🏷

Classifications

Harrison's Part

Mechanistic Nosology

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Inheritance

1

Autosomal recessive HP:0000007

Sudden cardiac failure, infantile is inherited in an autosomal recessive manner due to homozygous or compound heterozygous pathogenic variants in PPA2. At least one hypomorphic missense allele is required for postnatal viability because complete loss of mitochondrial pyrophosphatase activity is cell-lethal; clinical expressivity varies with residual enzyme activity and environmental triggers such as febrile viral infection or alcohol exposure.

Autosomal recessive inheritance Expressivity: VARIABLE

Show evidence (2 references)

PMID:27523598 SUPPORT Human Clinical

"Here we report seven individuals from three families affected by sudden and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome sequencing revealed compound heterozygous missense mutations in PPA2 in affected infants of each family."

Identifies compound heterozygous biallelic PPA2 variants in multiple affected siblingships with unaffected carrier parents, establishing autosomal recessive inheritance.

PMID:34400813 SUPPORT Human Clinical

"In this study, we report a cohort of 34 individuals with biallelic PPA2 variants from 20 families, enlarging the number of reported patients to 56 from 30 families worldwide."

Confirms autosomal recessive biallelic inheritance across 56 affected individuals from 30 unrelated families and demonstrates variable clinical expressivity ranging from infantile cardiac arrest to adult-onset cardiomyopathy and neuropathy.

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Pathophysiology

8

Mitochondrial inorganic pyrophosphatase 2 (PPA2) enzymatic deficiency

Biallelic hypomorphic missense variants or compound heterozygous missense/truncating variants in PPA2 severely reduce mitochondrial inorganic pyrophosphatase activity in the mitochondrial matrix. Because PPA2 catalyzes the hydrolysis of inorganic pyrophosphate (PPi) into two orthophosphate ions, reduced PPA2 activity impairs PPi clearance during high-flux mitochondrial biosynthetic reactions (DNA, RNA, protein, and lipid synthesis) and short-chain fatty-acid/acetate activation. Residual enzymatic activity of recombinant mutant PPA2 proteins correlates with age at onset and clinical severity: variants associated with neonatal or early infantile lethality (such as p.Pro167Leu and p.Glu172Lys) retain only 5%–10% wild-type activity, whereas variants permissive for survival into adolescence (such as p.Pro228Leu) retain 24%–28% activity. Furthermore, missense PPA2 variants exhibit temperature sensitivity in vitro, so febrile viral illnesses or modest ethanol/acetic acid loads acutely overwhelm residual PPi hydrolysis capacity.

cardiac muscle cell CL:0000746 fibroblast CL:0000057

PPA2 hgnc:28883

inorganic diphosphate phosphatase activity GO:0004427 ↓ DECREASED

mitochondrial matrix GO:0005759

myocardium UBERON:0002349

Downstream

Mitochondrial matrix inorganic pyrophosphate accumulation Loss of mitochondrial inorganic pyrophosphatase catalytic activity and temperature-induced inactivation of residual mutant PPA2 prevent clearance of intramitochondrial inorganic pyrophosphate (PPi), causing PPi buildup within the mitochondrial matrix.

Show evidence (4 references)

PMID:27523598 SUPPORT Human Clinical

"PPA2 encodes the mitochondrial pyrophosphatase, which hydrolyzes inorganic pyrophosphate into two phosphates. This is an essential activity for many biosynthetic reactions and for energy metabolism of the cell."

Defines the canonical molecular function of PPA2 as mitochondrial inorganic pyrophosphate hydrolysis required for cellular biosynthetic reactions and energy metabolism.

PMID:27523597 SUPPORT In Vitro

"Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with..."

Demonstrates significantly reduced mitochondrial pyrophosphatase activity in patient fibroblast mitochondria and establishes that residual activity of recombinant mutant PPA2 enzymes correlates with clinical severity.

PMID:27523597 SUPPORT In Vitro

"Compared to wild-type, the p.Pro167Leu and p.Glu172Lys variants showed 5%–10% residual activity at PPi substrate concentrations 18–500 μmol/L. The p.Pro228Leu variant had a residual activity of 24%–28% in this concentration range compared to wild-type (Figure 3D)."

Quantifies residual pyrophosphatase activity for key pathogenic missense variants, linking lower residual enzymatic activity (5%–10% for p.Pro167Leu and p.Glu172Lys) to infantile onset and higher residual activity (24%–28% for p.Pro228Leu) to later-onset alcohol-triggered presentations.

+ 1 more reference

Mitochondrial matrix inorganic pyrophosphate accumulation

Impaired hydrolysis of inorganic pyrophosphate (PPi) by deficient PPA2—and acute PPi surges generated by thermal inactivation during febrile viral illness or by ACSS1-mediated activation of ethanol-derived acetic acid to acetyl-CoA—results in accumulation of PPi within the mitochondrial matrix, inhibiting PPi-producing biosynthetic reactions and mitochondrial energy transduction.

cardiac muscle cell CL:0000746

mitochondrial matrix GO:0005759

myocardium UBERON:0002349

Downstream

Mitochondrial inner membrane potential dissipation Unresolved intramitochondrial PPi accumulation inactivates the mitochondrial energy-transducing system and prevents maintenance of a sufficient electrical potential across the inner mitochondrial membrane.

Show evidence (2 references)

PMID:34400813 SUPPORT INDIRECT Human Clinical

"We propose that viral infections in affected individuals may tip the cardiac muscle into ATP deficit, due to a build-up of PPi following the effects of temperature increase on the already deficient PPA2 enzyme of these individuals."

Identifies intramitochondrial build-up of PPi as the proximal metabolic consequence of reduced PPA2 enzymatic activity.

PMID:27523597 SUPPORT BACKGROUND Human Clinical

"Ethanol is oxidized to acetaldehyde and further to acetic acid.13 Resulting acetic acid has to be activated to acetyl-coenzyme A, which is accompanied by the formation of equimolar amounts of PPi (Figure S7). This esterification reaction is catalyzed by short-chain acyl-CoA synthetases encoded,..."

Describes the biochemical source of intramitochondrial PPi formation in heart mitochondria during acetate/ethanol activation.

Mitochondrial inner membrane potential dissipation

Failure of intramitochondrial PPi hydrolysis rapidly inactivates the mitochondrial energy-transducing machinery and prevents maintenance of a sufficient electrical potential across the inner mitochondrial membrane, destabilizing mitochondrial integrity and leading to organelle loss under metabolic stress.

cardiac muscle cell CL:0000746

regulation of mitochondrial membrane potential GO:0051881 ↕ DYSREGULATED

mitochondrial inner membrane GO:0005743

myocardium UBERON:0002349

Downstream

Mitochondrial bioenergetic failure and ATP depletion Collapse of the inner mitochondrial membrane potential and loss of functional mitochondria impair oxidative phosphorylation (including cardiac complex I and IV activities) and precipitate cellular ATP depletion.

Show evidence (1 reference)

PMID:27523598 SUPPORT Model Organism

"Using a regulatable (doxycycline-repressible) gene expression system, we found that the pathogenic PPA2 mutations rapidly inactivate the mitochondrial energy transducing system and prevent the maintenance of a sufficient electrical potential across the inner membrane, which explains the..."

Establishes that PPA2 deficiency prevents maintenance of the electrical potential across the mitochondrial inner membrane and causes subsequent loss of mitochondria.

Mitochondrial bioenergetic failure and ATP depletion

Dissipation of the inner mitochondrial membrane potential and impaired oxidative phosphorylation (with normal-to-moderately reduced complex I and IV respiratory chain activities in cardiac tissue) cause acute or chronic cellular ATP depletion in high-energy-demand tissues. Cardiomyocytes are most vulnerable during acute metabolic or thermal stress, while neonates with severe alleles develop systemic lactic acidosis, seizures, and hypotonia, and older survivors develop chronic ATP-deficiency injury in peripheral nerves, extraocular/eyelid muscles, and cerebellar pathways.

cardiac muscle cell CL:0000746

ATP biosynthetic process GO:0006754 ↓ DECREASED mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED

mitochondrion GO:0005739

myocardium UBERON:0002349

Downstream

Cardiomyocyte loss and myofibrillar disarray Bioenergetic collapse and ATP deficit in cardiomyocytes lead to myocyte necrosis/loss and myofibrillar disarray across the ventricular myocardium.

Lactic acidosis Impaired mitochondrial oxidative phosphorylation and pyruvate oxidation during metabolic decompensation cause systemic lactic acidosis, especially in neonatal and early infantile presentations.

