MT-ATP6/MT-ATP8-Related Infantile Hypertrophic Cardiomyopathy

Mendelian MONDO:0010777 Pathograph 17 Show in embeddings browser hereditary disease mitochondrial disease

Maternally inherited, infantile-onset hypertrophic cardiomyopathy caused by pathogenic point mutations in the overlapping reading frames of the two mitochondrial DNA-encoded subunits of ATP synthase (complex V), MT-ATP6 and MT-ATP8 (OMIM 500006). The reference lesion is m.8528T>C, reported by Ware and colleagues in four unrelated infants who presented with isolated hypertrophic cardiomyopathy: because ATP6 and ATP8 are read in overlapping frames, this single nucleotide substitution simultaneously destroys the ATP6 initiation codon and replaces a strictly conserved tryptophan at ATP8 position 55 with arginine, so one base change compromises both mtDNA-encoded subunits of the enzyme at once. ATP6 and ATP8 are the only two components of the 29-subunit human ATP synthase encoded by mitochondrial rather than nuclear DNA, and they are inserted last into the membrane (Fo) domain; without them the holoenzyme cannot be completed and the terminal, ATP-producing step of oxidative phosphorylation fails in a tissue whose energy demand is among the highest in the body. The mutation is heteroplasmic and segregates with disease within maternal kindreds, and very high cardiac heteroplasmy has been documented in a fatal infantile case. This entry is deliberately distinct from the several nuclear-gene mitochondrial disorders in this knowledge base that also present with infantile hypertrophic cardiomyopathy (COX15-related COX deficiency, MRPL44 deficiency, MTO1 deficiency, cardiomyopathy-hypotonia-lactic acidosis syndrome/SLC25A3, mitochondrial DNA depletion syndrome 14B/OPA1). Those are autosomal recessive nuclear defects of complex IV assembly, mitochondrial translation, phosphate supply, or mtDNA maintenance. The entity curated here is mitochondrially encoded and maternally transmitted, its defect is in complex V itself, and its distinguishing molecular feature - a single base altering two proteins through overlapping open reading frames - has no counterpart in the nuclear entries.

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1
Inheritance
10
Pathophys.
9
Phenotypes
2
Gaps
17
Pathograph
2
Genes
2
Variants
3
Medical Actions
2
Differentials
3
References
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Deep Research
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Classifications

Harrison's Part
CARDIOVASCULAR
Mechanistic Nosology
mitochondrial disease
👪

Inheritance

1
Mitochondrial inheritance HP:0001427
The causal variant lies in mitochondrial DNA and is therefore transmitted exclusively through the maternal line. It is heteroplasmic, so the proportion of mutant genomes varies between family members and between tissues, and clinical expression tracks that proportion rather than following a Mendelian segregation ratio.
Mitochondrial inheritance
Show evidence (1 reference)
PMID:19188198 SUPPORT Human Clinical
"Testing of the relatives of one patient indicated that the mutation is heteroplasmic and correlated with disease."
Family testing establishing heteroplasmy that correlates with disease status is the direct evidence for maternal, heteroplasmy-dependent mitochondrial inheritance.
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Discussions and Knowledge Gaps

2
Is the infantile cardiomyopathy of m.8528T>C driven by loss of the MT-ATP6 initiation codon, by the MT-ATP8 p.Trp55Arg substitution, or does it require both?
KNOWLEDGE GAP OPEN atp6_vs_atp8_driver
Attached to
pathophysiology#m.8528T>C Substitution in the MT-ATP6/MT-ATP8 Overlap
The variant's two consequences fall in different genes and are not separable in patients, because the overlapping reading frames make it impossible for a natural allele to carry one without the other. The current best inference, stated in the 2024 ATP synthase review, is that loss of subunit a is the primary driver of the assembly defect - and the natural experiment supports it, since the adjacent m.8529G>A variant truncates only A6L, spares subunit a, and produces later-onset (about four years), substantially milder disease at comparably high heteroplasmy. But the review reaches that conclusion by analogy to a different MT-ATP6 variant rather than by measurement, and it immediately notes that the A6L-only lesion still destabilises the complex. No cybrid or transmitochondrial study of m.8528T>C itself has been reported, so the relative contribution of the two arms remains an inference.
Proposed experiments
Transmitochondrial cybrids carrying m.8528T>C
exp_cmih_m8528_cybrids
Generate cybrid clones spanning a range of m.8528T>C heteroplasmy and measure complex V assembly by blue native PAGE, ATP synthesis rate, and steady-state ATP6 and ATP8 protein levels, to establish which subunit is lost and at what mutant load the defect appears.
Separated-frame expression of the two consequences
exp_cmih_separated_frames
Express the ATP6 start-codon change and the ATP8 p.Trp55Arg substitution independently in a recoded or heterologous system to attribute the assembly defect to one arm, the other, or their combination.
Show evidence (2 references)
PMID:39016153 SUPPORT Other
"one would expect that the lack of subunit a is the primary driver of diminished assembly/stability of complex V in the case of m.8528T>C substitution."
The review states the leading hypothesis in explicitly hypothetical terms ("one would expect"), which is why this remains an open knowledge gap rather than a curated mechanism.
PMID:39016153 SUPPORT Human Clinical
"m.8529G>A variant exhibited a high degree of heteroplasmy (over 90 %), yet the disease course was rather milder, with later onset at 4 years of age."
The allelic comparison at matched heteroplasmy is the strongest available argument that the ATP6/subunit a arm accounts for the infantile severity of m.8528T>C.
Why is the phenotype of m.8528T>C cardiac-restricted when the mutant genome is present in every tissue?
KNOWLEDGE GAP OPEN cardiac_restriction
Attached to
pathophysiology#Cardiac Heteroplasmy Threshold
The index series described isolated hypertrophic cardiomyopathy without the encephalopathy, myopathy or optic involvement typical of other MT-ATP6 disease, and the one variant carrier with tissue data had 90% cardiac heteroplasmy. Whether the restriction reflects tissue-specific segregation of mutant genomes, a lower threshold in a tissue with extreme ATP demand, or both has not been determined, and no systematic multi-tissue heteroplasmy survey of this variant exists.
Proposed experiments
Multi-tissue heteroplasmy mapping in autopsy material
exp_cmih_multitissue_heteroplasmy
Quantify m.8528T>C heteroplasmy across heart, skeletal muscle, brain, liver and blood in the same individuals to test whether the cardiac predominance is a segregation effect or a threshold effect.
Show evidence (1 reference)
PMID:40112238 SUPPORT Human Clinical
"The CNS was the most frequently affected tissue (93%), followed by the muscle (75%), eye (46%), and heart (18%)."
Across MT-ATP6/MT-ATP8 deficiency the heart is the least often involved of the four main tissues, which is what makes a cardiac-restricted presentation for m.8528T>C a question worth posing rather than the expected default.
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Pathophysiology

10
m.8528T>C Substitution in the MT-ATP6/MT-ATP8 Overlap
MT-ATP8 and MT-ATP6 are transcribed as a bicistronic message whose reading frames overlap by 46 nucleotides. Position 8528 falls inside that overlap. The m.8528T>C substitution therefore has two simultaneous consequences in two different proteins: it converts the ATP6 initiation codon (ATG) so that the encoded residue is threonine rather than methionine, and it replaces tryptophan 55 of ATP8, a strictly conserved hydrophobic residue, with the strongly basic arginine. This is the defining molecular lesion of the entity, and the first reported mutation to hit both mtDNA-encoded complex V subunits at once.
MT-ATP6 hgnc:7414 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MT-ATP6 (hgnc:7414). hgnc:7414 is a gene from the HUGO Gene Nomenclature Committee. MT-ATP8 hgnc:7415 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MT-ATP8 (hgnc:7415). hgnc:7415 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Failure to Insert ATP6 and ATP8 into the ATP Synthase Membrane Domain Loss of the ATP6 start codon and a charge-reversing substitution in the membrane-embedded ATP8 protein both act on the availability and integrability of the two mtDNA-encoded Fo subunits.
Show evidence (4 references)
PMID:19188198 SUPPORT Human Clinical
"This results in a change of the initiation codon in ATPase 6 to threonine and a concurrent change from a highly conserved hydrophobic amino acid, tryptophan, at position 55 of ATPase 8 to a highly basic arginine."
States both consequences of the single substitution, which is the whole basis for treating this as one lesion affecting two gene products.
PMID:19188198 SUPPORT Human Clinical
"To our knowledge, this is the first report of a mutation affecting both mitochondrial genome-encoded complex V subunit proteins."
Confirms that both mtDNA-encoded complex V subunits are affected by the same variant.
PMID:39016153 SUPPORT Human Clinical
"The majority of patients carry m.8528T>C missense variant of MT-ATP8/MT-ATP6 overlapping region, which affects both subunits."
A 2024 review of isolated ATP synthase defects identifies m.8528T>C as the dominant reported MT-ATP8/MT-ATP6 overlap allele and restates the dual-subunit consequence.
+ 1 more reference
Failure to Insert ATP6 and ATP8 into the ATP Synthase Membrane Domain
Human ATP synthase is an assembly of 29 subunits of 18 kinds, of which only ATP6 and ATP8 are encoded in mitochondrial DNA. Assembly proceeds through a nuclear-encoded intermediate - the F1-c8 complex attached to the peripheral stalk with subunits e, f and g - into which ATP6 and ATP8, translated on mitochondrial ribosomes, are inserted last; the 6.8 proteolipid then locks them in place and only at that point is the complex coupled to ATP synthesis. A lesion that removes or destabilises either mtDNA-encoded subunit therefore arrests assembly at the final, coupling-conferring step rather than preventing formation of the F1 head.
mitochondrial ATP synthase complex assembly GO:0033615 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial ATP synthase complex assembly, annotated with mitochondrial proton-transporting ATP synthase complex assembly (GO:0033615). GO:0033615 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.
Downstream
Complex V Holoenzyme Deficiency with Accumulation of Subcomplexes Without stable incorporation of the mtDNA-encoded subunits the holoenzyme cannot be completed, and the partially assembled species persist.
Show evidence (2 references)
PMID:29440398 SUPPORT In Vitro
"All but two membrane components are encoded in nuclear genes, synthesized on cytoplasmic ribosomes, and imported into the matrix of the organelle, where they are assembled into the complex with ATP6 and ATP8, the products of overlapping genes in mitochondrial DNA."
Identifies ATP6 and ATP8 as the only mtDNA-encoded membrane components and names the overlapping-gene arrangement that makes a single substitution able to hit both.
PMID:29440398 SUPPORT In Vitro
"Their association with the complex is stabilized by addition of the 6.8 proteolipid, and the complex is coupled to ATP synthesis at this point."
Places ATP6/ATP8 incorporation at the step that confers coupling, so failure here leaves an uncoupled or incomplete enzyme rather than merely a smaller one.
Complex V Holoenzyme Deficiency with Accumulation of Subcomplexes
The biochemical consequence is an isolated deficiency of assembled, catalytically competent ATP synthase. In the closest characterised human model - a homoplasmic MT-ATP8 nonsense variant one base away, at m.8529 - patient fibroblasts, muscle and transmitochondrial cybrids all showed reduced complex V activity, absent holocomplex V, an excess of ATP synthase subcomplexes, and in-gel activity of free F1-ATPase, i.e. an unattached catalytic head no longer coupled to a proton channel.
proton-transporting ATP synthase complex GO:0045259 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves decreased proton-transporting ATP synthase complex (GO:0045259). GO:0045259 is a protein complex from the Gene Ontology.
proton-transporting ATP synthase activity, rotational mechanism GO:0046933 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased proton-transporting ATP synthase activity, rotational mechanism (GO:0046933). GO:0046933 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Proton-Coupled Mitochondrial ATP Synthesis A holoenzyme that cannot be completed cannot use the proton-motive force to make ATP.
Disrupted ATP Synthase Dimerisation and Cristae Architecture ATP synthase monomers dimerise through contacts between ATP6 subunits, so a defect in ATP6 incorporation also removes the oligomerisation that shapes the inner membrane.
Show evidence (2 references)
PMID:17954552 SUPPORT In Vitro
"Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNA."
Cybrid transfer assigns the complex V defect to the patient's mitochondrial DNA rather than to nuclear background, which is the key control for an mtDNA-encoded subunit lesion.
PMID:17954552 SUPPORT In Vitro
"An in-gel activity assay of ATP hydrolysis showed activity of free F(1)-ATPase in the patient's muscle tissue and in the cybrid clones."
Free F1-ATPase is the signature of a catalytic head that was never joined to an intact Fo domain, confirming where assembly stalls.
Impaired Proton-Coupled Mitochondrial ATP Synthesis
Loss of a functional Fo proton channel uncouples the respiratory-chain proton gradient from phosphorylation, so oxidative ATP output falls even though electron transport upstream of complex V may be intact. This is an isolated complex V lesion rather than a combined respiratory chain defect.
proton motive force-driven mitochondrial ATP synthesis GO:0042776 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proton motive force-driven mitochondrial ATP synthesis (GO:0042776). GO:0042776 is a biological process from the Gene Ontology. ↓ DECREASED proton transmembrane transport GO:1902600 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proton transmembrane transport (GO:1902600). GO:1902600 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Cardiomyocyte Energy Deficit Cardiac muscle sustains continuous contractile work and is among the most ATP-dependent tissues, so a fall in oxidative ATP supply is felt there first.
Show evidence (1 reference)
PMID:33600551 SUPPORT Model Organism
"We previously showed that the equivalent mutation (aL173R) dramatically compromises respiratory growth of Saccharomyces cerevisiae and causes a 90% drop in the rate of mitochondrial ATP synthesis."
Quantifies how severely a single pathogenic ATP6 substitution can suppress mitochondrial ATP synthesis in a tractable model of the same subunit.
Disrupted ATP Synthase Dimerisation and Cristae Architecture
Beyond catalysis, ATP synthase dimers and their oligomeric rows along the cristae edges impose the curvature of the inner mitochondrial membrane. Failure to incorporate ATP6 therefore has a structural consequence as well as a bioenergetic one, degrading the cristae surface on which the whole respiratory chain is organised. This arm is inferred from the assembly and membrane-shaping literature rather than from ultrastructural study of m.8528T>C hearts.
cristae formation GO:0042407 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cristae formation (GO:0042407). GO:0042407 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.
Downstream
Cardiomyocyte Energy Deficit Loss of cristae surface reduces the membrane area available for oxidative phosphorylation, compounding the direct catalytic deficit.
Show evidence (1 reference)
PMID:11823415 SUPPORT Model Organism
"The present data show that there is a link between dimerization of the mitochondrial ATP synthase and cristae morphology."
Establishes the dimerisation-to-cristae link in yeast, which is the basis for expecting a membrane-architecture consequence when ATP6 incorporation fails.
Cardiomyocyte Energy Deficit
Cardiomyocytes carrying a high burden of mutant genomes cannot meet contractile ATP demand from oxidative phosphorylation. The shortfall is partly offset by glycolysis, at the cost of lactate production, and drives the compensatory responses that produce the hypertrophic phenotype.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
ATP biosynthetic process GO:0006754 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ATP biosynthetic process (GO:0006754). GO:0006754 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Compensatory Cardiomyocyte Hypertrophy The failing myocardium responds with cell growth and remodelling.
Systemic Lactate Accumulation Glycolytic compensation for the oxidative shortfall raises lactate output.
Show evidence (1 reference)
PMID:33718303 SUPPORT Human Clinical
"HCM is the most common form of mitochondrial cardiomyopathy; however, other forms of cardiomyopathies are possible."
Links the mitochondrial energy defect in cardiomyocytes to a predominantly hypertrophic, rather than dilated, cardiac phenotype.
Compensatory Cardiomyocyte Hypertrophy
Energy-deficient cardiomyocytes enlarge, and the ventricular wall thickens. In this disorder the hypertrophy is not a response to abnormal loading - outflow obstruction or hypertension - but to an intrinsic metabolic defect, which is why the entity is classified as a non-sarcomeric, secondary hypertrophic cardiomyopathy.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac muscle hypertrophy GO:0003300 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cardiac muscle hypertrophy (GO:0003300). GO:0003300 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Progressive Heart Failure of Infancy Hypertrophic remodelling in a myocardium that cannot generate ATP progresses to pump failure rather than stabilising.
Show evidence (1 reference)
PMID:33718303 SUPPORT Human Clinical
"Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by left ventricular hypertrophy not solely explained by abnormal loading conditions."
Defines the hypertrophy as load-independent, which is what a primary metabolic cause implies.
Systemic Lactate Accumulation
Reliance on glycolysis where oxidative phosphorylation is blocked raises circulating lactate. Elevated lactate is the classic, though neither sensitive nor specific, systemic marker of a primary mitochondrial disorder, and in an infant with unexplained hypertrophic cardiomyopathy it is one of the findings that redirects investigation toward mitochondrial DNA.
Show evidence (1 reference)
PMID:40112238 SUPPORT Human Clinical
"Reduced citrulline levels and increased alanine and lactate levels were reported in 56%, 49%, and 71% of patients, respectively, suggesting their role as potential biomarkers."
Lactate elevation is the commonest laboratory abnormality across MT-ATP6/MT-ATP8 deficiency. Marked PARTIAL because the cohort spans the whole spectrum, which is dominated by neurological m.8993 disease rather than by this cardiac entity.
Cardiac Heteroplasmy Threshold
Because the variant is heteroplasmic, each tissue carries a mixture of mutant and wild-type mitochondrial genomes and expresses a biochemical defect only once the mutant load passes a tissue-specific threshold. This is what makes the phenotype cardiac-predominant despite a genome present in every cell, and it accounts for the variable expression seen among maternal relatives. In a fatal infantile case the cardiac heteroplasmy level of m.8528T>C was 90%.
Downstream
Cardiomyocyte Energy Deficit The biochemical defect becomes manifest in cardiomyocytes only above the threshold mutant load.
Show evidence (4 references)
PMID:30642647 SUPPORT Human Clinical
"In the three patients with mitochondrial DNA mutations whose cardiac tissues were available, high heteroplasmy rates in the cardiac tissue were observed for m.8528T>C (90%, died at 2 months of age)"
Directly quantifies cardiac mutant load for this variant and ties a very high level to fatal infantile disease.
PMID:19188198 SUPPORT Human Clinical
"Testing of the relatives of one patient indicated that the mutation is heteroplasmic and correlated with disease."
Establishes that clinical status within a kindred tracks mutant load rather than mere presence of the variant.
PMID:39016153 SUPPORT Human Clinical
"The variant is typically present at a high heteroplasmy level, exceeding 90 %"
Gives the mutant-load range at which m.8528T>C is typically found in affected individuals.
+ 1 more reference
Progressive Heart Failure of Infancy
The clinical endpoint is a rapidly progressive infantile cardiomyopathy with high mortality. In a large paediatric mitochondrial disease cohort, children with cardiomyopathy had markedly worse survival than those without, and a child with the m.8528T>C variant died at two months of age.
Show evidence (2 references)
PMID:30642647 SUPPORT Human Clinical
"Ten-year Kaplan-Meier estimates of overall survival were 18 and 67%, respectively."
Quantifies the survival gap between paediatric mitochondrial disease with and without cardiomyopathy.
PMID:19188198 SUPPORT Human Clinical
"Infantile cardiomyopathy is a genetically heterogeneous disorder with significant morbidity and mortality."
States the clinical severity of the presentation this entity falls within.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MT-ATP6/MT-ATP8-Related Infantile Hypertrophic Cardiomyopathy 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

