Dilated Cardiomyopathy 1GG

Mendelian MONDO:0013339 Pathograph 12 Show in embeddings browser Familial Dilated Cardiomyopathy Mitochondrial Disease

Dilated cardiomyopathy 1GG is the cardiac-restricted phenotype of biallelic SDHA deficiency: a recessive, neonatal-onset dilated cardiomyopathy in which the heart fails while the nervous system and skeletal muscle are clinically spared. SDHA encodes the flavoprotein (Fp) catalytic subunit of mitochondrial complex II (succinate:ubiquinone oxidoreductase), the only respiratory-chain complex encoded entirely in the nuclear genome and the only one that belongs simultaneously to the tricarboxylic acid cycle and the electron transport chain. The entity rests almost entirely on one report: fifteen patients from two large consanguineous Bedouin families, all homozygous for the same SDHA missense allele, presenting with dilated cardiomyopathy in the neonatal period or the first months of life. What makes this a disease worth curating separately is not a distinct lesion but a distinct distribution of one. The residual succinate dehydrogenase activity in these patients is severely reduced in cardiac muscle while substantial activity is retained in skeletal muscle and in lymphoblastoid cells - and the clinical picture follows the enzymology rather than the genotype, with psychomotor development appropriate for age and no seizures. That tissue restriction is also the entity's unexplained fact, and the reporting authors say so themselves. Every subunit of the complex II holoenzyme is nuclear-encoded, so there is no heteroplasmy to invoke; SDHB, SDHD and SDHAF1 were sequenced and carried no modifier. The mechanism of the allele itself is better understood than its tissue selectivity: the substituted residue sits in the domain through which the flavoprotein contacts the iron-sulfur subunit, and the assembled 130 kDa holoenzyme is lost to a greater degree than either individual subunit, which identifies the defect as a destabilised subunit interface rather than a null allele. The same homozygous allele has twice been published with non-cardiac phenotypes - a lethal infantile presentation and a relatively mild Leigh syndrome - with comparable enzyme activities and stability between patients. So the boundary between this disease and mitochondrial complex II deficiency, nuclear type 1 is not drawn by the variant, the zygosity, or the biochemistry. It is drawn by which organ failed, and nothing published explains why.

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1
Inheritance
6
Pathophys.
8
Phenotypes
4
Gaps
12
Pathograph
1
Genes
3
Medical Actions
3
Differentials
2
Models
12
References
1
Deep Research
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Classifications

Harrison's Part
CARDIOVASCULAR
Mechanistic Nosology
mitochondrial disease
ICIMD (Inherited Metabolic Disorders)
complex ii subunits and assembly factors
👪

Inheritance

1
Autosomal recessive HP:0000007
Homozygosity for a single SDHA missense allele, in two consanguineous kindreds from the same founder population. Heterozygous parents are unaffected, but so was one homozygote: the father of one patient carried two copies of the allele with a normal cardiac assessment, so inheritance is autosomal recessive with incomplete penetrance rather than fully penetrant recessive. The detail is curated on the genetic record.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
States the recessive inheritance and the consanguineous pedigree structure that establishes it.
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Discussions and Knowledge Gaps

4
Why is the succinate dehydrogenase deficit severe in myocardium and only partial in skeletal muscle and lymphoblastoid cells, when every subunit and assembly factor of complex II is nuclear-encoded and the causal allele is homozygous in every cell?
KNOWLEDGE GAP OPEN dcm1gg_cardiac_tissue_restriction
Attached to
pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity disease#Dilated Cardiomyopathy 1GG
This is the entity's defining unexplained fact, and the reporting authors raise it themselves rather than leaving it to a reader. The usual explanation for tissue-restricted respiratory-chain disease is heteroplasmy, and it is unavailable here: complex II is the only respiratory-chain complex encoded entirely in the nuclear genome, so gene dosage is identical in every tissue. The obvious alternative, a modifier in another complex II gene, was tested and excluded - SDHB, SDHD and SDHAF1 were sequenced and carried nothing. What remains untested is whether cardiac mitochondria assemble or degrade the destabilised holoenzyme differently, or whether the myocardium simply has the lowest tolerance for a given residual activity because of its continuous contractile demand. The question is not academic: it is the reason this disease is separable from mitochondrial complex II deficiency, nuclear type 1 at all, and answering it would determine whether the boundary between those two entities is mechanistic or merely descriptive.
Proposed experiments
Comparative complex II assembly and turnover across cardiac and skeletal muscle mitochondria
dcm1gg_tissue_assembly_comparison
Measure assembled complex II holoenzyme abundance, subunit steady-state levels and subunit turnover rate in cardiac versus skeletal muscle mitochondria carrying the homozygous p.Gly555Glu allele, to test whether the tissue difference lies in assembly efficiency or in degradation of the destabilised complex rather than in downstream tolerance.
Would support
pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
Would refute
pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
Supporting outcome
  • Assembled holoenzyme is disproportionately reduced in cardiac mitochondria relative to skeletal muscle at equal subunit expression, locating the tissue difference at assembly or turnover.
Refuting outcome
  • Assembly and turnover are equivalent between the two tissues, which would move the explanation downstream to differential tolerance of a shared enzymatic deficit and leave this node's framing as a tissue-level assembly phenomenon unsupported.
Why does one homozygous SDHA genotype, p.Gly555Glu, produce isolated neonatal dilated cardiomyopathy in two Bedouin kindreds, a lethal infantile multisystem presentation in one proband, and a relatively mild Leigh syndrome in another?
KNOWLEDGE GAP OPEN dcm1gg_one_genotype_three_phenotypes
Attached to
genetic#SDHA pathophysiology#SDHA p.Gly555Glu Homozygosity
Marked phenotypic heterogeneity is expected of heteroplasmic mitochondrial DNA mutations and is unusual for a nuclear allele, and the source that reports the Leigh presentation says exactly that. It also closes off the most obvious explanation: enzyme activities and enzyme stability were comparable between the patients with different phenotypes, so the divergence is not a matter of one patient having less residual complex II than another. That leaves unidentified genetic background, environmental or perinatal factors, or stochastic developmental effects, none of which has been investigated. This gap is the reason this entry cannot claim that its genotype is diagnostic of its phenotype, and it bears directly on the differential with mitochondrial complex II deficiency, nuclear type 1.
No in vivo model carries SDHA p.Gly555Glu, and the one cardiac complex II model that exists disables an assembly factor in a tissue chosen by the experimenter. What model would let the tissue selectivity of this disease be studied rather than assumed?
KNOWLEDGE GAP OPEN dcm1gg_no_animal_model
Attached to
pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity disease#Dilated Cardiomyopathy 1GG
No model of this disorder's allele exists, but the gap is narrower than "no model", and the distinction matters. A conditional cardiac knockout of Sdhaf4, the assembly factor that brings SDHA together with SDHB, is curated in this entry's animal models: it reproduces the SDHA-SDHB interface failure, the loss of assembled complex II, and progressive lethal dilated cardiomyopathy, and it is the model in which fumarate rescue was demonstrated. What it does not and cannot provide is the two things peculiar to this disease. It carries a null allele of a different gene rather than a hypomorphic missense substitution in the flavoprotein, so it cannot test whether an assembled but destabilised holoenzyme behaves the same way; and its cardiac restriction is imposed by the Cre driver rather than arising on its own, so it cannot address why a homozygous allele present in every cell disables the heart alone. Searches run on 2026-08-31 for Sdha knockout, knock-in, conditional-deletion and heterozygous mouse models, for Drosophila SdhA models, and for Caenorhabditis elegans complex II mutants returned no SDHA-subunit model of cardiomyopathy; the well-known nematode complex II mutant mev-1 is a cytochrome b (SDHC) allele, not an SDHA one, and the recently modelled SDHD H50R is a different subunit again. Beyond the Sdhaf4 mouse, the published functional work on this entity's allele is confined to patient material and to a human knockout cell line, both curated in this entry. Scarcity of models is a recognised field-wide obstacle for complex II disease rather than a gap peculiar to this disorder. The consequence here is specific: the tissue-restriction question above cannot be settled in patient tissue alone, because the cardiac samples that would be needed come only from autopsy.
Proposed experiments
Knock-in mouse carrying the orthologous Sdha Gly555Glu substitution
dcm1gg_sdha_g555e_knockin_mouse
Generate a homozygous knock-in of the residue-equivalent substitution and compare succinate dehydrogenase activity, assembled complex II abundance and contractile function across heart, skeletal muscle and brain, to test whether the tissue restriction reproduces outside the human founder background.
Would support
pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
Would refute
pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
Supporting outcome
  • Homozygous animals show a cardiac-predominant enzyme deficit and dilated cardiomyopathy with preserved neurological function, reproducing the human tissue distribution.
Refuting outcome
  • Homozygous animals show a uniform enzyme deficit across tissues, or an encephalopathic rather than cardiac phenotype, indicating that the tissue restriction depends on human-specific or founder-background factors rather than on the allele.
Show evidence (1 reference)
PMID:23174333 SUPPORT Other
"Further progress in understanding the role of complex II in disease, and in the development of new therapeutic approaches, is now being hampered by the lack of relevant cell and animal models."
Published confirmation that the absence of models is a recognised, field-wide obstacle for complex II disease rather than an artefact of this entry's searching. Graded OTHER because it is a review.
Complex II is the only respiratory-chain complex with a flavin cofactor, and riboflavin has been given to patients with complex II deficiency. Has it ever been tried in the cardiac-restricted form, and would it be expected to help an allele whose defect is a destabilised subunit interface rather than impaired flavinylation?
KNOWLEDGE GAP OPEN dcm1gg_riboflavin_untested
Attached to
treatments#Heart Failure Supportive Care pathophysiology#Destabilised Flavoprotein-Iron-Sulfur Subunit Interface
No treatment is curated for the enzyme defect in this entry because none is supported for it, and this discussion records why rather than leaving the omission unexplained. The evidence that exists is about complex II deficiency as a biochemical class, is weak, and points in both directions: a systematic review of riboflavin across inherited metabolic diseases classifies its effect in complex II deficiency as uncertain by an explicit threshold, meaning fewer than three-quarters of patients responded, while individual reports describe mild improvement on mitochondrial cocktails that include riboflavin. None of that evidence comes from a patient with this disorder. There is also a mechanistic reason for caution specific to this allele: the defect here is a destabilised interface between the flavoprotein and the iron-sulfur subunit, not a failure to acquire the flavin cofactor, so cofactor supplementation does not have an obvious target. Curating riboflavin as a treatment of this disease would assert an indication the literature does not support.
Show evidence (3 references)
PMID:42046426 SUPPORT Human Clinical
"The effect was uncertain in complex I and II deficiency, ethylmalonic encephalopathy, FAD synthase deficiency, glutaric aciduria type 1, L2 hydroxyglutaric aciduria, and MADD type 2."
The systematic review's verdict for the biochemical class this disorder belongs to. Graded HUMAN_CLINICAL because the review synthesises reported patient outcomes.
PMID:42046426 SUPPORT Human Clinical
"RF therapy was considered "effective" in an IMD if more than 75% of patients showed a positive response, "uncertain" in case of a positive response in fewer than 75% of patients"
Defines what the "uncertain" verdict means, so the finding above is not read as a stronger or weaker claim than it is.
PMID:37064335 SUPPORT Human Clinical
"some reported patients showed clinical improvement following riboflavin therapy"
The countervailing observation, stated as a review of reported cases within a case report. Cited for the treatment landscape of complex II deficiency; neither of this report's patients has this disorder.
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Pathophysiology

6
SDHA p.Gly555Glu Homozygosity
Homozygosity for SDHA c.1664G>A, which substitutes a small uncharged glycine at position 555 of the flavoprotein subunit with glutamic acid. The residue lies in the region through which the flavoprotein contacts the iron-sulfur subunit, and the substitution introduces a charged side chain into that interface. This is a missense, interface-destabilising allele rather than a null: residual enzyme activity is measurable in every tissue examined, which is why the functional impact is recorded as partial rather than complete loss of function.
SDHA hgnc:10680 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SDHA (hgnc:10680). hgnc:10680 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: VARIANT variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrion (GO:0005739). GO:0005739 is a cellular component from the Gene Ontology.
Downstream
Destabilised Flavoprotein-Iron-Sulfur Subunit Interface
Show evidence (2 references)
PMID:12794685 SUPPORT Human Clinical
"The c1664G-->A transition detected, predicted the substitution of the small uncharged glycine at position 555 by glutamic acid."
Defines the allele at nucleotide and protein level, which is what this node is.
PMID:20551992 SUPPORT Human Clinical
"we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
Establishes that this allele, in the homozygous state, is the cause of the cardiac phenotype curated here.
Destabilised Flavoprotein-Iron-Sulfur Subunit Interface
The molecular consequence of the substitution, and the step at which the published biochemistry is most direct. In the proband studied by immunochemistry, the amount of flavoprotein and of the iron-containing subunit were both reduced, and the assembled 130 kDa holoenzyme was reduced further still. A loss of assembled complex that exceeds the loss of its individual subunits is the signature of an interaction that has become labile rather than of a subunit that is absent, which is the basis for placing residue 555 in the interacting domain. An independent human cell system reaches the same conclusion by a different route. A clonal SDHA-knockout line into which SDHA missense variants are reintroduced singly, and in which succinate dehydrogenase activity is then measured directly, includes p.Gly555Glu in its panel; the variant scores at the low end of enzymatic activity and the authors attribute its effect to disruption of SDHA-SDHB binding. That per-variant result is a full-text derivation and is recorded as such in this entry's notes, not as a verified quotation.
mitochondrial respiratory chain complex II assembly GO:0034553 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial respiratory chain complex II assembly (GO:0034553). GO:0034553 is a biological process from the Gene Ontology. ↓ DECREASED
mitochondrial inner membrane GO:0005743 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrial inner membrane (GO:0005743). GO:0005743 is a cellular component from the Gene Ontology.
Experimental models
HAP1 SDHA-knockout cell line with single-variant reintroduction CELL LINE The system measures the enzymatic consequence of the single allele on a null background, isolating the variant's effect from genetic modifiers and from the patient's tissue context. It agrees with the independent immunochemical evidence from patient material that the lesion is at the SDHA-SDHB interface.
Animal models
Sdhaf4 conditional-null mouse Mouse partially recapitulates The model reproduces the molecular lesion at the level of the SDHA-SDHB interaction and its consequence, subunit degradation and loss of assembled complex II, which is what the human immunochemistry shows. It reaches that state by removing the assembly factor rather than by destabilising the interface from within the flavoprotein.
Downstream
Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
Show evidence (4 references)
PMID:12794685 SUPPORT In Vitro
"In this proband, CRM for flavoprotein as well as iron-containing protein (Ip) was decreased, CRM for the entire complex II (130 kDa) being reduced even more."
The measurement this node rests on - assembled holoenzyme lost disproportionately relative to its subunits. Graded IN_VITRO because it is an immunochemical quantification performed on patient material outside the organism, not a clinical observation.
PMID:12794685 SUPPORT In Vitro
"This observation prompts speculation of a labile interaction between Ip and Fp polypeptides and of a key role of the amino acid at position 555 in the interacting domain."
The authors' interpretation of that measurement, which is the mechanism this node asserts. Note the hedging in the source: it is offered as speculation prompted by the immunochemistry, and this entry does not state it more strongly than the source does.
PMID:7550341 SUPPORT Human Clinical
"Both patients were homozygous for an Arg554Trp substitution in the Fp subunit."
Independent evidence that the immediately adjacent residue is also disease-relevant when substituted, supporting the claim that this part of the flavoprotein is a functionally critical domain. Cited for the domain only - these patients had Leigh syndrome, not this disorder.
+ 1 more reference
Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
The node that distinguishes this disease from every other SDHA phenotype, and the one nothing published explains. The same homozygous allele, present in every cell, produces a severe deficit of succinate dehydrogenase activity in cardiac muscle while substantial activity persists in skeletal muscle and in lymphoblastoid cells. The measured residual activities - roughly 15-21% of control in heart against 50-56% in skeletal muscle and 60-63% in lymphoblastoid cells - are a full-text derivation recorded in this entry's notes; the cached abstract states the pattern qualitatively. Every explanation available for tissue-restricted respiratory-chain disease elsewhere is unavailable here. There is no heteroplasmy to invoke, because all four complex II subunits and both relevant assembly factors are nuclear-encoded and therefore present at the same dose in every tissue. The reporting authors sequenced SDHB, SDHD and SDHAF1 and found no modifier allele. What remains is a tissue-dependent difference in how much residual complex II a cell can tolerate, or in how efficiently the destabilised interface is assembled or degraded in cardiac mitochondria, and neither has been tested.
succinate dehydrogenase activity GO:0000104 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased succinate dehydrogenase activity (GO:0000104). GO:0000104 is a molecular function from the Gene Ontology. ↓ DECREASED
myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cardiomyocyte Bioenergetic Failure
Show evidence (1 reference)
PMID:20551992 SUPPORT In Vitro
"The cardiomyopathy is presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle, whereas substantial activity is retained in the skeletal muscle and lymphoblastoid cells."
The tissue-restriction claim this node makes, in the source's own words, including its own hedge ("presumably"). Graded IN_VITRO because the statement reports enzyme activities assayed in tissue and cell samples, which is what the sentence is about, even though the paper as a whole is a clinical genetics report.
Cardiomyocyte Bioenergetic Failure
Loss of complex II activity in the cardiomyocyte interrupts two coupled pathways at once, which is the specific consequence of the lesion sitting in this enzyme rather than in any other respiratory-chain complex. Succinate is no longer efficiently oxidised to fumarate, so tricarboxylic acid cycle flux is impaired; and the electrons that oxidation would have delivered no longer reach ubiquinone, so that entry point into the electron transport chain is lost. The result is a chronic shortfall in oxidative ATP supply in a tissue with continuous, non-negotiable contractile demand and little capacity to reduce it.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
tricarboxylic acid cycle GO:0006099 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased tricarboxylic acid cycle (GO:0006099). GO:0006099 is a biological process from the Gene Ontology. ↓ DECREASED mitochondrial electron transport, succinate to ubiquinone GO:0006121 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial electron transport, succinate to ubiquinone (GO:0006121). GO:0006121 is a biological process from the Gene Ontology. ↓ DECREASED oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Sdhaf4 conditional-null mouse Mouse rescues The model's rescue arms are the only in vivo evidence that the cardiac phenotype of complex II assembly failure is metabolically tractable: replacing the missing downstream metabolite with fumarate, or blocking the mitochondrial fission that the energetic deficit provokes, partially restores cardiac function and prolongs survival. This is recorded because it is the closest thing to a therapeutic lead this disease has, not because it has been tried in patients.
Downstream
Left Ventricular Dilatation and Systolic Dysfunction
Show evidence (2 references)
PMID:33162331 SUPPORT Other
"it oxidises succinate to fumarate in the tricarboxylic acid cycle and the electrons are used to reduce FAD to FADH2, ultimately reducing ubiquinone to ubiquinol in the respiratory chain"
Establishes the dual pathway membership that makes a single complex II lesion block both the TCA cycle and electron transport, which is the claim this node makes. Graded OTHER because it is a review statement of established biochemistry.
PMID:11692162 SUPPORT Other
"Complex II oxidizes succinate to fumarate in the Krebs cycle and is involved in the mitochondrial electron transport chain."
Independent statement of the same coupling from a second review. Graded OTHER for the same reason.
Left Ventricular Dilatation and Systolic Dysfunction
The structural and functional cardiac phenotype: chamber dilatation with impaired contraction, the defining morphology of dilated cardiomyopathy, arising here from a metabolic rather than a sarcomeric insult. In this cohort it is present from the neonatal period or the first months of life, and in one patient it was detected before birth.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Sdhaf4 conditional-null mouse Mouse recapitulates Cardiac complex II assembly failure produces the same structural and functional cardiac endpoint as the human disease: ventricular chamber dilation with reduced fractional shortening and impaired contraction, progressing to lethal heart failure.
Downstream
Congestive Heart Failure and Death in Infancy
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"the most frequent form is dilated cardiomyopathy (DCM), which is characterized by dilatation of the left or both ventricles and impaired systolic function"
Defines the structural phenotype this node asserts. The sentence is the paper's general definition of DCM rather than a measurement in this cohort, and is used only for the definition.
Congestive Heart Failure and Death in Infancy
The clinical endpoint. Presentation is with heart failure or cardiogenic shock in the neonatal period or the first months of life, and the majority of the reported cohort died of cardiac causes in infancy. Survivors reported exercise intolerance but had normal neuromuscular function and psychomotor development, which is the observation that makes this an isolated cardiomyopathy rather than a mitochondrial syndrome with a cardiac component.
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"This condition, unfortunately, is marked by high mortality, with two-thirds succumbing to cardiac failure."
The cohort's own mortality and its mode, which is what this node asserts. Replaces an earlier revision's use of the paper's general framing sentence about DCM.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dilated Cardiomyopathy 1GG 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