Seizure Severe neonatal mitochondrial bioenergetic failure and lactic acidosis impair neuronal energy homeostasis, causing early-infantile seizures.

Hypotonia Impaired ATP availability in skeletal muscle and central motor pathways causes muscular hypotonia in severely affected neonates and infants.

Peripheral axonal neuropathy Chronic mitochondrial dysfunction and suboptimal ATP availability in long peripheral axons cause progressive distal axonal degeneration and peripheral axonal neuropathy in surviving patients.

External ophthalmoplegia Chronic mitochondrial bioenergetic insufficiency in extraocular muscles causes progressive external ophthalmoplegia in adult survivors.

Ptosis Mitochondrial ATP deficiency in levator palpebrae superioris muscle fibers produces eyelid ptosis in surviving adults with multisystemic PPA2 deficiency.

Progressive cerebellar ataxia Chronic mitochondrial bioenergetic dysfunction in high-ATP-demand cerebellar and spinocerebellar neurons leads to adolescent- or adult-onset progressive spastic cerebellar ataxia in surviving individuals.

Show evidence (2 references)

PMID:27523597 SUPPORT Human Clinical

"Respiratory chain function varied from normal to moderate reduction in complex I and IV activities in cardiac tissue and was normal in fibroblasts and skeletal muscle tissue."

Documents normal-to-moderately reduced mitochondrial respiratory chain complex I and IV activities in cardiac tissue from affected individuals.

PMID:34400813 SUPPORT Human Clinical

"These observations are consistent with mitochondrial depletion or dysfunction affecting tissues requiring optimal levels of ATP availability such as muscle and nerve cells."

Links mitochondrial depletion and impaired ATP availability to tissue injury in high-energy-demand muscle and nerve cells.

Cardiomyocyte loss and myofibrillar disarray

Acute or recurrent bioenergetic collapse in PPA2-deficient cardiomyocytes causes focal or patchy cardiomyocyte dropout (myocyte loss) and myofibrillar disarray across the ventricular myocardium, initiating reparative replacement fibrosis and impairing ventricular contractility.

cardiac muscle cell CL:0000746

myocardium UBERON:0002349

Downstream

Focal myocardial replacement fibrosis Necrotic loss of energy-depleted cardiomyocytes triggers cardiac fibroblast activation and extracellular matrix deposition, producing focal and mid-myocardial replacement fibrosis.

Acute myocardial contractile failure Loss of functional cardiomyocytes and myofibrillar disarray directly reduce ventricular systolic force generation.

Show evidence (1 reference)

PMID:27523597 SUPPORT Human Clinical

"In affected individuals homozygous for c.500C>T (p.Pro167Leu), the clinical presentation involved lactic acidosis, seizures, hypotonia, and cardiac arrhythmia within the first months of life. Myocyte loss, disarray, or fibrosis was present in all individuals."

Documents universal myocyte loss, disarray, or fibrosis on cardiac histopathology in affected individuals.

Focal myocardial replacement fibrosis

Following cardiomyocyte loss, cardiac fibroblasts deposit collagen-rich extracellular matrix, producing prominent focal, patchy, or circumferential mid-myocardial and subepicardial replacement fibrosis (occasionally accompanied by mild secondary inflammatory infiltrates). Myocardial fibrosis is the histopathological and cardiac MRI hallmark of biallelic PPA2 deficiency, observed in nearly all examined hearts (15 of 17 evaluated cases in the 2021 international cohort) and often detectable on cardiac MRI even in clinically asymptomatic siblings prior to arrhythmic or heart-failure decompensation.

fibroblast of cardiac tissue CL:0002548

extracellular matrix organization GO:0030198 ↕ DYSREGULATED

myocardium UBERON:0002349 heart left ventricle UBERON:0002084

Downstream

Myocardial fibrosis Focal and mid-myocardial collagen deposition manifests clinically and radiologically as myocardial fibrosis on late gadolinium enhancement cardiac MRI and autopsy histology.

Ventricular arrhythmia and electrical instability Patchy mid-myocardial fibrosis creates conduction heterogeneity and re-entrant circuits that, together with acute bioenergetic crisis, trigger malignant ventricular tachyarrhythmias and sudden cardiac arrest.

Acute myocardial contractile failure Extensive mid-myocardial replacement fibrosis stiffens and weakens the ventricular walls, contributing to dilated cardiomyopathy, acute heart failure, and cardiogenic shock.

Show evidence (2 references)

PMID:34400813 SUPPORT Human Clinical

"Focal myocardial fibrosis upon histology and/or cardiac MRI was reported in 15 of 17 cases for which data were available. Such an observation should alert physicians to possible PPA2 dysfunction regardless of the clinical presentation and even in asymptomatic individuals."

Establishes focal myocardial fibrosis as the consistent tissue-level hallmark across 15 of 17 evaluated patients on histology and/or cardiac MRI.

PMID:27523597 SUPPORT Human Clinical

"Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4 shown in Figure 2). They subsequently each received an implantable defibrillator for primary prophylaxis of sudden arrhythmic cardiac death, although no events have occurred to date."

Demonstrates marked mid-myocardial fibrosis on cardiac MRI in surviving biallelic siblings.

Ventricular arrhythmia and electrical instability

Combined acute bioenergetic failure and focal mid-myocardial fibrosis destabilize cardiomyocyte action potential propagation and repolarization, producing malignant ventricular arrhythmias including ventricular tachycardia, torsades de pointes, ventricular fibrillation, bradycardia, or pulseless electrical activity, culminating in sudden unexpected cardiac arrest and sudden cardiac death.

cardiac muscle cell CL:0000746

cardiac muscle cell action potential GO:0086001 ↕ DYSREGULATED

myocardium UBERON:0002349

Downstream

Ventricular fibrillation Electrical instability in the fibrotic, energy-depleted myocardium degenerates into lethal ventricular fibrillation.

Ventricular tachycardia Myocardial electrical instability manifests as pulseless or sustained ventricular tachycardia.

Cardiac arrest Malignant ventricular arrhythmias and pulseless electrical activity cause abrupt cessation of effective cardiac mechanical output.

Sudden cardiac death Refractory ventricular fibrillation, pulseless ventricular tachycardia, or asystole/PEA frequently resists resuscitation and results in sudden cardiac death.

Show evidence (2 references)

PMID:34400813 SUPPORT Human Clinical

"In the latter group of 13 individuals, dilated cardiomyopathy or ventricular dysfunction was usually diagnosed by echocardiography, rapidly followed by multiorgan failure and/or ventricular fibrillation (VF, reported for six cases)."

Documents rapid progression to malignant ventricular fibrillation in six patients with ventricular dysfunction, alongside primary sudden cardiac arrest in 15 patients.

PMID:33028643 SUPPORT Human Clinical

"The underlying rhythm was primarily pulseless electrical activity (PEA), with one incidence of pulseless ventricular tachycardia, for which the patient was unsuccessfully defibrillated."

Documents lethal pulseless electrical activity and pulseless ventricular tachycardia in a neonate with biallelic PPA2 variants.

Acute myocardial contractile failure

Severe cardiomyocyte bioenergetic depletion and replacement fibrosis impair left and biventricular systolic contractility, causing rapid-onset dilated cardiomyopathy, congestive heart failure, refractory cardiogenic shock, and multiorgan failure.

cardiac muscle cell CL:0000746

cardiac muscle contraction GO:0060048 ↓ DECREASED

heart UBERON:0000948 heart left ventricle UBERON:0002084

Downstream

Dilated cardiomyopathy Impaired myocardial contractility and myocyte loss manifest structurally as left ventricular or biventricular dilation and systolic dysfunction on echocardiography.

Congestive heart failure Severe ventricular systolic failure leads to acute or rapidly progressive heart failure.

Cardiogenic shock Fulminant pump failure in infants and young children produces acute cardiogenic shock and multiorgan failure.

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"In the latter group of 13 individuals, dilated cardiomyopathy or ventricular dysfunction was usually diagnosed by echocardiography, rapidly followed by multiorgan failure and/or ventricular fibrillation (VF, reported for six cases)."

Demonstrates that acute ventricular systolic dysfunction and dilated cardiomyopathy rapidly progress to multiorgan failure and death in nearly half of affected infants and children.

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Pathograph

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Phenotypes

18

Cardiovascular 8

Cardiac arrest VERY_FREQUENT HP:0001695

Show evidence (2 references)

PMID:27523598 SUPPORT Human Clinical

"Here we report seven individuals from three families affected by sudden and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome sequencing revealed compound heterozygous missense mutations in PPA2 in affected infants of each family."