9
Cardiovascular 3
Hypertrophic Cardiomyopathy VERY_FREQUENT HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19188198 SUPPORT Human Clinical
"This study aimed to identify the mutation present in four unrelated patients who presented as infants with isolated hypertrophic cardiomyopathy."
All four probands in the defining series presented with isolated infantile hypertrophic cardiomyopathy, which supports both the phenotype and the VERY_FREQUENT band within the reported cohort.
Left Ventricular Hypertrophy 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:33718303 SUPPORT Human Clinical
"Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by left ventricular hypertrophy not solely explained by abnormal loading conditions."
Defines left ventricular hypertrophy as the anatomical finding underlying an HCM diagnosis in children, including the non-sarcomeric causes this entity belongs to.
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:30642647 SUPPORT Human Clinical
"BACKGROUND: Cardiomyopathy is a reported indicator of poor prognosis in children with mitochondrial disease."
Supports cardiac decompensation as the prognosis-determining course of paediatric mitochondrial cardiomyopathy.
Digestive 1
Feeding Difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39016153 SUPPORT Human Clinical
"feeding difficulties, developed, and two patients died within a few months of life."
Names feeding difficulties among the reported features and records the fatal outcome in two of the reported infants.
Metabolism 2
Metabolic Crises Episodic metabolic acidosis HP:0004911 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic crises, annotated with Episodic metabolic acidosis (HP:0004911). HP:0004911 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39016153 SUPPORT Human Clinical
"including heart failure, metabolic crises, hypotonia, failure to thrive (FTT),"
Lists metabolic crises among the life-threatening features developing in m.8528T>C patients, alongside the cardiac, tone, and growth manifestations this entry already curates from the same sentence.
Hyperammonemia HP:0001987 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperammonemia (HP:0001987). HP:0001987 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33180048 SUPPORT Human Clinical
"Here we describe a new case of adenosine-triphosphate (ATP) synthase deficiency due to m.8528T>C mutation as a novel cause of severe neonatal hyperammonemia."
Directly reports hyperammonemia in a patient carrying the defining variant.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39016153 SUPPORT Human Clinical
"including heart failure, metabolic crises, hypotonia, failure to thrive (FTT),"
Lists hypotonia among the features developing in m.8528T>C patients.
Growth 1
Failure to Thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39016153 SUPPORT Human Clinical
"including heart failure, metabolic crises, hypotonia, failure to thrive (FTT),"
Lists failure to thrive among the life-threatening features developing in m.8528T>C patients.
Other 1
Biventricular Hypertrophy HP:0001714 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular hypertrophy (HP:0001714). HP:0001714 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39016153 SUPPORT Human Clinical
"biventricular hypertrophy was found in almost all patients, with an early onset from prenatal to five months of life."
States that ventricular hypertrophy in this variant may be biventricular and gives the onset window.
🧬

Genetic Associations

2
MT-ATP6 (Mitochondrially encoded subunit a of ATP synthase. The m.8528T>C variant lies in the MT-ATP8/MT-ATP6 overlap and abolishes the MT-ATP6 initiation codon, so the reading frame's normal start methionine is replaced by threonine.)
Gene: MT-ATP6 hgnc:7414 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MT-ATP6 (hgnc:7414). hgnc:7414 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Mitochondrial inheritance
Show evidence (1 reference)
PMID:19188198 SUPPORT Human Clinical
"This results in a change of the initiation codon in ATPase 6 to threonine and a concurrent change from a highly conserved hydrophobic amino acid, tryptophan, at position 55 of ATPase 8 to a highly basic arginine."
States the MT-ATP6 consequence of the causal variant.
MT-ATP8 (Mitochondrially encoded subunit 8 of ATP synthase. The same m.8528T>C substitution replaces the strictly conserved tryptophan at position 55 with arginine, a hydrophobic-to-basic change in a membrane-embedded protein. An adjacent nonsense variant at m.8529 truncating the same residue is independently established as pathogenic and causes an assembly-level complex V defect.)
Gene: MT-ATP8 hgnc:7415 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MT-ATP8 (hgnc:7415). hgnc:7415 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Mitochondrial inheritance
Show evidence (2 references)
PMID:19188198 SUPPORT Human Clinical
"To our knowledge, this is the first report of a mutation affecting both mitochondrial genome-encoded complex V subunit proteins."
Confirms MT-ATP8 is affected alongside MT-ATP6 by the causal variant.
PMID:17954552 SUPPORT In Vitro
"We describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme."
Independently establishes MT-ATP8 as a gene in which loss of function produces complex V disease, supporting the MT-ATP8 arm of the m.8528T>C lesion.
🔬

Variants

2
m.8528T>C Pathogenic
Gene: MT-ATP6 hgnc:7414 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MT-ATP6 (hgnc:7414). hgnc:7414 is a gene from the HUGO Gene Nomenclature Committee.
Mitochondrial DNA substitution in the 46-nucleotide MT-ATP8/MT-ATP6 overlap. It changes the MT-ATP6 initiation codon so that threonine replaces the start methionine and, in the other reading frame, substitutes arginine for the conserved tryptophan at MT-ATP8 position 55. Heteroplasmic; identified in four unrelated infants with isolated hypertrophic cardiomyopathy, and subsequently reported at 90% cardiac heteroplasmy in a child who died at two months.
Show evidence (1 reference)
PMID:19188198 SUPPORT Human Clinical
"In all four, a novel mitochondrial m.8528T-->C mutation was identified."
Identifies the variant in all four probands of the defining series.
m.8529G>A (MT-ATP8 p.Trp55X) Pathogenic
Gene: MT-ATP8 hgnc:7415 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MT-ATP8 (hgnc:7415). hgnc:7415 is a gene from the HUGO Gene Nomenclature Committee.
Homoplasmic MT-ATP8 nonsense variant one nucleotide downstream of m.8528, truncating the same tryptophan residue. Reported in a 16-year-old with apical hypertrophic cardiomyopathy and neuropathy rather than in infantile disease, so it is curated here as allelic mechanistic context rather than as a variant of this entity.
Show evidence (1 reference)
PMID:17954552 SUPPORT Human Clinical
"A homoplasmic nonsense mutation m.8529G-->A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue."
Establishes the adjacent MT-ATP8 nonsense variant and its homoplasmic state.
💊

Medical Actions

3
Supportive Heart Failure Management
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
No disease-modifying therapy exists. Management is the standard supportive care of infantile cardiomyopathy - anticongestive therapy, nutritional support, and avoidance of catabolic stress - together with genetic counselling for maternal relatives.
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:33718303 SUPPORT Human Clinical
"To date, the only mitochondrial disorders with an etiologic treatment are those caused by CoQ10 deficiency and thiamine-responsive disorders"
Establishes that no etiologic therapy is available for mitochondrial disorders outside the CoQ10 and thiamine-responsive groups, which is why management here is supportive.
Heart 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
Cardiac transplantation is feasible in children with mitochondrial disease and isolated or dominant cardiac involvement. Post-transplant survival is comparable to that of other paediatric cardiomyopathy recipients, though with higher rates of stroke, prolonged ventilation and longer intensive care stays, so mitochondrial disease is not by itself an absolute contraindication. Extracardiac disease burden governs candidacy.
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 (2 references)
PMID:31711761 SUPPORT Human Clinical
"These results suggest that the presence of mitochondrial disease should not be an absolute contraindication to heart transplantation in the appropriate clinical setting."
Directly supports transplantation as an option in this population.
PMID:31711761 SUPPORT Human Clinical
"Patients with mitochondrial disease were more likely to have a stroke after heart transplantation (11% vs 3%; P = .009)"
Quantifies the excess perioperative morbidity that qualifies the recommendation.
Genetic Counselling for Maternal Relatives
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
Because transmission is exclusively maternal and heteroplasmy levels vary between offspring, counselling addresses recurrence risk for all children of a carrier mother and the limited predictive value of blood heteroplasmy measurement.
Show evidence (1 reference)
PMID:19188198 SUPPORT Human Clinical
"Testing of the relatives of one patient indicated that the mutation is heteroplasmic and correlated with disease."
Family testing that established heteroplasmic maternal transmission is the basis for counselling maternal relatives.
🔬

Biochemical Markers

3
Decreased Mitochondrial ATP Synthase (Complex V) Activity
Context: Isolated reduction of assembled complex V activity is the enzymological signature. It is measurable in skeletal muscle and in cultured fibroblasts, and can be assigned to the mitochondrial genome by cybrid transfer.
Show evidence (1 reference)
PMID:17954552 SUPPORT In Vitro
"Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNA."
Demonstrates the measurable enzymatic deficit and its mtDNA origin.
Reduced Synthesis of ATP6 and ATP8 and Reduced Complex V Levels
Context: Pulse-labelling and complex-level measurements in patients carrying m.8528T>C show markedly reduced synthesis of both mtDNA-encoded subunits and correspondingly low amounts of fully assembled ATP synthase, which is the biochemical demonstration that the variant acts through the subunits it encodes rather than through some indirect route.
Show evidence (1 reference)
PMID:39016153 SUPPORT In Vitro
"This pathogenic variant was shown to cause impaired synthesis of both subunits a and A6L, with low levels of complete ATP synthase detected in patient samples."
Reports the two biochemical consequences - loss of both subunits and loss of assembled complex V - specifically for m.8528T>C.
Elevated Plasma Lactate
Context: Raised lactate is the commonest laboratory abnormality across MT-ATP6/MT-ATP8 deficiency and reflects glycolytic compensation for blocked oxidative phosphorylation. The figure quoted is for the whole MT-ATP6/MT-ATP8 cohort, which is dominated by m.8993 neurological disease, not for m.8528T>C specifically.
Show evidence (1 reference)
PMID:40112238 SUPPORT Human Clinical
"Reduced citrulline levels and increased alanine and lactate levels were reported in 56%, 49%, and 71% of patients, respectively, suggesting their role as potential biomarkers."
Quantifies lactate elevation across the MT-ATP6/MT-ATP8 deficiency cohort; marked PARTIAL because the cohort is broader than this cardiac entity.
🔬