8
Cardiovascular 5
Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644), qualified as neonatal onset. HP:0001644 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (2 references)
PMID:20551992 SUPPORT Human Clinical
"we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
Names dilated cardiomyopathy as the phenotype of the whole reported cohort.
PMID:20551992 SUPPORT Human Clinical
"In all, 15 Bedouin patients of one tribe who presented with cardiomyopathy, between the ages of 32 weeks"
The cohort's own age range at presentation, beginning in utero, which is what the onset descriptor on this phenotype records.
Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"This condition, unfortunately, is marked by high mortality, with two-thirds succumbing to cardiac failure."
Cardiac failure as the clinical course in this cohort, rather than the paper's general framing sentence about dilated cardiomyopathy at large.
Death from cardiac failure FREQUENT Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"This condition, unfortunately, is marked by high mortality, with two-thirds succumbing to cardiac failure."
States the mortality rate and, specifically, that the mode of death is cardiac failure. This is the sentence that fixes the direction of the earlier overstatement.
Left ventricular noncompaction FREQUENT HP:0030682 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular noncompaction (HP:0030682). HP:0030682 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"Eight infants were diagnosed with LVNC."
The count this phenotype and its FREQUENT band rest on: eight of the fifteen enrolled patients, which is 53%.
Left ventricular hypertrophy OBLIGATE HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"The electrocardiogram of all patients was sinus rhythm with LV hypertrophy and normal QTC interval."
Reports the finding in all patients, which is the basis for the OBLIGATE frequency band, and simultaneously records the normal rhythm and QTc.
Metabolism 1
Increased circulating lactate concentration OCCASIONAL HP:0002151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating lactate concentration (HP:0002151). HP:0002151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"The laboratory indices were normal except for mildly increased lactate of 3.7 mmol/l."
The only abnormal laboratory finding reported, and its magnitude. The sentence also supports the description's point that everything else was normal.
Cellular 1
Decreased activity of mitochondrial complex II HP:0008314 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased activity of mitochondrial complex II (HP:0008314). HP:0008314 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20551992 SUPPORT In Vitro
"The cardiomyopathy is presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle, whereas substantial activity is retained in the skeletal muscle and lymphoblastoid cells."
Reports the enzyme deficiency and, critically, its tissue distribution. Graded IN_VITRO because the sentence reports enzyme activity measured in tissue and cell samples.
Other 1
Normal neuromuscular examination and psychomotor development OBLIGATE
No HP term is bound. This is the documented absence of a phenotype rather than a phenotypic abnormality, and HPO's phenotypic-abnormality branch has no term for "normal neuromuscular examination"; binding a normality to an abnormality term would invert the claim.
Show evidence (2 references)
PMID:20551992 SUPPORT Human Clinical
"During follow-up visits, the neuromuscular examinations remained normal and none of the patients had seizures."
Documents sustained absence of neurological involvement, which is the discriminating negative finding for this entity.
PMID:20551992 SUPPORT Human Clinical
"In two patients, a brain MRI was performed without any evidence of focal lesions in the basal ganglia or grey matter or cortex or brainstem, ruling out Leigh's syndrome."
The imaging that excludes the alternative SDHA phenotype in this cohort, in the source's own words.
🧬

Genetic Associations

1
SDHA
Gene: SDHA hgnc:10680 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SDHA (hgnc:10680). hgnc:10680 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (6 references)
PMID:20551992 SUPPORT Human Clinical
"we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
The gene-disease association this record asserts.
PMID:20551992 SUPPORT Human Clinical
"Notably, the same mutation was previously reported to cause a multisystemic failure leading to neonatal death and Leigh's syndrome."
The founding report itself records that the allele is shared with a different SDHA phenotype, which is the basis for the caveat in this record's description.
PMID:16798039 SUPPORT Human Clinical
"We report a patient with relatively mild Leigh syndrome and mitochondrial respiratory chain complex II deficiency caused by a homozygous G555E mutation in the nuclear encoded flavoprotein subunit of succinate dehydrogenase."
Independent documentation of the same homozygous allele producing Leigh syndrome rather than isolated cardiomyopathy. Cited for the allele's phenotypic range, not as a phenotype of this disorder.
+ 3 more references
🗃️

External Assertions

1
OMIM cardiomyopathy, dilated, 1GG record
OMIM disease record OMIM:613642
The OMIM record that MONDO:0013339 is anchored on. Its clinical and molecular content derives from the single 2010 report of the two Bedouin kindreds.
💊

Medical Actions

3
Heart Failure Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
There is no disease-specific therapy. Management is the supportive care of neonatal and infantile heart failure, directed at the congestive heart failure curated in this entry's phenotypes rather than at the enzyme defect. Its inclusion here reflects the clinical need the disorder creates, not a treatment shown to alter this disorder's course.
Target Phenotypes: Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37064335 SUPPORT Human Clinical
"There is no cure for complex II deficiency"
Establishes that no curative therapy exists for complex II deficiency, which is why management is supportive. Cited for the treatment landscape of the biochemical class; this report's own patients do not have this disorder.
Cardiac Transplantation
Action: Organ TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. NCIT:C15289
Platform: Surgery
The definitive intervention when medical management fails, and the reason the cohort's mortality is not simply inevitable. It is class-level management of paediatric dilated cardiomyopathy rather than a therapy shown to work in this genotype, and no transplant outcome has been reported for a p.Gly555Glu patient. The indication is the congestive heart failure curated in this entry's phenotypes. Note the mechanistic caveat that makes this reasonable rather than merely conventional: the enzyme defect is severe in myocardium and only partial elsewhere, so replacing the heart replaces the tissue in which the lesion actually matters.
Target Phenotypes: Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"DCM is the most frequent form of cardiomyopathy and the major cause of cardiac transplantation in children, accounting for >50% of all cardiac transplantations performed in patients between 1 and 10 years of age."
Establishes transplantation as the standard endpoint intervention for paediatric dilated cardiomyopathy, which is the class this disorder belongs to. Stated by this entity's own founding report, though as background rather than as a cohort result.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Both reported kindreds are consanguineous and share one founder allele, so carrier testing and reproductive counselling are directly actionable for the extended family and for the wider founder population. The indication is the autosomal recessive inheritance curated in this entry. Cascade testing of relatives needs one caveat stated up front, because the founding report ran into it: a homozygous result does not predict disease. The father of one patient carried two copies of the allele and was clinically normal, so an asymptomatic homozygous relative should be offered cardiac surveillance rather than a diagnosis.
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
The recessive inheritance in consanguineous kindreds that makes carrier counselling the actionable intervention for these families.
🔬

Biochemical Markers

1
Succinate dehydrogenase activity in cardiac muscle
Show evidence (1 reference)
PMID:20551992 SUPPORT In Vitro
"The cardiomyopathy is presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle, whereas substantial activity is retained in the skeletal muscle and lymphoblastoid cells."
The tissue-dependence of the assay result, which is what makes cardiac tissue the informative sample. Graded IN_VITRO as an enzyme assay on tissue samples.
🔬

Diagnosis

2
Molecular genetic testing of SDHA
Sequencing SDHA is the definitive test and, in a family from the founder population with a neonatal dilated cardiomyopathy, targeted testing for the c.1664G>A allele is the direct route. Because the same genotype occurs in patients with Leigh syndrome, a positive result establishes biallelic SDHA deficiency but does not by itself assign the patient to this disease rather than to mitochondrial complex II deficiency, nuclear type 1; that assignment rests on the clinical distribution.
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
Establishes SDHA genotyping as the test that identifies affected individuals.
Respiratory-chain enzymology on cardiac tissue
Measuring succinate dehydrogenase activity establishes the biochemical diagnosis, but the tissue chosen determines whether the defect is seen. Cardiac muscle shows the severe deficit; skeletal muscle and lymphoblastoid cells retain substantial activity, so a near-normal result in those tissues does not exclude the disorder.
Show evidence (1 reference)
PMID:20551992 SUPPORT In Vitro
"The cardiomyopathy is presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle, whereas substantial activity is retained in the skeletal muscle and lymphoblastoid cells."
The basis for the tissue-choice caveat that makes this a diagnostic pitfall. Graded IN_VITRO as an enzyme assay on tissue samples.
📊

Prevalence

1
Bedouin population of southern Israel
Cases In Literature Ultra Rare
No population prevalence estimate exists for this disorder and none is constructed here. The whole published experience is fifteen patients in two extended consanguineous Bedouin families sharing one founder allele, which is a case count in a single kindred set rather than a rate. `ULTRA_RARE` is used in preference to a numeric Orphanet band because no denominator has ever been reported; MONDO:0013339 carries no ORPHA cross-reference through which an Orphanet epidemiology class could be cited.
Show evidence (1 reference)
PMID:20551992 SUPPORT Human Clinical
"we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
The patient count and the founder-population context behind this record.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1GG:

Mitochondrial complex II deficiency, nuclear type 1 MONDO:0100294
Overlapping Features The primary differential and the genuinely hard one, curated separately in `kb/disorders/Mitochondrial_Complex_II_Deficiency_Nuclear_Type_1.yaml`. It is not a mimicking disease but the other phenotypic outcome of the same lesion, and unlike the boundary with NDAXOA it cannot be drawn by zygosity: both are biallelic, and the p.Gly555Glu allele this entry is built on has itself been reported homozygous in a lethal infantile presentation and in Leigh syndrome. The discriminator is which organ failed, and nothing published explains why it differs.
Distinguishing Features
  • Neurological involvement is the discriminator. MC2DN1 presents with Leigh syndrome, leukodystrophy, developmental regression or seizures; the DCM1GG cohort had psychomotor development appropriate for age and no seizures.
  • Zygosity does not separate them. Both are recessive and biallelic, and the same homozygous p.Gly555Glu genotype has been published in both phenotypes.
  • Where cardiomyopathy occurs in MC2DN1 it is accompanied by other organ involvement, such as the reported patient with cardiomyopathy and leukodystrophy; in DCM1GG the cardiac disease is isolated.
  • The tissue distribution of the enzyme deficit differs in kind: in DCM1GG the deficiency is severe in myocardium and partial elsewhere, whereas isolated complex II deficiency in MC2DN1 is characteristically demonstrable in skeletal muscle or fibroblasts.
Show evidence (2 references)
PMID:22972948 SUPPORT Human Clinical
"the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations"
Documents the combination that marks the other side of this boundary - cardiac disease accompanied by white-matter disease, in a patient with different SDHA alleles - against which this entry's isolated cardiac phenotype is defined.
PMID:16798039 SUPPORT Human Clinical
"This mutation has previously been reported in a lethal-infantile presentation of complex II deficiency."
Establishes that the allele underlying this entry has also produced non-cardiac disease, which is why the genotype cannot serve as the discriminator between these two entities.
Pheochromocytoma/paraganglioma syndrome 5 Not Yet Curated MONDO:0013602
Overlapping Features The fourth SDHA disease term, and the one that dominates an SDHA literature search while having no clinical overlap with this entity. It is included because the shared gene means a DCM1GG genotype result will be read by clinicians against a tumour surveillance background, not because the two present alike.
Distinguishing Features
  • PGL5 arises from single heterozygous germline alleles acting as tumour-suppressor first hits and requires a somatic second hit in the tumour; DCM1GG is a constitutive biallelic enzymatic deficit with no second hit.
  • The mechanisms diverge at succinate: in PGL5 its accumulation acts as an oncometabolite driving pseudohypoxia and epigenetic remodelling, whereas the pathogenic consequence curated here is bioenergetic failure in myocardium.
  • No tumour has been reported in the DCM1GG kindreds and no paraganglioma family has reported neonatal dilated cardiomyopathy.
Show evidence (2 references)
PMID:11692162 SUPPORT Other
"While mutations in SDHA display a phenotype resembling other mitochondrial and Krebs cycle gene defects, those in SDHB, SDHC and SDHD cause hereditary paraganglioma."
States the dichotomy this differential rests on, and specifically places SDHA on the mitochondrial-disease side of it. Graded OTHER because it is a review.
PMID:33162331 SUPPORT Other
"either susceptibility to cancer in the case of single, heterozygous germline variants, or a mitochondrial disease presentation, almost exclusively due to bi-allelic recessive variants"
Ties the two clinical outcomes of complex II defects to zygosity, which is the feature that separates this entity from the tumour syndrome.
🧫

Experimental Models

1
HAP1 SDHA-knockout cell line with single-variant reintroduction CELL_LINE
A clonal human SDHA-knockout line into which individual SDHA missense variants are reintroduced by site-specific recombination, after which succinate dehydrogenase activity and SDHA protein abundance are measured for each variant. It is the only published system in which this disorder's allele has been assayed in isolation in a human genetic background. The panel includes p.Gly555Glu, which scores at the low end of enzymatic activity, and the authors attribute its effect to disruption of SDHA-SDHB binding - a full-text derivation recorded in this entry's notes rather than a verified quotation, because the cached reference is abstract-only and names no individual variant.
Publication
PMID:39321216
Pathograph links
Destabilised Flavoprotein-Iron-Sulfur Subunit Interface measures fidelity: moderate The system measures the enzymatic consequence of the single allele on a null background, isolating the variant's effect from genetic modifiers and from the patient's tissue context. It agrees with the independent immunochemical evidence from patient material that the lesion is at the SDHA-SDHB interface.
Limitations: The study was designed to classify cancer-associated variants, not to model a cardiomyopathy, and HAP1 is a near-haploid chronic myelogenous leukaemia derivative rather than a cardiomyocyte - so it cannot address the tissue restriction that defines this disease, which is its central mechanistic question. The assay measures variant function on a knockout background at non-native expression, not the biology of a homozygous germline allele in myocardium. The authors themselves note that activity-score similarity between p.Gly555Glu and an unrelated cancer variant may reflect artefacts of this model system.
Show evidence (2 references)
PMID:39321216 SUPPORT In Vitro
"SDHA variants were introduced into a clonal SDHA-knockout cell line via Bxb1-mediated recombination. SDH activity and SDHA abundance were determined for each variant"
Describes the system and the measurement, which is what makes it informative for the interface node. Scoped to the abstract's account of the assay design; the inclusion of p.Gly555Glu in the panel is a full-text derivation and is not claimed by this snippet.
+ 1 more reference
🐁