Establishes sudden and unexpected cardiac arrest between 4 and 20 months of age as the defining presentation in the original three-family cohort.

PMID:34400813 SUPPORT Human Clinical

"The most common clinical presentation remains sudden unexpected cardiac arrest, reported in all of the deceased teenagers and half of the children who died before their teens, while the other half presented with dilated cardiomyopathy, cardiogenic shock, or arrhythmia before death."

Confirms across 34 patients that sudden unexpected cardiac arrest is the single most common presentation of biallelic PPA2 deficiency.

Sudden cardiac death VERY_FREQUENT HP:0001645

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure."

Quantifies mortality in the 34-patient cohort, showing 28 deaths (82%) in infancy or adolescence from sudden cardiac arrest or acute heart failure.

Myocardial fibrosis VERY_FREQUENT HP:0001685

Show evidence (2 references)

PMID:34400813 SUPPORT Human Clinical

"Focal myocardial fibrosis upon histology and/or cardiac MRI was reported in 15 of 17 cases for which data were available. Such an observation should alert physicians to possible PPA2 dysfunction regardless of the clinical presentation and even in asymptomatic individuals."

Documents focal myocardial fibrosis in 15 of 17 (88%, VERY_FREQUENT) evaluated patients on histology and/or cardiac MRI, including asymptomatic siblings.

PMID:27523597 SUPPORT Human Clinical

"Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4 shown in Figure 2). They subsequently each received an implantable defibrillator for primary prophylaxis of sudden arrhythmic cardiac death, although no events have occurred to date."

Demonstrates marked mid-myocardial fibrosis on cardiac MRI in surviving biallelic siblings.

Dilated cardiomyopathy FREQUENT HP:0001644

Show evidence (2 references)

PMID:34400813 SUPPORT Human Clinical

"In the latter group of 13 individuals, dilated cardiomyopathy or ventricular dysfunction was usually diagnosed by echocardiography, rapidly followed by multiorgan failure and/or ventricular fibrillation (VF, reported for six cases)."

Documents dilated cardiomyopathy or ventricular dysfunction diagnosed by echocardiography in 13 of 28 deceased patients (plus surviving patients who underwent heart transplantation or adult cardiomyopathy management).

CGGV:assertion_35b7716c-4c72-4ca2-b176-e732d136ed0d-2025-05-16T160000.000Z SUPPORT Other

"| PPA2 | HGNC:28883 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong | SOP10 | Dilated Cardiomyopathy Gene Curation Expert Panel | 2025-05-16T16:00:00.000Z |"

ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel classifies autosomal recessive PPA2 deficiency as a Strong cause of dilated cardiomyopathy.

Congestive heart failure FREQUENT HP:0001635

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure."

Shows that 13 of 28 fatal cases (46%, FREQUENT) died of acute heart failure.

Cardiogenic shock FREQUENT HP:0030149

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"The most common clinical presentation remains sudden unexpected cardiac arrest, reported in all of the deceased teenagers and half of the children who died before their teens, while the other half presented with dilated cardiomyopathy, cardiogenic shock, or arrhythmia before death."

Documents cardiogenic shock among the half of affected children who present with acute myocardial failure prior to death.

Ventricular fibrillation OCCASIONAL HP:0001663

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"In the latter group of 13 individuals, dilated cardiomyopathy or ventricular dysfunction was usually diagnosed by echocardiography, rapidly followed by multiorgan failure and/or ventricular fibrillation (VF, reported for six cases)."

Documents ventricular fibrillation in 6 cases within the 13-patient acute ventricular-dysfunction/heart-failure subgroup.

Ventricular tachycardia OCCASIONAL HP:0004756

Show evidence (1 reference)

PMID:33028643 SUPPORT Human Clinical

"The underlying rhythm was primarily pulseless electrical activity (PEA), with one incidence of pulseless ventricular tachycardia, for which the patient was unsuccessfully defibrillated."

Documents pulseless ventricular tachycardia during fatal neonatal cardiac arrest due to compound heterozygous PPA2 variants.

Digestive 2

Vomiting HP:0002013

Show evidence (1 reference)

PMID:31705601 SUPPORT Human Clinical

"In the 2 days before death, she experienced fever, vomiting, diarrhea, and poor appetite."

Documents prodromal vomiting and diarrhea with fever immediately preceding sudden cardiac death in an infant with biallelic PPA2 variants.

Diarrhea HP:0002014

Show evidence (1 reference)

PMID:31705601 SUPPORT Human Clinical

"In the 2 days before death, she experienced fever, vomiting, diarrhea, and poor appetite."

Documents diarrhea as part of the acute febrile prodrome before fatal cardiac arrest.

Eye 2

External ophthalmoplegia RARE HP:0000544

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Individual II-1 from family 17 is alive aged 40 years. She was diagnosed with multisystemic mitochondrial disease with cardiomyopathy at 17 years and has had a history of progressive distal weakness and bilateral foot drop with peripheral axonal neuropathy identified by electromyography,..."

Documents adult-onset external ophthalmoplegia and ptosis in a patient with biallelic PPA2 variants.

Ptosis RARE HP:0000508

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Individual II-1 from family 17 is alive aged 40 years. She was diagnosed with multisystemic mitochondrial disease with cardiomyopathy at 17 years and has had a history of progressive distal weakness and bilateral foot drop with peripheral axonal neuropathy identified by electromyography,..."

Documents ptosis as part of the adult neurological spectrum of biallelic PPA2 deficiency.

Metabolism 1

Lactic acidosis OCCASIONAL HP:0003128

Show evidence (1 reference)

PMID:27523597 SUPPORT Human Clinical

"In affected individuals homozygous for c.500C>T (p.Pro167Leu), the clinical presentation involved lactic acidosis, seizures, hypotonia, and cardiac arrhythmia within the first months of life. Myocyte loss, disarray, or fibrosis was present in all individuals."

Documents lactic acidosis in infants with severe biallelic PPA2 deficiency.

Musculoskeletal 1

Hypotonia OCCASIONAL HP:0001252

Show evidence (1 reference)

PMID:27523597 SUPPORT Human Clinical

"In affected individuals homozygous for c.500C>T (p.Pro167Leu), the clinical presentation involved lactic acidosis, seizures, hypotonia, and cardiac arrhythmia within the first months of life. Myocyte loss, disarray, or fibrosis was present in all individuals."

Documents hypotonia within the first months of life in severely affected infants.

Nervous System 4

Seizure OCCASIONAL HP:0001250

Show evidence (1 reference)

PMID:27523597 SUPPORT Human Clinical

"In affected individuals homozygous for c.500C>T (p.Pro167Leu), the clinical presentation involved lactic acidosis, seizures, hypotonia, and cardiac arrhythmia within the first months of life. Myocyte loss, disarray, or fibrosis was present in all individuals."

Documents seizures in the first months of life in infants homozygous for p.Pro167Leu.

Vocal cord paralysis RARE HP:0001605

Show evidence (1 reference)

PMID:33028643 SUPPORT Human Clinical

"We report a 5-wk-old male with bilateral vocal cord paralysis and hypertension who had a sudden unexpected cardiac death. Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a paternally inherited,..."

Documents bilateral vocal cord paralysis in a neonate with compound heterozygous PPA2 variants who subsequently died of sudden cardiac arrest.

Peripheral axonal neuropathy OCCASIONAL HP:0003477

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Individual II-1 from family 17 is alive aged 40 years. She was diagnosed with multisystemic mitochondrial disease with cardiomyopathy at 17 years and has had a history of progressive distal weakness and bilateral foot drop with peripheral axonal neuropathy identified by electromyography,..."

Documents EMG-confirmed peripheral axonal neuropathy with distal weakness and bilateral foot drop in an adult survivor with biallelic PPA2 deficiency.

Progressive cerebellar ataxia RARE HP:0002073

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Individual II-4 in family 4 (this report) displayed signs of progressive spastic cerebellar ataxia with distal weakness starting from 14 years of age."

Documents adolescent-onset progressive spastic cerebellar ataxia in a surviving patient with biallelic PPA2 variants.

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Genetic Associations

1

PPA2 (Causative)

Gene: PPA2 hgnc:28883 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (4 references)

PMID:27523598 SUPPORT Human Clinical

"Altogether these data demonstrate that PPA2 is an essential gene in yeast and that biallelic mutations in PPA2 cause a mitochondrial disease leading to sudden cardiac arrest in infants."