Diagnosis

2
Mitochondrial Genome Sequencing
Whole mitochondrial genome sequencing is the diagnostic test that identifies this entity, and is explicitly recommended in infants with hypertrophic cardiomyopathy. Because the variant is heteroplasmic and cardiac-predominant, a negative or low-level result in blood does not exclude it; heteroplasmy is best assessed in affected tissue, and dried blood spots have been used to demonstrate a high mutant load in severe infantile cardiomyopathy.
Show evidence (1 reference)
PMID:19188198 SUPPORT Human Clinical
"Mitochondrial genome sequencing should be considered in patients with infantile hypertrophic cardiomyopathy."
The defining study's own diagnostic recommendation.
Respiratory Chain Enzymology with Complex V Assembly Analysis
Measurement of complex V activity in muscle or fibroblasts, with blue native PAGE to assess holoenzyme assembly and detect free F1-ATPase, distinguishes an ATP synthase assembly defect from other respiratory chain lesions.
Show evidence (1 reference)
PMID:17954552 SUPPORT In Vitro
"Immunoblotting after blue native polyacrylamide gel electrophoresis showed a lack of holocomplex V and increased amounts of mitochondrial ATP synthase subcomplexes."
Describes the assay pattern that identifies an ATP synthase assembly defect.
📈

Progression

1
Prenatal-to-infantile onset with rapid cardiac progression
Age: Prenatal to 5 months
Onset of the cardiac phenotype ranges from prenatal detection to five months of age, and progression from hypertrophy through heart failure and metabolic crisis can be rapid; two of the reported infants died within months of birth. In the broader MT-ATP6/MT-ATP8 deficiency cohort, cardiomyopathy is concentrated in the infantile-onset group and becomes progressively less frequent with later onset, which is consistent with cardiac involvement being a marker of the most severe end of the spectrum.
Show evidence (2 references)
PMID:39016153 SUPPORT Human Clinical
"biventricular hypertrophy was found in almost all patients, with an early onset from prenatal to five months of life."
Defines the onset window for the cardiac phenotype of m.8528T>C.
PMID:40112238 SUPPORT Human Clinical
"cardiomyopathy was more prevalent in the infantile-onset group and progressively reduced in pediatric and adult patients"
Places cardiac involvement at the infantile, most severe end of the MT-ATP6/MT-ATP8 spectrum; PARTIAL because the cohort is the whole MT-ATP6/MT-ATP8 spectrum rather than this entity.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Ultra Rare
Six patients carrying m.8528T>C had been described as of the 2021 report that added a seventh. The entity is known only from individual case reports and small series; no population-based frequency has been estimated, and none should be inferred from these counts.
Show evidence (1 reference)
PMID:33180048 SUPPORT Human Clinical
"So far six patients with this mutation have been described but none of them was reported to need hemodialysis in the first days of life."
Gives the published case count for m.8528T>C at the time of that report.
⚖️

Clinical Burden

High
Onset is prenatal to five months, progression to heart failure and metabolic crisis can be measured in weeks, two of the small number of reported infants died within months of birth, and no disease-modifying therapy exists. The burden falls on the family as well as the child, since maternal transmission puts every subsequent pregnancy at an unpredictable risk.
Show evidence (1 reference)
PMID:39016153 SUPPORT Human Clinical
"feeding difficulties, developed, and two patients died within a few months of life."
Records fatal outcome in infancy among the small reported m.8528T>C cohort.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from MT-ATP6/MT-ATP8-Related Infantile Hypertrophic Cardiomyopathy:

Non-Mitochondrial Non-Sarcomeric Infantile Hypertrophic Cardiomyopathy
Overlapping Features Inborn errors of metabolism (glycogen and lysosomal storage diseases, fatty acid oxidation defects), RASopathies and neuromuscular disease together account for the majority of hypertrophic cardiomyopathy presenting under one year of age, and must be excluded before an mtDNA cause is assumed.
Show evidence (1 reference)
PMID:33718303 SUPPORT Human Clinical
"childhood HCM includes a high prevalence of non-sarcomeric causes, including inherited errors of metabolism (i.e., glycogen storage diseases, lysosomal storage diseases, and fatty acid oxidation disorders), malformation syndromes, neuromuscular diseases, and mitochondrial disease, which globally..."
Enumerates the differential for non-sarcomeric paediatric hypertrophic cardiomyopathy and its collective size.
{ }

Source YAML

click to show 
name: MT-ATP6/MT-ATP8-Related Infantile Hypertrophic Cardiomyopathy
creation_date: "2026-08-19T15:00:00Z"
category: Mendelian
synonyms:
- Cardiomyopathy, infantile hypertrophic
- Infantile hypertrophic cardiomyopathy, mitochondrial
- Maternally inherited infantile hypertrophic cardiomyopathy
- Mitochondrial complex V (ATP synthase) deficiency, mitochondrial type, infantile cardiomyopathy
description: >-
  Maternally inherited, infantile-onset hypertrophic cardiomyopathy caused by
  pathogenic point mutations in the overlapping reading frames of the two
  mitochondrial DNA-encoded subunits of ATP synthase (complex V), MT-ATP6 and
  MT-ATP8 (OMIM 500006). The reference lesion is m.8528T>C, reported by Ware and
  colleagues in four unrelated infants who presented with isolated hypertrophic
  cardiomyopathy: because ATP6 and ATP8 are read in overlapping frames, this
  single nucleotide substitution simultaneously destroys the ATP6 initiation
  codon and replaces a strictly conserved tryptophan at ATP8 position 55 with
  arginine, so one base change compromises both mtDNA-encoded subunits of the
  enzyme at once. ATP6 and ATP8 are the only two components of the 29-subunit
  human ATP synthase encoded by mitochondrial rather than nuclear DNA, and they
  are inserted last into the membrane (Fo) domain; without them the holoenzyme
  cannot be completed and the terminal, ATP-producing step of oxidative
  phosphorylation fails in a tissue whose energy demand is among the highest in
  the body. The mutation is heteroplasmic and segregates with disease within
  maternal kindreds, and very high cardiac heteroplasmy has been documented in a
  fatal infantile case.