Animal Models

1
Sdhaf4 conditional-null mouse GENETIC
The closest published in vivo model of the process this disease destroys, though not of its gene. Conditional deletion of Sdhaf4, the assembly factor that brings SDHA together with SDHB, suppresses complex II assembly in the heart and produces progressive dilated cardiomyopathy and lethal heart failure, with no mutant surviving beyond twelve weeks. Two independent Cre drivers give the same result, one muscle-directed and one tamoxifen-inducible and cardiomyocyte-specific, which establishes the phenotype as cardiomyocyte-autonomous rather than an artefact of one deletion strategy. Its relevance to this entry is specific and mechanistic rather than generic: loss of Sdhaf4 attenuates the SDHA-SDHB interaction and leads to subunit degradation, which is the same interface failure that the p.Gly555Glu substitution produces by a different route. The authors make the connection themselves, citing the human G555E cardiomyopathy report as the reason to expect complex II assembly to matter for cardiac homeostasis.
Species
Mouse
Genotype
Sdhaf4 fl/fl; Ckmm-Cre (muscle-directed) and Sdhaf4 fl/fl; Mer-CreMer (tamoxifen-inducible, cardiomyocyte-specific)
Background
Conditional knockout of the complex II assembly factor Sdhaf4
Genes
SDHAF4 hgnc:20957 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns SDHAF4 (hgnc:20957). hgnc:20957 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:35803927
Pathograph links
Destabilised Flavoprotein-Iron-Sulfur Subunit Interface partially recapitulates fidelity: moderate The model reproduces the molecular lesion at the level of the SDHA-SDHB interaction and its consequence, subunit degradation and loss of assembled complex II, which is what the human immunochemistry shows. It reaches that state by removing the assembly factor rather than by destabilising the interface from within the flavoprotein.
Limitations: The lesion is in a different gene. Sdhaf4 is an assembly factor, not a structural subunit, and the model is a conditional null rather than a hypomorphic missense allele, so residual complex II is likely lower and the failure mode is absence of assembly rather than instability of an assembled interface. Nothing in the model speaks to whether a p.Gly555Glu holoenzyme behaves the same way once assembled.
Readouts
Coimmunoprecipitation of SDHB with SDHA from cardiac left ventricle
Direction: DECREASED
Interpretation: Reduced recovery of SDHB with SDHA indicates that the interaction between the flavoprotein and the iron-sulfur subunit is weakened, which is the molecular event this node asserts.
Show evidence (1 reference)
PMID:35803927 SUPPORT Model Organism
"Immunoprecipitation assays using cardiac muscle tissues showed that abrogation of Sdhaf4 attenuated the interaction between SDHA and SDHB"
Reports the coimmunoprecipitation measurement behind this readout.
Show evidence (2 references)
PMID:35803927 SUPPORT Model Organism
"Cardiac loss of Sdhaf4 suppresses complex II assembly and results in subunit degradation and complex II deficiency in fetal mice."
Establishes that the model produces the assembly failure and subunit loss that make it informative for this node.
+ 1 more reference
Left Ventricular Dilatation and Systolic Dysfunction recapitulates fidelity: moderate Cardiac complex II assembly failure produces the same structural and functional cardiac endpoint as the human disease: ventricular chamber dilation with reduced fractional shortening and impaired contraction, progressing to lethal heart failure.
Limitations: The timing and the tissue distribution are both engineered rather than emergent. The human disease presents in the neonatal period and its cardiac restriction is unexplained, whereas in the mouse the restriction is imposed by the Cre driver, so the model cannot address the tissue-selectivity question that defines this disorder. Mouse disease also develops over weeks in the postnatal animal rather than in utero or in the first months, and the mutant hearts show hypertrophic and fibrotic remodelling with collagen deposition that has not been reported in patients with this disorder.
Readouts
Left ventricular fractional shortening by echocardiography
Direction: DECREASED
Interpretation: Reduced fractional shortening is the functional correlate of the systolic dysfunction this node asserts.
Show evidence (1 reference)
PMID:35803927 SUPPORT Model Organism
"a significant decrease in left ventricular fractional shortening (FS%) and deregulated cardiac contraction were detected in the mutants, indicating that the loss of Sdhaf4 impairs heart function"
Reports the echocardiographic measurement behind this readout.
Ventricular chamber dilation on gross morphology and histology
Direction: INCREASED
Interpretation: Progressive chamber dilation is the structural correlate of the dilated phenotype this node asserts.
Show evidence (1 reference)
PMID:35803927 SUPPORT Model Organism
"Dilation of the ventricular chambers was observed at later stages, suggesting that the loss of Sdhaf4 in muscle results in progressive cardiac remodeling and DCM"
Reports the morphological observation behind this readout.
Show evidence (1 reference)
PMID:35803927 SUPPORT Model Organism
"thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals"
States the cardiac endpoint that makes this model informative for the human structural phenotype.
Cardiomyocyte Bioenergetic Failure rescues fidelity: low The model's rescue arms are the only in vivo evidence that the cardiac phenotype of complex II assembly failure is metabolically tractable: replacing the missing downstream metabolite with fumarate, or blocking the mitochondrial fission that the energetic deficit provokes, partially restores cardiac function and prolongs survival. This is recorded because it is the closest thing to a therapeutic lead this disease has, not because it has been tried in patients.
Limitations: Fidelity is recorded as LOW because the rescue was performed in an assembly-factor knockout, not in an SDHA missense model, and never in a patient. Whether fumarate supplementation would benefit a p.Gly555Glu heart is untested, and the rescue is explicitly partial in the mouse. No treatment is curated in this entry on the strength of it.
Readouts
Cardiac function and lifespan after fumarate supplementation or fission inhibition
Direction: RESTORED
Interpretation: Partial functional recovery on metabolite replacement indicates that the bioenergetic deficit is a driver of the cardiac phenotype rather than a bystander.
Show evidence (1 reference)
PMID:35803927 SUPPORT Model Organism
"Targeting mitochondria via supplementation with fumarate or inhibiting mitochondrial fission improves mitochondrial dynamics, partially restores cardiac function and prolongs the lifespan of mutant mice."
Reports the rescue result behind this readout, including its own "partially" qualifier.
Show evidence (1 reference)
PMID:35803927 SUPPORT Model Organism
"These findings reveal a vital role for complex II assembly in the development of dilated cardiomyopathy and provide additional insights into therapeutic interventions for heart diseases."
The authors' own summary of why the rescue matters for complex II-driven dilated cardiomyopathy.
Notes
`genes:` records SDHAF4, the gene this model actually deletes, not SDHA, the gene of the disease it informs. That follows the convention in the rest of the KB - the ADGRG1 polymicrogyria entry carries a Col3a1-null mouse under `genes: Col3a1`, and Adams-Oliver Syndrome carries a conditional Rac1 deletion under `genes: RAC1` - and it keeps the field consistent with the `limitations` on the links below, which say the lesion is in a different gene. The connection to SDHA is the mechanism links themselves, not the gene binding.
{ }

Source YAML

click to show 
name: Dilated Cardiomyopathy 1GG
category: Mendelian
creation_date: "2026-08-31T11:20:00Z"
synonyms:
- CMD1GG
- cardiomyopathy, dilated, 1GG
- dilated cardiomyopathy type 1GG
- SDHA familial isolated dilated cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in SDHA
description: >-
  Dilated cardiomyopathy 1GG is the cardiac-restricted phenotype of biallelic SDHA
  deficiency: a recessive, neonatal-onset dilated cardiomyopathy in which the heart
  fails while the nervous system and skeletal muscle are clinically spared. SDHA
  encodes the flavoprotein (Fp) catalytic subunit of mitochondrial complex II
  (succinate:ubiquinone oxidoreductase), the only respiratory-chain complex encoded
  entirely in the nuclear genome and the only one that belongs simultaneously to the
  tricarboxylic acid cycle and the electron transport chain.

  The entity rests almost entirely on one report: fifteen patients from two large
  consanguineous Bedouin families, all homozygous for the same SDHA missense allele,
  presenting with dilated cardiomyopathy in the neonatal period or the first months
  of life. What makes this a disease worth curating separately is not a distinct
  lesion but a distinct distribution of one. The residual succinate dehydrogenase
  activity in these patients is severely reduced in cardiac muscle while substantial
  activity is retained in skeletal muscle and in lymphoblastoid cells - and the
  clinical picture follows the enzymology rather than the genotype, with psychomotor
  development appropriate for age and no seizures.

  That tissue restriction is also the entity's unexplained fact, and the reporting
  authors say so themselves. Every subunit of the complex II holoenzyme is
  nuclear-encoded, so there is no heteroplasmy to invoke; SDHB, SDHD and SDHAF1 were
  sequenced and carried no modifier. The mechanism of the allele itself is better
  understood than its tissue selectivity: the substituted residue sits in the domain
  through which the flavoprotein contacts the iron-sulfur subunit, and the assembled
  130 kDa holoenzyme is lost to a greater degree than either individual subunit, which
  identifies the defect as a destabilised subunit interface rather than a null allele.

  The same homozygous allele has twice been published with non-cardiac phenotypes -
  a lethal infantile presentation and a relatively mild Leigh syndrome - with
  comparable enzyme activities and stability between patients. So the boundary between
  this disease and mitochondrial complex II deficiency, nuclear type 1 is not drawn by
  the variant, the zygosity, or the biochemistry. It is drawn by which organ failed,
  and nothing published explains why.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
    notes: >-
      The defining and effectively the only morbidity is cardiac: neonatal dilated
      cardiomyopathy progressing to congestive heart failure and death, with
      psychomotor development appropriate for age and no seizures in the reported
      cohort. A NEUROLOGIC assignment is deliberately not made, because the absence
      of neurological involvement is precisely what separates this entity from the
      other recessive SDHA phenotype.
    evidence:
    - reference: PMID:20551992
      reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
      explanation: The founding report characterises the entity as an isolated dilated cardiomyopathy, which is the basis for a cardiovascular-only chapter assignment.
  mechanistic_category:
  - classification_value: mitochondrial disease
    notes: >-
      A nuclear-encoded oxidative-phosphorylation disorder. The mutated gene is
      nuclear but the failing organelle and the failing chemistry are mitochondrial.
  icimd_category:
  - classification_value: complex_ii_subunits_and_assembly_factors
    notes: >-
      ICIMD category 7, nuclear-encoded disorders of oxidative phosphorylation,
      subgroup complex II subunit and assembly-factor defects. SDHA encodes the
      catalytic flavoprotein subunit. As with the other SDHA entities, ICIMD does not
      separate this cardiac-restricted phenotype from the Leigh/leukodystrophy
      phenotype; both fall in the same ICIMD cell, which is why the MONDO-level split
      carries the distinction instead.
disease_term:
  preferred_term: dilated cardiomyopathy 1GG
  term:
    id: MONDO:0013339
    label: dilated cardiomyopathy 1GG
parents:
- Familial Dilated Cardiomyopathy
- Mitochondrial Disease
external_assertions:
- name: OMIM cardiomyopathy, dilated, 1GG record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:613642
  description: >-
    The OMIM record that MONDO:0013339 is anchored on. Its clinical and molecular
    content derives from the single 2010 report of the two Bedouin kindreds.
notes: >-
  Entity resolution. `MONDO:0013339` is bound here with the label "dilated
  cardiomyopathy 1GG" as recorded in `cache/mondo/terms.csv`. Its single MONDO parent
  is MONDO:0700335 (familial isolated dilated cardiomyopathy) and it carries
  `RO:0004003 hgnc:10680 ! SDHA`; both were verified with OAK on 2026-08-01 during
  curation of `kb/disorders/SDHA-Related_Neurodegeneration_With_Ataxia_And_Optic_Atrophy.yaml`
  and are recorded in that entry's notes. That same OAK query
  (`runoak relationships --direction down -p RO:0004003 HGNC:10680`) returned exactly
  four SDHA disease terms and no others: MONDO:0013339 this entry (OMIM:613642),
  MONDO:0013602 pheochromocytoma/paraganglioma syndrome 5 (OMIM:614165), MONDO:0031006
  neurodegeneration with ataxia and late-onset optic atrophy (OMIM:619259) and
  MONDO:0100294 mitochondrial complex II deficiency nuclear type 1 (OMIM:252011). The
  other three are curated below as differentials, mirroring the reciprocal differential
  that the NDAXOA entry already carries for this term. Those results are reused rather
  than re-derived.

  Named Entity Confusion preflight. The named risk for SDHA is not a different gene but
  a different SDHA disease, and it applies here more sharply than anywhere else in the
  gene's phenotype set, because the allele this entry is built on is shared with the
  disease next door. Every clinical source used here was checked for which phenotype its
  patients had, not merely for which gene was named. PMID:20551992 is the only source
  cited for the cardiac phenotype of this entity. PMID:12794685 and PMID:16798039 are
  cited only for what they establish about the p.Gly555Glu allele - its molecular
  consequence and its phenotypic range - and never as evidence for a DCM1GG phenotype;
  both of their probands had non-cardiac disease and belong to MONDO:0100294.
  PMID:37064335 is used only for the treatment landscape of complex II deficiency as a
  whole; its two probands carry different SDHA genotypes and one has Leigh syndrome, so
  it contributes nothing to this entity's phenotype. PMID:7550341 is cited for the
  conserved Fp domain and for the first demonstration that a nuclear gene defect causes
  respiratory-chain disease; its patients had Leigh syndrome and a different substitution
  (Arg554Trp). Specifically excluded as off-entity: PMID:42325549 (SDHA downregulation as
  a candidate target in acquired ischemic heart disease) and PMID:41647802 (an SDHA
  variant of uncertain significance reported incidentally in MYBPC3-related hypertrophic
  cardiomyopathy) are not this disorder and are not cited anywhere in this entry.

  Provenance limits on statements not taken from a cached abstract. Three facts used in
  the prose of this entry are full-text derivations and are not snippet-verified.
  (i) No longer applies. `references_cache/PMID_20551992.md` was initially cached
  abstract-only, and an earlier revision of this entry scoped every snippet from it to the
  abstract's qualitative statements. Re-fetching it with `just fetch-reference` on
  2026-08-31 returned `content_type: full_text_html`, so the residual activity figures,
  the LVNC count, the normal neurological findings and the unaffected homozygous father
  are all quoted directly from the cache and verified. The one figure not carried over is
  the lymphoblastoid residual activity range, which is in the paper's tables rather than
  its running text; the entry quotes the cardiac and skeletal-muscle figures the text
  states (15-18% and 50-60%) and does not assert the third. Per-patient tabulated details
  that appear only in Table 1 - the individual counts for respiratory distress, mitral
  valve insufficiency and exercise intolerance - remain outside the cached text and are
  deliberately not curated as phenotypes.
  (ii) That the 2020 compendium tabulates seventeen homozygous p.(Gly555Glu) cases, of
  which fifteen are the Bedouin families, and that it describes the Leigh-SDHA
  association as blurred by cardiomyopathy reports, were read from the full text of
  PMC7758838 on 2026-08-31; `references_cache/PMID_33162331.md` is abstract-only and
  reports only the whole-complex-II totals (61 patients, 32 variants across four genes).
  (iii) That the HAP1 SDHA-knockout variant panel includes p.Gly555Glu, with a low
  measured activity score and an authors' interpretation that the substitution disrupts
  SDHA-SDHB binding, was read from the full text of PMC11611653 on 2026-08-31;
  `references_cache/PMID_39321216.md` is abstract-only and names no individual variant,
  so snippets from it are scoped to its aggregate design and results, exactly as the
  NDAXOA entry scopes the same reference.

  GeneReviews. No GeneReviews chapter exists for this entity or for SDHA. Searched
  2026-08-31: PubMed `SDHA[Book] OR SDHA[Title] AND GeneReviews[Book]` and
  `complex II deficiency GeneReviews[Book]` both returned zero records, while the same
  `[Book]` field returned PMID:20301715 (Hereditary Paraganglioma-Pheochromocytoma
  Syndromes) on an adjacent query, which confirms the field was resolving rather than
  silently failing. The generic `Dilated Cardiomyopathy Overview` chapter
  (PMID:20301486), cited by fourteen sibling DCM entries, was read and not used: its
  cached content is a purpose statement with no finding attributable to this entity, and
  quoting it would produce a title-like snippet rather than evidence.

  Coverage overlap that this entry does not resolve.
  `kb/disorders/Mitochondrial_Complex_II_Deficiency_Nuclear_Type_1.yaml` already cites
  PMID:20551992 under a `Cardiomyopathy` phenotype node, so the fifteen Bedouin patients
  are currently claimed by MONDO:0100294 as well as by the MONDO:0013339 term OMIM
  assigns them. That file was read and deliberately not modified: deciding whether the
  cardiac cohort should be withdrawn from the complex II deficiency entry is a change to
  a curated entry that belongs in its own pull request, not a side effect of adding this
  one. The overlap is real and is recorded here rather than papered over.

  Ontology and module decisions taken deliberately. No `conforms_to` declaration is
  made on any pathophysiology node. Conformance to
  `cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling` was considered and
  declined because that module node expects cardiac fibroblast activation, extracellular
  matrix deposition and cardiomyocyte apoptosis, none of which has been reported in
  patients with this disorder - the fibrotic remodelling seen in the Sdhaf4 mouse curated
  below is a mouse of a different gene and is recorded as a limitation there; conformance to
  `cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult` was declined
  because that node expects abnormal sarcomere organization, which is likewise not
  reported here. Declaring conformance without the expected content would assert
  mechanism this entry cannot support. An earlier revision of this note said that left
  ventricular noncompaction, listed among the clinical features of this concept in MedGen,
  was not stated in the founding report. That was wrong: eight of the fifteen patients were
  diagnosed with LVNC, and it is now curated as a FREQUENT phenotype bound to HP:0030682.
  (HP:0031689 is not a member of the PhenotypeTerm enum cache and is not used.) A ClinGen gene-disease validity row would be a
  strong nosology citation here, but `just clingen-refresh` currently fails with a
  sha256 mismatch against the snapshot pinned in `data/clingen/MANIFEST.yaml`
  (2026-08-13), so no `CGGV:` reference could be generated for this entry without
  bumping that pin and rebuilding unrelated cache files.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygosity for a single SDHA missense allele, in two consanguineous kindreds from
    the same founder population. Heterozygous parents are unaffected, but so was one
    homozygote: the father of one patient carried two copies of the allele with a normal
    cardiac assessment, so inheritance is autosomal recessive with incomplete penetrance
    rather than fully penetrant recessive. The detail is curated on the genetic record.
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
    explanation: States the recessive inheritance and the consanguineous pedigree structure that establishes it.
prevalence:
- population: Bedouin population of southern Israel
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate exists for this disorder and none is constructed
    here. The whole published experience is fifteen patients in two extended
    consanguineous Bedouin families sharing one founder allele, which is a case count in
    a single kindred set rather than a rate. `ULTRA_RARE` is used in preference to a
    numeric Orphanet band because no denominator has ever been reported; MONDO:0013339
    carries no ORPHA cross-reference through which an Orphanet epidemiology class could
    be cited.
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
    explanation: The patient count and the founder-population context behind this record.
pathophysiology:
- name: SDHA p.Gly555Glu Homozygosity
  description: >-
    Homozygosity for SDHA c.1664G>A, which substitutes a small uncharged glycine at
    position 555 of the flavoprotein subunit with glutamic acid. The residue lies in the
    region through which the flavoprotein contacts the iron-sulfur subunit, and the
    substitution introduces a charged side chain into that interface. This is a
    missense, interface-destabilising allele rather than a null: residual enzyme activity
    is measurable in every tissue examined, which is why the functional impact is
    recorded as partial rather than complete loss of function.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SDHA
    term:
      id: hgnc:10680
      label: SDHA
  genetic_context:
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    allele_type: VARIANT
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  downstream:
  - target: Destabilised Flavoprotein-Iron-Sulfur Subunit Interface
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:12794685
    reference_title: "Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The c1664G-->A transition detected, predicted the substitution of the small uncharged glycine at position 555 by glutamic acid."
    explanation: Defines the allele at nucleotide and protein level, which is what this node is.
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
    explanation: Establishes that this allele, in the homozygous state, is the cause of the cardiac phenotype curated here.
- name: Destabilised Flavoprotein-Iron-Sulfur Subunit Interface
  description: >-
    The molecular consequence of the substitution, and the step at which the published
    biochemistry is most direct. In the proband studied by immunochemistry, the amount
    of flavoprotein and of the iron-containing subunit were both reduced, and the
    assembled 130 kDa holoenzyme was reduced further still. A loss of assembled complex
    that exceeds the loss of its individual subunits is the signature of an interaction
    that has become labile rather than of a subunit that is absent, which is the basis
    for placing residue 555 in the interacting domain.