Establishes that biallelic pathogenic mutations in PPA2 cause autosomal recessive mitochondrial disease presenting with infantile sudden cardiac arrest.

PMID:34400813 SUPPORT Human Clinical

"Of note, the most frequent pathogenic PPA2 variant is c.514G>A; p.(Glu172Lys), identified in 11 of the 20 families in our cohort, and has been reported in several families in previous studies."

Identifies c.514G>A (p.Glu172Lys) as the most frequent recurrent pathogenic PPA2 allele across published cohorts.

PMID:34400813 SUPPORT Human Clinical

"The two truncating variants: c.250C>T; p.(Arg84*) and c.938C>A; p.(Ser313*), lie in exons 3 and 10 respectively (of 12 exons in total) and are predicted to induce nonsense-mediated messenger RNA (mRNA) decay."

Documents nonsense loss-of-function alleles occurring in trans with hypomorphic missense alleles in affected individuals.

+ 1 more reference

Variants (4)

c.514G>A (p.Glu172Lys)

Most frequent recurrent pathogenic PPA2 missense allele in European-ancestry cohorts (identified in 11 of 20 families in the 2021 international series). Recombinant p.Glu172Lys retains 5%–10% residual inorganic pyrophosphatase activity; compound heterozygosity with a severe missense or truncating allele causes infantile sudden cardiac failure (MONDO:0014973), whereas compound heterozygosity with p.Pro228Leu causes adolescent/adult alcohol-induced sudden cardiac failure (MONDO:0014974).

Show evidence (2 references)

PMID:34400813 SUPPORT Human Clinical

"Of note, the most frequent pathogenic PPA2 variant is c.514G>A; p.(Glu172Lys), identified in 11 of the 20 families in our cohort, and has been reported in several families in previous studies."

Establishes c.514G>A (p.Glu172Lys) as the most frequent recurrent pathogenic PPA2 variant.

PMID:27523597 SUPPORT In Vitro

"Compared to wild-type, the p.Pro167Leu and p.Glu172Lys variants showed 5%–10% residual activity at PPi substrate concentrations 18–500 μmol/L. The p.Pro228Leu variant had a residual activity of 24%–28% in this concentration range compared to wild-type (Figure 3D)."

Quantifies 5%–10% residual enzymatic activity for recombinant p.Glu172Lys.

c.500C>T (p.Pro167Leu)

Severe hypomorphic missense variant retaining 5%–10% residual enzymatic activity; homozygosity causes neonatal/early-infantile lactic acidosis, seizures, hypotonia, cardiac arrhythmia, and fatal heart failure within the first months of life.

Show evidence (1 reference)

PMID:27523597 SUPPORT Human Clinical

"In affected individuals homozygous for c.500C>T (p.Pro167Leu), the clinical presentation involved lactic acidosis, seizures, hypotonia, and cardiac arrhythmia within the first months of life. Myocyte loss, disarray, or fibrosis was present in all individuals."

Documents the severe early-infantile clinical phenotype associated with homozygous c.500C>T (p.Pro167Leu).

c.683C>T (p.Pro228Leu)

Milder hypomorphic missense allele retaining 24%–28% residual activity in recombinant enzyme assays across PPi substrate concentrations of 18–500 μmol/L.

Show evidence (1 reference)

PMID:27523597 SUPPORT In Vitro

"Compared to wild-type, the p.Pro167Leu and p.Glu172Lys variants showed 5%–10% residual activity at PPi substrate concentrations 18–500 μmol/L. The p.Pro228Leu variant had a residual activity of 24%–28% in this concentration range compared to wild-type (Figure 3D)."

Demonstrates 24%–28% residual catalytic activity for recombinant p.Pro228Leu.

c.379C>T (p.Arg127Cys)

De novo pathogenic missense variant identified in trans with a maternal nonsense PPA2 allele (c.524C>G; p.Ser175*) in a patient with infantile sudden cardiac failure.

Show evidence (1 reference)

PMID:33826954 SUPPORT Human Clinical

"Whole exome and Sanger sequencing revealed two variants in PPA2, with one novel nonsense variant (c.524C > G; p.Ser175*) inherited from the mother and one de novo missense variant (c.379C > T; p.Arg127Cys)."

Documents de novo c.379C>T (p.Arg127Cys) in trans with maternal nonsense c.524C>G (p.Ser175*) in an infant with sudden cardiac failure.

💊

Medical Actions

4

Implantable cardioverter-defibrillator (ICD) placement

Category: Therapeutic Action: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Platform: Device

Primary or secondary prophylactic placement of an implantable cardioverter-defibrillator is used in surviving children, adolescents, and adults with biallelic PPA2 variants (especially those with mid-myocardial fibrosis on cardiac MRI) to prevent sudden arrhythmic death from ventricular tachycardia or ventricular fibrillation.

Mechanism Target:

MODULATES Ventricular arrhythmia and electrical instability — Detects and terminates malignant ventricular tachyarrhythmias via defibrillation or antitachycardia pacing, preventing progression to fatal cardiac arrest.

Show evidence (1 reference)

PMID:27523597 SUPPORT Human Clinical

"Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4 shown in Figure 2). They subsequently each received an implantable defibrillator for primary prophylaxis of sudden arrhythmic cardiac death, although no events have occurred to date."

Documents prophylactic ICD implantation in surviving biallelic PPA2 siblings with mid-myocardial fibrosis to prevent sudden arrhythmic cardiac death.

Target Phenotypes: Sudden cardiac death HP:0001645 Ventricular fibrillation HP:0001663 Ventricular tachycardia HP:0004756

Show evidence (2 references)

PMID:27523597 SUPPORT Human Clinical

"Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4 shown in Figure 2). They subsequently each received an implantable defibrillator for primary prophylaxis of sudden arrhythmic cardiac death, although no events have occurred to date."

Supports primary prophylactic ICD placement in surviving patients with PPA2-related myocardial fibrosis.

PMID:34400813 SUPPORT Human Clinical

"At-risk patients may benefit from cardiac MRI monitoring, treatment of fever, exclusion of alcohol consumption, avoidance of vinegar and vinegar-containing foods, repeated neurological evaluation, and consideration for early heart transplantation or implantation of a cardioverter defibrillator."

Recommends consideration of cardioverter-defibrillator implantation as a core management strategy for at-risk biallelic PPA2 patients.

Orthotopic heart transplantation

Category: Therapeutic Action: Heart Transplantation NCIT:C15246

Platform: Surgery

Early orthotopic heart transplantation is a life-saving intervention for children with severe, rapid-onset dilated cardiomyopathy and refractory heart failure due to biallelic PPA2 deficiency, correcting the primary cardiac bioenergetic defect while requiring ongoing surveillance for potential late-onset extra-cardiac neurological manifestations.

Mechanism Target:

RESTORES Acute myocardial contractile failure — Replaces the PPA2-deficient, fibrotic myocardium with a donor heart that has normal mitochondrial inorganic pyrophosphatase activity and contractile function.

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Individual II-1 from family 12 is noteworthy having received a heart transplant for severe and rapid-onset dilated cardiomyopathy leading to heart failure at 3 years 9 months. He remains alive and well 20 months post-transplantation."

Demonstrates successful orthotopic heart transplantation with sustained survival in a young child with severe PPA2-related dilated cardiomyopathy and heart failure.

Target Phenotypes: Dilated cardiomyopathy HP:0001644 Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Individual II-1 from family 12 is noteworthy having received a heart transplant for severe and rapid-onset dilated cardiomyopathy leading to heart failure at 3 years 9 months. He remains alive and well 20 months post-transplantation."

Provides clinical evidence of durable survival following heart transplantation for severe PPA2-related dilated cardiomyopathy.

Strict avoidance of alcohol and vinegar/acetic acid-containing foods and prompt antipyretic management of fever

Category: Therapeutic Action: Lifestyle Counseling NCIT:C180632

Platform: Behavioral / lifestyle

Patients with biallelic PPA2 deficiency must strictly avoid alcohol (including alcohol-containing medications) and vinegar/acetic acid-containing foods to prevent ACSS1-driven intramitochondrial PPi surges, and should receive prompt antipyretic treatment during febrile illnesses to prevent thermal inactivation of residual mutant PPA2 enzyme activity.

Mechanism Target:

MODULATES Mitochondrial inorganic pyrophosphatase 2 (PPA2) enzymatic deficiency — Controlling fever prevents thermal denaturation of residual mutant PPA2, while excluding ethanol and acetic acid prevents acute ACSS1-mediated PPi overload in cardiac mitochondria.