  This entry is deliberately distinct from the several nuclear-gene mitochondrial
  disorders in this knowledge base that also present with infantile hypertrophic
  cardiomyopathy (COX15-related COX deficiency, MRPL44 deficiency, MTO1
  deficiency, cardiomyopathy-hypotonia-lactic acidosis syndrome/SLC25A3,
  mitochondrial DNA depletion syndrome 14B/OPA1). Those are autosomal recessive
  nuclear defects of complex IV assembly, mitochondrial translation, phosphate
  supply, or mtDNA maintenance. The entity curated here is mitochondrially
  encoded and maternally transmitted, its defect is in complex V itself, and its
  distinguishing molecular feature - a single base altering two proteins through
  overlapping open reading frames - has no counterpart in the nuclear entries.
parents:
- hereditary disease
- mitochondrial disease
disease_term:
  preferred_term: cardiomyopathy, infantile hypertrophic
  term:
    id: MONDO:0010777
    label: cardiomyopathy, infantile hypertrophic
references:
- reference: PMID:19188198
  title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
- reference: PMID:26803244
  title: Rapidly progressive infantile cardiomyopathy with mitochondrial respiratory chain complex V deficiency due to loss of ATPase 6 and 8 protein.
- reference: PMID:27409572
  title: Dried blood spots for newborn screening allows easy determination of a high heteroplasmy rate in severe infantile cardiomyopathy.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
    evidence:
    - reference: PMID:19188198
      reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This study aimed to identify the mutation present in four unrelated
        patients who presented as infants with isolated hypertrophic
        cardiomyopathy.
      explanation: >-
        The presenting and defining feature in the index series was isolated
        hypertrophic cardiomyopathy, placing the entry in the cardiovascular
        chapter.
  mechanistic_category:
  - classification_value: mitochondrial disease
    evidence:
    - reference: PMID:19188198
      reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        To our knowledge, this is the first report of a mutation affecting both
        mitochondrial genome-encoded complex V subunit proteins.
      explanation: >-
        The causal lesion is in mitochondrial DNA and disables subunits of an
        oxidative phosphorylation complex, which defines this as a primary
        mitochondrial disease.
inheritance:
- name: Mitochondrial inheritance
  inheritance_term:
    preferred_term: Mitochondrial inheritance
    term:
      id: HP:0001427
      label: Mitochondrial inheritance
  description: >-
    The causal variant lies in mitochondrial DNA and is therefore transmitted
    exclusively through the maternal line. It is heteroplasmic, so the
    proportion of mutant genomes varies between family members and between
    tissues, and clinical expression tracks that proportion rather than
    following a Mendelian segregation ratio.
  evidence:
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Testing of the relatives of one patient indicated that the mutation is
      heteroplasmic and correlated with disease.
    explanation: >-
      Family testing establishing heteroplasmy that correlates with disease
      status is the direct evidence for maternal, heteroplasmy-dependent
      mitochondrial inheritance.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Onset is prenatal to five months, progression to heart failure and metabolic
    crisis can be measured in weeks, two of the small number of reported infants
    died within months of birth, and no disease-modifying therapy exists. The
    burden falls on the family as well as the child, since maternal transmission
    puts every subsequent pregnancy at an unpredictable risk.
  evidence:
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      feeding difficulties, developed, and two patients died within a few months
      of life.
    explanation: >-
      Records fatal outcome in infancy among the small reported m.8528T>C
      cohort.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Six patients carrying m.8528T>C had been described as of the 2021 report
    that added a seventh. The entity is known only from individual case reports
    and small series; no population-based frequency has been estimated, and none
    should be inferred from these counts.
  evidence:
  - reference: PMID:33180048
    reference_title: ATP synthase deficiency due to m.8528T>C mutation - a novel cause of severe neonatal hyperammonemia requiring hemodialysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far six patients with this mutation have been described but none of
      them was reported to need hemodialysis in the first days of life.
    explanation: >-
      Gives the published case count for m.8528T>C at the time of that report.
progression:
- phase: Prenatal-to-infantile onset with rapid cardiac progression
  age_range: Prenatal to 5 months
  notes: >-
    Onset of the cardiac phenotype ranges from prenatal detection to five months
    of age, and progression from hypertrophy through heart failure and metabolic
    crisis can be rapid; two of the reported infants died within months of
    birth. In the broader MT-ATP6/MT-ATP8 deficiency cohort, cardiomyopathy is
    concentrated in the infantile-onset group and becomes progressively less
    frequent with later onset, which is consistent with cardiac involvement
    being a marker of the most severe end of the spectrum.
  evidence:
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      biventricular hypertrophy was found in almost all patients, with an early
      onset from prenatal to five months of life.
    explanation: >-
      Defines the onset window for the cardiac phenotype of m.8528T>C.
  - reference: PMID:40112238
    reference_title: Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cardiomyopathy was more prevalent in the infantile-onset group and
      progressively reduced in pediatric and adult patients
    explanation: >-
      Places cardiac involvement at the infantile, most severe end of the
      MT-ATP6/MT-ATP8 spectrum; PARTIAL because the cohort is the whole
      MT-ATP6/MT-ATP8 spectrum rather than this entity.
pathophysiology:
- name: m.8528T>C Substitution in the MT-ATP6/MT-ATP8 Overlap
  biological_scale: MOLECULAR
  description: >-
    MT-ATP8 and MT-ATP6 are transcribed as a bicistronic message whose reading
    frames overlap by 46 nucleotides. Position 8528 falls inside that overlap.
    The m.8528T>C substitution therefore has two simultaneous consequences in
    two different proteins: it converts the ATP6 initiation codon (ATG) so that
    the encoded residue is threonine rather than methionine, and it replaces
    tryptophan 55 of ATP8, a strictly conserved hydrophobic residue, with the
    strongly basic arginine. This is the defining molecular lesion of the
    entity, and the first reported mutation to hit both mtDNA-encoded complex V
    subunits at once.
  genes:
  - preferred_term: MT-ATP6
    term:
      id: hgnc:7414
      label: MT-ATP6
  - preferred_term: MT-ATP8
    term:
      id: hgnc:7415
      label: MT-ATP8
  evidence:
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This results in a change of the initiation codon in ATPase 6 to threonine
      and a concurrent change from a highly conserved hydrophobic amino acid,
      tryptophan, at position 55 of ATPase 8 to a highly basic arginine.
    explanation: >-
      States both consequences of the single substitution, which is the whole
      basis for treating this as one lesion affecting two gene products.
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To our knowledge, this is the first report of a mutation affecting both
      mitochondrial genome-encoded complex V subunit proteins.
    explanation: >-
      Confirms that both mtDNA-encoded complex V subunits are affected by the
      same variant.
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients carry m.8528T>C missense variant of
      MT-ATP8/MT-ATP6 overlapping region, which affects both subunits.
    explanation: >-
      A 2024 review of isolated ATP synthase defects identifies m.8528T>C as the
      dominant reported MT-ATP8/MT-ATP6 overlap allele and restates the
      dual-subunit consequence.
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant replaces highly conserved tryptophan 55 to arginine in A6L
      subunit and methionine 1 to threonine in the case of subunit a
    explanation: >-
      Independent restatement of the two protein-level consequences, naming the
      affected subunits by their structural designations (A6L and subunit a).
  downstream:
  - target: Failure to Insert ATP6 and ATP8 into the ATP Synthase Membrane Domain
    description: >-
      Loss of the ATP6 start codon and a charge-reversing substitution in the
      membrane-embedded ATP8 protein both act on the availability and
      integrability of the two mtDNA-encoded Fo subunits.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29440398
      reference_title: Assembly of the membrane domain of ATP synthase in human mitochondria.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This intermediate provides the template for insertion of ATP6 and ATP8,
        which are synthesized on mitochondrial ribosomes.
      explanation: >-
        Establishes that ATP6 and ATP8 are inserted as translated mitochondrial
        gene products into a pre-formed assembly intermediate, so a lesion in
        their mtDNA genes acts at exactly this step.
- name: Failure to Insert ATP6 and ATP8 into the ATP Synthase Membrane Domain
  biological_scale: MOLECULAR
  description: >-
    Human ATP synthase is an assembly of 29 subunits of 18 kinds, of which only
    ATP6 and ATP8 are encoded in mitochondrial DNA. Assembly proceeds through a
    nuclear-encoded intermediate - the F1-c8 complex attached to the peripheral
    stalk with subunits e, f and g - into which ATP6 and ATP8, translated on
    mitochondrial ribosomes, are inserted last; the 6.8 proteolipid then locks
    them in place and only at that point is the complex coupled to ATP
    synthesis. A lesion that removes or destabilises either mtDNA-encoded
    subunit therefore arrests assembly at the final, coupling-conferring step
    rather than preventing formation of the F1 head.
  cellular_components:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  biological_processes:
  - preferred_term: mitochondrial ATP synthase complex assembly
    modifier: DECREASED
    term:
      id: GO:0033615
      label: mitochondrial proton-transporting ATP synthase complex assembly
  evidence:
  - reference: PMID:29440398
    reference_title: Assembly of the membrane domain of ATP synthase in human mitochondria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All but two membrane components are encoded in nuclear genes, synthesized
      on cytoplasmic ribosomes, and imported into the matrix of the organelle,
      where they are assembled into the complex with ATP6 and ATP8, the products
      of overlapping genes in mitochondrial DNA.
    explanation: >-
      Identifies ATP6 and ATP8 as the only mtDNA-encoded membrane components and
      names the overlapping-gene arrangement that makes a single substitution
      able to hit both.
  - reference: PMID:29440398
    reference_title: Assembly of the membrane domain of ATP synthase in human mitochondria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Their association with the complex is stabilized by addition of the 6.8
      proteolipid, and the complex is coupled to ATP synthesis at this point.
    explanation: >-
      Places ATP6/ATP8 incorporation at the step that confers coupling, so
      failure here leaves an uncoupled or incomplete enzyme rather than merely a
      smaller one.
  downstream:
  - target: Complex V Holoenzyme Deficiency with Accumulation of Subcomplexes
    description: >-
      Without stable incorporation of the mtDNA-encoded subunits the holoenzyme
      cannot be completed, and the partially assembled species persist.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17954552
      reference_title: A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Immunoblotting after blue native polyacrylamide gel electrophoresis
        showed a lack of holocomplex V and increased amounts of mitochondrial
        ATP synthase subcomplexes.
      explanation: >-
        Direct demonstration in patient tissue and cybrids that loss of ATP8
        blocks holoenzyme formation and leaves subcomplexes behind.
- name: Complex V Holoenzyme Deficiency with Accumulation of Subcomplexes
  biological_scale: MOLECULAR
  description: >-
    The biochemical consequence is an isolated deficiency of assembled,
    catalytically competent ATP synthase. In the closest characterised human
    model - a homoplasmic MT-ATP8 nonsense variant one base away, at m.8529 -
    patient fibroblasts, muscle and transmitochondrial cybrids all showed
    reduced complex V activity, absent holocomplex V, an excess of ATP synthase
    subcomplexes, and in-gel activity of free F1-ATPase, i.e. an unattached
    catalytic head no longer coupled to a proton channel.
  protein_complexes:
  - preferred_term: proton-transporting ATP synthase complex
    modifier: DECREASED
    term:
      id: GO:0045259
      label: proton-transporting ATP synthase complex
  molecular_functions:
  - preferred_term: proton-transporting ATP synthase activity, rotational mechanism
    modifier: DECREASED
    term:
      id: GO:0046933
      label: proton-transporting ATP synthase activity, rotational mechanism
  evidence:
  - reference: PMID:17954552
    reference_title: A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Reduced complex V activity was measured in the patient's fibroblasts and
      muscle tissue, and was confirmed in cybrid clones containing
      patient-derived mitochondrial DNA.
    explanation: >-
      Cybrid transfer assigns the complex V defect to the patient's mitochondrial
      DNA rather than to nuclear background, which is the key control for an
      mtDNA-encoded subunit lesion.
  - reference: PMID:17954552
    reference_title: A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An in-gel activity assay of ATP hydrolysis showed activity of free
      F(1)-ATPase in the patient's muscle tissue and in the cybrid clones.
    explanation: >-
      Free F1-ATPase is the signature of a catalytic head that was never joined
      to an intact Fo domain, confirming where assembly stalls.
  notes: >-
    The mechanistic evidence quoted here is from m.8529G>A (p.Trp55X), a
    homoplasmic MT-ATP8 nonsense variant in an adolescent with apical
    hypertrophic cardiomyopathy and neuropathy, not from m.8528T>C itself. It is
    cited because it is the best-characterised demonstration that loss of an
    mtDNA-encoded complex V subunit in this overlap region produces an assembly
    defect; the corresponding cellular experiments have not been reported for
    m.8528T>C.
  downstream:
  - target: Impaired Proton-Coupled Mitochondrial ATP Synthesis
    description: >-
      A holoenzyme that cannot be completed cannot use the proton-motive force
      to make ATP.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33600551
      reference_title: The pathogenic m.8993 T > G mutation in mitochondrial ATP6 gene prevents proton release from the subunit c-ring rotor of ATP synthase.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Subunit a, together with an oligomeric ring of c-subunit (c-ring), forms
        the proton pathway responsible for the transport of protons through the
        mitochondrial inner membrane, coupled to rotation of the c-ring and ATP
        synthesis.
      explanation: >-
        Defines the function that ATP6 (subunit a) contributes, so its loss
        directly severs proton translocation from ATP synthesis.
  - target: Disrupted ATP Synthase Dimerisation and Cristae Architecture
    description: >-
      ATP synthase monomers dimerise through contacts between ATP6 subunits, so
      a defect in ATP6 incorporation also removes the oligomerisation that
      shapes the inner membrane.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29440398
      reference_title: Assembly of the membrane domain of ATP synthase in human mitochondria.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The human 6.8 proteolipid (yeast j subunit) locks ATP6 and ATP8 into the
        membrane assembly, and the monomeric complexes then dimerize via
        interactions between ATP6 subunits and between 6.8 proteolipids (j
        subunits).
      explanation: >-
        ATP6-ATP6 contacts are the dimerisation interface, so failure to
        incorporate ATP6 removes the structural basis for dimer and oligomer
        formation.
- name: Impaired Proton-Coupled Mitochondrial ATP Synthesis
  biological_scale: CELLULAR
  description: >-
    Loss of a functional Fo proton channel uncouples the respiratory-chain
    proton gradient from phosphorylation, so oxidative ATP output falls even
    though electron transport upstream of complex V may be intact. This is an
    isolated complex V lesion rather than a combined respiratory chain defect.
  biological_processes:
  - preferred_term: proton motive force-driven mitochondrial ATP synthesis
    modifier: DECREASED
    term:
      id: GO:0042776
      label: proton motive force-driven mitochondrial ATP synthesis
  - preferred_term: proton transmembrane transport
    modifier: DECREASED
    term:
      id: GO:1902600
      label: proton transmembrane transport
  evidence:
  - reference: PMID:33600551
    reference_title: The pathogenic m.8993 T > G mutation in mitochondrial ATP6 gene prevents proton release from the subunit c-ring rotor of ATP synthase.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We previously showed that the equivalent mutation (aL173R) dramatically
      compromises respiratory growth of Saccharomyces cerevisiae and causes a
      90% drop in the rate of mitochondrial ATP synthesis.
    explanation: >-
      Quantifies how severely a single pathogenic ATP6 substitution can suppress
      mitochondrial ATP synthesis in a tractable model of the same subunit.
  downstream:
  - target: Cardiomyocyte Energy Deficit
    description: >-
      Cardiac muscle sustains continuous contractile work and is among the most
      ATP-dependent tissues, so a fall in oxidative ATP supply is felt there
      first.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33718303
      reference_title: "Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-sarcomeric Causes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Because cardiac muscle is one of the high-energy-demanding tissues, the
        myocardial involvement (i.e., mitochondrial cardiomyopathy) occurs in
        about 20-40% of children with mitochondrial disease
      explanation: >-
        States the energetic reason the heart is the organ that declares this
        class of defect, and quantifies how often it does so.
- name: Disrupted ATP Synthase Dimerisation and Cristae Architecture
  biological_scale: CELLULAR
  description: >-
    Beyond catalysis, ATP synthase dimers and their oligomeric rows along the
    cristae edges impose the curvature of the inner mitochondrial membrane.
    Failure to incorporate ATP6 therefore has a structural consequence as well
    as a bioenergetic one, degrading the cristae surface on which the whole
    respiratory chain is organised. This arm is inferred from the assembly and
    membrane-shaping literature rather than from ultrastructural study of
    m.8528T>C hearts.
  cellular_components:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  biological_processes:
  - preferred_term: cristae formation
    modifier: DECREASED
    term:
      id: GO:0042407
      label: cristae formation
  evidence:
  - reference: PMID:11823415
    reference_title: The ATP synthase is involved in generating mitochondrial cristae morphology.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The present data show that there is a link between dimerization of the
      mitochondrial ATP synthase and cristae morphology.
    explanation: >-
      Establishes the dimerisation-to-cristae link in yeast, which is the basis
      for expecting a membrane-architecture consequence when ATP6 incorporation
      fails.
  notes: >-
    Curated as a mechanistically expected parallel arm, not as an observed
    finding in this disorder. No ultrastructural study of myocardium carrying
    m.8528T>C has been published, so this node should not be read as an
    established human phenotype.
  downstream:
  - target: Cardiomyocyte Energy Deficit
    description: >-
      Loss of cristae surface reduces the membrane area available for oxidative
      phosphorylation, compounding the direct catalytic deficit.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced inner-membrane surface area available for oxidative phosphorylation
    - Disorganised respiratory-chain supercomplex packing along the cristae
- name: Cardiomyocyte Energy Deficit
  biological_scale: CELLULAR
  description: >-
    Cardiomyocytes carrying a high burden of mutant genomes cannot meet
    contractile ATP demand from oxidative phosphorylation. The shortfall is
    partly offset by glycolysis, at the cost of lactate production, and drives
    the compensatory responses that produce the hypertrophic phenotype.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: ATP biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006754
      label: ATP biosynthetic process
  evidence:
  - reference: PMID:33718303
    reference_title: "Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-sarcomeric Causes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HCM is the most common form of mitochondrial cardiomyopathy; however,
      other forms of cardiomyopathies are possible.
    explanation: >-
      Links the mitochondrial energy defect in cardiomyocytes to a
      predominantly hypertrophic, rather than dilated, cardiac phenotype.
  downstream:
  - target: Compensatory Cardiomyocyte Hypertrophy
    description: >-
      The failing myocardium responds with cell growth and remodelling.
    causal_link_type: DIRECT
  - target: Systemic Lactate Accumulation
    description: >-
      Glycolytic compensation for the oxidative shortfall raises lactate output.
    causal_link_type: DIRECT
- name: Compensatory Cardiomyocyte Hypertrophy
  biological_scale: TISSUE
  description: >-
    Energy-deficient cardiomyocytes enlarge, and the ventricular wall thickens.
    In this disorder the hypertrophy is not a response to abnormal loading -
    outflow obstruction or hypertension - but to an intrinsic metabolic defect,
    which is why the entity is classified as a non-sarcomeric, secondary
    hypertrophic cardiomyopathy.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    modifier: INCREASED
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
  evidence:
  - reference: PMID:33718303
    reference_title: "Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-sarcomeric Causes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by
      left ventricular hypertrophy not solely explained by abnormal loading
      conditions.
    explanation: >-
      Defines the hypertrophy as load-independent, which is what a primary
      metabolic cause implies.
  downstream:
  - target: Progressive Heart Failure of Infancy
    description: >-
      Hypertrophic remodelling in a myocardium that cannot generate ATP
      progresses to pump failure rather than stabilising.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30642647
      reference_title: "Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        After a median follow-up of 35 months, the overall survival rate was
        significantly lower in patients with cardiomyopathy than in those
        without (p < 0.001).
      explanation: >-
        Cardiomyopathy in paediatric mitochondrial disease is progressive and
        mortality-defining rather than an incidental finding.
- name: Systemic Lactate Accumulation
  biological_scale: ORGANISM
  description: >-
    Reliance on glycolysis where oxidative phosphorylation is blocked raises
    circulating lactate. Elevated lactate is the classic, though neither
    sensitive nor specific, systemic marker of a primary mitochondrial disorder,
    and in an infant with unexplained hypertrophic cardiomyopathy it is one of
    the findings that redirects investigation toward mitochondrial DNA.
  evidence:
  - reference: PMID:40112238
    reference_title: Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reduced citrulline levels and increased alanine and lactate levels were
      reported in 56%, 49%, and 71% of patients, respectively, suggesting their
      role as potential biomarkers.
    explanation: >-
      Lactate elevation is the commonest laboratory abnormality across
      MT-ATP6/MT-ATP8 deficiency. Marked PARTIAL because the cohort spans the
      whole spectrum, which is dominated by neurological m.8993 disease rather
      than by this cardiac entity.
  notes: >-
    Hyperlactataemia is curated as the expected systemic consequence of blocked
    oxidative phosphorylation, quantified only at the level of the whole
    MT-ATP6/MT-ATP8 spectrum. The index m.8528T>C series describes the cardiac
    phenotype as isolated and does not report lactate values, so lactic acidosis
    is not curated as a frequency-bearing phenotype of this entry.
- name: Cardiac Heteroplasmy Threshold
  biological_scale: CELLULAR
  description: >-
    Because the variant is heteroplasmic, each tissue carries a mixture of
    mutant and wild-type mitochondrial genomes and expresses a biochemical
    defect only once the mutant load passes a tissue-specific threshold. This
    is what makes the phenotype cardiac-predominant despite a genome present in
    every cell, and it accounts for the variable expression seen among maternal
    relatives. In a fatal infantile case the cardiac heteroplasmy level of
    m.8528T>C was 90%.
  evidence:
  - reference: PMID:30642647
    reference_title: "Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the three patients with mitochondrial DNA mutations whose cardiac
      tissues were available, high heteroplasmy rates in the cardiac tissue were
      observed for m.8528T>C (90%, died at 2 months of age)
    explanation: >-
      Directly quantifies cardiac mutant load for this variant and ties a very
      high level to fatal infantile disease.
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Testing of the relatives of one patient indicated that the mutation is
      heteroplasmic and correlated with disease.
    explanation: >-
      Establishes that clinical status within a kindred tracks mutant load
      rather than mere presence of the variant.
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant is typically present at a high heteroplasmy level, exceeding 90 %
    explanation: >-
      Gives the mutant-load range at which m.8528T>C is typically found in
      affected individuals.
  - reference: PMID:30763462
    reference_title: "MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite extensive overlap in the heteroplasmy levels of MT-ATP6 variant
      carriers with and without a wide range of clinical symptoms, previously
      reported symptomatic subjects had significantly higher heteroplasmy load
    explanation: >-
      Establishes the threshold relationship across MT-ATP6 disease while
      explicitly recording that carrier heteroplasmy distributions overlap, so
      no single cut-off separates affected from unaffected. Marked PARTIAL