    An independent human cell system reaches the same conclusion by a different route.
    A clonal SDHA-knockout line into which SDHA missense variants are reintroduced
    singly, and in which succinate dehydrogenase activity is then measured directly,
    includes p.Gly555Glu in its panel; the variant scores at the low end of enzymatic
    activity and the authors attribute its effect to disruption of SDHA-SDHB binding.
    That per-variant result is a full-text derivation and is recorded as such in this
    entry's notes, not as a verified quotation.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex II assembly
    modifier: DECREASED
    term:
      id: GO:0034553
      label: mitochondrial respiratory chain complex II assembly
  cellular_components:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  downstream:
  - target: Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:12794685
    reference_title: "Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In this proband, CRM for flavoprotein as well as iron-containing protein (Ip) was decreased, CRM for the entire complex II (130 kDa) being reduced even more."
    explanation: >-
      The measurement this node rests on - assembled holoenzyme lost disproportionately
      relative to its subunits. Graded IN_VITRO because it is an immunochemical
      quantification performed on patient material outside the organism, not a clinical
      observation.
  - reference: PMID:12794685
    reference_title: "Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This observation prompts speculation of a labile interaction between Ip and Fp polypeptides and of a key role of the amino acid at position 555 in the interacting domain."
    explanation: >-
      The authors' interpretation of that measurement, which is the mechanism this node
      asserts. Note the hedging in the source: it is offered as speculation prompted by
      the immunochemistry, and this entry does not state it more strongly than the source
      does.
  - reference: PMID:7550341
    reference_title: "Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients were homozygous for an Arg554Trp substitution in the Fp subunit."
    explanation: >-
      Independent evidence that the immediately adjacent residue is also disease-relevant
      when substituted, supporting the claim that this part of the flavoprotein is a
      functionally critical domain. Cited for the domain only - these patients had Leigh
      syndrome, not this disorder.
  - reference: PMID:33162331
    reference_title: "The genetic basis of isolated mitochondrial complex II deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the missense variants that do occur tend to induce substitutions at highly conserved residues in regions of the proteins that are critical for binding to other subunits or substrates"
    explanation: >-
      Places this allele in the general pattern the compendium reports for complex II
      missense variants, which is exactly the interface-disruption mechanism this node
      describes. Graded OTHER because it is a literature compendium rather than primary
      data.
- name: Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
  description: >-
    The node that distinguishes this disease from every other SDHA phenotype, and the
    one nothing published explains. The same homozygous allele, present in every cell,
    produces a severe deficit of succinate dehydrogenase activity in cardiac muscle
    while substantial activity persists in skeletal muscle and in lymphoblastoid cells.
    The measured residual activities - roughly 15-21% of control in heart against
    50-56% in skeletal muscle and 60-63% in lymphoblastoid cells - are a full-text
    derivation recorded in this entry's notes; the cached abstract states the pattern
    qualitatively.

    Every explanation available for tissue-restricted respiratory-chain disease
    elsewhere is unavailable here. There is no heteroplasmy to invoke, because all four
    complex II subunits and both relevant assembly factors are nuclear-encoded and
    therefore present at the same dose in every tissue. The reporting authors sequenced
    SDHB, SDHD and SDHAF1 and found no modifier allele. What remains is a
    tissue-dependent difference in how much residual complex II a cell can tolerate, or
    in how efficiently the destabilised interface is assembled or degraded in cardiac
    mitochondria, and neither has been tested.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: succinate dehydrogenase activity
    modifier: DECREASED
    term:
      id: GO:0000104
      label: succinate dehydrogenase activity
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  downstream:
  - target: Cardiomyocyte Bioenergetic Failure
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The cardiomyopathy is presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle, whereas substantial activity is retained in the skeletal muscle and lymphoblastoid cells."
    explanation: >-
      The tissue-restriction claim this node makes, in the source's own words, including
      its own hedge ("presumably"). Graded IN_VITRO because the statement reports enzyme
      activities assayed in tissue and cell samples, which is what the sentence is about,
      even though the paper as a whole is a clinical genetics report.
- name: Cardiomyocyte Bioenergetic Failure
  description: >-
    Loss of complex II activity in the cardiomyocyte interrupts two coupled pathways at
    once, which is the specific consequence of the lesion sitting in this enzyme rather
    than in any other respiratory-chain complex. Succinate is no longer efficiently
    oxidised to fumarate, so tricarboxylic acid cycle flux is impaired; and the electrons
    that oxidation would have delivered no longer reach ubiquinone, so that entry point
    into the electron transport chain is lost. The result is a chronic shortfall in
    oxidative ATP supply in a tissue with continuous, non-negotiable contractile demand
    and little capacity to reduce it.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: tricarboxylic acid cycle
    modifier: DECREASED
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
  - preferred_term: "mitochondrial electron transport, succinate to ubiquinone"
    modifier: DECREASED
    term:
      id: GO:0006121
      label: "mitochondrial electron transport, succinate to ubiquinone"
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  downstream:
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33162331
    reference_title: "The genetic basis of isolated mitochondrial complex II deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "it oxidises succinate to fumarate in the tricarboxylic acid cycle and the electrons are used to reduce FAD to FADH2, ultimately reducing ubiquinone to ubiquinol in the respiratory chain"
    explanation: >-
      Establishes the dual pathway membership that makes a single complex II lesion block
      both the TCA cycle and electron transport, which is the claim this node makes.
      Graded OTHER because it is a review statement of established biochemistry.
  - reference: PMID:11692162
    reference_title: "Phenotypic dichotomy in mitochondrial complex II genetic disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Complex II oxidizes succinate to fumarate in the Krebs cycle and is involved in the mitochondrial electron transport chain."
    explanation: >-
      Independent statement of the same coupling from a second review. Graded OTHER for
      the same reason.
- name: Left Ventricular Dilatation and Systolic Dysfunction
  description: >-
    The structural and functional cardiac phenotype: chamber dilatation with impaired
    contraction, the defining morphology of dilated cardiomyopathy, arising here from a
    metabolic rather than a sarcomeric insult. In this cohort it is present from the
    neonatal period or the first months of life, and in one patient it was detected
    before birth.
  biological_scale: TISSUE
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  downstream:
  - target: Congestive Heart Failure and Death in Infancy
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most frequent form is dilated cardiomyopathy (DCM), which is characterized by dilatation of the left or both ventricles and impaired systolic function"
    explanation: >-
      Defines the structural phenotype this node asserts. The sentence is the paper's
      general definition of DCM rather than a measurement in this cohort, and is used
      only for the definition.
- name: Congestive Heart Failure and Death in Infancy
  description: >-
    The clinical endpoint. Presentation is with heart failure or cardiogenic shock in
    the neonatal period or the first months of life, and the majority of the reported
    cohort died of cardiac causes in infancy. Survivors reported exercise intolerance
    but had normal neuromuscular function and psychomotor development, which is the
    observation that makes this an isolated cardiomyopathy rather than a mitochondrial
    syndrome with a cardiac component.
  biological_scale: ORGANISM
  downstream: []
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This condition, unfortunately, is marked by high mortality, with two-thirds succumbing to cardiac failure."
    explanation: >-
      The cohort's own mortality and its mode, which is what this node asserts. Replaces
      an earlier revision's use of the paper's general framing sentence about DCM.
phenotypes:
- category: Cardiovascular
  name: Dilated cardiomyopathy
  description: >-
    The defining feature, present in every reported patient, with onset in the neonatal
    period or the first months of life.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    onset:
      onset_category: NEONATAL
      notes: >-
        Onset is neonatal or within the first months of life, and in one patient the
        cardiomyopathy was detected in utero. This timing is what separates the entity
        from adult-onset familial dilated cardiomyopathy. Recorded as a structured onset
        descriptor rather than as a separate HP:0003623 phenotype, because onset terms
        are not members of the PhenotypeTerm enum.
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
    explanation: Names dilated cardiomyopathy as the phenotype of the whole reported cohort.
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all, 15 Bedouin patients of one tribe who presented with cardiomyopathy, between the ages of 32 weeks"
    explanation: >-
      The cohort's own age range at presentation, beginning in utero, which is what the
      onset descriptor on this phenotype records.
- category: Cardiovascular
  name: Congestive heart failure
  description: >-
    Presentation is with heart failure or cardiogenic shock, and heart failure was the
    cause of death in the patients who died.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This condition, unfortunately, is marked by high mortality, with two-thirds succumbing to cardiac failure."
    explanation: >-
      Cardiac failure as the clinical course in this cohort, rather than the paper's
      general framing sentence about dilated cardiomyopathy at large.
- category: Cardiovascular
  name: Death from cardiac failure
  description: >-
    Mortality is high and the mode of death is heart failure, not arrhythmia. Two-thirds
    of the cohort died of cardiac failure; a single sudden death is recorded in the
    patient table. An earlier revision of this entry described sudden cardiac death as
    the outcome in the majority, which the source does not support and which is corrected
    here.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This condition, unfortunately, is marked by high mortality, with two-thirds succumbing to cardiac failure."
    explanation: >-
      States the mortality rate and, specifically, that the mode of death is cardiac
      failure. This is the sentence that fixes the direction of the earlier overstatement.
- category: Metabolic
  name: Decreased activity of mitochondrial complex II
  description: >-
    Reduced succinate dehydrogenase activity is demonstrable on assay, but severely so
    only in cardiac muscle; skeletal muscle and lymphoblastoid cells retain substantial
    activity. A normal skeletal-muscle result therefore does not exclude the diagnosis,
    which is the practical consequence of the tissue restriction.
  phenotype_term:
    preferred_term: Decreased activity of mitochondrial complex II
    term:
      id: HP:0008314
      label: Decreased activity of mitochondrial complex II
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The cardiomyopathy is presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle, whereas substantial activity is retained in the skeletal muscle and lymphoblastoid cells."
    explanation: >-
      Reports the enzyme deficiency and, critically, its tissue distribution. Graded
      IN_VITRO because the sentence reports enzyme activity measured in tissue and cell
      samples.
- category: Cardiovascular
  name: Left ventricular noncompaction
  description: >-
    Eight of the fifteen patients met echocardiographic criteria for left ventricular
    noncompaction, so it is a common accompaniment of the dilated phenotype in this cohort
    rather than an incidental finding.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Left ventricular noncompaction
    term:
      id: HP:0030682
      label: Left ventricular noncompaction
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight infants were diagnosed with LVNC."
    explanation: >-
      The count this phenotype and its FREQUENT band rest on: eight of the fifteen
      enrolled patients, which is 53%.
- category: Cardiovascular
  name: Left ventricular hypertrophy
  description: >-
    Electrocardiography showed left ventricular hypertrophy in every patient, with a
    normal corrected QT interval and sinus rhythm - so the electrical phenotype is one of
    chamber overload rather than of a primary arrhythmia syndrome.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The electrocardiogram of all patients was sinus rhythm with LV hypertrophy and normal QTC interval."
    explanation: >-
      Reports the finding in all patients, which is the basis for the OBLIGATE frequency
      band, and simultaneously records the normal rhythm and QTc.
- category: Metabolic
  name: Increased circulating lactate concentration
  description: >-
    Lactate was mildly elevated at 3.7 mmol/l, and was the only abnormal laboratory index
    reported. The mildness matters clinically: this is not the marked lactic acidosis that
    would point towards Leigh syndrome, and its absence should not be taken to exclude the
    diagnosis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The laboratory indices were normal except for mildly increased lactate of 3.7 mmol/l."
    explanation: >-
      The only abnormal laboratory finding reported, and its magnitude. The sentence also
      supports the description's point that everything else was normal.
- category: Neurologic
  name: Normal neuromuscular examination and psychomotor development
  description: >-
    Recorded as a phenotype because its absence is what defines the entity. Growth,
    neuromuscular examination and psychomotor development were normal at presentation and
    remained normal on follow-up, no patient had seizures, and brain MRI in two patients
    showed no basal ganglia or cortical lesions, explicitly ruling out Leigh syndrome.
    This is the observation that separates DCM1GG from mitochondrial complex II
    deficiency, nuclear type 1 in a patient carrying the same allele.
  frequency: OBLIGATE
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During follow-up visits, the neuromuscular examinations remained normal and none of the patients had seizures."
    explanation: >-
      Documents sustained absence of neurological involvement, which is the discriminating
      negative finding for this entity.
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two patients, a brain MRI was performed without any evidence of focal lesions in the basal ganglia or grey matter or cortex or brainstem, ruling out Leigh's syndrome."
    explanation: >-
      The imaging that excludes the alternative SDHA phenotype in this cohort, in the
      source's own words.
  notes: >-
    No HP term is bound. This is the documented absence of a phenotype rather than a
    phenotypic abnormality, and HPO's phenotypic-abnormality branch has no term for
    "normal neuromuscular examination"; binding a normality to an abnormality term would
    invert the claim.
genetic:
- name: SDHA
  notes: >-
    The only gene implicated in this disorder. All fifteen reported patients are
    homozygous for the same missense allele, c.1664G>A p.(Gly555Glu), inherited within
    two consanguineous kindreds from one founder population. The allele is not private
    to this phenotype: the same homozygous genotype has been reported in a lethal
    infantile presentation and in a relatively mild Leigh syndrome, which is why the
    genotype cannot be used to assign a patient to this disease rather than to
    mitochondrial complex II deficiency, nuclear type 1.

    Penetrance is incomplete, and the exception was found inside the reported kindred
    rather than inferred. The father of one patient proved to be homozygous for the same
    allele while being clinically unaffected, with a normal physical assessment,
    electrocardiogram and echocardiogram. His complex II enzymatic activity in
    lymphoblastoid cells was reduced by 42%, closer to the patients than to the
    heterozygous mother or to controls. So neither the genotype nor the measurable enzyme
    deficit in an accessible tissue is sufficient for disease, and the counselling
    consequence is direct: a homozygous result in an asymptomatic relative does not
    predict cardiomyopathy.
  gene_term:
    preferred_term: SDHA
    term:
      id: hgnc:10680
      label: SDHA
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
    explanation: The gene-disease association this record asserts.
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, the same mutation was previously reported to cause a multisystemic failure leading to neonatal death and Leigh's syndrome."
    explanation: >-
      The founding report itself records that the allele is shared with a different SDHA
      phenotype, which is the basis for the caveat in this record's description.
  - reference: PMID:16798039
    reference_title: "Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a patient with relatively mild Leigh syndrome and mitochondrial respiratory chain complex II deficiency caused by a homozygous G555E mutation in the nuclear encoded flavoprotein subunit of succinate dehydrogenase."
    explanation: >-
      Independent documentation of the same homozygous allele producing Leigh syndrome
      rather than isolated cardiomyopathy. Cited for the allele's phenotypic range, not
      as a phenotype of this disorder.
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our surprise, the father of patient A2 was homozygous for the mutation."
    explanation: >-
      The penetrance finding. A homozygote in the same kindred was ascertained as an
      unaffected parent, so homozygosity for this allele is not sufficient for disease.
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His physical assessment was negative for any symptoms or other suspicious factors."
    explanation: >-
      Confirms the homozygous father was clinically unaffected on examination, which is
      what makes this reduced penetrance rather than an unrecognised mild case.
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The enzymatic activity of the father's complex was decreased by 42%, being more similar to that of the patients compared with the heterozygous mother and controls"
    explanation: >-
      The decisive part of the penetrance finding: the unaffected homozygote's enzyme
      deficit resembles the patients', not the carriers', so residual complex II activity
      in an accessible tissue does not predict who becomes ill. Graded IN_VITRO because it
      is an enzyme assay on lymphoblastoid cells.
biochemical:
- name: Succinate dehydrogenase activity in cardiac muscle
  notes: >-
    Respiratory-chain enzymology on cardiac tissue is the assay that demonstrates the
    lesion in this disorder, and it is the only tissue in which the deficit is severe.
    Assays on skeletal muscle or on cultured blood-derived cells retain substantial
    activity and can therefore be misleadingly close to normal.
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The cardiomyopathy is presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle, whereas substantial activity is retained in the skeletal muscle and lymphoblastoid cells."
    explanation: >-
      The tissue-dependence of the assay result, which is what makes cardiac tissue the
      informative sample. Graded IN_VITRO as an enzyme assay on tissue samples.
diagnosis:
- name: Molecular genetic testing of SDHA
  description: >-
    Sequencing SDHA is the definitive test and, in a family from the founder population
    with a neonatal dilated cardiomyopathy, targeted testing for the c.1664G>A allele is
    the direct route. Because the same genotype occurs in patients with Leigh syndrome,
    a positive result establishes biallelic SDHA deficiency but does not by itself
    assign the patient to this disease rather than to mitochondrial complex II
    deficiency, nuclear type 1; that assignment rests on the clinical distribution.
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
    explanation: Establishes SDHA genotyping as the test that identifies affected individuals.
- name: Respiratory-chain enzymology on cardiac tissue
  description: >-
    Measuring succinate dehydrogenase activity establishes the biochemical diagnosis,
    but the tissue chosen determines whether the defect is seen. Cardiac muscle shows the
    severe deficit; skeletal muscle and lymphoblastoid cells retain substantial activity,
    so a near-normal result in those tissues does not exclude the disorder.
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The cardiomyopathy is presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle, whereas substantial activity is retained in the skeletal muscle and lymphoblastoid cells."
    explanation: >-
      The basis for the tissue-choice caveat that makes this a diagnostic pitfall.
      Graded IN_VITRO as an enzyme assay on tissue samples.
treatments:
- name: Heart Failure Supportive Care
  description: >-
    There is no disease-specific therapy. Management is the supportive care of neonatal
    and infantile heart failure, directed at the congestive heart failure curated in this
    entry's phenotypes rather than at the enzyme defect. Its inclusion here reflects the
    clinical need the disorder creates, not a treatment shown to alter this disorder's
    course.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:37064335
    reference_title: "Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no cure for complex II deficiency"
    explanation: >-
      Establishes that no curative therapy exists for complex II deficiency, which is why
      management is supportive. Cited for the treatment landscape of the biochemical
      class; this report's own patients do not have this disorder.
- name: Cardiac Transplantation
  description: >-
    The definitive intervention when medical management fails, and the reason the cohort's
    mortality is not simply inevitable. It is class-level management of paediatric dilated
    cardiomyopathy rather than a therapy shown to work in this genotype, and no transplant
    outcome has been reported for a p.Gly555Glu patient. The indication is the congestive
    heart failure curated in this entry's phenotypes. Note the mechanistic caveat that
    makes this reasonable rather than merely conventional: the enzyme defect is severe in
    myocardium and only partial elsewhere, so replacing the heart replaces the tissue in
    which the lesion actually matters.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Organ Transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DCM is the most frequent form of cardiomyopathy and the major cause of cardiac transplantation in children, accounting for >50% of all cardiac transplantations performed in patients between 1 and 10 years of age."
    explanation: >-
      Establishes transplantation as the standard endpoint intervention for paediatric
      dilated cardiomyopathy, which is the class this disorder belongs to. Stated by this
      entity's own founding report, though as background rather than as a cohort result.
- name: Genetic Counseling
  description: >-
    Both reported kindreds are consanguineous and share one founder allele, so carrier
    testing and reproductive counselling are directly actionable for the extended family
    and for the wider founder population. The indication is the autosomal recessive
    inheritance curated in this entry. Cascade testing of relatives needs one caveat
    stated up front, because the founding report ran into it: a homozygous result does not
    predict disease. The father of one patient carried two copies of the allele and was
    clinically normal, so an asymptomatic homozygous relative should be offered cardiac
    surveillance rather than a diagnosis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20551992
    reference_title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families."
    explanation: >-
      The recessive inheritance in consanguineous kindreds that makes carrier counselling
      the actionable intervention for these families.
experimental_models:
- name: HAP1 SDHA-knockout cell line with single-variant reintroduction
  experimental_model_type: CELL_LINE
  description: >-
    A clonal human SDHA-knockout line into which individual SDHA missense variants are
    reintroduced by site-specific recombination, after which succinate dehydrogenase
    activity and SDHA protein abundance are measured for each variant. It is the only
    published system in which this disorder's allele has been assayed in isolation in a
    human genetic background. The panel includes p.Gly555Glu, which scores at the low end
    of enzymatic activity, and the authors attribute its effect to disruption of
    SDHA-SDHB binding - a full-text derivation recorded in this entry's notes rather than
    a verified quotation, because the cached reference is abstract-only and names no
    individual variant.
  publication: PMID:39321216
  modeled_mechanisms:
  - target: Destabilised Flavoprotein-Iron-Sulfur Subunit Interface
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      The system measures the enzymatic consequence of the single allele on a null
      background, isolating the variant's effect from genetic modifiers and from the
      patient's tissue context. It agrees with the independent immunochemical evidence
      from patient material that the lesion is at the SDHA-SDHB interface.
    limitations: >-
      The study was designed to classify cancer-associated variants, not to model a
      cardiomyopathy, and HAP1 is a near-haploid chronic myelogenous leukaemia derivative
      rather than a cardiomyocyte - so it cannot address the tissue restriction that
      defines this disease, which is its central mechanistic question. The assay measures
      variant function on a knockout background at non-native expression, not the
      biology of a homozygous germline allele in myocardium. The authors themselves note
      that activity-score similarity between p.Gly555Glu and an unrelated cancer variant
      may reflect artefacts of this model system.
    evidence:
    - reference: PMID:39321216
      reference_title: "A Novel Human SDHA-Knockout Cell Line Model for the Functional Analysis of Clinically Relevant SDHA Variants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "SDHA variants were introduced into a clonal SDHA-knockout cell line via Bxb1-mediated recombination. SDH activity and SDHA abundance were determined for each variant"
      explanation: >-
        Describes the system and the measurement, which is what makes it informative for
        the interface node. Scoped to the abstract's account of the assay design; the
        inclusion of p.Gly555Glu in the panel is a full-text derivation and is not
        claimed by this snippet.
    - reference: PMID:39321216
      reference_title: "A Novel Human SDHA-Knockout Cell Line Model for the Functional Analysis of Clinically Relevant SDHA Variants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In total, we characterized 72 variants, developed criteria for obtaining functional evidence, and demonstrated the potential of this evidence for clinical variant interpretation."
      explanation: >-
        The scale of the panel, which is the aggregate statement that can be quoted from
        the cached abstract in support of this variant having been assayed among them.
animal_models:
- name: Sdhaf4 conditional-null mouse
  species: Mouse
  genotype: Sdhaf4 fl/fl; Ckmm-Cre (muscle-directed) and Sdhaf4 fl/fl; Mer-CreMer (tamoxifen-inducible, cardiomyocyte-specific)
  background: Conditional knockout of the complex II assembly factor Sdhaf4
  category: GENETIC
  description: >-
    The closest published in vivo model of the process this disease destroys, though not
    of its gene. Conditional deletion of Sdhaf4, the assembly factor that brings SDHA
    together with SDHB, suppresses complex II assembly in the heart and produces
    progressive dilated cardiomyopathy and lethal heart failure, with no mutant surviving
    beyond twelve weeks. Two independent Cre drivers give the same result, one
    muscle-directed and one tamoxifen-inducible and cardiomyocyte-specific, which
    establishes the phenotype as cardiomyocyte-autonomous rather than an artefact of one
    deletion strategy.