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"At-risk patients may benefit from cardiac MRI monitoring, treatment of fever, exclusion of alcohol consumption, avoidance of vinegar and vinegar-containing foods, repeated neurological evaluation, and consideration for early heart transplantation or implantation of a cardioverter defibrillator."

Recommends fever control, exclusion of alcohol consumption, and avoidance of vinegar-containing foods to prevent acute metabolic overload of residual PPA2 activity.

Target Phenotypes: Cardiac arrest HP:0001695 Sudden cardiac death HP:0001645

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"At-risk patients may benefit from cardiac MRI monitoring, treatment of fever, exclusion of alcohol consumption, avoidance of vinegar and vinegar-containing foods, repeated neurological evaluation, and consideration for early heart transplantation or implantation of a cardioverter defibrillator."

Establishes trigger avoidance (alcohol and vinegar exclusion, prompt treatment of fever) as standard preventive management in biallelic PPA2 deficiency.

Longitudinal cardiac MRI and neurological surveillance

Category: Monitoring Action: Longitudinal cardiac MRI and neurological monitoring Ontology label: Magnetic Resonance Imaging of the Heart NCIT:C137915

Regular cardiac MRI monitoring to detect or track myocardial fibrosis and repeated neurological evaluations for peripheral axonal neuropathy, ophthalmoplegia, or cerebellar ataxia are recommended for all diagnosed and at-risk biallelic PPA2 individuals, alongside cascade genetic counseling and testing of siblings.

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"At-risk patients may benefit from cardiac MRI monitoring, treatment of fever, exclusion of alcohol consumption, avoidance of vinegar and vinegar-containing foods, repeated neurological evaluation, and consideration for early heart transplantation or implantation of a cardioverter defibrillator."

Supports longitudinal cardiac MRI monitoring and repeated neurological evaluations for individuals with biallelic PPA2 deficiency.

🌍

Environmental Factors

2

Viral infection and febrile illness (hyperthermia)

Mild intercurrent viral infections (respiratory or gastrointestinal) and the accompanying febrile response (hyperthermia) frequently precipitate acute cardiac decompensation or sudden cardiac arrest in infants and young children with biallelic PPA2 variants. Elevated body temperature further destabilizes thermolabile mutant PPA2 enzymes, causing acute intramitochondrial PPi accumulation and myocardial ATP crisis.

Show evidence (3 references)

PMID:34400813 SUPPORT INDIRECT Human Clinical

"Infection induces the cellular response of hyperthermia, which in the case of PPA2-deficient individuals may mean a further reduction in residual PPA2 enzyme function. We propose that this may be the mechanism that affects their cardiac tissue, ultimately resulting in sudden death."

Proposes how infection-induced hyperthermia further reduces residual mutant PPA2 activity and triggers acute cardiac decompensation and sudden death.

PMID:34400813 SUPPORT INDIRECT Human Clinical

"We propose that viral infections in affected individuals may tip the cardiac muscle into ATP deficit, due to a build-up of PPi following the effects of temperature increase on the already deficient PPA2 enzyme of these individuals."

Links viral infection and fever to PPi buildup and myocardial ATP deficit in PPA2-deficient patients.

PMID:34400813 SUPPORT In Vitro

"For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity."

Demonstrates experimentally that pathogenic recombinant PPA2 variants are temperature-sensitive in vitro.

Mechanism Target:

EXACERBATES Mitochondrial inorganic pyrophosphatase 2 (PPA2) enzymatic deficiency — Fever/hyperthermia during viral infection further reduces the residual catalytic activity of temperature-sensitive mutant PPA2 enzymes.

Show evidence (2 references)

PMID:34400813 SUPPORT In Vitro

"For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity."

Directly demonstrates in vitro temperature sensitivity of mutant recombinant PPA2 enzymes.

PMID:34400813 SUPPORT INDIRECT Human Clinical

"Infection induces the cellular response of hyperthermia, which in the case of PPA2-deficient individuals may mean a further reduction in residual PPA2 enzyme function. We propose that this may be the mechanism that affects their cardiac tissue, ultimately resulting in sudden death."

Supports thermal exacerbation of residual PPA2 enzymatic deficiency during febrile viral illness.

Ethanol (alcohol) and acetic acid / vinegar exposure

Shared metabolic trigger across the PPA2 deficiency spectrum: in older surviving individuals and those carrying milder hypomorphic genotypes (corresponding to the allelic presentation sudden cardiac failure, alcohol-induced; MONDO:0014974), ingestion of even small amounts of ethanol (alcohol) or acetic acid/vinegar-containing foods can precipitate acute cardiac arrest. Ethanol is oxidized via acetaldehyde to acetic acid, which is activated to acetyl-CoA in cardiac mitochondria by short-chain acyl-CoA synthetases (such as ACSS1), generating equimolar intramitochondrial inorganic pyrophosphate (PPi) that overwhelms deficient PPA2 activity.

Show evidence (1 reference)

PMID:27523597 SUPPORT BACKGROUND Human Clinical

"Ethanol is oxidized to acetaldehyde and further to acetic acid.13 Resulting acetic acid has to be activated to acetyl-coenzyme A, which is accompanied by the formation of equimolar amounts of PPi (Figure S7). This esterification reaction is catalyzed by short-chain acyl-CoA synthetases encoded,..."

Defines the biochemical mechanism by which ethanol oxidation and ACSS1-mediated acetate activation generate intramitochondrial PPi in cardiomyocytes, precipitating acute decompensation in PPA2 deficiency.

Mechanism Target:

TRIGGERS Mitochondrial matrix inorganic pyrophosphate accumulation — ACSS1-mediated esterification of ethanol-derived acetic acid generates an acute intramitochondrial PPi surge that cannot be hydrolyzed by deficient PPA2, directly exacerbating mitochondrial matrix PPi accumulation.

Show evidence (1 reference)

PMID:27523597 SUPPORT BACKGROUND Human Clinical

"Ethanol is oxidized to acetaldehyde and further to acetic acid.13 Resulting acetic acid has to be activated to acetyl-coenzyme A, which is accompanied by the formation of equimolar amounts of PPi (Figure S7). This esterification reaction is catalyzed by short-chain acyl-CoA synthetases encoded,..."

Establishes that ethanol-derived acetic acid activation generates equimolar PPi in heart mitochondria, directly overloading the PPi-dependent mitochondrial energy-transducing system.

🔬

Diagnosis

3

Molecular genetic testing of PPA2

Definitive diagnosis requires identification of biallelic pathogenic variants in PPA2. Because respiratory chain enzyme activities in skeletal muscle and skin fibroblasts are typically normal, molecular genetic testing and cascade carrier/sibling screening are essential for diagnosis, including postmortem molecular autopsy in unexplained infantile sudden death or suspected viral myocarditis.

Genetic Testing NCIT:C15709

Results: Identification of biallelic (homozygous or compound heterozygous) pathogenic variants in PPA2 by multigene cardiomyopathy/arrhythmia panel, exome or genome sequencing (including postmortem molecular autopsy from dried blood spots), or long-read sequencing to phase de novo or structural variants.

Show evidence (2 references)

PMID:27523598 SUPPORT Human Clinical

"Here we report seven individuals from three families affected by sudden and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome sequencing revealed compound heterozygous missense mutations in PPA2 in affected infants of each family."

Demonstrates that whole-exome sequencing establishes the molecular diagnosis by identifying biallelic PPA2 mutations in affected infants.

PMID:33028643 SUPPORT Human Clinical

"Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a paternally inherited, pathogenic missense variant (c.514G > A; p.Glu172Lys) and a novel, maternally inherited missense variant of uncertain..."

Demonstrates postmortem diagnosis of biallelic PPA2 deficiency by whole-genome sequencing from archived newborn dried blood spots.

Cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement

Cardiac MRI is the most sensitive non-invasive modality to detect subclinical or overt myocardial fibrosis in PPA2 deficiency and is recommended for evaluation and longitudinal surveillance of at-risk or biallelic siblings.

Magnetic Resonance Imaging of the Heart NCIT:C137915

Results: Demonstrates focal, patchy, or circumferential mid-myocardial and subepicardial late gadolinium enhancement (myocardial fibrosis), frequently present even in clinically asymptomatic individuals with biallelic PPA2 variants.

Show evidence (2 references)

PMID:34400813 SUPPORT Human Clinical

"Focal myocardial fibrosis upon histology and/or cardiac MRI was reported in 15 of 17 cases for which data were available. Such an observation should alert physicians to possible PPA2 dysfunction regardless of the clinical presentation and even in asymptomatic individuals."