      because the analysis covers MT-ATP6 variants generally rather than
      m.8528T>C.
  notes: >-
    Heteroplasmy is not a clean switch. A mother carrying 82% m.8528T>C in blood
    was reported as an asymptomatic carrier, and one affected infant with
    hypertrophic cardiomyopathy had only 59% mutant load in blood, so blood
    heteroplasmy neither predicts nor excludes cardiac disease and the
    cardiac-tissue level is the meaningful measurement.
  downstream:
  - target: Cardiomyocyte Energy Deficit
    description: >-
      The biochemical defect becomes manifest in cardiomyocytes only above the
      threshold mutant load.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30763462
      reference_title: "MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most common findings were reduced ATP synthesis rate, preserved ATP
        hydrolysis capacity, and abnormally increased mitochondrial membrane
        potential.
      explanation: >-
        Names reduced ATP synthesis as the commonest measured consequence in
        symptomatic MT-ATP6 variant carriers, linking mutant load to the
        bioenergetic deficit. PARTIAL because it is measured across MT-ATP6
        disease rather than in m.8528T>C myocardium.
- name: Progressive Heart Failure of Infancy
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint is a rapidly progressive infantile cardiomyopathy with
    high mortality. In a large paediatric mitochondrial disease cohort, children
    with cardiomyopathy had markedly worse survival than those without, and a
    child with the m.8528T>C variant died at two months of age.
  evidence:
  - reference: PMID:30642647
    reference_title: "Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten-year Kaplan-Meier estimates of overall survival were 18 and 67%,
      respectively.
    explanation: >-
      Quantifies the survival gap between paediatric mitochondrial disease with
      and without cardiomyopathy.
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infantile cardiomyopathy is a genetically heterogeneous disorder with
      significant morbidity and mortality.
    explanation: >-
      States the clinical severity of the presentation this entity falls within.
phenotypes:
- category: Cardiovascular
  name: Hypertrophic Cardiomyopathy
  description: >-
    Isolated hypertrophic cardiomyopathy presenting in infancy is the defining
    and, in the index series, the sole clinical feature.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study aimed to identify the mutation present in four unrelated
      patients who presented as infants with isolated hypertrophic
      cardiomyopathy.
    explanation: >-
      All four probands in the defining series presented with isolated infantile
      hypertrophic cardiomyopathy, which supports both the phenotype and the
      VERY_FREQUENT band within the reported cohort.
- category: Cardiovascular
  name: Left Ventricular Hypertrophy
  description: >-
    Increased left ventricular wall thickness not explained by abnormal loading
    conditions is the echocardiographic substrate of the hypertrophic
    cardiomyopathy phenotype.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:33718303
    reference_title: "Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-sarcomeric Causes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by
      left ventricular hypertrophy not solely explained by abnormal loading
      conditions.
    explanation: >-
      Defines left ventricular hypertrophy as the anatomical finding underlying
      an HCM diagnosis in children, including the non-sarcomeric causes this
      entity belongs to.
- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Progression of the hypertrophic myocardium to pump failure is the usual
    cause of death in infantile mitochondrial cardiomyopathy.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:30642647
    reference_title: "Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BACKGROUND: Cardiomyopathy is a reported indicator of poor prognosis in
      children with mitochondrial disease.
    explanation: >-
      Supports cardiac decompensation as the prognosis-determining course of
      paediatric mitochondrial cardiomyopathy.
- category: Cardiovascular
  name: Biventricular Hypertrophy
  description: >-
    Hypertrophy is not confined to the left ventricle; biventricular
    hypertrophy is reported in the m.8528T>C series alongside classical
    hypertrophic cardiomyopathy.
  phenotype_term:
    preferred_term: Ventricular hypertrophy
    term:
      id: HP:0001714
      label: Ventricular hypertrophy
  evidence:
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      biventricular hypertrophy was found in almost all patients, with an early
      onset from prenatal to five months of life.
    explanation: >-
      States that ventricular hypertrophy in this variant may be biventricular
      and gives the onset window.
- category: Growth
  name: Failure to Thrive
  description: >-
    Poor growth accompanies the cardiac disease in reported m.8528T>C patients.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including heart failure, metabolic crises, hypotonia, failure to thrive (FTT),
    explanation: >-
      Lists failure to thrive among the life-threatening features developing in
      m.8528T>C patients.
- category: Metabolic
  name: Metabolic Crises
  description: >-
    Episodic metabolic decompensation, the systemic counterpart of the cardiac
    disease. Complex V failure limits oxidative ATP synthesis, so intercurrent
    catabolic stress is met by anaerobic glycolysis and an acute acidotic crisis
    rather than by increased oxidative flux.
  phenotype_term:
    preferred_term: Metabolic crises
    term:
      id: HP:0004911
      label: Episodic metabolic acidosis
  evidence:
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including heart failure, metabolic crises, hypotonia, failure to thrive (FTT),
    explanation: >-
      Lists metabolic crises among the life-threatening features developing in
      m.8528T>C patients, alongside the cardiac, tone, and growth manifestations
      this entry already curates from the same sentence.
- category: Neuromuscular
  name: Hypotonia
  description: >-
    Generalised low tone is reported in m.8528T>C patients and is the expected
    consequence of a systemic oxidative phosphorylation defect in skeletal
    muscle.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including heart failure, metabolic crises, hypotonia, failure to thrive (FTT),
    explanation: >-
      Lists hypotonia among the features developing in m.8528T>C patients.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding difficulty is a major functional burden in affected infants and
    contributes to the growth failure.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      feeding difficulties, developed, and two patients died within a few months
      of life.
    explanation: >-
      Names feeding difficulties among the reported features and records the
      fatal outcome in two of the reported infants.
- category: Metabolic
  name: Hyperammonemia
  description: >-
    Severe neonatal hyperammonemia requiring haemodialysis has been reported as
    a presenting feature in one m.8528T>C patient, widening the differential of
    neonatal hyperammonemia to include ATP synthase deficiency. Reported in a
    single case, so no frequency is assigned.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:33180048
    reference_title: ATP synthase deficiency due to m.8528T>C mutation - a novel cause of severe neonatal hyperammonemia requiring hemodialysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe a new case of adenosine-triphosphate (ATP) synthase
      deficiency due to m.8528T>C mutation as a novel cause of severe neonatal
      hyperammonemia.
    explanation: >-
      Directly reports hyperammonemia in a patient carrying the defining variant.
biochemical:
- name: Decreased Mitochondrial ATP Synthase (Complex V) Activity
  context: >-
    Isolated reduction of assembled complex V activity is the enzymological
    signature. It is measurable in skeletal muscle and in cultured fibroblasts,
    and can be assigned to the mitochondrial genome by cybrid transfer.
  biomarker_term:
    preferred_term: Decreased activity of mitochondrial ATP synthase complex
    term:
      id: HP:0011925
      label: Decreased activity of mitochondrial ATP synthase complex
  evidence:
  - reference: PMID:17954552
    reference_title: A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Reduced complex V activity was measured in the patient's fibroblasts and
      muscle tissue, and was confirmed in cybrid clones containing
      patient-derived mitochondrial DNA.
    explanation: >-
      Demonstrates the measurable enzymatic deficit and its mtDNA origin.
  notes: >-
    Quantified for the adjacent MT-ATP8 nonsense variant m.8529G>A rather than
    for m.8528T>C; see the knowledge-gap discussion on this entry.
- name: Reduced Synthesis of ATP6 and ATP8 and Reduced Complex V Levels
  context: >-
    Pulse-labelling and complex-level measurements in patients carrying
    m.8528T>C show markedly reduced synthesis of both mtDNA-encoded subunits and
    correspondingly low amounts of fully assembled ATP synthase, which is the
    biochemical demonstration that the variant acts through the subunits it
    encodes rather than through some indirect route.
  evidence:
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This pathogenic variant was shown to cause impaired synthesis of both
      subunits a and A6L, with low levels of complete ATP synthase detected in
      patient samples.
    explanation: >-
      Reports the two biochemical consequences - loss of both subunits and loss
      of assembled complex V - specifically for m.8528T>C.
- name: Elevated Plasma Lactate
  context: >-
    Raised lactate is the commonest laboratory abnormality across MT-ATP6/MT-ATP8
    deficiency and reflects glycolytic compensation for blocked oxidative
    phosphorylation. The figure quoted is for the whole MT-ATP6/MT-ATP8 cohort,
    which is dominated by m.8993 neurological disease, not for m.8528T>C
    specifically.
  biomarker_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:40112238
    reference_title: Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reduced citrulline levels and increased alanine and lactate levels were
      reported in 56%, 49%, and 71% of patients, respectively, suggesting their
      role as potential biomarkers.
    explanation: >-
      Quantifies lactate elevation across the MT-ATP6/MT-ATP8 deficiency cohort;
      marked PARTIAL because the cohort is broader than this cardiac entity.
genetic:
- name: MT-ATP6
  gene_term:
    preferred_term: MT-ATP6
    term:
      id: hgnc:7414
      label: MT-ATP6
  association: >-
    Mitochondrially encoded subunit a of ATP synthase. The m.8528T>C variant
    lies in the MT-ATP8/MT-ATP6 overlap and abolishes the MT-ATP6 initiation
    codon, so the reading frame's normal start methionine is replaced by
    threonine.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This results in a change of the initiation codon in ATPase 6 to threonine
      and a concurrent change from a highly conserved hydrophobic amino acid,
      tryptophan, at position 55 of ATPase 8 to a highly basic arginine.
    explanation: >-
      States the MT-ATP6 consequence of the causal variant.
  inheritance:
  - name: Mitochondrial inheritance
    inheritance_term:
      preferred_term: Mitochondrial inheritance
      term:
        id: HP:0001427
        label: Mitochondrial inheritance
    evidence:
    - reference: PMID:19188198
      reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Testing of the relatives of one patient indicated that the mutation is
        heteroplasmic and correlated with disease.
      explanation: >-
        Family segregation of a heteroplasmic mtDNA variant is the direct
        evidence for maternal mitochondrial inheritance at this locus.
- name: MT-ATP8
  gene_term:
    preferred_term: MT-ATP8
    term:
      id: hgnc:7415
      label: MT-ATP8
  association: >-
    Mitochondrially encoded subunit 8 of ATP synthase. The same m.8528T>C
    substitution replaces the strictly conserved tryptophan at position 55 with
    arginine, a hydrophobic-to-basic change in a membrane-embedded protein. An
    adjacent nonsense variant at m.8529 truncating the same residue is
    independently established as pathogenic and causes an assembly-level complex
    V defect.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To our knowledge, this is the first report of a mutation affecting both
      mitochondrial genome-encoded complex V subunit proteins.
    explanation: >-
      Confirms MT-ATP8 is affected alongside MT-ATP6 by the causal variant.
  - reference: PMID:17954552
    reference_title: A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We describe the first pathogenic mutation in the mitochondrial ATP8 gene,
      resulting in an improper assembly and reduced activity of the complex V
      holoenzyme.
    explanation: >-
      Independently establishes MT-ATP8 as a gene in which loss of function
      produces complex V disease, supporting the MT-ATP8 arm of the m.8528T>C
      lesion.
  inheritance:
  - name: Mitochondrial inheritance
    inheritance_term:
      preferred_term: Mitochondrial inheritance
      term:
        id: HP:0001427
        label: Mitochondrial inheritance
    evidence:
    - reference: PMID:19188198
      reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Testing of the relatives of one patient indicated that the mutation is
        heteroplasmic and correlated with disease.
      explanation: >-
        Family segregation of a heteroplasmic mtDNA variant is the direct
        evidence for maternal mitochondrial inheritance at this locus.
variants:
- name: m.8528T>C
  description: >-
    Mitochondrial DNA substitution in the 46-nucleotide MT-ATP8/MT-ATP6 overlap.
    It changes the MT-ATP6 initiation codon so that threonine replaces the start
    methionine and, in the other reading frame, substitutes arginine for the
    conserved tryptophan at MT-ATP8 position 55. Heteroplasmic; identified in
    four unrelated infants with isolated hypertrophic cardiomyopathy, and
    subsequently reported at 90% cardiac heteroplasmy in a child who died at two
    months.
  gene:
    preferred_term: MT-ATP6
    term:
      id: hgnc:7414
      label: MT-ATP6
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all four, a novel mitochondrial m.8528T-->C mutation was identified.
    explanation: >-
      Identifies the variant in all four probands of the defining series.
- name: m.8529G>A (MT-ATP8 p.Trp55X)
  description: >-
    Homoplasmic MT-ATP8 nonsense variant one nucleotide downstream of m.8528,
    truncating the same tryptophan residue. Reported in a 16-year-old with
    apical hypertrophic cardiomyopathy and neuropathy rather than in infantile
    disease, so it is curated here as allelic mechanistic context rather than as
    a variant of this entity.
  gene:
    preferred_term: MT-ATP8
    term:
      id: hgnc:7415
      label: MT-ATP8
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:17954552
    reference_title: A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homoplasmic nonsense mutation m.8529G-->A (p.Trp55X) was found in the
      mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue.
    explanation: >-
      Establishes the adjacent MT-ATP8 nonsense variant and its homoplasmic
      state.
diagnosis:
- name: Mitochondrial Genome Sequencing
  description: >-
    Whole mitochondrial genome sequencing is the diagnostic test that identifies
    this entity, and is explicitly recommended in infants with hypertrophic
    cardiomyopathy. Because the variant is heteroplasmic and cardiac-predominant,
    a negative or low-level result in blood does not exclude it; heteroplasmy is
    best assessed in affected tissue, and dried blood spots have been used to
    demonstrate a high mutant load in severe infantile cardiomyopathy.
  evidence:
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mitochondrial genome sequencing should be considered in patients with
      infantile hypertrophic cardiomyopathy.
    explanation: >-
      The defining study's own diagnostic recommendation.
- name: Respiratory Chain Enzymology with Complex V Assembly Analysis
  description: >-
    Measurement of complex V activity in muscle or fibroblasts, with blue native
    PAGE to assess holoenzyme assembly and detect free F1-ATPase, distinguishes
    an ATP synthase assembly defect from other respiratory chain lesions.
  evidence:
  - reference: PMID:17954552
    reference_title: A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunoblotting after blue native polyacrylamide gel electrophoresis showed
      a lack of holocomplex V and increased amounts of mitochondrial ATP
      synthase subcomplexes.
    explanation: >-
      Describes the assay pattern that identifies an ATP synthase assembly
      defect.
treatments:
- name: Supportive Heart Failure Management
  description: >-
    No disease-modifying therapy exists. Management is the standard supportive
    care of infantile cardiomyopathy - anticongestive therapy, nutritional
    support, and avoidance of catabolic stress - together with genetic
    counselling for maternal relatives.
  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:33718303
    reference_title: "Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-sarcomeric Causes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, the only mitochondrial disorders with an etiologic treatment are
      those caused by CoQ10 deficiency and thiamine-responsive disorders
    explanation: >-
      Establishes that no etiologic therapy is available for mitochondrial
      disorders outside the CoQ10 and thiamine-responsive groups, which is why
      management here is supportive.
- name: Heart Transplantation
  description: >-
    Cardiac transplantation is feasible in children with mitochondrial disease
    and isolated or dominant cardiac involvement. Post-transplant survival is
    comparable to that of other paediatric cardiomyopathy recipients, though
    with higher rates of stroke, prolonged ventilation and longer intensive care
    stays, so mitochondrial disease is not by itself an absolute
    contraindication. Extracardiac disease burden governs candidacy.
  treatment_term:
    preferred_term: Organ Transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:31711761
    reference_title: Heart Transplantation in Children with Mitochondrial Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results suggest that the presence of mitochondrial disease should
      not be an absolute contraindication to heart transplantation in the
      appropriate clinical setting.
    explanation: >-
      Directly supports transplantation as an option in this population.
  - reference: PMID:31711761
    reference_title: Heart Transplantation in Children with Mitochondrial Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with mitochondrial disease were more likely to have a stroke
      after heart transplantation (11% vs 3%; P = .009)
    explanation: >-
      Quantifies the excess perioperative morbidity that qualifies the
      recommendation.
- name: Genetic Counselling for Maternal Relatives
  description: >-
    Because transmission is exclusively maternal and heteroplasmy levels vary
    between offspring, counselling addresses recurrence risk for all children of
    a carrier mother and the limited predictive value of blood heteroplasmy
    measurement.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:19188198
    reference_title: Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Testing of the relatives of one patient indicated that the mutation is
      heteroplasmic and correlated with disease.
    explanation: >-
      Family testing that established heteroplasmic maternal transmission is the
      basis for counselling maternal relatives.
differential_diagnoses:
- name: TMEM70-Related Nuclear ATP Synthase Deficiency
  description: >-
    The commonest nuclear cause of isolated complex V deficiency. It produces
    the same enzymatic lesion by a different route - loss of an assembly factor
    rather than of a structural subunit - and presents with neonatal hypertrophic
    cardiomyopathy, lactic acidosis and 3-methylglutaconic aciduria. Inheritance
    is autosomal recessive, so the pedigree pattern and the 3-methylglutaconic
    aciduria distinguish it.
  evidence:
  - reference: PMID:22986587
    reference_title: "TMEM70: a mutational hot spot in nuclear ATP synthase deficiency with a pivotal role in complex V biogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the clinical and molecular findings in three patients presenting
      lactic acidosis, 3-methylglutaconic aciduria, and hypertrophic
      cardiomyopathy.
    explanation: >-
      Describes the nuclear complex V deficiency phenotype that most closely
      mimics this entity.
- name: Non-Mitochondrial Non-Sarcomeric Infantile Hypertrophic Cardiomyopathy
  description: >-
    Inborn errors of metabolism (glycogen and lysosomal storage diseases, fatty
    acid oxidation defects), RASopathies and neuromuscular disease together
    account for the majority of hypertrophic cardiomyopathy presenting under one
    year of age, and must be excluded before an mtDNA cause is assumed.
  evidence:
  - reference: PMID:33718303
    reference_title: "Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-sarcomeric Causes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      childhood HCM includes a high prevalence of non-sarcomeric causes,
      including inherited errors of metabolism (i.e., glycogen storage diseases,
      lysosomal storage diseases, and fatty acid oxidation disorders),
      malformation syndromes, neuromuscular diseases, and mitochondrial disease,
      which globally represent up to 35% of children with HCM
    explanation: >-
      Enumerates the differential for non-sarcomeric paediatric hypertrophic
      cardiomyopathy and its collective size.
discussions:
- discussion_id: atp6_vs_atp8_driver
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the infantile cardiomyopathy of m.8528T>C driven by loss of the MT-ATP6
    initiation codon, by the MT-ATP8 p.Trp55Arg substitution, or does it require
    both?
  attaches_to:
  - pathophysiology#m.8528T>C Substitution in the MT-ATP6/MT-ATP8 Overlap
  rationale: >-
    The variant's two consequences fall in different genes and are not
    separable in patients, because the overlapping reading frames make it
    impossible for a natural allele to carry one without the other. The current
    best inference, stated in the 2024 ATP synthase review, is that loss of
    subunit a is the primary driver of the assembly defect - and the natural
    experiment supports it, since the adjacent m.8529G>A variant truncates only
    A6L, spares subunit a, and produces later-onset (about four years),
    substantially milder disease at comparably high heteroplasmy. But the review
    reaches that conclusion by analogy to a different MT-ATP6 variant rather
    than by measurement, and it immediately notes that the A6L-only lesion still
    destabilises the complex. No cybrid or transmitochondrial study of m.8528T>C
    itself has been reported, so the relative contribution of the two arms
    remains an inference.
  evidence:
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      one would expect that the lack of subunit a is the primary driver of
      diminished assembly/stability of complex V in the case of m.8528T>C
      substitution.
    explanation: >-
      The review states the leading hypothesis in explicitly hypothetical terms
      ("one would expect"), which is why this remains an open knowledge gap
      rather than a curated mechanism.
  - reference: PMID:39016153
    reference_title: Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      m.8529G>A variant exhibited a high degree of heteroplasmy (over 90 %), yet
      the disease course was rather milder, with later onset at 4 years of age.
    explanation: >-
      The allelic comparison at matched heteroplasmy is the strongest available
      argument that the ATP6/subunit a arm accounts for the infantile severity
      of m.8528T>C.
  proposed_experiments:
  - experiment_id: exp_cmih_m8528_cybrids
    name: Transmitochondrial cybrids carrying m.8528T>C
    description: >-
      Generate cybrid clones spanning a range of m.8528T>C heteroplasmy and
      measure complex V assembly by blue native PAGE, ATP synthesis rate, and
      steady-state ATP6 and ATP8 protein levels, to establish which subunit is
      lost and at what mutant load the defect appears.
  - experiment_id: exp_cmih_separated_frames
    name: Separated-frame expression of the two consequences
    description: >-
      Express the ATP6 start-codon change and the ATP8 p.Trp55Arg substitution
      independently in a recoded or heterologous system to attribute the
      assembly defect to one arm, the other, or their combination.
- discussion_id: cardiac_restriction
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why is the phenotype of m.8528T>C cardiac-restricted when the mutant genome
    is present in every tissue?
  attaches_to:
  - pathophysiology#Cardiac Heteroplasmy Threshold
  rationale: >-
    The index series described isolated hypertrophic cardiomyopathy without the
    encephalopathy, myopathy or optic involvement typical of other MT-ATP6
    disease, and the one variant carrier with tissue data had 90% cardiac
    heteroplasmy. Whether the restriction reflects tissue-specific segregation
    of mutant genomes, a lower threshold in a tissue with extreme ATP demand, or
    both has not been determined, and no systematic multi-tissue heteroplasmy
    survey of this variant exists.
  evidence:
  - reference: PMID:40112238
    reference_title: Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The CNS was the most frequently affected tissue (93%), followed by the
      muscle (75%), eye (46%), and heart (18%).
    explanation: >-
      Across MT-ATP6/MT-ATP8 deficiency the heart is the least often involved of
      the four main tissues, which is what makes a cardiac-restricted
      presentation for m.8528T>C a question worth posing rather than the
      expected default.
  proposed_experiments:
  - experiment_id: exp_cmih_multitissue_heteroplasmy
    name: Multi-tissue heteroplasmy mapping in autopsy material
    description: >-
      Quantify m.8528T>C heteroplasmy across heart, skeletal muscle, brain,
      liver and blood in the same individuals to test whether the cardiac
      predominance is a segregation effect or a threshold effect.
notes: >-
  Named Entity Confusion preflight. MONDO:0010777 records no causal-gene
  relationship, so the automated gene-frequency check cannot adjudicate this
  entity. Identity was anchored manually on the OMIM xref: MONDO:0010777 maps to
  OMIM:500006, a phenotype number in the 500000 (mitochondrial inheritance)
  series, and the MedGen record for the same concept (MedGen 412660) lists
  OMIM 516060 (MT-ATP6) and 516070 (MT-ATP8) as the gene entries carrying the
  same phenotype name. The literature entry point for OMIM 500006 is Ware et al.
  2009 (PMID:19188198), whose four infants with isolated hypertrophic
  cardiomyopathy carry m.8528T>C in the MT-ATP6/MT-ATP8 overlap. This entry is
  therefore the mtDNA complex V entity, not any of the nuclear-gene mitochondrial
  cardiomyopathies already in this knowledge base.

