    limitations: >
      iPSC-derived cardiomyocytes are immature relative to adult myocardium and
      are studied in isolation from the hemodynamic load and neurohormonal
      context that shape hypertrophic remodeling in vivo; only two patient
      genotypes were assayed.
    evidence:
    - reference: PMID:29193756
      reference_title: "Investigating the cardiac pathology of SCO2-mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell-derived cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we found in the mutated iPSC-CMs major ultrastructural abnormalities and markedly attenuated response to the inotropic interventions and caffeine, as well as delayed afterdepolarizations (DADs) and increased BRV, suggesting impaired SR Ca2+ handling due to attenuated SERCA activity caused by ATP shortage."
      explanation: Establishes that the patient-derived cardiomyocyte model reproduces the bioenergetic-failure node with a measurable cardiac functional readout.
  evidence:
  - reference: PMID:29193756
    reference_title: "Investigating the cardiac pathology of SCO2-mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell-derived cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our novel results show that iPSC-CMs are useful for investigating the pathophysiological mechanisms underlying the SCO2 mutation syndrome."
    explanation: The authors' own assessment that this model is informative for SCO2 disease mechanism.
animal_models:
- name: Sco2 E129K knock-in and knock-in/knock-out mouse
  species: Mouse
  genotype: >
    Sco2 knock-out (KO) allele and Sco2 E129K knock-in (KI) allele (orthologous
    to the human p.E140K); homozygous KI and compound heterozygous KI/KO animals
  publication: PMID:19837698
  description: >
    Allele-matched mouse models of the recurrent human SCO2 variant. Homozygous
    KO animals are embryonic lethal; homozygous KI and KI/KO animals are viable
    with muscle weakness, respiratory chain deficiency, Complex IV assembly
    defects across tissues, and reduced mitochondrial copper content.
  modeled_mechanisms:
  - target: SCO2 Loss and Defective Copper Delivery to COX
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >
      The viable KI and KI/KO genotypes reproduce the molecular lesion —
      Complex IV assembly failure with a selective reduction in mitochondrial
      copper content — in an allele-matched genetic background.
    limitations: >
      The null allele is embryonic lethal, so the human genotype range cannot be
      modeled across its full severity, and the viable allele-matched genotypes
      develop muscle weakness without the hypertrophic cardiomyopathy and fatal
      infantile course that define the human disease. See the
      HUMAN_MODEL_MISMATCH discussion.
    readouts:
    - name: Mitochondrial copper content
      target: SCO2 Loss and Defective Copper Delivery to COX
      direction: DECREASED
      interpretation: >
        Selective mitochondrial copper depletion without a fall in total tissue
        copper is the direct correlate of failed Sco2-mediated copper delivery.
      evidence:
      - reference: PMID:19837698
        reference_title: "Analysis of mouse models of cytochrome c oxidase deficiency owing to mutations in Sco2."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "There was a concomitant reduction in mitochondrial copper content, but the total amount of copper in examined tissues was not reduced."
        explanation: Reports the mitochondrial-copper measurement behind this readout.
    evidence:
    - reference: PMID:19837698
      reference_title: "Analysis of mouse models of cytochrome c oxidase deficiency owing to mutations in Sco2."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Whereas homozygous KO mice were embryonic lethals, homozygous KI and compound heterozygous KI/KO mice were viable, but had muscle weakness; biochemically, they had respiratory chain deficiencies as well as complex IV assembly defects in multiple tissues."
      explanation: Establishes that the allele-matched mouse reproduces the Complex IV assembly defect while diverging from the human phenotype.
treatments:
- name: Supportive and Metabolic Care
  description: >
    No curative therapy; supportive management of cardiomyopathy, lactic
    acidosis, and metabolic decompensation, including ventilatory and
    nutritional support.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Copper-Histidine Supplementation
  description: >
    Mechanism-based copper-histidine (Cu-his) supplementation, rationalized by
    the SCO2 copper-delivery defect. Addition of copper-histidine to the culture
    medium fully rescued COX activity in SCO2-deficient patient myoblasts, and
    subcutaneous Cu-his was the most likely explanation for resolution of severe
    hypertrophic cardiomyopathy in a single reported patient. Evidence remains
    in vitro plus a single case; benefit is presumed to require treatment before
    irreversible injury in post-mitotic tissue.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: copper-histidine
      term:
        id: CHEBI:29036
        label: copper(2+)
  target_mechanisms:
  - target: SCO2 Loss and Defective Copper Delivery to COX
    treatment_effect: BYPASSES
    description: >
      Exogenous copper-histidine bypasses or supplements the failing
      Sco2-dependent copper-delivery step, restoring COX activity in patient
      cells.
    evidence:
    - reference: PMID:11751685
      reference_title: "Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "COX activity in patient myoblasts was completely rescued by transduction with a retroviral vector expressing the human SCO2 coding sequence, and more interestingly by addition of copper-histidine (300 microM) to the culture medium."
      explanation: Direct in vitro demonstration that copper-histidine acts on the SCO2 copper-delivery lesion.
  evidence:
  - reference: PMID:11751685
    reference_title: "Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Whatever the mechanism, this result suggests a possible therapy for the early treatment of this fatal infantile disease."
    explanation: The authors propose early copper supplementation as a candidate therapy on the strength of the myoblast rescue.