Establishes cardiac MRI detection of focal myocardial fibrosis as a key diagnostic clue to PPA2 dysfunction, even in asymptomatic individuals.

PMID:27523597 SUPPORT Human Clinical

"Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4 shown in Figure 2). They subsequently each received an implantable defibrillator for primary prophylaxis of sudden arrhythmic cardiac death, although no events have occurred to date."

Demonstrates that cardiac MRI detects marked mid-myocardial fibrosis in asymptomatic biallelic siblings, guiding prophylactic ICD placement.

Transthoracic echocardiography

Echocardiography diagnoses dilated cardiomyopathy and ventricular systolic dysfunction in patients presenting with acute heart failure, though a normal echocardiogram does not exclude PPA2 deficiency or myocardial fibrosis.

Echocardiography Test NCIT:C16525

Results: May show acute or chronic left ventricular dilation and systolic dysfunction (dilated cardiomyopathy) during decompensation, or may be entirely normal prior to sudden arrhythmic cardiac arrest despite underlying mid-myocardial fibrosis on cardiac MRI.

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"In the latter group of 13 individuals, dilated cardiomyopathy or ventricular dysfunction was usually diagnosed by echocardiography, rapidly followed by multiorgan failure and/or ventricular fibrillation (VF, reported for six cases)."

Documents echocardiography as the primary modality diagnosing dilated cardiomyopathy and ventricular dysfunction in patients presenting with acute heart failure.

📊

Prevalence

2

Worldwide

Cases In Literature Ultra Rare

As of the 2021 international cohort series by Guimier et al., 56 affected individuals from 30 families had been reported worldwide, with additional families subsequently identified by postmortem molecular autopsy and rapid exome sequencing.

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"In this study, we report a cohort of 34 individuals with biallelic PPA2 variants from 20 families, enlarging the number of reported patients to 56 from 30 families worldwide."

Documents 56 reported patients from 30 families worldwide as of 2021, establishing that biallelic PPA2 deficiency is an ultra-rare disorder in the published literature.

ExAC population database (calculated from heterozygous carrier frequency)

Point Prevalence 0.58 per 100,000 1–9 per 1,000,000

Calculated genetic prevalence of 0.58 per 100,000 (approximately 1 in 170,000) derived from the cumulative heterozygous carrier frequency (0.0024) of likely pathogenic PPA2 variants in 60,506 individuals in the ExAC database.

Show evidence (1 reference)

PMID:27523597 SUPPORT Human Clinical

"The cumulative heterozygous carrier frequency of these likely pathogenic PPA2 mutations is 0.0024, which would result in a calculated prevalence for compound heterozygous or homozygous pathogenic PPA2 mutations of 0.58 per 100,000 (1 in 170,000)."

Provides a population-genetics estimate of biallelic pathogenic PPA2 prevalence (0.58 per 100,000, or 1 in 170,000) from ExAC allele frequencies.

⚖️

Clinical Burden

High

Biallelic PPA2 deficiency carries an exceptionally high mortality rate in infancy, early childhood, and adolescence: in the largest international cohort of 34 affected individuals, 28 (82%) died—23 before 2 years of age and 5 between 14 and 16 years of age—from sudden unexpected cardiac arrest or acute heart failure. Survivors require lifelong cardiology surveillance, strict avoidance of alcohol and fever triggers, implantable cardioverter-defibrillator placement, or orthotopic heart transplantation, and may develop progressive peripheral axonal neuropathy, external ophthalmoplegia, or cerebellar ataxia in adulthood.

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure."

Demonstrates the high lethality of biallelic PPA2 deficiency, with 28 of 34 patients in the series dying in infancy or adolescence from sudden cardiac arrest or acute heart failure.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Sudden cardiac failure, infantile:

Viral myocarditis Not Yet Curated MONDO:0023161

Overlapping Features Infants and young children with biallelic PPA2 deficiency frequently present with acute heart failure, cardiogenic shock, or sudden cardiac arrest shortly after a febrile viral respiratory or gastrointestinal illness, and a subset show mild myocardial inflammatory infiltrates on autopsy or biopsy, closely mimicking acute viral myocarditis.

Distinguishing Features

Prominent focal or mid-myocardial collagen fibrosis (present in ~88% of evaluated PPA2 cases and always accompanying any inflammatory infiltrate) on cardiac MRI or histology
Familial recurrence of sudden unexpected cardiac arrest or acute heart failure in siblings
Identification of biallelic pathogenic variants in PPA2 on molecular genetic testing

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Irrespective of the main clinical presentation, myocardial fibrosis was reported in 15 cases in our cohort, either at necropsy or on cardiac MRI, whereas an inflammatory infiltrate was noted in only 6 cases and always in combination with fibrosis. Thus, fibrosis may help discriminate between..."

Highlights viral myocarditis as the principal clinical differential diagnosis during acute heart failure and identifies prominent myocardial fibrosis and PPA2 genetic testing as the key discriminating features.

Sudden cardiac failure, alcohol-induced Not Yet Curated MONDO:0014974

Overlapping Features Sudden cardiac failure, alcohol-induced (SCFAI; OMIM:617223; MONDO:0014974) is an allelic autosomal recessive disorder caused by biallelic hypomorphic variants in PPA2—classically compound heterozygosity pairing the milder hypomorphic allele p.Pro228Leu (24%–28% residual enzymatic activity) in trans with a lower-activity allele such as p.Glu172Lys (5%–10% residual activity)—in which sudden cardiac arrest is triggered in adolescence or adulthood by ingestion of small amounts of alcohol.

Distinguishing Features

SCFI (MONDO:0014973) typically presents in the neonatal, infantile, or early-childhood period (often triggered by febrile viral illness) in individuals whose biallelic PPA2 genotypes confer lower total residual enzymatic activity (e.g., 5%–10% for p.Pro167Leu and p.Glu172Lys)
SCFAI (MONDO:0014974) typically presents in adolescence or adulthood with sudden cardiac arrest precipitated by small amounts of alcohol in individuals carrying at least one milder hypomorphic allele with higher residual PPA2 activity (~24%–28% for p.Pro228Leu, often in compound heterozygosity with p.Glu172Lys)

Show evidence (1 reference)

PMID:27523597 SUPPORT In Vitro

"Compared to wild-type, the p.Pro167Leu and p.Glu172Lys variants showed 5%–10% residual activity at PPi substrate concentrations 18–500 μmol/L. The p.Pro228Leu variant had a residual activity of 24%–28% in this concentration range compared to wild-type (Figure 3D)."

Demonstrates that the infantile-onset (MONDO:0014973) and adolescent alcohol-induced (MONDO:0014974) forms of PPA2 deficiency are stratified by the residual mitochondrial pyrophosphatase activity of the underlying missense alleles (5%–10% for p.Pro167Leu and p.Glu172Lys versus 24%–28% for p.Pro228Leu).