  `just preflight-dr` on the Edison/falcon report returns SKIP, as expected for a
  MONDO term with no recorded causal gene, but its gene census is strongly
  confirmatory: MT-ATP6 is mentioned 45 times and MT-ATP8 22 times, with no rival
  gene above two mentions. The report cites OMIM 516060 (the MT-ATP6 gene entry
  that MedGen ties to this phenotype name) but not 500006 itself, and also
  discusses OMIM 256000 and 551500 as the broader Leigh/NARP context; that
  broader material was read as context and not curated into this entry, which is
  restricted to the overlap-region cardiac phenotype.

  No GeneReviews chapter exists for this disorder. A PubMed search returned the
  general "Primary Mitochondrial Disorders Overview" (PMID:20301403), whose
  abstract states only the chapter's purpose and carries no disease-specific
  clinical characteristics, so it was deliberately not cited as a phenotype
  baseline.

  Two reference records used here, PMID:26803244 (Imai 2016, the second primary
  report of loss of ATPase 6 and 8 protein in infantile cardiomyopathy) and
  PMID:27409572 (Imai 2016, dried blood spots and heteroplasmy), cache as
  metadata with no abstract. They are listed under top-level `references` for
  discoverability but are deliberately not used as evidence items, since the only
  quotable text in those records is the title.
📚

References & Deep Research

References

3
PMID:19188198
Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.
No top-level findings curated for this source.
PMID:26803244
Rapidly progressive infantile cardiomyopathy with mitochondrial respiratory chain complex V deficiency due to loss of ATPase 6 and 8 protein.
No top-level findings curated for this source.
PMID:27409572
Dried blood spots for newborn screening allows easy determination of a high heteroplasmy rate in severe infantile cardiomyopathy.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 33 citations 2026-08-19T09:21:41.547961

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: MT-ATP6/MT-ATP8-Related Infantile Hypertrophic Cardiomyopathy
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on MT-ATP6/MT-ATP8-Related Infantile Hypertrophic Cardiomyopathy 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

  • 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
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  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
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11. Outcome/Prognosis

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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
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  • Immunization: Vaccine strategies (if applicable)

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

  • Screening and Early Detection:
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    Search first: NSGC resources, ACMG guidelines, GeneReviews

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  • Prophylaxis: Preventive medications or procedures

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14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

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    Search first: VBO (Vertebrate Breed Ontology)

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15. Model Organisms

  • Model Types:
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  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

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

MT-ATP6/MT-ATP8–Related Infantile Hypertrophic Cardiomyopathy

Executive summary and scope

MT-ATP6/MT-ATP8–related infantile hypertrophic cardiomyopathy (HCM) is best treated as an ultra-rare phenotypic subset of mitochondrial ATP-synthase (complex V) deficiency, rather than a fully established standalone nosologic entity. The strongest direct association is with m.8528T>C, which lies in the overlapping coding region of MT-ATP8 and MT-ATP6. It changes both proteins—ATP8/A6L p.Trp55Arg and the ATP6/subunit-a initiation methionine p.Met1Thr—and has produced prenatal-to-5-month-onset hypertrophic or biventricular cardiomyopathy, heart failure, metabolic crises, feeding failure, hypotonia, and early death. Available cases usually had mutant loads above 90%, although 59% in blood was reported in one patient. Biochemical studies showed markedly reduced ATP6/ATP8 synthesis, complex V abundance, and ATP production. (tauchmannova2024variabilityofclinical pages 5-7)

This distinction matters: common MT-ATP6 alleles such as m.8993T>G/C and m.9176T>G/C cause a much broader Leigh/NARP spectrum in which cardiomyopathy may occur, but they should not automatically be labeled “MT-ATP6/MT-ATP8-related infantile HCM.” The 2025 natural-history cohort is therefore useful for context, not a prevalence study of the narrowly defined cardiac phenotype.

Evidence base. Direct disease-specific evidence consists mainly of individual patients and small case series, supplemented by aggregated variant reviews and a broader 111-person MT-ATP6/8 natural-history cohort. Thus, patient-level frequencies should not be inferred from the case reports, and broader cohort frequencies should not be assumed to describe m.8528T>C specifically.

Variant Genes / protein change Genetic state Onset / cardiac phenotype Extracardiac / biochemical features Functional consequence Evidence / source
m.8528T>C Overlapping MT-ATP8/MT-ATP6 variant; affects A6L p.Trp55Arg and ATP6 start codon/subunit a p.Met1Thr Usually high heteroplasmy >90%; one reported patient had 59% in blood Directly associated with infantile HCM: prenatal to 5 months; hypertrophic cardiomyopathy / biventricular hypertrophy, heart failure; some cases rapidly progressive and fatal in months Hypotonia, failure to thrive, feeding difficulties, metabolic crises, 3-methylglutaconic aciduria, hyperketonemia; reported arrhythmia/WPW, pulmonary arterial hypertension, LV noncompaction, anemia, thrombocytopenia, myopathy/progressive weakness Marked reduction in synthesis of both ATPase 6 and 8, reduced complex V levels/assembly-stability, decreased ATP synthesis; review states loss of subunit a is primary driver Core infantile HCM allele; summarized from 2024 review and cited primary infantile cardiomyopathy reports (tauchmannova2024variabilityofclinical pages 5-7, tauchmannova2024variabilityofclinical pages 8-10, jackson2017anovelmitochondrial pages 15-19)
m.8529G>A Overlapping MT-ATP8/MT-ATP6 variant; primarily affects A6L p.Trp55Ter; nearby allelic comparator Reported high heteroplasmy >90% Not a direct infantile HCM allele in available evidence; later onset (~4 years) with HCM reported in one patient, milder than m.8528T>C Neuropathy, ataxia, ophthalmoplegia, psychomotor retardation Decreased ATP synthase stability; unlike m.8528T>C, mainly affects A6L rather than causing loss of subunit a Useful allelic comparison showing overlapping-region variants can differ markedly in severity and age at onset (tauchmannova2024variabilityofclinical pages 8-10, dotto2024variantsinhuman pages 23-24)
m.8993T>G MT-ATP6; ATP6 p.Leu156Arg Often high heteroplasmy; >90% strongly associated with severe Leigh/MILS spectrum Broader MT-ATP6 disease context; cardiomyopathy can occur, but available evidence does not support it as a specific core allele for infantile HCM Leigh syndrome/MILS, lactic acidosis, developmental delay/regression, seizures, brainstem dysfunction, peripheral neuropathy, optic atrophy; low citrulline in broader MT-ATP6 disease Impaired ATP synthase assembly, decreased ATP synthesis, abnormal membrane potential; severity tracks with heteroplasmy Major disease-context allele; common in cohorts, including infantile-onset MT-ATP6/8 disease, but not specific for infantile HCM (uittenbogaard2018novelinsightsinto pages 1-3, ganetzky2019mt‐atp6mitochondrialdisease pages 3-4, carli2025naturalhistoryof pages 5-7)
m.8993T>C MT-ATP6; same codon as m.8993T>G with different substitution Heteroplasmic; higher loads linked to more severe disease Broader MT-ATP6 disease context; review notes cardiomyopathy has been linked, but phenotype is predominantly neurodegenerative and often later than overlapping-region infantile HCM NARP/Leigh spectrum, variable neurologic disease; biomarkers in MT-ATP6/8 cohorts include lactate elevation, alanine elevation, reduced citrulline Complex V dysfunction with variable biochemical findings; no single universal assay abnormality Included to frame broader genotype-phenotype spectrum without over-attributing infantile HCM (tauchmannova2024variabilityofclinical pages 8-10, carli2025naturalhistoryof pages 1-2, ganetzky2019mt‐atp6mitochondrialdisease pages 1-3)
m.9176T>G / m.9176T>C MT-ATP6 codon 217 variants Heteroplasmic to homoplasmic; severe disease more likely at high mutant load Broader MT-ATP6 disease context; can be associated with Leigh-spectrum disease and cardiomyopathy/non-neurologic manifestations, but not established here as a defining infantile HCM allele Newborn-screened MT-ATP6 cases with low citrulline and/or elevated C5-OH included m.9176T>G; neurologic phenotypes range from asymptomatic to hypertonia/intellectual disability; hypertrophic cardiomyopathy recognized among MT-ATP6 manifestations overall ATP synthase dysfunction; therapeutic research includes mitoTALEN targeting of m.9176T>C in murine oocytes in experimental prevention studies Important contextual alleles for diagnosis/screening and experimental therapy, not the core infantile HCM genotype in available evidence (peretz2021prospectivediagnosisof pages 6-8, peretz2021prospectivediagnosisof pages 1-3, dotto2024variantsinhuman pages 23-24)

Table: This table summarizes the strongest available genotype-phenotype evidence for MT-ATP6/MT-ATP8-related infantile hypertrophic cardiomyopathy, centered on the overlapping-region m.8528T>C allele. It also places neighboring and common MT-ATP6 alleles in context while distinguishing direct infantile HCM evidence from broader mitochondrial disease associations.