    Its relevance to this entry is specific and mechanistic rather than generic: loss of
    Sdhaf4 attenuates the SDHA-SDHB interaction and leads to subunit degradation, which is
    the same interface failure that the p.Gly555Glu substitution produces by a different
    route. The authors make the connection themselves, citing the human G555E
    cardiomyopathy report as the reason to expect complex II assembly to matter for
    cardiac homeostasis.
  publication: PMID:35803927
  genes:
  - preferred_term: SDHAF4
    term:
      id: hgnc:20957
      label: SDHAF4
  notes: >-
    `genes:` records SDHAF4, the gene this model actually deletes, not SDHA, the gene of
    the disease it informs. That follows the convention in the rest of the KB - the
    ADGRG1 polymicrogyria entry carries a Col3a1-null mouse under `genes: Col3a1`, and
    Adams-Oliver Syndrome carries a conditional Rac1 deletion under `genes: RAC1` - and
    it keeps the field consistent with the `limitations` on the links below, which say
    the lesion is in a different gene. The connection to SDHA is the mechanism links
    themselves, not the gene binding.
  modeled_mechanisms:
  - target: Destabilised Flavoprotein-Iron-Sulfur Subunit Interface
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model reproduces the molecular lesion at the level of the SDHA-SDHB interaction
      and its consequence, subunit degradation and loss of assembled complex II, which is
      what the human immunochemistry shows. It reaches that state by removing the
      assembly factor rather than by destabilising the interface from within the
      flavoprotein.
    limitations: >-
      The lesion is in a different gene. Sdhaf4 is an assembly factor, not a structural
      subunit, and the model is a conditional null rather than a hypomorphic missense
      allele, so residual complex II is likely lower and the failure mode is absence of
      assembly rather than instability of an assembled interface. Nothing in the model
      speaks to whether a p.Gly555Glu holoenzyme behaves the same way once assembled.
    readouts:
    - name: Coimmunoprecipitation of SDHB with SDHA from cardiac left ventricle
      target: Destabilised Flavoprotein-Iron-Sulfur Subunit Interface
      direction: DECREASED
      interpretation: >-
        Reduced recovery of SDHB with SDHA indicates that the interaction between the
        flavoprotein and the iron-sulfur subunit is weakened, which is the molecular event
        this node asserts.
      evidence:
      - reference: PMID:35803927
        reference_title: "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Immunoprecipitation assays using cardiac muscle tissues showed that abrogation of Sdhaf4 attenuated the interaction between SDHA and SDHB"
        explanation: Reports the coimmunoprecipitation measurement behind this readout.
    evidence:
    - reference: PMID:35803927
      reference_title: "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cardiac loss of Sdhaf4 suppresses complex II assembly and results in subunit degradation and complex II deficiency in fetal mice."
      explanation: >-
        Establishes that the model produces the assembly failure and subunit loss that
        make it informative for this node.
    - reference: PMID:35803927
      reference_title: "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A G555E mutation in the SDHA gene has been reported to cause DCM10, thereby indicating that the normal function of complex II is required to maintain cardiac homeostasis."
      explanation: >-
        The model's authors cite this entity's own allele as the human precedent for their
        premise, which is the explicit link between the model and this disease. The
        trailing digits are a superscript reference marker in the source text and are
        quoted as they appear.
  - target: Left Ventricular Dilatation and Systolic Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cardiac complex II assembly failure produces the same structural and functional
      cardiac endpoint as the human disease: ventricular chamber dilation with reduced
      fractional shortening and impaired contraction, progressing to lethal heart failure.
    limitations: >-
      The timing and the tissue distribution are both engineered rather than emergent. The
      human disease presents in the neonatal period and its cardiac restriction is
      unexplained, whereas in the mouse the restriction is imposed by the Cre driver, so
      the model cannot address the tissue-selectivity question that defines this disorder.
      Mouse disease also develops over weeks in the postnatal animal rather than in
      utero or in the first months, and the mutant hearts show hypertrophic and fibrotic
      remodelling with collagen deposition that has not been reported in patients with
      this disorder.
    readouts:
    - name: Left ventricular fractional shortening by echocardiography
      target: Left Ventricular Dilatation and Systolic Dysfunction
      direction: DECREASED
      interpretation: >-
        Reduced fractional shortening is the functional correlate of the systolic
        dysfunction this node asserts.
      evidence:
      - reference: PMID:35803927
        reference_title: "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "a significant decrease in left ventricular fractional shortening (FS%) and deregulated cardiac contraction were detected in the mutants, indicating that the loss of Sdhaf4 impairs heart function"
        explanation: Reports the echocardiographic measurement behind this readout.
    - name: Ventricular chamber dilation on gross morphology and histology
      target: Left Ventricular Dilatation and Systolic Dysfunction
      direction: INCREASED
      interpretation: >-
        Progressive chamber dilation is the structural correlate of the dilated phenotype
        this node asserts.
      evidence:
      - reference: PMID:35803927
        reference_title: "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Dilation of the ventricular chambers was observed at later stages, suggesting that the loss of Sdhaf4 in muscle results in progressive cardiac remodeling and DCM"
        explanation: Reports the morphological observation behind this readout.
    evidence:
    - reference: PMID:35803927
      reference_title: "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals"
      explanation: >-
        States the cardiac endpoint that makes this model informative for the human
        structural phenotype.
  - target: Cardiomyocyte Bioenergetic Failure
    relationship: RESCUES
    fidelity: LOW
    description: >-
      The model's rescue arms are the only in vivo evidence that the cardiac phenotype of
      complex II assembly failure is metabolically tractable: replacing the missing
      downstream metabolite with fumarate, or blocking the mitochondrial fission that the
      energetic deficit provokes, partially restores cardiac function and prolongs
      survival. This is recorded because it is the closest thing to a therapeutic lead
      this disease has, not because it has been tried in patients.
    limitations: >-
      Fidelity is recorded as LOW because the rescue was performed in an assembly-factor
      knockout, not in an SDHA missense model, and never in a patient. Whether fumarate
      supplementation would benefit a p.Gly555Glu heart is untested, and the rescue is
      explicitly partial in the mouse. No treatment is curated in this entry on the
      strength of it.
    readouts:
    - name: Cardiac function and lifespan after fumarate supplementation or fission inhibition
      target: Cardiomyocyte Bioenergetic Failure
      direction: RESTORED
      interpretation: >-
        Partial functional recovery on metabolite replacement indicates that the
        bioenergetic deficit is a driver of the cardiac phenotype rather than a bystander.
      evidence:
      - reference: PMID:35803927
        reference_title: "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Targeting mitochondria via supplementation with fumarate or inhibiting mitochondrial fission improves mitochondrial dynamics, partially restores cardiac function and prolongs the lifespan of mutant mice."
        explanation: Reports the rescue result behind this readout, including its own "partially" qualifier.
    evidence:
    - reference: PMID:35803927
      reference_title: "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings reveal a vital role for complex II assembly in the development of dilated cardiomyopathy and provide additional insights into therapeutic interventions for heart diseases."
      explanation: >-
        The authors' own summary of why the rescue matters for complex II-driven dilated
        cardiomyopathy.
differential_diagnoses:
- name: Mitochondrial complex II deficiency, nuclear type 1
  disease_term:
    preferred_term: mitochondrial complex II deficiency, nuclear type 1
    term:
      id: MONDO:0100294
      label: mitochondrial complex II deficiency, nuclear type 1
  description: >-
    The primary differential and the genuinely hard one, curated separately in
    `kb/disorders/Mitochondrial_Complex_II_Deficiency_Nuclear_Type_1.yaml`. It is not a
    mimicking disease but the other phenotypic outcome of the same lesion, and unlike the
    boundary with NDAXOA it cannot be drawn by zygosity: both are biallelic, and the
    p.Gly555Glu allele this entry is built on has itself been reported homozygous in a
    lethal infantile presentation and in Leigh syndrome. The discriminator is which organ
    failed, and nothing published explains why it differs.
  distinguishing_features:
  - Neurological involvement is the discriminator. MC2DN1 presents with Leigh syndrome, leukodystrophy, developmental regression or seizures; the DCM1GG cohort had psychomotor development appropriate for age and no seizures.
  - Zygosity does not separate them. Both are recessive and biallelic, and the same homozygous p.Gly555Glu genotype has been published in both phenotypes.
  - Where cardiomyopathy occurs in MC2DN1 it is accompanied by other organ involvement, such as the reported patient with cardiomyopathy and leukodystrophy; in DCM1GG the cardiac disease is isolated.
  - "The tissue distribution of the enzyme deficit differs in kind: in DCM1GG the deficiency is severe in myocardium and partial elsewhere, whereas isolated complex II deficiency in MC2DN1 is characteristically demonstrable in skeletal muscle or fibroblasts."
  notes: >-
    This differential is also a coverage overlap rather than only a clinical contrast.
    The MC2DN1 entry already cites PMID:20551992, the founding report of this entity,
    under a `Cardiomyopathy` phenotype node. That file was read and deliberately not
    modified here; the overlap is recorded in this entry's top-level notes.
  evidence:
  - reference: PMID:22972948
    reference_title: "Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations"
    explanation: >-
      Documents the combination that marks the other side of this boundary - cardiac
      disease accompanied by white-matter disease, in a patient with different SDHA
      alleles - against which this entry's isolated cardiac phenotype is defined.
  - reference: PMID:16798039
    reference_title: "Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation has previously been reported in a lethal-infantile presentation of complex II deficiency."
    explanation: >-
      Establishes that the allele underlying this entry has also produced non-cardiac
      disease, which is why the genotype cannot serve as the discriminator between these
      two entities.
- name: SDHA-related neurodegeneration with ataxia and late-onset optic atrophy
  disease_term:
    preferred_term: neurodegeneration with ataxia and late-onset optic atrophy
    term:
      id: MONDO:0031006
      label: neurodegeneration with ataxia and late-onset optic atrophy
  description: >-
    The dominant SDHA phenotype, curated in
    `kb/disorders/SDHA-Related_Neurodegeneration_With_Ataxia_And_Optic_Atrophy.yaml`,
    which already carries this disorder as a reciprocal differential. It is a relevant
    differential in exactly one situation: an infant with cardiomyopathy and an SDHA
    variant, because cardiomyopathy was the presenting and lethal feature in the
    paediatric carriers of one NDAXOA pedigree. The statements below are written to agree
    with that entry's.
  distinguishing_features:
  - Zygosity separates these two. DCM1GG is recessive and homozygous; NDAXOA arises from a single heterozygous missense allele, so a parent is either affected or the variant is de novo.
  - DCM1GG is cardiac-predominant without the optic atrophy that defines NDAXOA, so a family history of visual loss argues for NDAXOA.
  - The NDAXOA pedigree with childhood cardiomyopathy also contained an adult with optic atrophy carrying the same allele; DCM1GG families have reported no ophthalmological or neurological disease.
  - MONDO keeps the two as separate terms with separate OMIM anchors, MONDO:0013339/OMIM:613642 and MONDO:0031006/OMIM:619259, both mapped to SDHA.
  notes: >-
    These distinguishing features are the reciprocal of those recorded in the NDAXOA
    entry's differential for MONDO:0013339 and are deliberately consistent with them
    rather than independently derived. That entry states that the distinction rests on
    zygosity and on whether neurological or ophthalmological features later appear in the
    family, which the founding report of this entity supports: its patients are
    homozygous, and their neuromuscular function and psychomotor development were normal.
- name: Pheochromocytoma/paraganglioma syndrome 5
  disease_term:
    preferred_term: pheochromocytoma/paraganglioma syndrome 5
    term:
      id: MONDO:0013602
      label: pheochromocytoma/paraganglioma syndrome 5
  description: >-
    The fourth SDHA disease term, and the one that dominates an SDHA literature search
    while having no clinical overlap with this entity. It is included because the shared
    gene means a DCM1GG genotype result will be read by clinicians against a tumour
    surveillance background, not because the two present alike.
  distinguishing_features:
  - PGL5 arises from single heterozygous germline alleles acting as tumour-suppressor first hits and requires a somatic second hit in the tumour; DCM1GG is a constitutive biallelic enzymatic deficit with no second hit.
  - "The mechanisms diverge at succinate: in PGL5 its accumulation acts as an oncometabolite driving pseudohypoxia and epigenetic remodelling, whereas the pathogenic consequence curated here is bioenergetic failure in myocardium."
  - No tumour has been reported in the DCM1GG kindreds and no paraganglioma family has reported neonatal dilated cardiomyopathy.
  evidence:
  - reference: PMID:11692162
    reference_title: "Phenotypic dichotomy in mitochondrial complex II genetic disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While mutations in SDHA display a phenotype resembling other mitochondrial and Krebs cycle gene defects, those in SDHB, SDHC and SDHD cause hereditary paraganglioma."
    explanation: >-
      States the dichotomy this differential rests on, and specifically places SDHA on
      the mitochondrial-disease side of it. Graded OTHER because it is a review.
  - reference: PMID:33162331
    reference_title: "The genetic basis of isolated mitochondrial complex II deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "either susceptibility to cancer in the case of single, heterozygous germline variants, or a mitochondrial disease presentation, almost exclusively due to bi-allelic recessive variants"
    explanation: >-
      Ties the two clinical outcomes of complex II defects to zygosity, which is the
      feature that separates this entity from the tumour syndrome.
discussions:
- discussion_id: dcm1gg_cardiac_tissue_restriction
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why is the succinate dehydrogenase deficit severe in myocardium and only partial in
    skeletal muscle and lymphoblastoid cells, when every subunit and assembly factor of
    complex II is nuclear-encoded and the causal allele is homozygous in every cell?
  attaches_to:
  - pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
  - disease#Dilated Cardiomyopathy 1GG
  rationale: >-
    This is the entity's defining unexplained fact, and the reporting authors raise it
    themselves rather than leaving it to a reader. The usual explanation for
    tissue-restricted respiratory-chain disease is heteroplasmy, and it is unavailable
    here: complex II is the only respiratory-chain complex encoded entirely in the
    nuclear genome, so gene dosage is identical in every tissue. The obvious alternative,
    a modifier in another complex II gene, was tested and excluded - SDHB, SDHD and
    SDHAF1 were sequenced and carried nothing. What remains untested is whether cardiac
    mitochondria assemble or degrade the destabilised holoenzyme differently, or whether
    the myocardium simply has the lowest tolerance for a given residual activity because
    of its continuous contractile demand. The question is not academic: it is the reason
    this disease is separable from mitochondrial complex II deficiency, nuclear type 1
    at all, and answering it would determine whether the boundary between those two
    entities is mechanistic or merely descriptive.
  proposed_experiments:
  - experiment_id: dcm1gg_tissue_assembly_comparison
    name: Comparative complex II assembly and turnover across cardiac and skeletal muscle mitochondria
    description: >-
      Measure assembled complex II holoenzyme abundance, subunit steady-state levels and
      subunit turnover rate in cardiac versus skeletal muscle mitochondria carrying the
      homozygous p.Gly555Glu allele, to test whether the tissue difference lies in
      assembly efficiency or in degradation of the destabilised complex rather than in
      downstream tolerance.
    would_support:
    - pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
    supporting_outcome:
    - >-
        Assembled holoenzyme is disproportionately reduced in cardiac mitochondria relative
        to skeletal muscle at equal subunit expression, locating the tissue difference at
        assembly or turnover.
    would_refute:
    - pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
    refuting_outcome:
    - >-
        Assembly and turnover are equivalent between the two tissues, which would move the
        explanation downstream to differential tolerance of a shared enzymatic deficit and
        leave this node's framing as a tissue-level assembly phenomenon unsupported.
- discussion_id: dcm1gg_one_genotype_three_phenotypes
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does one homozygous SDHA genotype, p.Gly555Glu, produce isolated neonatal dilated
    cardiomyopathy in two Bedouin kindreds, a lethal infantile multisystem presentation in
    one proband, and a relatively mild Leigh syndrome in another?
  attaches_to:
  - genetic#SDHA
  - pathophysiology#SDHA p.Gly555Glu Homozygosity
  rationale: >-
    Marked phenotypic heterogeneity is expected of heteroplasmic mitochondrial DNA
    mutations and is unusual for a nuclear allele, and the source that reports the Leigh
    presentation says exactly that. It also closes off the most obvious explanation:
    enzyme activities and enzyme stability were comparable between the patients with
    different phenotypes, so the divergence is not a matter of one patient having less
    residual complex II than another. That leaves unidentified genetic background,
    environmental or perinatal factors, or stochastic developmental effects, none of which
    has been investigated. This gap is the reason this entry cannot claim that its
    genotype is diagnostic of its phenotype, and it bears directly on the differential
    with mitochondrial complex II deficiency, nuclear type 1.
- discussion_id: dcm1gg_no_animal_model
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    No in vivo model carries SDHA p.Gly555Glu, and the one cardiac complex II model that
    exists disables an assembly factor in a tissue chosen by the experimenter. What model
    would let the tissue selectivity of this disease be studied rather than assumed?
  attaches_to:
  - pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
  - disease#Dilated Cardiomyopathy 1GG
  rationale: >-
    No model of this disorder's allele exists, but the gap is narrower than "no model",
    and the distinction matters. A conditional cardiac knockout of Sdhaf4, the assembly
    factor that brings SDHA together with SDHB, is curated in this entry's animal models:
    it reproduces the SDHA-SDHB interface failure, the loss of assembled complex II, and
    progressive lethal dilated cardiomyopathy, and it is the model in which fumarate
    rescue was demonstrated. What it does not and cannot provide is the two things
    peculiar to this disease. It carries a null allele of a different gene rather than a
    hypomorphic missense substitution in the flavoprotein, so it cannot test whether an
    assembled but destabilised holoenzyme behaves the same way; and its cardiac
    restriction is imposed by the Cre driver rather than arising on its own, so it cannot
    address why a homozygous allele present in every cell disables the heart alone.