{ }

Source YAML

click to show

name: Sudden cardiac failure, infantile
creation_date: '2026-10-14T11:36:00Z'
category: Mendelian
synonyms:
- SCFI
- sudden cardiac failure, infantile, autosomal recessive
- PPA2-related sudden cardiac death
- PPA2-associated sudden cardiac death
- mitochondrial inorganic pyrophosphatase 2 deficiency
description: >-
  Sudden cardiac failure, infantile (SCFI; MONDO:0014973) is an autosomal
  recessive mitochondrial cardiomyopathy and sudden cardiac death disorder
  caused by biallelic hypomorphic or compound heterozygous pathogenic variants
  in PPA2, which encodes mitochondrial inorganic pyrophosphatase 2. PPA2
  hydrolyzes inorganic pyrophosphate (PPi) to orthophosphate within the
  mitochondrial matrix, driving PPi-generating biosynthetic and metabolic
  reactions forward. Deficient PPA2 activity causes intramitochondrial PPi
  accumulation, impairs mitochondrial inner membrane potential maintenance and
  oxidative phosphorylation energy transduction in cardiomyocytes, and leads to
  cardiomyocyte loss, focal or mid-myocardial replacement fibrosis, dilated
  cardiomyopathy, ventricular tachyarrhythmias (including ventricular
  fibrillation), acute cardiogenic shock, and sudden unexpected cardiac arrest.
  SCFI classically presents in the neonatal period, infancy, or early childhood
  (frequently precipitated by febrile viral illness), with severe alleles also
  causing neonatal lactic acidosis, seizures, and hypotonia, and surviving
  patients remaining at risk for chronic progressive neurological manifestations
  (peripheral axonal neuropathy, external ophthalmoplegia, ptosis, and spastic
  cerebellar ataxia). It is allelic with sudden cardiac failure, alcohol-induced
  (SCFAI; MONDO:0014974), a distinct MONDO disorder in which biallelic PPA2
  genotypes retaining higher residual enzymatic activity (such as compound
  heterozygosity pairing p.Pro228Leu with p.Glu172Lys) present in adolescence or
  adulthood with sudden cardiac arrest triggered by small amounts of alcohol.
parents:
- Mitochondrial Disease
- Metabolic Cardiomyopathy
disease_term:
  preferred_term: sudden cardiac failure, infantile
  term:
    id: MONDO:0014973
    label: sudden cardiac failure, infantile
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:27523598
      reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Altogether these data demonstrate that PPA2 is an essential gene in yeast
        and that biallelic mutations in PPA2 cause a mitochondrial disease leading
        to sudden cardiac arrest in infants.
      explanation: >-
        Establishes that biallelic inherited mutations in PPA2 cause this
        Mendelian mitochondrial disorder.
  - classification_value: CARDIOVASCULAR
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most common clinical presentation remains sudden unexpected cardiac
        arrest, reported in all of the deceased teenagers and half of the
        children who died before their teens, while the other half presented
        with dilated cardiomyopathy, cardiogenic shock, or arrhythmia before
        death.
      explanation: >-
        Confirms that cardiovascular manifestations (sudden cardiac arrest,
        dilated cardiomyopathy, cardiogenic shock, and arrhythmia) are the
        defining clinical presentation.
  mechanistic_category:
  - classification_value: mitochondrial disease
    evidence:
    - reference: PMID:27523598
      reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Altogether these data demonstrate that PPA2 is an essential gene in yeast
        and that biallelic mutations in PPA2 cause a mitochondrial disease leading
        to sudden cardiac arrest in infants.
      explanation: >-
        Directly classifies biallelic PPA2 deficiency as a mitochondrial
        disease.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  description: >-
    Sudden cardiac failure, infantile is inherited in an autosomal recessive
    manner due to homozygous or compound heterozygous pathogenic variants in
    PPA2. At least one hypomorphic missense allele is required for postnatal
    viability because complete loss of mitochondrial pyrophosphatase activity is
    cell-lethal; clinical expressivity varies with residual enzyme activity and
    environmental triggers such as febrile viral infection or alcohol exposure.
  evidence:
  - reference: PMID:27523598
    reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report seven individuals from three families affected by sudden
      and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome
      sequencing revealed compound heterozygous missense mutations in PPA2 in
      affected infants of each family.
    explanation: >-
      Identifies compound heterozygous biallelic PPA2 variants in multiple
      affected siblingships with unaffected carrier parents, establishing
      autosomal recessive inheritance.
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we report a cohort of 34 individuals with biallelic PPA2
      variants from 20 families, enlarging the number of reported patients to 56
      from 30 families worldwide.
    explanation: >-
      Confirms autosomal recessive biallelic inheritance across 56 affected
      individuals from 30 unrelated families and demonstrates variable clinical
      expressivity ranging from infantile cardiac arrest to adult-onset
      cardiomyopathy and neuropathy.
prevalence:
- measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  population: Worldwide
  notes: >-
    As of the 2021 international cohort series by Guimier et al., 56 affected
    individuals from 30 families had been reported worldwide, with additional
    families subsequently identified by postmortem molecular autopsy and rapid
    exome sequencing.
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we report a cohort of 34 individuals with biallelic PPA2
      variants from 20 families, enlarging the number of reported patients to 56
      from 30 families worldwide.
    explanation: >-
      Documents 56 reported patients from 30 families worldwide as of 2021,
      establishing that biallelic PPA2 deficiency is an ultra-rare disorder in
      the published literature.
- measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.58
  population: ExAC population database (calculated from heterozygous carrier frequency)
  notes: >-
    Calculated genetic prevalence of 0.58 per 100,000 (approximately 1 in
    170,000) derived from the cumulative heterozygous carrier frequency (0.0024)
    of likely pathogenic PPA2 variants in 60,506 individuals in the ExAC
    database.
  evidence:
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cumulative heterozygous carrier frequency of these likely pathogenic
      PPA2 mutations is 0.0024, which would result in a calculated prevalence
      for compound heterozygous or homozygous pathogenic PPA2 mutations of 0.58
      per 100,000 (1 in 170,000).
    explanation: >-
      Provides a population-genetics estimate of biallelic pathogenic PPA2
      prevalence (0.58 per 100,000, or 1 in 170,000) from ExAC allele
      frequencies.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Biallelic PPA2 deficiency carries an exceptionally high mortality rate in
    infancy, early childhood, and adolescence: in the largest international
    cohort of 34 affected individuals, 28 (82%) died—23 before 2 years of age
    and 5 between 14 and 16 years of age—from sudden unexpected cardiac arrest
    or acute heart failure. Survivors require lifelong cardiology surveillance,
    strict avoidance of alcohol and fever triggers, implantable
    cardioverter-defibrillator placement, or orthotopic heart transplantation,
    and may develop progressive peripheral axonal neuropathy, external
    ophthalmoplegia, or cerebellar ataxia in adulthood.
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 34 individuals, only 6 remain alive. Twenty-three died before
      the age of 2 years while five died between 14 and 16 years. Within these
      28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure.
    explanation: >-
      Demonstrates the high lethality of biallelic PPA2 deficiency, with 28 of
      34 patients in the series dying in infancy or adolescence from sudden
      cardiac arrest or acute heart failure.
pathophysiology:
- name: Mitochondrial inorganic pyrophosphatase 2 (PPA2) enzymatic deficiency
  description: >-
    Biallelic hypomorphic missense variants or compound heterozygous
    missense/truncating variants in PPA2 severely reduce mitochondrial inorganic
    pyrophosphatase activity in the mitochondrial matrix. Because PPA2
    catalyzes the hydrolysis of inorganic pyrophosphate (PPi) into two
    orthophosphate ions, reduced PPA2 activity impairs PPi clearance during
    high-flux mitochondrial biosynthetic reactions (DNA, RNA, protein, and
    lipid synthesis) and short-chain fatty-acid/acetate activation. Residual
    enzymatic activity of recombinant mutant PPA2 proteins correlates with age
    at onset and clinical severity: variants associated with neonatal or early
    infantile lethality (such as p.Pro167Leu and p.Glu172Lys) retain only
    5%–10% wild-type activity, whereas variants permissive for survival into
    adolescence (such as p.Pro228Leu) retain 24%–28% activity. Furthermore,
    missense PPA2 variants exhibit temperature sensitivity in vitro, so febrile
    viral illnesses or modest ethanol/acetic acid loads acutely overwhelm
    residual PPi hydrolysis capacity.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PPA2
    term:
      id: hgnc:28883
      label: PPA2
  molecular_functions:
  - preferred_term: inorganic diphosphate phosphatase activity
    term:
      id: GO:0004427
      label: inorganic diphosphate phosphatase activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:27523598
    reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PPA2 encodes the mitochondrial pyrophosphatase, which hydrolyzes inorganic
      pyrophosphate into two phosphates. This is an essential activity for many
      biosynthetic reactions and for energy metabolism of the cell.
    explanation: >-
      Defines the canonical molecular function of PPA2 as mitochondrial
      inorganic pyrophosphate hydrolysis required for cellular biosynthetic
      reactions and energy metabolism.
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Comparison of normal and mutant PPA2-containing mitochondria from
      fibroblasts showed that the activity of inorganic pyrophosphatase was
      significantly reduced in affected individuals. Recombinant PPA2 enzymes
      modeling hypomorphic missense mutations had decreased activity that
      correlated with disease severity.
    explanation: >-
      Demonstrates significantly reduced mitochondrial pyrophosphatase activity
      in patient fibroblast mitochondria and establishes that residual activity
      of recombinant mutant PPA2 enzymes correlates with clinical severity.
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Compared to wild-type, the p.Pro167Leu and p.Glu172Lys variants showed