1. Disease information

Definition and terminology

The disorder is a primary mitochondrial cardiomyopathy caused by defective mitochondrial ATP synthase. Suggested synonyms are:

  • MT-ATP6/MT-ATP8 overlapping-region mitochondrial cardiomyopathy
  • ATP synthase subunit 6/8 deficiency with infantile hypertrophic cardiomyopathy
  • Complex V deficiency with infantile cardiomyopathy
  • Rapidly progressive infantile cardiomyopathy due to loss of ATPase 6 and 8 proteins—the wording used in the 2016 primary report title (DOI: 10.1016/j.ijcard.2016.01.026). The later literature identifies this report as infantile cardiomyopathy with complex V deficiency caused by loss of both ATPase proteins. (tauchmannova2024variabilityofclinical pages 26-27, jackson2017anovelmitochondrial pages 15-19)

Identifiers

No dedicated MONDO, OMIM, Orphanet, MeSH, ICD-10, or ICD-11 identifier for this exact genotype-plus-infantile-HCM entity was established from the retrieved literature. It should therefore be represented as a compositional knowledge-base entity linking:

  1. mitochondrial ATP synthase deficiency / primary mitochondrial disease;
  2. hypertrophic cardiomyopathy;
  3. MT-ATP6 and MT-ATP8;
  4. the causal mtDNA variant, especially m.8528T>C.

Relevant broader OMIM phenotypes include NARP, OMIM 551500, and maternally inherited Leigh syndrome, OMIM 516060, but neither is synonymous with the cardiac entity. The literature also references Leigh syndrome OMIM 256000 in the broader MT-ATP6 spectrum. (dotto2024variantsinhuman pages 18-20, uittenbogaard2018novelinsightsinto pages 1-3)

Suggested coding: HCM—I42.2 (ICD-10-CM) plus a mitochondrial-metabolism code where local coding rules permit; this is pragmatic coding, not a disease-specific identifier.

2. Etiology

Causal factors and genetic risk

The primary cause is a germline mitochondrial-DNA variant affecting complex V. The core allele, m.8528T>C, occurs where MT-ATP8 and MT-ATP6 overlap and simultaneously alters two polypeptides. Its high heteroplasmy, dual-protein effect, marked complex V deficiency, and recurrence with early cardiomyopathy provide the strongest causal evidence. (tauchmannova2024variabilityofclinical pages 5-7)

Risk is governed principally by:

  • Mutant heteroplasmy: higher loads generally predict earlier and more severe disease. Across published MT-ATP6 cases, affected individuals had much higher heteroplasmy than asymptomatic relatives; younger onset correlated inversely with heteroplasmy (r=−0.37, p=1.6×10⁻⁷). Nevertheless, overlap between affected and unaffected carriers prevents use of a single deterministic threshold. (ganetzky2019mt‐atp6mitochondrialdisease pages 3-4, ganetzky2019mt‐atp6mitochondrialdisease pages 1-3)
  • Tissue distribution: blood heteroplasmy may not equal myocardium, muscle, urine, or other tissues.
  • Mitochondrial and nuclear background: severe variation among persons with similar loads implies modifying haplogroup, nuclear-genetic, developmental, and tissue-threshold effects. (peretz2021prospectivediagnosisof pages 6-8, uittenbogaard2018novelinsightsinto pages 1-3)

The m.8993T>G allele illustrates the threshold principle: below approximately 60% can be asymptomatic, 75–90% is often associated with NARP, and >90% with Leigh/MILS, although these are probabilistic rather than absolute boundaries. (uittenbogaard2018novelinsightsinto pages 1-3)

Environmental, lifestyle, infectious, and protective factors

No toxin, infection, lifestyle exposure, sex, or occupational factor is known to cause this Mendelian mitochondrial disorder. Fever, fasting, dehydration, anesthesia, and intercurrent infection may plausibly precipitate energetic decompensation in mitochondrial disease, but disease-specific interaction estimates were not found. No validated protective allele or environmental factor has been identified.

Early recognition, avoidance of catabolism, and prompt treatment of intercurrent illness are clinically protective strategies rather than primary prevention. In six newborn-screened MT-ATP6 patients treated prospectively, no metabolic crises or developmental regression occurred, but this uncontrolled observation cannot establish efficacy. (peretz2021prospectivediagnosisof pages 1-3)

3. Phenotypes

Core m.8528T>C phenotype

Phenotype Characterization Suggested HPO term
Hypertrophic/biventricular cardiomyopathy Prenatal to 5 months; severe and rapidly progressive; defining manifestation HP:0001639 Hypertrophic cardiomyopathy
Heart failure Infantile, severe; may be fatal HP:0001635 Congestive heart failure
Ventricular hypertrophy Can involve both ventricles HP:0001712 Left ventricular hypertrophy; right-ventricular hypertrophy term as applicable
Arrhythmia/Wolff–Parkinson–White Reported in the allelic case spectrum HP:0011675 Arrhythmia; HP:0001716 WPW syndrome
LV noncompaction Reported but not universal HP:0011663 Left ventricular noncompaction
Pulmonary arterial hypertension Reported complication HP:0002092 Pulmonary arterial hypertension
Metabolic crisis/acidosis Episodic deterioration, sometimes with hyperketonemia or hyperammonemia HP:0001942 Metabolic acidosis; HP:0001987 Hyperammonemia
Hypotonia/weakness Early and potentially progressive HP:0001252 Hypotonia; HP:0001324 Muscle weakness
Feeding difficulty/failure to thrive Severe infant functional impact HP:0011968 Feeding difficulties; HP:0001508 Failure to thrive
3-methylglutaconic aciduria Biochemical abnormality in some cases HP:0003535 3-methylglutaconic aciduria
Cytopenias Anemia and thrombocytopenia reported HP:0001903 Anemia; HP:0001873 Thrombocytopenia

These manifestations and the prenatal-to-five-month onset derive from sparse case reports; two reported infants died within months. They must not be interpreted as reliable percentages. (tauchmannova2024variabilityofclinical pages 5-7)

Broader MT-ATP6/8 spectrum

The 2025 multicenter cohort included 111 genetically confirmed patients: 44% had onset before age 1 year, 36% at 1–12 years, and 20% after age 12. CNS, muscle, eye, and heart involvement occurred in 93%, 75%, 46%, and 18%, respectively. Among infantile-onset patients, cardiomyopathy occurred in 29% and HCM in 21%; corresponding cardiomyopathy frequencies were 9% in pediatric-onset and 5% in late-onset groups. These are broader ATP6/8-deficiency statistics, not m.8528T>C-specific estimates. (carli2025naturalhistoryof pages 5-7, carli2025naturalhistoryof pages 1-2)

Neurologic findings include developmental delay/regression, hypotonia, dystonia, spasticity, chorea, ataxia, peripheral neuropathy, seizures, retinitis pigmentosa, optic disease, and Leigh-pattern MRI lesions. In the natural-history cohort, 91% of 86 imaged patients had abnormal MRI; 54% had Leigh-like lesions, 10% cerebellar atrophy, and 21% white-matter abnormalities. Eleven percent were wheelchair-dependent, while 19% of those with walking data never acquired walking. (peretz2021prospectivediagnosisof pages 1-3, carli2025naturalhistoryof pages 2-3)

Quality of life: no disease-specific EQ-5D, SF-36, or pediatric quality-of-life dataset was found. Severe heart failure, feeding dependence, hospitalization during metabolic crises, inability to walk, and multisystem impairment imply major patient and caregiver burden.

4. Genetic and molecular information

Genes

  • MT-ATP6: mitochondrially encoded ATP synthase membrane subunit a/6; part of the proton-translocating F(_o) sector.
  • MT-ATP8: mitochondrially encoded ATP synthase subunit 8/A6L.
  • Both are mtDNA protein-coding genes with a short overlapping coding region.

Suggested annotations: HGNC symbols MT-ATP6 and MT-ATP8; GO molecular function/pathway annotations should emphasize proton-transporting ATP synthase activity and oxidative phosphorylation.

Variant interpretation

m.8528T>C is a missense/start-loss–like overlapping variant: ATP8 p.Trp55Arg and ATP6 p.Met1Thr. The latter may disrupt translation initiation, and biochemical data indicate that loss of ATP6/subunit a is the major driver of reduced complex V assembly or stability. Most affected patients had >90% mutant load. (tauchmannova2024variabilityofclinical pages 5-7, tauchmannova2024variabilityofclinical pages 8-10)

m.8529G>A, an informative comparator, produces ATP8 p.Trp55Ter but primarily spares ATP6. A >90%-heteroplasmic patient developed HCM and neurologic disease around age four—substantially later than m.8528T>C—supporting the greater severity of losing ATP6/subunit a. (tauchmannova2024variabilityofclinical pages 8-10)

Across the 111-patient cohort, 26 pathogenic variants were identified: 20 in MT-ATP6, three in MT-ATP8, and three in the overlap. m.8993T>G accounted for 46%, m.8993T>C for 17%, and m.9185T>C for 9%. Median blood heteroplasmy was higher in infantile-onset (92.5%) than pediatric-onset (86.8%) or late-onset disease (80.6%). (carli2025naturalhistoryof pages 5-7)

Population frequency: no defensible gnomAD-mtDNA/TOPMed frequency for m.8528T>C was recovered. Given its severity, recurrence only in rare patients, and high heteroplasmy requirement, population carrier frequency cannot be estimated from current reports. mtDNA variants are germline/maternally transmitted or de novo, not somatic cancer mutations in this context.

Modifiers, epigenetics, and chromosomal abnormalities: no validated modifier gene, disease-specific methylation signature, chromosomal rearrangement, or anticipation mechanism is established. Apparent generational changes reflect mtDNA bottleneck and heteroplasmy segregation, not classical repeat-expansion anticipation.

5. Environmental information

No causal pollution, radiation, toxin, diet, smoking, alcohol, or infectious agent is implicated. Environmental stressors can affect demand on an already constrained oxidative-phosphorylation system, but quantitative gene–environment studies specific to this cardiomyopathy are absent. Infection-associated catabolism may unmask or worsen disease; it does not create the pathogenic genotype.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream genetic lesion: m.8528T>C alters ATP8 and the ATP6 initiation codon.
  2. Protein/assembly defect: synthesis of both mitochondrially encoded proteins falls; subunit-a deficiency destabilizes or prevents normal complex V assembly.
  3. Bioenergetic defect: ATP synthase abundance and ATP-production rate decrease; pathogenic MT-ATP6 variants may also cause abnormally elevated mitochondrial membrane potential, although biochemical signatures vary by allele. (tauchmannova2024variabilityofclinical pages 5-7, ganetzky2019mt‐atp6mitochondrialdisease pages 3-4)
  4. Cellular compensation/injury: inadequate oxidative phosphorylation, altered proton utilization, redox imbalance, abnormal calcium handling, and secondary reactive-oxygen-species stress are expected in energy-demanding cardiomyocytes. The literature emphasizes that no single biochemical abnormality is universal across MT-ATP6 disease. (ganetzky2019mt‐atp6mitochondrialdisease pages 1-3, dotto2024variantsinhuman pages 20-22)
  5. Tissue phenotype: fetal/infant cardiomyocytes have continuous ATP demand. Energetic insufficiency and maladaptive hypertrophic remodeling produce myocardial thickening, impaired filling/contractility, conduction disease, and heart failure; systemic energy failure produces hypotonia, feeding failure, lactic/metabolic crises, and neurologic injury.

Ontology suggestions

  • GO biological process: oxidative phosphorylation (GO:0006119); ATP synthesis coupled proton transport (GO:0015986); mitochondrial ATP synthesis coupled proton transport (GO:0042776); cellular response to oxidative stress (GO:0034599).
  • GO cellular component: mitochondrion (GO:0005739); mitochondrial inner membrane (GO:0005743); proton-transporting ATP synthase complex (GO:0045259).
  • Cell Ontology: cardiomyocyte (CL:0000746); ventricular cardiac muscle cell; skeletal muscle cell; neuron; retinal photoreceptor cell.
  • Chemical entities: ATP (CHEBI:15422), ADP (CHEBI:16761), L-lactic acid/lactate, L-citrulline, L-alanine.

Molecular profiling gaps

No disease-specific cardiac single-cell atlas, spatial transcriptomic dataset, systematic transcriptomic/proteomic/lipidomic signature, epigenomic study, or CRISPR screen was identified. Available “omics” evidence is principally mtDNA sequencing plus targeted respiratory-chain and metabolite assays. This is a major knowledge gap.

7. Anatomical structures affected

Primary organ: heart, especially ventricular myocardium; both ventricles may be hypertrophied. Suggested terms: UBERON:0000948 heart, myocardium, left ventricle, right ventricle; CL:0000746 cardiomyocyte.

Secondary systems: brain/CNS, peripheral nerves, skeletal muscle, retina/optic system, pulmonary vasculature, liver/metabolic system, and hematopoietic system. In broader ATP6/8 deficiency, CNS and muscle involvement substantially exceed cardiac involvement. (carli2025naturalhistoryof pages 2-3, carli2025naturalhistoryof pages 1-2)

Subcellular site: mitochondrial inner membrane and F(_o) sector of ATP synthase. No lateralization applies.