    Searches run on 2026-08-31 for Sdha knockout, knock-in, conditional-deletion and
    heterozygous mouse models, for Drosophila SdhA models, and for Caenorhabditis elegans
    complex II mutants returned no SDHA-subunit model of cardiomyopathy; the well-known
    nematode complex II mutant mev-1 is a cytochrome b (SDHC) allele, not an SDHA one, and
    the recently modelled SDHD H50R is a different subunit again. Beyond the Sdhaf4 mouse,
    the published functional work on this entity's allele is confined to patient material
    and to a human knockout cell line, both curated in this entry. Scarcity of models is a
    recognised field-wide obstacle for complex II disease rather than a gap peculiar to
    this disorder. The consequence here is specific: the tissue-restriction question above
    cannot be settled in patient tissue alone, because the cardiac samples that would be
    needed come only from autopsy.
  proposed_experiments:
  - experiment_id: dcm1gg_sdha_g555e_knockin_mouse
    name: Knock-in mouse carrying the orthologous Sdha Gly555Glu substitution
    description: >-
      Generate a homozygous knock-in of the residue-equivalent substitution and compare
      succinate dehydrogenase activity, assembled complex II abundance and contractile
      function across heart, skeletal muscle and brain, to test whether the tissue
      restriction reproduces outside the human founder background.
    would_support:
    - pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
    supporting_outcome:
    - >-
        Homozygous animals show a cardiac-predominant enzyme deficit and dilated
        cardiomyopathy with preserved neurological function, reproducing the human tissue
        distribution.
    would_refute:
    - pathophysiology#Myocardium-Restricted Loss of Succinate Dehydrogenase Activity
    refuting_outcome:
    - >-
        Homozygous animals show a uniform enzyme deficit across tissues, or an
        encephalopathic rather than cardiac phenotype, indicating that the tissue
        restriction depends on human-specific or founder-background factors rather than on
        the allele.
  evidence:
  - reference: PMID:23174333
    reference_title: "The role of complex II in disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Further progress in understanding the role of complex II in disease, and in the development of new therapeutic approaches, is now being hampered by the lack of relevant cell and animal models."
    explanation: >-
      Published confirmation that the absence of models is a recognised, field-wide
      obstacle for complex II disease rather than an artefact of this entry's searching.
      Graded OTHER because it is a review.
- discussion_id: dcm1gg_riboflavin_untested
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Complex II is the only respiratory-chain complex with a flavin cofactor, and
    riboflavin has been given to patients with complex II deficiency. Has it ever been
    tried in the cardiac-restricted form, and would it be expected to help an allele whose
    defect is a destabilised subunit interface rather than impaired flavinylation?
  attaches_to:
  - treatments#Heart Failure Supportive Care
  - pathophysiology#Destabilised Flavoprotein-Iron-Sulfur Subunit Interface
  rationale: >-
    No treatment is curated for the enzyme defect in this entry because none is supported
    for it, and this discussion records why rather than leaving the omission unexplained.
    The evidence that exists is about complex II deficiency as a biochemical class, is
    weak, and points in both directions: a systematic review of riboflavin across
    inherited metabolic diseases classifies its effect in complex II deficiency as
    uncertain by an explicit threshold, meaning fewer than three-quarters of patients
    responded, while individual reports describe mild improvement on mitochondrial
    cocktails that include riboflavin. None of that evidence comes from a patient with
    this disorder. There is also a mechanistic reason for caution specific to this allele:
    the defect here is a destabilised interface between the flavoprotein and the
    iron-sulfur subunit, not a failure to acquire the flavin cofactor, so cofactor
    supplementation does not have an obvious target. Curating riboflavin as a treatment of
    this disease would assert an indication the literature does not support.
  evidence:
  - reference: PMID:42046426
    reference_title: "Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The effect was uncertain in complex I and II deficiency, ethylmalonic encephalopathy, FAD synthase deficiency, glutaric aciduria type 1, L2 hydroxyglutaric aciduria, and MADD type 2."
    explanation: >-
      The systematic review's verdict for the biochemical class this disorder belongs to.
      Graded HUMAN_CLINICAL because the review synthesises reported patient outcomes.
  - reference: PMID:42046426
    reference_title: "Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RF therapy was considered \"effective\" in an IMD if more than 75% of patients showed a positive response, \"uncertain\" in case of a positive response in fewer than 75% of patients"
    explanation: >-
      Defines what the "uncertain" verdict means, so the finding above is not read as a
      stronger or weaker claim than it is.
  - reference: PMID:37064335
    reference_title: "Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some reported patients showed clinical improvement following riboflavin therapy"
    explanation: >-
      The countervailing observation, stated as a review of reported cases within a case
      report. Cited for the treatment landscape of complex II deficiency; neither of this
      report's patients has this disorder.
references:
- reference: PMID:20551992
  title: "Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase."
- reference: PMID:12794685
  title: "Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II."
- reference: PMID:16798039
  title: "Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II."
- reference: PMID:33162331
  title: "The genetic basis of isolated mitochondrial complex II deficiency."
- reference: PMID:7550341
  title: "Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency."
- reference: PMID:11692162
  title: "Phenotypic dichotomy in mitochondrial complex II genetic disorders."
- reference: PMID:23174333
  title: "The role of complex II in disease."
- reference: PMID:22972948
  title: "Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency."
- reference: PMID:39321216
  title: "A Novel Human SDHA-Knockout Cell Line Model for the Functional Analysis of Clinically Relevant SDHA Variants."
- reference: PMID:42046426
  title: "Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review."
- reference: PMID:37064335
  title: "Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report."
- reference: PMID:35803927
  title: "Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy."
📚

References & Deep Research

References

12
PMID:20551992
Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase.
No top-level findings curated for this source.
PMID:12794685
Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II.
No top-level findings curated for this source.
PMID:16798039
Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II.
No top-level findings curated for this source.
PMID:33162331
The genetic basis of isolated mitochondrial complex II deficiency.
No top-level findings curated for this source.
PMID:7550341
Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency.
No top-level findings curated for this source.
PMID:11692162
Phenotypic dichotomy in mitochondrial complex II genetic disorders.
No top-level findings curated for this source.
PMID:23174333
The role of complex II in disease.
No top-level findings curated for this source.
PMID:22972948
Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.
No top-level findings curated for this source.
PMID:39321216
A Novel Human SDHA-Knockout Cell Line Model for the Functional Analysis of Clinically Relevant SDHA Variants.
No top-level findings curated for this source.
PMID:42046426
Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review.
No top-level findings curated for this source.
PMID:37064335
Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report.
No top-level findings curated for this source.
PMID:35803927
Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy.
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: Dilated Cardiomyopathy 1GG (MONDO:0013339, SDHA) · 2026-08-31T17:33:03Z · View source

Curated de novo as entry_type DISEASE. The entity rests on one primary report (PMID:20551992): 15 patients from two consanguineous Bedouin families homozygous for SDHA c.1664G>A p.(Gly555Glu), presenting with neonatal isolated dilated cardiomyopathy. The pathograph is built around the tissue restriction of the enzyme defect, which is the entity's defining and unexplained feature: severe loss of succinate dehydrogenase activity in myocardium with substantial activity retained in skeletal muscle and lymphoblastoid cells. The molecular mechanism is a destabilised SDHA-SDHB interface, evidenced independently by patient immunochemistry (PMID:12794685) and by a human SDHA-knockout cell line panel (PMID:39321216, per-variant result full-text derived). A conditional cardiac Sdhaf4 knockout mouse (PMID:35803927) is curated in animal_models with three mechanism links; it was surfaced by the falcon deep-research report and reproduces the SDHA-SDHB interface failure and the dilated phenotype but not the allele or the tissue selectivity. Four knowledge gaps are recorded, the central one being why a homozygous allele present in every cell disables only the heart. No treatment is curated for the enzyme defect; riboflavin is recorded as a knowledge gap with opposed evidence rather than as a treatment. The MC2DN1 coverage overlap and the declined module conformance are disclosed in the entry notes. Validated with just validate (exit 0, 46/46 snippets verified against cached references).

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 15 citations 2026-08-31T10:21:40.372367

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Dilated Cardiomyopathy 1GG
  • MONDO ID: MONDO:0013339 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Dilated Cardiomyopathy 1GG covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
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14. Other Species / Natural Disease

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  • Resources:
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Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Dilated Cardiomyopathy 1GG (DCM1GG): disease-characteristics report

Executive summary and evidence limits

Dilated cardiomyopathy 1GG is an exceptionally rare, predominantly neonatal/infantile, autosomal-recessive cardiomyopathy attributed to biallelic SDHA dysfunction. The defining evidence remains a 2010 study of 15 affected members of consanguineous Bedouin kindreds carrying homozygous SDHA c.1664G>A (p.Gly555Glu; G555E). Thus, most subtype-specific frequency and outcome estimates derive from one founder cohort and should not be generalized to every biallelic SDHA genotype. Open Targets independently associates SDHA with dilated, familial, and familial-isolated DCM, but this is aggregated secondary evidence rather than a new cohort (OpenTargets Search: Dilated cardiomyopathy-SDHA, levitas2010familialneonatalisolated pages 1-2).

The evidence can be summarized as follows:

domain finding evidence type/strength key source
Disease identity Dilated Cardiomyopathy 1GG is a Mendelian DCM subtype linked to SDHA; foundational reported causal variant is c.1664G>A (p.Gly555Glu / G555E) in homozygosity Human primary family study; strong for variant-disease association in reported kindreds Levitas et al., 2010 (levitas2010familialneonatalisolated pages 1-2, levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 5-6)
Inheritance Autosomal recessive inheritance in consanguineous families; affected individuals homozygous, available parents typically heterozygous Human segregation evidence; strong within families Levitas et al., 2010 (levitas2010familialneonatalisolated pages 1-2, levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 4-5)
Cohort/founder context 15 Bedouin patients from two large consanguineous families of one tribe; authors infer a common founder Human cohort description; moderate-strong Levitas et al., 2010 (levitas2010familialneonatalisolated pages 1-2, levitas2010familialneonatalisolated pages 2-3)
Onset/clinical spectrum Onset ranged from 32 weeks gestation to 10 years; prominent pediatric/neonatal isolated cardiomyopathy with LV dilation and systolic dysfunction Human case-series evidence; strong descriptive Levitas et al., 2010 (levitas2010familialneonatalisolated pages 1-2, levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 3-4)
Core phenotype Frequent features included respiratory distress, congestive heart failure, cardiogenic shock, cardiomegaly, LV dilation, reduced fractional shortening, and LV noncompaction in 8 infants Human phenotype evidence; strong descriptive Levitas et al., 2010 (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 3-4)
Mortality/course Condition showed high mortality, with about two-thirds succumbing to cardiac failure; rapid deterioration resembles mitochondrial cardiomyopathy burden Human case-series evidence; moderate-strong Levitas et al., 2010 (levitas2010familialneonatalisolated pages 5-6)
Cardiac testing ECG reportedly showed sinus rhythm, LV hypertrophy, normal QTc; lactate was usually normal except mild elevation to 3.7 mmol/L; two brain MRIs lacked Leigh-syndrome lesions Human clinical testing evidence; moderate Levitas et al., 2010 (levitas2010familialneonatalisolated pages 2-3)
Biochemical defect Respiratory-chain testing showed tissue-specific complex II deficiency: skeletal muscle residual activity about 50-60%, versus myocardium about 15-18% for succinate dehydrogenase/complex II; succinate oxidation in muscle 26% in one assay Human biochemical evidence; strong Levitas et al., 2010 (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 4-5, levitas2010familialneonatalisolated pages 5-6)
Specificity/variability Partial complex I decrease occurred in one patient, but normal aconitase argued against generalized iron-sulfur metabolism failure; phenotype showed marked intrafamilial variability Human biochemical/clinical evidence; moderate Levitas et al., 2010 (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 5-6)
Reduced penetrance One adult father was homozygous for the variant yet clinically unaffected on exam, ECG, and echocardiography despite reduced lymphoblast complex II activity, indicating nonpenetrance/reduced penetrance Human observation; important but based on single individual Levitas et al., 2010 (levitas2010familialneonatalisolated pages 4-5, levitas2010familialneonatalisolated pages 5-6)
Mechanistic interpretation Authors concluded disease is “presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle,” while retaining more activity in skeletal muscle and lymphoblastoid cells Human mechanistic inference anchored by enzyme assays; moderate Levitas et al., 2010 (levitas2010familialneonatalisolated pages 1-2, levitas2010familialneonatalisolated pages 5-6)
Supporting disease-gene mapping Independent target-disease aggregation resources also map SDHA to dilated/familial isolated DCM Aggregated database evidence; supportive but secondary Open Targets association (OpenTargets Search: Dilated cardiomyopathy-SDHA)
Experimental mechanism relevance In mice, cardiac Sdhaf4 loss impaired complex II assembly, promoted SDHA/SDHB degradation, metabolic impairment, DRP1-mediated mitochondrial fission/mitophagy, and progressive dilated cardiomyopathy/lethal heart failure Mouse mechanistic study; strong for complex-II-to-DCM biology, indirect for DCM1GG Wang et al., 2022 (wang2022cardiacdisruptionof pages 1-2, wang2022cardiacdisruptionof pages 10-12)
Experimental rescue relevance In the Sdhaf4 mouse model, fumarate supplementation or mitochondrial fission inhibition partially restored cardiac function and prolonged lifespan Mouse interventional evidence; hypothesis-generating, not subtype-specific clinical proof Wang et al., 2022 (wang2022cardiacdisruptionof pages 1-2, wang2022cardiacdisruptionof pages 10-12)
Current diagnosis Contemporary cardiomyopathy guidance emphasizes deep phenotyping, ECG, biomarkers, echocardiography/CMR, and genetic workup for hereditary cardiomyopathy Recent guideline/review evidence; strong for general DCM practice ESC-guideline summary 2024; guideline review 2025 (grasso2024thenew2023 pages 1-2, sorella2025diagnosisandmanagement pages 12-13)
Current family management Genetic counselling and cascade screening of at-risk relatives are recommended when a pathogenic variant is identified; advanced HF care may require transplant/device evaluation Recent guideline/review evidence; strong for general DCM practice Guideline review 2025 (sorella2025diagnosisandmanagement pages 12-13)
Subtype-specific treatment evidence No approved therapy, no validated SDHA/DCM1GG-specific treatment algorithm, and no clearly identified clinical trial dedicated to this subtype were found in the available evidence Evidence gap / negative finding from searched literature and trials; moderate confidence Available evidence corpus and trial searches (sorella2025diagnosisandmanagement pages 12-13, grasso2024thenew2023 pages 1-2)

Table: This table compacts the strongest available evidence for Dilated Cardiomyopathy 1GG, separating direct human subtype evidence from indirect mechanistic and guideline evidence. It is useful for quickly identifying what is established, what is inferred, and where current evidence gaps remain.

Evidence notation used below: human-direct means observations in DCM1GG patients; human-indirect means findings in broader DCM or other SDHA disease; model means animal/cellular evidence not yet demonstrated in DCM1GG patients.