  - reference: PMID:14970747
    reference_title: "Reversion of hypertrophic cardiomyopathy in a patient with deficiency of the mitochondrial copper binding protein Sco2: is there a potential effect of copper?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a patient with SCO 2 mutations and with resolution of severe hypertrophic cardiomyopathy."
    explanation: Single-patient report of cardiomyopathy resolution attributed to subcutaneous copper-histidine; anecdotal, hence PARTIAL.
- name: Genetic Counseling
  description: >
    Autosomal recessive inheritance carries a 25% recurrence risk for carrier
    parents; molecular confirmation of the familial SCO2 variants enables
    prenatal and preimplantation genetic diagnosis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:23407777
    reference_title: "Mitochondrial cardioencephalomyopathy due to a novel SCO2 mutation in a Brazilian patient: case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the accurate diagnosis of SCO2 mutations is particularly important for genetic counseling."
    explanation: Establishes molecular diagnosis of SCO2 as the basis for genetic counseling in affected families.
discussions:
- discussion_id: sco2_mouse_cardiac_phenotype_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - "pathophysiology#SCO2 Loss and Defective Copper Delivery to COX"
  - "pathophysiology#Impaired Terminal Electron Transfer and ATP Synthesis"
  prompt: >-
    Do the existing Sco2 mouse models reproduce the human hypertrophic
    cardiomyopathy and fatal infantile course, or does the model-human gap limit
    their use for preclinical testing of therapies such as copper-histidine?
  rationale: >-
    The mouse models are allele-matched and biochemically faithful yet
    phenotypically divergent, which is exactly the situation HUMAN_MODEL_MISMATCH
    is for: the evidence exists, but its translational validity is the open
    question. Constitutive Sco2 knockout mice are embryonic lethal, while the
    E129K knock-in (orthologous to the recurrent human p.E140K allele) and the
    compound KI/KO animals are viable and show respiratory chain deficiency,
    Complex IV assembly defects across tissues, and reduced mitochondrial copper
    content — but muscle weakness rather than the hypertrophic cardiomyopathy and
    infantile lethality that define the human disorder. The most genetically
    faithful models therefore fail to express the defining cardiac endpoint, so a
    therapeutic effect measured in them cannot be read directly as a prediction of
    cardiac benefit in patients. This matters concretely for copper-histidine,
    whose human support is one case report and whose in vitro support is a myoblast
    rescue.
  proposed_experiments:
  - experiment_id: exp_sco2_ipsc_cardiomyocyte_copper_rescue
    name: Copper-histidine rescue in SCO2 patient iPSC-derived cardiomyocytes
    description: >-
      Use patient-derived and isogenic-corrected SCO2-mutant iPSC-derived
      cardiomyocytes to test whether copper-histidine restores oxidative ATP
      production, sarcoplasmic-reticulum calcium handling, and inotropic
      responsiveness in the human cardiac cell type the mouse models fail to
      model, with genotype stratification across p.E140K and p.G193S.
    supporting_outcome:
    - Genotype-dependent restoration of ATP production and calcium handling would support copper delivery as the rate-limiting, druggable step in human cardiomyocytes.
    refuting_outcome:
    - Failure to rescue human cardiomyocytes despite rescue of patient myoblasts would indicate a cardiomyocyte-specific block downstream of copper availability.
  - experiment_id: exp_sco2_cardiac_stress_phenotyping_ki_mouse
    name: Cardiac stress phenotyping of viable Sco2 KI and KI/KO mice
    description: >-
      Subject homozygous E129K knock-in and compound KI/KO animals to defined
      hemodynamic or adrenergic stress and assess left ventricular wall thickness,
      diastolic function, and survival, to test whether the absent cardiomyopathy
      reflects a genuine species difference or an unstressed baseline.
    supporting_outcome:
    - Emergence of hypertrophy under stress would restore the model's usefulness for cardiac preclinical work, with load as a required cofactor.
    refuting_outcome:
    - A persistently normal heart under stress would confirm a species-level divergence in cardiac vulnerability to Sco2 deficiency.
  evidence:
  - reference: PMID:19837698
    reference_title: "Analysis of mouse models of cytochrome c oxidase deficiency owing to mutations in Sco2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Whereas homozygous KO mice were embryonic lethals, homozygous KI and compound heterozygous KI/KO mice were viable, but had muscle weakness; biochemically, they had respiratory chain deficiencies as well as complex IV assembly defects in multiple tissues."
    explanation: Documents that the allele-matched viable mouse genotypes show the biochemical lesion with myopathy rather than the human cardiomyopathy, defining the mismatch.
  - reference: PMID:29193756
    reference_title: "Investigating the cardiac pathology of SCO2-mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell-derived cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "To date, none of the recent pertaining reports provide deep understanding of the SCO2 disease pathophysiology."
    explanation: Motivates the human iPSC-cardiomyocyte route as the proposed resolution to the model gap.
notes: >
  Harvested content from PR #5064 (issue #5060), which proposed a separate
  gene-agnostic "Fatal Infantile Encephalocardiomyopathy" (MONDO:0015487) Disease
  entry. That umbrella is a MONDO disease_series_by_gene pattern parent and is
  already represented in this repository by the
  `Mitochondrial_Complex_IV_Deficiency` grouping, of which this entry is a
  member; the SCO2-specific evidence from that PR was moved here instead.

SCO2-Related Fatal Infantile Cardioencephalomyopathy

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