8. Temporal development

The defining cardiac phenotype is congenital or early infantile, with reported onset prenatally through five months. Progression may be rapid—from hypertrophy to heart failure, arrhythmia, metabolic decompensation, multiorgan failure, and death within months. (tauchmannova2024variabilityofclinical pages 5-7)

In broader MT-ATP6/8 disease, onset spans birth to 58 years (median one year). Approximately 55% of early-onset patients experienced metabolic acidosis or acute deterioration. The course may therefore combine chronic neurologic/myopathic progression with episodic metabolic crises. (carli2025naturalhistoryof pages 2-3, carli2025naturalhistoryof pages 1-2)

No reproducible spontaneous remission pattern is known. The neonatal period, intercurrent illness, and first metabolic decompensation are likely critical intervention windows, but prospective disease-specific evidence is lacking.

9. Inheritance and population

Inheritance

Inheritance is mitochondrial/maternal when the mother carries the variant, with marked recurrence-risk uncertainty because the oocyte bottleneck causes wide heteroplasmy segregation. De novo mtDNA events also occur. Fathers do not transmit mtDNA. Penetrance is incomplete and load-/tissue-/age-dependent; expressivity is highly variable. (peretz2021prospectivediagnosisof pages 6-8, ganetzky2019mt‐atp6mitochondrialdisease pages 1-3)

Maternal blood testing alone cannot reliably quantify recurrence risk or exclude low-level/tissue-restricted heteroplasmy. “Germline mosaicism” is better represented here as maternal heteroplasmy across oocytes and tissues. Consanguinity is not a causal feature of mtDNA transmission, although it remains relevant when considering recessive nuclear mitochondrial disorders.

Epidemiology

No incidence, prevalence, carrier-frequency, founder-effect, geographic enrichment, or ethnicity-specific rate exists for the narrow infantile-HCM phenotype. The 111-person cohort had 55 males and 56 females, consistent with no sex-linked transmission; 44% had infantile onset and 18% had cardiac involvement. These registry data cannot yield population prevalence. (carli2025naturalhistoryof pages 1-2)

10. Diagnostics

Recommended workflow

  1. Recognize mitochondrial HCM: neonatal/infantile HCM plus lactic or metabolic acidosis, hyperammonemia, hypotonia, feeding failure, neurologic abnormalities, unexplained cytopenias, or maternal family history.
  2. Cardiac evaluation: echocardiography with wall thickness, ventricular function, outflow obstruction, diastolic function and noncompaction assessment; ECG/telemetry for pre-excitation and arrhythmia; BNP/NT-proBNP and troponin as clinically indicated; cardiac MRI when stable and feasible.
  3. Metabolic studies: blood gas, lactate, pyruvate, glucose, ammonia, liver enzymes, CK, plasma amino acids—especially citrulline and alanine—acylcarnitines including C5-OH, urine organic acids including 3-methylglutaconic acid, ketones, and renal/hepatic function. In the broader cohort, lactate was elevated in 71%, alanine in 49%, and citrulline reduced in 56%. These are supportive, not diagnostic. (carli2025naturalhistoryof pages 1-2)
  4. Genetic confirmation: high-depth whole-mitochondrial-genome sequencing with heteroplasmy quantification, explicitly covering the MT-ATP8/MT-ATP6 overlap. Test blood promptly, but add urine epithelium, buccal cells, muscle, or available cardiac tissue if suspicion remains high or load appears discordant.
  5. Dual-genome testing: a cardiomyopathy/mitochondrial panel or genome/exome analysis should assess nuclear mitochondrial and sarcomeric genes concurrently. Exome off-target mtDNA analysis can increase yield but a negative result does not exclude mtDNA disease and may require targeted deep sequencing in another tissue.
  6. Functional confirmation for novel/VUS alleles: blue-native PAGE/complex V assembly, ATP synthesis, oxygen-consumption rate, membrane potential, respiratory-chain enzymology, and protein/translation studies in fibroblasts, muscle, or cybrids. No single assay is universally abnormal. (ganetzky2019mt‐atp6mitochondrialdisease pages 3-4, ganetzky2019mt‐atp6mitochondrialdisease pages 1-3)

Newborn screening

Six infants with pathogenic MT-ATP6 variants were prospectively identified through low citrulline and/or elevated C5-OH, then confirmed by mtDNA sequencing. The proposed algorithm combines both markers and confirms abnormalities with plasma amino acids and acylcarnitines. This is an emerging secondary finding, not a universally adopted population screen, and the study involved m.8993T>G or m.9176T>G rather than the core m.8528T>C cardiac allele. (peretz2021prospectivediagnosisof pages 1-3, peretz2021prospectivediagnosisof pages 6-8)

Differential diagnosis

Exclude sarcomeric HCM; Pompe disease; fatty-acid oxidation defects; glycogen-storage disease; congenital disorders of glycosylation; RASopathies; lysosomal disease; and nuclear mitochondrial cardiomyopathies including TMEM70, ATP5F1E/ATP5E, MRPL44, MRPS14, NDUFB7, and other OXPHOS assembly/translation defects. Distinguishing clues are maternal inheritance, mtDNA heteroplasmy, multisystem energy failure, low citrulline, lactate elevation, and isolated complex V deficiency.

CMA, karyotype, FISH, and repeat-expansion testing are not first-line unless another phenotype suggests them. WES that ignores mtDNA is insufficient.

11. Outcome and prognosis

For m.8528T>C infantile cardiomyopathy, prognosis can be poor: rapid progression and death within the first months occurred in at least two reported patients. Reliable 1-, 5-, or 10-year survival rates do not exist. (tauchmannova2024variabilityofclinical pages 5-7)

In the broader 111-patient cohort, 92% were alive at last follow-up, but survival was significantly worse in infantile/pediatric-onset than adult-onset disease (p=0.0349). Seven recorded deaths were attributed variously to pneumonia, respiratory failure, seizures, COVID-19 complications, multiorgan failure, and cardiomyopathy. These aggregate outcomes should not be substituted for prognosis in severe neonatal cardiac disease. (carli2025naturalhistoryof pages 5-7, carli2025naturalhistoryof pages 1-2)

Adverse prognostic features likely include prenatal/neonatal onset, very high heteroplasmy, biventricular disease, declining ventricular function, arrhythmia, recurrent metabolic acidosis, respiratory failure, and multiorgan involvement. No validated cardiac prognostic biomarker exists.

12. Treatment

Current clinical management

There is no approved variant-correcting or disease-specific therapy. Management should be coordinated by mitochondrial medicine, pediatric cardiology, intensive care, metabolic dietetics, neurology, genetics, and palliative care when appropriate.

  • Treat heart failure and arrhythmias according to pediatric physiology and hemodynamics; avoid routine extrapolation from adult HCM.
  • Prevent catabolism with adequate calories and prompt glucose-containing fluids during illness when appropriate; correct acidosis, hypoglycemia, electrolyte abnormalities, and hyperammonemia.
  • Provide feeding support, respiratory support, physical/occupational therapy, and developmental services.
  • Consider mechanical circulatory support or transplantation only through individualized multidisciplinary assessment; systemic mitochondrial disease and neurologic progression strongly influence candidacy. Disease-specific outcome data are absent.

Suggested NCIT intervention concepts include Supportive Care, Nutritional Support, Cardiac Monitoring, Mechanical Ventilation, Hemodialysis for severe hyperammonemia, and Heart Transplantation where applicable.

Supplements and investigational pharmacology

A newborn-screening cohort received L-citrulline 250 mg/kg/day in two doses, ubiquinol 8 mg/kg/day, and B-complex vitamins; the six patients had no crises or regression during reported follow-up. Because there was no control group and the variants were not m.8528T>C, this is low-level evidence, not proof of benefit for infantile HCM. (peretz2021prospectivediagnosisof pages 1-3, peretz2021prospectivediagnosisof pages 6-8)

Antioxidants, N-acetylcysteine, vitamin-E derivatives, selenium, melatonin, resveratrol, α-ketoglutarate/aspartate, rapamycin/mTOR modulation, and vatiquinone have shown cellular, animal, or broader mitochondrial-disease signals. None has demonstrated cardiac benefit for this genotype. (dotto2024variantsinhuman pages 22-23, dotto2024variantsinhuman pages 31-32, dotto2024variantsinhuman pages 20-22)

The trial search found broader inherited-mitochondrial-disease studies—e.g., vatiquinone NCT05218655 and NCT04378075, elamipretide NCT02976038/NCT05162768, and arginine/citrulline NCT02809170—but no trial specifically enrolling MT-ATP6/MT-ATP8 infantile HCM. Consequently, efficacy cannot be inferred for this disease.

Advanced therapeutics

Preclinical approaches include:

  • allotopic nuclear expression of recoded wild-type ATP6/ATP8;
  • mitochondrially targeted modified mRNA;
  • mtZFNs and mitoTALENs that selectively reduce mutant mtDNA;
  • experimental mitoTALEN targeting of m.9176T>C in murine oocytes.

Cybrid and mouse experiments have shown improved ATP, respiration, membrane potential, or stress growth, but import efficiency, heteroplasmy rebound, off-target cleavage, delivery to heart/CNS, and safety remain unresolved. These are not clinical treatments. (dotto2024variantsinhuman pages 23-24, dotto2024variantsinhuman pages 32-33)

No established pharmacogenomic dosing rule exists for MT-ATP6/MT-ATP8.

13. Prevention

Primary prevention by lifestyle modification is not possible. Reproductive options after identifying a maternal pathogenic variant include genetic counseling, prenatal diagnosis, preimplantation genetic testing with heteroplasmy assessment, donor oocytes, adoption, and—where legal and available—mitochondrial donation. Heteroplasmy can shift between sampled embryonic cells and later tissues, so residual risk must be explained.

Secondary prevention consists of cascade testing of maternal relatives, cardiac screening of carriers, prospective biochemical/developmental surveillance, and rapid evaluation of newborns. Low citrulline plus elevated C5-OH is a potential screening signature, but evidence remains limited to a small cohort. (peretz2021prospectivediagnosisof pages 1-3)

Tertiary prevention includes avoiding prolonged fasting/dehydration, maintaining emergency illness plans, early treatment of infection and catabolism, serial echocardiography/ECG, arrhythmia surveillance, nutritional support, vaccination according to standard schedules, and anesthetic planning. Vaccines do not prevent the genetic disease but can reduce infection-triggered decompensation.

14. Other species and natural disease

No naturally occurring companion-animal, livestock, or wildlife syndrome convincingly homologous to m.8528T>C infantile HCM was identified; no VBO breed association or zoonotic relevance applies. ATP synthase structure and oxidative phosphorylation are evolutionarily conserved, making cross-species functional modeling informative, but naturally occurring veterinary disease should be recorded as not established.

15. Model organisms and experimental systems

  • Saccharomyces cerevisiae (NCBI Taxonomy 4932): genetically tractable ATP6/ATP8 models support structure–function analysis and variant pathogenicity assessment. Limitations include species-specific mitochondrial translation, ATP-synthase architecture, and absence of a mammalian heart. The ATP-synthase review explicitly uses yeast to interpret human mutations against structural data. (dautant2018atpsynthasediseases pages 1-2)
  • Patient fibroblasts/myoblasts: retain the patient nuclear background and permit respiration, ATP, membrane-potential, translation, and complex-assembly studies; limitations include tissue heteroplasmy differences and low cardiac fidelity.
  • Transmitochondrial cybrids: isolate mtDNA effects in a standardized nuclear background; useful for m.8993T>G, m.8529G>A, antioxidants, allotopic expression, and nucleases. They cannot reproduce developmental cardiomyopathy or multisystem interactions. (dotto2024variantsinhuman pages 23-24)
  • Murine oocytes and transgenic mice (Mus musculus, NCBI Taxonomy 10090): used to test heteroplasmy-shifting nucleases and germline-transmission prevention. Delivery, off-target effects, and species-specific mtDNA biology limit translation. (dotto2024variantsinhuman pages 23-24)
  • iPSC-derived cardiomyocytes/organoids: conceptually well suited to cardiac disease, but no validated m.8528T>C-specific iPSC-cardiomyocyte or cardiac-organoid model was identified.

Recent authoritative developments

  1. 2024 systematic ATP-synthase review: Tauchmannová et al., published August 2024, consolidated the m.8528T>C cases and identified dual ATP8/ATP6 protein loss, high heteroplasmy, and prenatal-to-infantile HCM as the characteristic association. DOI: 10.33549/physiolres.935407. (tauchmannova2024variabilityofclinical pages 5-7)
  2. 2024 variant/therapy review: Del Dotto et al., published February 2024, integrated recent complex V structural biology with allotopic expression, modified RNA, and heteroplasmy-shifting nuclease strategies. DOI: 10.3390/ijms25042239. (dotto2024variantsinhuman pages 23-24)
  3. 2025 natural history: Carli et al. provided the largest multicenter ATP6/8 cohort to date—111 patients, 98 previously unreported—and quantitative onset, organ, biomarker, heteroplasmy, and survival data. DOI: 10.1212/WNL.0000000000213462. Although later than the requested 2023–2024 priority period, it is the strongest current disease-level dataset. (carli2025naturalhistoryof pages 5-7, carli2025naturalhistoryof pages 1-2)

Evidence limitations and knowledge-base recommendations

This entry should be labeled very low prevalence / prevalence unknown and limited clinical evidence. The narrow disease definition rests predominantly on m.8528T>C case reports; larger cohorts combine neurologic, myopathic, ophthalmic, and cardiac phenotypes across many alleles. No validated prevalence, controlled treatment trial, cardiac natural-history series, quality-of-life study, disease-specific biomarker threshold, single-cell dataset, or dedicated ontology identifier was found.

For knowledge-base implementation, use a compositional record linking m.8528T>C → MT-ATP8 p.Trp55Arg + MT-ATP6 p.Met1Thr/initiation defect → complex V deficiency → impaired ATP synthesis → infantile hypertrophic/biventricular cardiomyopathy and metabolic decompensation, and keep broader m.8993/m.9176 evidence in an explicitly labeled “MT-ATP6/8 spectrum” section rather than treating all alleles as equivalent.

References

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  14. (carli2025naturalhistoryof pages 2-3): Sara Carli, Anna Levarlet, Daria Diodato, Enrico Silvio Bertini, Diego Martinelli, Alessandro Malandrini, Diego Lopergolo, Gian Nicola Gallus, Rebecca D. Ganetzky, Chiara La Morgia, Valerio Carelli, Guido Primiano, Cristina Domínguez-González, Pablo Serrano-Lorenzo, Miguel A. Martín, Anna Ardissone, Costanza Lamperti, Valeria Nicoletta, Thomas Klopstock, Felix Distelmaier, Leopold Zeng, Boriana Büchner, Michelangelo Mancuso, Markus Schuelke, Alessandro Prigione, and Caterina Garone. Natural history of patients with mitochondrial atpase deficiency due to pathogenic variants of mt-atp6 and mt-atp8. Neurology, Apr 2025. URL: https://doi.org/10.1212/wnl.0000000000213462, doi:10.1212/wnl.0000000000213462. This article has 21 citations and is from a highest quality peer-reviewed journal.

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