1. Disease information

Definition

DCM1GG is a Mendelian mitochondrial-energy cardiomyopathy in which left or both ventricles become dilated and systolic function is impaired. In the defining families it was usually an isolated cardiac disorder, often beginning prenatally or in infancy, rather than the encephalomyopathic/Leigh phenotype also produced by biallelic SDHA variants. The paper’s exact abstract statement was: “we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families.” It further called the phenotype a “severe form of neonatal cardiomyopathy” with “extreme phenotypic variability” (published online 16 June 2010; PMID 20551992; DOI: https://doi.org/10.1038/ejhg.2010.83) (levitas2010familialneonatalisolated pages 1-2).

Identifiers and terminology

  • MONDO: MONDO:0013339, as supplied in the query; this should be retained as the knowledge-base primary identifier.
  • Disease name/synonyms: dilated cardiomyopathy 1GG; DCM1GG; SDHA-related dilated cardiomyopathy; SDHA-related recessive neonatal isolated cardiomyopathy; familial neonatal isolated cardiomyopathy caused by SDHA mutation.
  • Causal-gene identifier: SDHA, succinate dehydrogenase complex flavoprotein subunit A; Ensembl ENSG00000073578 (OpenTargets Search: Dilated cardiomyopathy-SDHA).
  • Parent/general disease: dilated cardiomyopathy, historically MIM 115200 in the primary paper (levitas2010familialneonatalisolated pages 1-2).
  • OMIM subtype number: not independently recoverable from the searched full text; it should be verified directly in OMIM before database ingestion rather than inferred from the suffix “1GG.”
  • Orphanet: no subtype-specific Orphanet identifier was established in the retrieved evidence.
  • ICD-10/ICD-11 and MeSH: coding is at the general DCM/cardiomyopathy level, not an SDHA-specific clinical code. Appropriate broad terms are ICD-10-CM I42.0 and MeSH Cardiomyopathy, Dilated; these should not be represented as uniquely identifying DCM1GG.

The foundational information is aggregated at disease/family level from deliberately recruited patients and medical-record review—not a population EHR analysis. The investigators reviewed growth, development, hospitalizations, laboratory studies, serial ECG and echocardiography, family examinations, and molecular/biochemical testing (levitas2010familialneonatalisolated pages 2-3).

2. Etiology

Causal factor and genetic risk

The demonstrated initiating lesion is germline homozygosity for SDHA c.1664G>A, p.Gly555Glu. All tested affected individuals were homozygous; healthy siblings were heterozygous or homozygous reference, and almost all available parents were heterozygous. Linkage/autozygosity mapping identified a 5.6-cM segment containing SDHA, followed by cDNA and genomic sequencing (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 4-5).

The variant had previously been associated with lethal infantile multisystem disease and Leigh syndrome. Previous functional work cited by the family study showed destabilization/assembly failure of mitochondrial complex II and approximately halved activity in muscle or fibroblasts; it was absent from 186 historical control chromosomes. A modern global allele frequency and current ClinVar ACMG classification were not established by the retrieved evidence and must be checked directly against the current ClinVar/gnomAD release before curation (levitas2010familialneonatalisolated pages 4-5, levitas2010familialneonatalisolated pages 5-6).

Risk, protective, and modifying factors

  • Established risk factors: biallelic pathogenic SDHA genotype, consanguinity, and family history. The reported families belonged to one Bedouin tribe and were considered to share a founder allele (levitas2010familialneonatalisolated pages 2-3).
  • Reduced penetrance/modification: one homozygous adult father had normal examination, ECG, and LV size/function despite lymphoblast complex-II activity similar to affected patients. This is direct evidence of reduced penetrance, although based on one person. SDHB, SDHD, and SDHAF1 sequencing did not explain the difference; unidentified genetic, epigenetic, or environmental modifiers remain plausible (levitas2010familialneonatalisolated pages 4-5, levitas2010familialneonatalisolated pages 5-6).
  • Environmental risks/protective factors: none were demonstrated specifically for DCM1GG. General myocardial stressors—viral myocarditis, cardiotoxic agents, ischemia, alcohol, pregnancy, metabolic stress—may worsen DCM, but extrapolation to this founder disorder is untested.
  • Gene–environment interaction: the historical G555E infant with lethal multisystem disease deteriorated following respiratory infection and severe hypoglycemia, suggesting that catabolic stress may unmask limited mitochondrial reserve; this was not proven in the isolated-DCM cohort (levitas2010familialneonatalisolated pages 1-2, levitas2010familialneonatalisolated pages 4-5).
  • Protective alleles/dietary protection: none established. The unaffected homozygous father strongly suggests modification, but no protective allele was identified (levitas2010familialneonatalisolated pages 5-6).

3. Phenotypes

The following frequencies are from the 15-person founder cohort unless otherwise stated.

  • Dilated left ventricle / cardiomegaly — structural sign; present across the reported affected series. LV end-diastolic diameters in the table ranged approximately 33–50 mm, with age-inappropriate dilation. Suggested HPO: Dilated cardiomyopathy (HP:0001644) and Cardiomegaly (HP:0001640) (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 3-4).
  • LV systolic dysfunction — functional sign; fractional shortening ranged from <10% to 26%, frequently severe. Suggested HPO: decreased left-ventricular systolic function and reduced ejection/fractional shortening; verify current HPO identifiers before ingestion (levitas2010familialneonatalisolated pages 3-4).
  • Congestive heart failure — clinical syndrome with respiratory distress, repeated admissions, feeding/exercise limitations, and sometimes cardiogenic shock. Suggested HPO: Congestive heart failure (HP:0001635) and Respiratory distress (HP:0002098) (levitas2010familialneonatalisolated pages 3-4).
  • Left-ventricular noncompaction/trabeculation — reported in 8 infants (8/15; 53%). Suggested HPO: Left ventricular noncompaction (HP:0031689). Contemporary ESC interpretation treats LV noncompaction as a morphologic trait that can occur in several settings, so it should be recorded alongside—not substituted for—the causal DCM diagnosis (levitas2010familialneonatalisolated pages 2-3, grasso2024thenew2023 pages 1-2).
  • LV hypertrophy and mitral insufficiency — usually mild/moderate and accompanying dilation in survivors. Suggested HPO: Left ventricular hypertrophy (HP:0001712) and Mitral regurgitation (HP:0001653) (levitas2010familialneonatalisolated pages 3-4).
  • ECG abnormality — sinus rhythm with LV hypertrophy and normal QTc in all assessed patients; no defining conduction phenotype was reported (levitas2010familialneonatalisolated pages 2-3).
  • Mild hyperlactatemia — lactate 3.7 mmol/L; otherwise routine indices were largely normal. Suggested HPO: Increased serum lactate (HP:0002151) (levitas2010familialneonatalisolated pages 2-3).
  • Neurologic/skeletal-muscle sparing in this phenotype — normal growth, age-appropriate development, muscle bulk/strength, reflexes, and gait; no seizures during follow-up. Two brain MRIs lacked basal-ganglia, cortex, gray-matter, or brainstem lesions, arguing against Leigh syndrome in those patients (levitas2010familialneonatalisolated pages 2-3).
  • Exercise intolerance — documented in several longer-term survivors. Suggested HPO: Exercise intolerance (HP:0003546) (levitas2010familialneonatalisolated pages 3-4).

Onset, severity, progression, and quality of life

The reported enrollment/presentation spectrum extended from 32 weeks’ gestation to 10 years, but most tabulated symptomatic onsets were prenatal or at 1–8 months. Severity ranged from asymptomatic cardiomegaly/mild dysfunction to shock and death. Progression was generally chronic and often rapidly progressive in infancy, with recurrent heart-failure admissions; some survivors attended normal school into ages 7–11 years but experienced exercise intolerance (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 3-4).

No DCM1GG-specific EQ-5D, SF-36, PROMIS, or pediatric quality-of-life data exist in the retrieved literature. Respiratory distress, frequent hospitalization, exercise intolerance, and early mortality imply major family and functional burden, but a quantitative utility estimate would be unsupported.

4. Genetic and molecular information

Gene and variant

  • Gene: SDHA, nuclear encoded, chromosome 5; protein is the FAD-containing flavoprotein catalytic subunit of succinate dehydrogenase/respiratory complex II.
  • Variant: c.1664G>A (p.Gly555Glu; G555E), exon 13 in the transcript used by the original investigators.
  • Origin: constitutional/germline.
  • Zygosity/inheritance: homozygous disease state; autosomal recessive.
  • Class: missense. Historical evidence supports pathogenicity through segregation, linkage, rarity in controls, recurrent disease association, complex-II instability, and deficient enzyme activity (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 4-5, levitas2010familialneonatalisolated pages 5-6).
  • Functional consequence: partial loss of complex-II stability/activity rather than complete null function. Cardiac SDH activity was only 15–18% of control, compared with 50–60% residual activity in skeletal muscle and approximately 60–63% in selected lymphoblast assays. Complex II+III activity in myocardium was 8–21% of control; succinate oxidation was 26% in one skeletal-muscle assay (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 4-5).

All four SDH subunits are nuclear encoded: soluble SDHA and SDHB are anchored to the inner mitochondrial membrane by SDHC and SDHD. SDHA oxidizes succinate to fumarate while passing electrons into the respiratory chain through ubiquinone, linking the tricarboxylic-acid cycle and oxidative phosphorylation (levitas2010familialneonatalisolated pages 1-2, wang2022cardiacdisruptionof pages 1-2).

Modifiers, epigenetics, and structural variation

No validated modifier gene, methylation signature, chromatin lesion, pathogenic copy-number change, translocation, inversion, or aneuploidy has been established for DCM1GG. SDHAF1 was investigated but did not account for intrafamilial variability. CMA/karyotype/FISH are therefore not first-line tests for this single-nucleotide founder disorder unless the patient has additional congenital anomalies or sequencing is unrevealing (levitas2010familialneonatalisolated pages 4-5, levitas2010familialneonatalisolated pages 5-6).

Heterozygous germline SDHA loss-of-function variants can confer tumor predisposition in other contexts, whereas DCM1GG is a recessive mitochondrial phenotype. These should not be conflated; cancer surveillance decisions require variant-specific genetics expertise and are not established from the G555E DCM cohort.

5. Environmental information

No toxin, radiation, pollutant, occupational exposure, smoking pattern, alcohol exposure, dietary factor, or infectious agent was shown to cause DCM1GG. The disease is genetic. Nevertheless, prudent mitochondrial/heart-failure care includes avoiding smoking, binge alcohol, illicit stimulants, unprescribed mitochondrial-toxic drugs, dehydration, prolonged fasting, and delayed treatment of infection. These are risk-management principles, not demonstrated primary prevention of the genotype.

Because the heart has high energy demand and patients have limited complex-II reserve, fever, fasting, hypoglycemia, major surgery, or infection are biologically plausible “second hits.” Evidence remains indirect; no controlled DCM1GG gene–environment study exists.

6. Mechanism/pathophysiology

Ordered causal chain

  1. Biallelic SDHA p.Gly555Glu leads to impaired stability/assembly and catalytic function of mitochondrial respiratory complex II in affected tissues. This is supported by prior functional observations and direct patient enzyme assays (levitas2010familialneonatalisolated pages 4-5, levitas2010familialneonatalisolated pages 5-6).
  2. Complex-II dysfunction leads to markedly reduced cardiac succinate-dehydrogenase and succinate-to-respiratory-chain flux; myocardium retains only 15–18% SDH activity, much less than skeletal muscle or lymphoblasts (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 4-5).
  3. Reduced succinate oxidation/electron transfer is inferred to lead to impaired TCA-cycle/oxidative-phosphorylation coupling and inadequate ATP-generating reserve in energy-intensive cardiomyocytes. ATP depletion was not directly measured in DCM1GG hearts.
  4. Complex-II metabolic failure is inferred to branch:
    4a. energetic insufficiency leads to impaired excitation–contraction and systolic function;
    4b. redox/TCA imbalance may lead to ROS injury, succinate accumulation, fumarate depletion, and mitochondrial damage. This branch is supported mainly by complex-II mouse models, not demonstrated in DCM1GG patients (wang2022cardiacdisruptionof pages 10-12, wang2022cardiacdisruptionof pages 1-2).
  5. Mitochondrial damage is inferred to lead to DRP1 activation, excess mitochondrial fission and mitophagy, reducing functional mitochondrial mass. This was demonstrated after cardiac Sdhaf4 loss in mice, not after human SDHA G555E (wang2022cardiacdisruptionof pages 1-2).
  6. Cardiomyocyte energetic and organelle failure leads to reduced contractility and maladaptive ventricular remodeling, producing LV dilation, reduced fractional shortening, noncompaction morphology, mitral insufficiency, and sometimes hypertrophy (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 3-4).
  7. Progressive pump dysfunction leads to pulmonary congestion/respiratory distress, recurrent CHF, cardiogenic shock, exercise intolerance, and early cardiac death (levitas2010familialneonatalisolated pages 3-4, levitas2010familialneonatalisolated pages 5-6).

Detailed pathways and evidence grading

Human-direct: the decisive biochemical abnormality is tissue-selective complex-II deficiency. Complexes III and IV were largely preserved; one patient had partial complex-I reduction, while normal aconitase argued against a generalized iron–sulfur assembly defect. Why the heart is much more affected than other tissues remains unresolved (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 4-5).

Mouse supporting mechanism: cardiac/muscle Sdhaf4 deletion suppresses SDHA–SDHB assembly, accelerates subunit degradation, increases ROS/protein oxidation, raises succinate, lowers fumarate, activates DRP1-dependent fission/mitophagy, and causes progressive DCM and lethal heart failure. Importantly, metabolic abnormalities precede gross remodeling, supporting complex-II failure as upstream rather than merely a consequence of heart failure. Fumarate supplementation or fission inhibition partially rescued function and survival in mice. The authors’ exact abstract wording was that loss of Sdhaf4 causes “globally impaired metabolic capacity and activation of dynamin-related protein 1, which induces excess mitochondrial fission and mitophagy, thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals” (published July 2022; DOI: https://doi.org/10.1038/s41467-022-31548-1) (wang2022cardiacdisruptionof pages 1-2, wang2022cardiacdisruptionof pages 10-12).

Omics: no DCM1GG patient-specific transcriptome, proteome, metabolome, lipidome, single-cell, spatial-transcriptomic, or integrated multi-omic dataset was found. Public human DCM expression data show reduced SDHAF4, but this is general DCM and does not establish the mechanism of SDHA G555E (wang2022cardiacdisruptionof pages 1-2).

Suggested ontology annotations:

  • GO: succinate dehydrogenase activity; tricarboxylic acid cycle; mitochondrial electron transport, succinate to ubiquinone; oxidative phosphorylation; ATP metabolic process; reactive oxygen species metabolic process; mitochondrial fission; mitophagy; cardiac muscle contraction; ventricular cardiac muscle tissue morphogenesis. Exact IDs should be resolved against the current GO release.
  • Cell Ontology: cardiomyocyte (CL:0000746), ventricular cardiomyocyte, cardiac fibroblast, vascular endothelial cell, and cardiac macrophage. Only cardiomyocytes have direct mechanistic priority; fibrosis/immune-cell involvement is plausible downstream biology, not subtype-demonstrated.
  • Cellular component: mitochondrial matrix, mitochondrial inner membrane, succinate dehydrogenase complex, respiratory-chain complex II.

7. Anatomical structures affected

The primary organ is the heart, especially the left ventricular myocardium; both ventricles can be involved under the broader DCM definition. Suggested anatomy terms include UBERON heart (UBERON:0000948), left ventricle (UBERON:0002084), myocardium, interventricular septum, papillary/mitral apparatus, and cardiac muscle tissue. Exact ontology IDs beyond the first two should be release-validated.

At tissue/cell level, ventricular cardiomyocytes are the primary affected population; secondary remodeling may involve cardiac fibroblasts, vascular cells, and inflammatory cells. Subcellular involvement is mitochondrial—matrix-facing catalytic complex II associated with the inner mitochondrial membrane. There is no lateralization; “left” denotes ventricular anatomy, not unilateral disease.

Secondary organ effects arise from low cardiac output and congestion: lungs/respiratory system, liver, kidneys, and systemic circulation may be affected in advanced failure. Neurologic and skeletal-muscle disease were notably absent in the defining isolated-cardiomyopathy cohort, although other biallelic SDHA phenotypes can involve brain and muscle (levitas2010familialneonatalisolated pages 2-3).

8. Temporal development

  • Typical onset: prenatal, neonatal, or infantile; outliers may be detected later in childhood.
  • Pattern: usually insidious structural dysfunction followed by acute decompensation, respiratory distress, or shock. Three patients were recognized at 32–33 gestational weeks (levitas2010familialneonatalisolated pages 3-4).
  • Early stage: cardiomegaly/LV dilation, sometimes asymptomatic; mildly reduced function.
  • Intermediate stage: declining shortening, noncompaction morphology, mitral insufficiency, exercise intolerance, recurrent CHF admissions.
  • Advanced stage: severe noncontractile LV, cardiogenic shock, refractory failure, or sudden death.
  • Course: chronic lifelong genetic vulnerability with highly variable progression. Several deaths occurred at 1–11 months, while survivors reached 7–11 years with normal school performance but sometimes exercise limitation (levitas2010familialneonatalisolated pages 3-4).
  • Remission/recovery: no robust spontaneous-remission rate or treatment-induced reverse-remodeling statistic is available. The clinically normal homozygous adult represents nonpenetrance rather than documented recovery (levitas2010familialneonatalisolated pages 4-5, levitas2010familialneonatalisolated pages 5-6).
  • Critical window: fetal life and the first year are the principal vulnerability period in the known cohort, supporting immediate evaluation after prenatal cardiomegaly, neonatal distress, or identification of an at-risk genotype.

9. Inheritance and population

Inheritance

Inheritance is autosomal recessive. For two confirmed heterozygous parents, each pregnancy has a 25% probability of an affected biallelic child, 50% of a heterozygous carrier, and 25% of a child inheriting neither familial allele. Expressivity is markedly variable and penetrance is incomplete, demonstrated by one clinically normal homozygous adult (levitas2010familialneonatalisolated pages 4-5, levitas2010familialneonatalisolated pages 5-6).

There is no evidence of anticipation. Germline mosaicism was not reported. Consanguinity was central to the reported pedigrees, and the shared tribal/family context supports a founder effect. Carrier frequency in the tribe and in global populations remains unknown. No reliable sex ratio can be estimated from 15 founder cases; both sexes were affected (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 3-4).

Epidemiology

No population prevalence or incidence exists for DCM1GG. Only 15 cases in the defining report were characterized, so any cases-per-100,000 estimate would be misleading. SDH deficiency broadly was described as approximately 2% of mitochondrial respiratory-chain disorders, but that is not the prevalence of DCM1GG (levitas2010familialneonatalisolated pages 1-2).

Geographic/ancestry evidence is limited to the reported consanguineous Bedouin tribe in Israel. The disease should not be characterized as exclusive to this population; rather, this particular founder variant and phenotype were discovered there.

10. Diagnostics

Clinical diagnosis

Current cardiomyopathy practice begins with a three-generation pedigree, physical examination, ECG, echocardiography, laboratory evaluation, and exclusion of coronary, hypertensive, valvular, congenital, toxic, infectious, and loading causes sufficient to explain the phenotype. The 2023 ESC definition describes cardiomyopathies as myocardial disorders with structural/functional abnormality absent those alternative causes. The 2024 ESC commentary emphasizes ECG, first-/second-level biomarkers, multimodality imaging, and a genetics pathway (published April 2024; DOI: https://doi.org/10.1093/eurheartjsupp/suae002) (grasso2024thenew2023 pages 1-2).

Recommended tests:

  1. Echocardiography: LV dimensions indexed to age/body size, shortening/ejection fraction, global/regional function, trabeculation/noncompaction, mitral regurgitation, RV involvement.
  2. ECG and rhythm monitoring: standard ECG, Holter/event monitoring where symptomatic or with ventricular dysfunction; DCM1GG has no established signature beyond LVH in the founder cohort.
  3. CMR: ventricular volumes/function, fibrosis by late gadolinium enhancement, edema/inflammation, and alternative diagnoses; sedation/instability may limit neonatal use.
  4. Laboratory studies: BNP/NT-proBNP and troponin for heart-failure/injury assessment; electrolytes, renal/liver function, CBC, thyroid studies, CK; lactate, pyruvate, glucose, amino/organic acids, acylcarnitines, and carnitine when mitochondrial/metabolic DCM is suspected. Biomarkers are supportive, not diagnostic. Recent guideline synthesis identifies natriuretic peptides and high-sensitivity troponin as consensus tests (sorella2025diagnosisandmanagement pages 12-13).
  5. Respiratory-chain testing: complex-II assays in muscle or myocardium can support causality. A normal/mild lymphoblast or skeletal-muscle result does not exclude severe cardiac deficiency because tissue specificity was profound (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 4-5).
  6. Biopsy: not routinely required solely to diagnose DCM1GG; consider when myocarditis, infiltrative disease, storage disease, or unresolved mitochondrial disease would change management. ESC commentary notes that biopsy remains reserved for selected indications (grasso2024thenew2023 pages 1-2).

Genetic testing

A cardiomyopathy/mitochondrial panel that includes SDHA, or trio exome/genome sequencing with CNV analysis, is appropriate for severe neonatal DCM, especially with consanguinity. If the familial variant is known, targeted testing for c.1664G>A is fastest and least expensive. Confirm in an accredited laboratory with segregation testing. WES/WGS is especially useful for phenotypic expansion, locus heterogeneity, deep intronic/structural variants, or a negative panel. RNA sequencing may resolve splice variants but has no established routine DCM1GG biomarker role.

CMA, karyotyping, and FISH have low expected yield for an isolated known SNV but may be used for syndromic congenital anomalies. mtDNA sequencing can be included in unexplained mitochondrial cardiomyopathy, although SDHA itself is nuclear encoded. Repeat-expansion testing is not relevant unless another phenotype indicates it.

Diagnostic criteria and differential diagnosis

A defensible molecular diagnosis requires (i) DCM phenotype, (ii) biallelic pathogenic/likely pathogenic SDHA variants with appropriate segregation, and (iii) exclusion of stronger alternative causes; complex-II biochemical deficiency strengthens the diagnosis. A VUS alone is insufficient.

Important differentials include viral/immune myocarditis, anomalous coronary origin or ischemia, congenital heart disease, tachycardia-induced cardiomyopathy, endocrine/nutritional causes, Barth syndrome (TAZ), mitochondrial translation/OXPHOS defects, fatty-acid oxidation disorders, CoQ deficiency, glycogen/storage disease, and other recessive DCM genes. Leigh syndrome should be evaluated if developmental regression, seizures, hypotonia, movement disorder, or characteristic MRI lesions occur. The founder cohort’s normal neuromuscular examinations and two negative brain MRIs support an isolated cardiac presentation, not exclusion of neurologic SDHA disease in every genotype (levitas2010familialneonatalisolated pages 2-3).

Family screening

Once a pathogenic familial genotype is established, offer genetic counseling and cascade testing. Biallelic relatives require cardiac evaluation even if asymptomatic because penetrance is variable; heterozygous relatives need reproductive counseling and individualized assessment. Contemporary ESC/AHA guidance strongly supports cascade screening after identification of a pathogenic variant (sorella2025diagnosisandmanagement pages 12-13).

11. Outcome and prognosis

The defining report states exactly that the condition was “marked by high mortality, with two-thirds succumbing to cardiac failure.” Given 15 cases, this corresponds to approximately ten deaths, although follow-up duration varied. Deaths in the table clustered in early infancy, including cardiogenic shock and one sudden death at home. Several children survived to 7–11 years with normal schooling, showing substantial within-genotype variability (levitas2010familialneonatalisolated pages 3-4, levitas2010familialneonatalisolated pages 5-6).

No reliable 5- or 10-year survival curve, median life expectancy, disability-adjusted life-year estimate, or validated subtype-specific prognostic score exists. Prognosis is likely worse with prenatal onset, severe LV dilation, fractional shortening <10%, recurrent CHF, cardiogenic shock, and failure to improve with therapy, but these have not been formally modeled.

Major complications are chronic/refractory heart failure, pulmonary congestion, mitral regurgitation, arrhythmia/sudden death, thromboembolism in severe ventricular dysfunction, end-organ hypoperfusion, mechanical-support requirement, and transplantation. Quality-of-life morbidity includes repeated hospitalization and exercise limitation; formal patient-reported outcomes are absent.

12. Treatment

Current clinical strategy

There is no approved SDHA- or DCM1GG-specific therapy. Treatment follows age-appropriate DCM and heart-failure guidance in a pediatric cardiomyopathy/mitochondrial center:

  • diuretics for congestion;
  • guideline-directed systolic-heart-failure therapy as age, blood pressure, renal function, and pediatric evidence permit—ACE inhibitor/ARB or ARNI, evidence-based beta blocker, mineralocorticoid-receptor antagonist, and in suitable older patients an SGLT2 inhibitor;
  • inotropes/vasoactive support for cardiogenic shock;
  • anticoagulation only for standard indications such as intracardiac thrombus, embolism, atrial arrhythmia, or severe dysfunction with additional risk;
  • rhythm surveillance and treatment; ICD/CRT decisions are individualized because no DCM1GG-specific threshold exists;
  • mechanical circulatory support as bridge to recovery/transplant and cardiac transplantation for refractory advanced disease. Guideline synthesis recommends transplantation for refractory NYHA III–IV disease and consideration of mechanical support as bridge therapy (sorella2025diagnosisandmanagement pages 12-13).

Suggested NCIt intervention concepts include heart-failure therapy, diuretic therapy, ACE-inhibitor therapy, beta-blocker therapy, implantable cardioverter-defibrillator, ventricular assist device, and heart transplantation; exact NCIt codes should be resolved in the current thesaurus.

Mitochondrial supplements and pharmacogenomics

Riboflavin, coenzyme Q10, carnitine, antioxidants, or other “mitochondrial cocktails” are sometimes used empirically in respiratory-chain disease, but no controlled efficacy evidence exists for SDHA G555E cardiomyopathy. They should not replace heart-failure therapy. No DCM1GG pharmacogenomic dosing rule is established.

Experimental therapies

Fumarate supplementation and DRP1/mitochondrial-fission inhibition improved function and survival in Sdhaf4-deficient mice, not DCM1GG patients. These findings are hypothesis-generating and do not justify clinical fumarate or fission-inhibitor use outside a protocol (wang2022cardiacdisruptionof pages 1-2, wang2022cardiacdisruptionof pages 10-12).

No dedicated DCM1GG clinical trial, approved gene replacement/editing therapy, ASO/siRNA therapy, or cell therapy was identified. ClinicalTrials.gov searches returned SDH-deficient oncology studies and a broad mitochondrial registry, not therapeutic DCM1GG trials; the oncology studies are not applicable to cardiomyopathy.

13. Prevention

Primary prevention of the genotype: carrier identification in the founder family/population, genetic counseling, partner testing, preimplantation genetic testing, prenatal diagnosis, and use of donor gametes where desired. There is no vaccine or medication preventing inheritance.

Secondary prevention: cascade testing followed by baseline and longitudinal ECG/echocardiography, with CMR and rhythm monitoring as appropriate. Prenatal/fetal echocardiography is reasonable in at-risk pregnancies because onset occurred as early as 32 weeks (levitas2010familialneonatalisolated pages 3-4).

Tertiary prevention: early treatment of ventricular dysfunction and congestion; vaccination according to routine schedules; prompt infection management; avoidance of smoking, cardiotoxic exposures, illicit stimulants, excessive alcohol, prolonged fasting/dehydration, and unsupervised intense exercise; and individualized arrhythmic/thromboembolic risk management.

Population-wide newborn screening is not established. Targeted founder/carrier screening may be reasonable only after local validation of variant frequency, analytical performance, counseling infrastructure, and community engagement.

14. Other species and natural disease

No naturally occurring animal disease specifically caused by the orthologous SDHA Gly555Glu variant was identified. Therefore, no validated breed association, VBO term, veterinary prevalence, zoonotic potential, or cross-species transmission exists. This is a noninfectious inherited disorder and is not zoonotic.

SDHA and complex-II biology are evolutionarily conserved across mammals and other eukaryotes. Comparative relevance lies in conserved succinate oxidation, electron transfer, mitochondrial energetics, and redox regulation—not in a documented naturally occurring veterinary DCM1GG syndrome.

15. Model organisms

Available models

  • Mouse, conditional Sdhaf4 loss: the strongest cardiac model of complex-II assembly failure. It reproduces complex-II deficiency, metabolic deterioration, excessive fission/mitophagy, progressive LV dilation/heart failure, and lethality. It enabled rescue experiments with fumarate and mitochondrial-fission inhibition (wang2022cardiacdisruptionof pages 1-2, wang2022cardiacdisruptionof pages 10-12).
  • Cellular/biochemical systems: patient lymphoblasts, skeletal-muscle mitochondria, and postmortem myocardium demonstrate tissue-specific enzyme loss, but they are assays rather than renewable cardiomyocyte disease models (levitas2010familialneonatalisolated pages 2-3, levitas2010familialneonatalisolated pages 4-5).
  • General SDH models: SDH-subunit knockout cell and zebrafish systems can study succinate accumulation and respiratory deficiency, but they do not reproduce the specific G555E cardiac phenotype and should be annotated as indirect.

Limitations and priority models

The Sdhaf4 mouse disrupts an assembly factor, not SDHA Gly555Glu, and deletion may be more severe or mechanistically different from a hypomorphic missense allele. No retrieved model reproduced the human tissue-selective penetrance or the unaffected homozygous adult.

High-priority future resources are: (1) CRISPR knock-in Sdha p.Gly555Glu mice; (2) patient-derived iPSC ventricular cardiomyocytes and engineered heart tissues; (3) isogenic corrected controls; (4) stress challenges such as pacing, hypoxia, fever-like temperature, or nutrient limitation; and (5) single-cell/spatial multi-omics to distinguish cardiomyocyte-autonomous failure from fibroblast, vascular, and immune remodeling.

Current understanding and 2023–2024 developments

The major 2023–2024 advance relevant to implementation is not a new DCM1GG cohort but the 2023 ESC cardiomyopathy framework, summarized in 2024, which makes advanced imaging, deep phenotyping, and genetics central to family-based care and cautions that LV noncompaction is a morphologic trait rather than necessarily a separate disease (grasso2024thenew2023 pages 1-2). The mechanistic field has advanced through cardiac complex-II models demonstrating that metabolic injury can precede structural DCM and may be partly reversible experimentally, but translation to SDHA G555E patients remains untested (wang2022cardiacdisruptionof pages 1-2, wang2022cardiacdisruptionof pages 10-12).

The key knowledge gaps are consequently substantial: modern ClinVar/gnomAD characterization of the founder allele; incidence and carrier frequency; prospective penetrance; long-term survival; arrhythmic risk; patient-derived cardiomyocyte models; direct ATP/redox/metabolomic measurements; modifier discovery; and genotype-directed therapy. Until these are addressed, authoritative interpretation should treat DCM1GG as a well-supported but extremely rare SDHA-associated founder cardiomyopathy whose numerical natural-history estimates are provisional.

References

  1. (OpenTargets Search: Dilated cardiomyopathy-SDHA): Open Targets Query (Dilated cardiomyopathy-SDHA, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (levitas2010familialneonatalisolated pages 1-2): Aviva Levitas, Emad Muhammad, Gali Harel, Ann Saada, Vered Chalifa Caspi, Esther Manor, John C Beck, Val Sheffield, and Ruti Parvari. Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. European Journal of Human Genetics, 18:1160-1165, Jun 2010. URL: https://doi.org/10.1038/ejhg.2010.83, doi:10.1038/ejhg.2010.83. This article has 142 citations and is from a domain leading peer-reviewed journal.

  3. (levitas2010familialneonatalisolated pages 2-3): Aviva Levitas, Emad Muhammad, Gali Harel, Ann Saada, Vered Chalifa Caspi, Esther Manor, John C Beck, Val Sheffield, and Ruti Parvari. Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. European Journal of Human Genetics, 18:1160-1165, Jun 2010. URL: https://doi.org/10.1038/ejhg.2010.83, doi:10.1038/ejhg.2010.83. This article has 142 citations and is from a domain leading peer-reviewed journal.

  4. (levitas2010familialneonatalisolated pages 5-6): Aviva Levitas, Emad Muhammad, Gali Harel, Ann Saada, Vered Chalifa Caspi, Esther Manor, John C Beck, Val Sheffield, and Ruti Parvari. Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. European Journal of Human Genetics, 18:1160-1165, Jun 2010. URL: https://doi.org/10.1038/ejhg.2010.83, doi:10.1038/ejhg.2010.83. This article has 142 citations and is from a domain leading peer-reviewed journal.

  5. (levitas2010familialneonatalisolated pages 4-5): Aviva Levitas, Emad Muhammad, Gali Harel, Ann Saada, Vered Chalifa Caspi, Esther Manor, John C Beck, Val Sheffield, and Ruti Parvari. Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. European Journal of Human Genetics, 18:1160-1165, Jun 2010. URL: https://doi.org/10.1038/ejhg.2010.83, doi:10.1038/ejhg.2010.83. This article has 142 citations and is from a domain leading peer-reviewed journal.

  6. (levitas2010familialneonatalisolated pages 3-4): Aviva Levitas, Emad Muhammad, Gali Harel, Ann Saada, Vered Chalifa Caspi, Esther Manor, John C Beck, Val Sheffield, and Ruti Parvari. Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase. European Journal of Human Genetics, 18:1160-1165, Jun 2010. URL: https://doi.org/10.1038/ejhg.2010.83, doi:10.1038/ejhg.2010.83. This article has 142 citations and is from a domain leading peer-reviewed journal.

  7. (wang2022cardiacdisruptionof pages 1-2): Xueqiang Wang, Xing Zhang, Ke Cao, Mengqi Zeng, Xuyang Fu, Adi Zheng, Feng Zhang, Feng Gao, Xuan Zou, Hao Li, Min Li, Weiqiang Lv, Jie Xu, Jiangang Long, Weijin Zang, Jinghai Chen, Feng Gao, Jian Ding, Jiankang Liu, and Zhihui Feng. Cardiac disruption of sdhaf4-mediated mitochondrial complex ii assembly promotes dilated cardiomyopathy. Nature Communications, Jul 2022. URL: https://doi.org/10.1038/s41467-022-31548-1, doi:10.1038/s41467-022-31548-1. This article has 67 citations and is from a highest quality peer-reviewed journal.

  8. (wang2022cardiacdisruptionof pages 10-12): Xueqiang Wang, Xing Zhang, Ke Cao, Mengqi Zeng, Xuyang Fu, Adi Zheng, Feng Zhang, Feng Gao, Xuan Zou, Hao Li, Min Li, Weiqiang Lv, Jie Xu, Jiangang Long, Weijin Zang, Jinghai Chen, Feng Gao, Jian Ding, Jiankang Liu, and Zhihui Feng. Cardiac disruption of sdhaf4-mediated mitochondrial complex ii assembly promotes dilated cardiomyopathy. Nature Communications, Jul 2022. URL: https://doi.org/10.1038/s41467-022-31548-1, doi:10.1038/s41467-022-31548-1. This article has 67 citations and is from a highest quality peer-reviewed journal.

  9. (grasso2024thenew2023 pages 1-2): Maurizia Grasso, Davide Bondavalli, Viviana Vilardo, Claudia Cavaliere, Ilaria Gatti, Alessandro Di Toro, Lorenzo Giuliani, Mario Urtis, Michela Ferrari, Barbara Cattadori, Alessandra Serio, Carlo Pellegrini, and Eloisa Arbustini. The new 2023 esc guidelines for the management of cardiomyopathies: a guiding path for cardiologist decisions. European Heart Journal Supplements : Journal of the European Society of Cardiology, 26:i1-i5, Apr 2024. URL: https://doi.org/10.1093/eurheartjsupp/suae002, doi:10.1093/eurheartjsupp/suae002. This article has 18 citations.

  10. (sorella2025diagnosisandmanagement pages 12-13): Anna Sorella, Kristian Galanti, Lorena Iezzi, Sabina Gallina, Selma F Mohammed, Neha Sekhri, Mohammed Majid Akhtar, Sanjay K Prasad, Choudhary Anwar Ahmed Chahal, Fabrizio Ricci, and Mohammed Yunus Khanji. Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations. European Heart Journal. Quality of Care & Clinical Outcomes, 11:206-222, Dec 2025. URL: https://doi.org/10.1093/ehjqcco/qcae109, doi:10.1093/ehjqcco/qcae109. This article has 45 citations.

Artifacts

Reference Validation

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References checked 4
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Quoted claims checked 1
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  • DOI:10.1038/ejhg.2010.83: "extreme phenotypic variability"
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Term Validation

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  • MONDO:0013339 (2 mentions) - the report calls it "if available"; MONDO calls it dilated cardiomyopathy 1GG

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  • CL:0000746 (1 mention) - the report calls it "Cell Ontology: cardiomyocyte"; CL calls it cardiac muscle cell**, and lists "cardiomyocyte" among its other names