      5%–10% residual activity at PPi substrate concentrations 18–500 μmol/L.
      The p.Pro228Leu variant had a residual activity of 24%–28% in this
      concentration range compared to wild-type (Figure 3D).
    explanation: >-
      Quantifies residual pyrophosphatase activity for key pathogenic missense
      variants, linking lower residual enzymatic activity (5%–10% for
      p.Pro167Leu and p.Glu172Lys) to infantile onset and higher residual
      activity (24%–28% for p.Pro228Leu) to later-onset alcohol-triggered
      presentations.
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      For 11 variants, recombinant PPA2 enzyme activities were significantly
      decreased and sensitive to temperature, compared to wild-type PPA2 enzyme
      activity.
    explanation: >-
      Experimentally confirms that pathogenic missense PPA2 variants have
      significantly reduced and temperature-sensitive enzymatic activity in
      vitro.
  downstream:
  - target: Mitochondrial matrix inorganic pyrophosphate accumulation
    description: >-
      Loss of mitochondrial inorganic pyrophosphatase catalytic activity and
      temperature-induced inactivation of residual mutant PPA2 prevent clearance
      of intramitochondrial inorganic pyrophosphate (PPi), causing PPi buildup
      within the mitochondrial matrix.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523598
      reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        PPA2 encodes the mitochondrial pyrophosphatase, which hydrolyzes
        inorganic pyrophosphate into two phosphates. This is an essential
        activity for many biosynthetic reactions and for energy metabolism of
        the cell.
      explanation: >-
        Establishes that PPA2 is the mitochondrial enzyme responsible for
        hydrolyzing intramitochondrial inorganic pyrophosphate.
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        We propose that viral infections in affected individuals may tip the
        cardiac muscle into ATP deficit, due to a build-up of PPi following the
        effects of temperature increase on the already deficient PPA2 enzyme of
        these individuals.
      explanation: >-
        Links deficient and temperature-sensitive PPA2 activity directly to
        intramitochondrial PPi accumulation.
- name: Mitochondrial matrix inorganic pyrophosphate accumulation
  description: >-
    Impaired hydrolysis of inorganic pyrophosphate (PPi) by deficient PPA2—and
    acute PPi surges generated by thermal inactivation during febrile viral
    illness or by ACSS1-mediated activation of ethanol-derived acetic acid to
    acetyl-CoA—results in accumulation of PPi within the mitochondrial matrix,
    inhibiting PPi-producing biosynthetic reactions and mitochondrial energy
    transduction.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      We propose that viral infections in affected individuals may tip the
      cardiac muscle into ATP deficit, due to a build-up of PPi following the
      effects of temperature increase on the already deficient PPA2 enzyme of
      these individuals.
    explanation: >-
      Identifies intramitochondrial build-up of PPi as the proximal metabolic
      consequence of reduced PPA2 enzymatic activity.
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Ethanol is oxidized to acetaldehyde and further to acetic acid.13
      Resulting acetic acid has to be activated to acetyl-coenzyme A, which is
      accompanied by the formation of equimolar amounts of PPi (Figure S7). This
      esterification reaction is catalyzed by short-chain acyl-CoA synthetases
      encoded, for example, by ACSS1 (MIM: 614355), an enzyme with high
      expression in heart mitochondria.14
    explanation: >-
      Describes the biochemical source of intramitochondrial PPi formation in
      heart mitochondria during acetate/ethanol activation.
  downstream:
  - target: Mitochondrial inner membrane potential dissipation
    description: >-
      Unresolved intramitochondrial PPi accumulation inactivates the
      mitochondrial energy-transducing system and prevents maintenance of a
      sufficient electrical potential across the inner mitochondrial membrane.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523598
      reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Using a regulatable (doxycycline-repressible) gene expression system, we
        found that the pathogenic PPA2 mutations rapidly inactivate the
        mitochondrial energy transducing system and prevent the maintenance of a
        sufficient electrical potential across the inner membrane, which
        explains the subsequent disappearance of mitochondria from the mutant
        yeast cells.
      explanation: >-
        Demonstrates that loss of mitochondrial pyrophosphatase activity rapidly
        inactivates the mitochondrial energy-transducing system and collapses
        the inner membrane electrical potential.
- name: Mitochondrial inner membrane potential dissipation
  description: >-
    Failure of intramitochondrial PPi hydrolysis rapidly inactivates the
    mitochondrial energy-transducing machinery and prevents maintenance of a
    sufficient electrical potential across the inner mitochondrial membrane,
    destabilizing mitochondrial integrity and leading to organelle loss under
    metabolic stress.
  biological_scale: CELLULAR
  cellular_components:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  biological_processes:
  - preferred_term: regulation of mitochondrial membrane potential
    term:
      id: GO:0051881
      label: regulation of mitochondrial membrane potential
    modifier: DYSREGULATED
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:27523598
    reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using a regulatable (doxycycline-repressible) gene expression system, we
      found that the pathogenic PPA2 mutations rapidly inactivate the
      mitochondrial energy transducing system and prevent the maintenance of a
      sufficient electrical potential across the inner membrane, which explains
      the subsequent disappearance of mitochondria from the mutant yeast cells.
    explanation: >-
      Establishes that PPA2 deficiency prevents maintenance of the electrical
      potential across the mitochondrial inner membrane and causes subsequent
      loss of mitochondria.
  downstream:
  - target: Mitochondrial bioenergetic failure and ATP depletion
    description: >-
      Collapse of the inner mitochondrial membrane potential and loss of
      functional mitochondria impair oxidative phosphorylation (including
      cardiac complex I and IV activities) and precipitate cellular ATP
      depletion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523598
      reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Using a regulatable (doxycycline-repressible) gene expression system, we
        found that the pathogenic PPA2 mutations rapidly inactivate the
        mitochondrial energy transducing system and prevent the maintenance of a
        sufficient electrical potential across the inner membrane, which
        explains the subsequent disappearance of mitochondria from the mutant
        yeast cells.
      explanation: >-
        Shows that collapse of the inner membrane potential inactivates the
        mitochondrial energy-transducing system and depletes functional
        mitochondria.
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Respiratory chain function varied from normal to moderate reduction in
        complex I and IV activities in cardiac tissue and was normal in
        fibroblasts and skeletal muscle tissue.
      explanation: >-
        Documents secondary reduction of respiratory chain complex I and IV
        activities in affected human cardiac tissue.
- name: Mitochondrial bioenergetic failure and ATP depletion
  description: >-
    Dissipation of the inner mitochondrial membrane potential and impaired
    oxidative phosphorylation (with normal-to-moderately reduced complex I and
    IV respiratory chain activities in cardiac tissue) cause acute or chronic
    cellular ATP depletion in high-energy-demand tissues. Cardiomyocytes are
    most vulnerable during acute metabolic or thermal stress, while neonates
    with severe alleles develop systemic lactic acidosis, seizures, and
    hypotonia, and older survivors develop chronic ATP-deficiency injury in
    peripheral nerves, extraocular/eyelid muscles, and cerebellar pathways.
  biological_scale: CELLULAR
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  biological_processes:
  - preferred_term: ATP biosynthetic process
    term:
      id: GO:0006754
      label: ATP biosynthetic process
    modifier: DECREASED
  - preferred_term: mitochondrial ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Respiratory chain function varied from normal to moderate reduction in
      complex I and IV activities in cardiac tissue and was normal in
      fibroblasts and skeletal muscle tissue.
    explanation: >-
      Documents normal-to-moderately reduced mitochondrial respiratory chain
      complex I and IV activities in cardiac tissue from affected individuals.
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These observations are consistent with mitochondrial depletion or
      dysfunction affecting tissues requiring optimal levels of ATP availability
      such as muscle and nerve cells.
    explanation: >-
      Links mitochondrial depletion and impaired ATP availability to tissue
      injury in high-energy-demand muscle and nerve cells.
  downstream:
  - target: Cardiomyocyte loss and myofibrillar disarray
    description: >-
      Bioenergetic collapse and ATP deficit in cardiomyocytes lead to myocyte
      necrosis/loss and myofibrillar disarray across the ventricular myocardium.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
        clinical presentation involved lactic acidosis, seizures, hypotonia, and
        cardiac arrhythmia within the first months of life. Myocyte loss,
        disarray, or fibrosis was present in all individuals.
      explanation: >-
        Demonstrates that severe PPA2-related mitochondrial bioenergetic failure
        consistently produces cardiomyocyte loss and disarray in affected
        infants.
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        We propose that viral infections in affected individuals may tip the
        cardiac muscle into ATP deficit, due to a build-up of PPi following the
        effects of temperature increase on the already deficient PPA2 enzyme of
        these individuals.
      explanation: >-
        Supports myocardial ATP deficit as the cellular mechanism damaging
        cardiac muscle in PPA2-deficient individuals.
  - target: Lactic acidosis
    description: >-
      Impaired mitochondrial oxidative phosphorylation and pyruvate oxidation
      during metabolic decompensation cause systemic lactic acidosis, especially
      in neonatal and early infantile presentations.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
        clinical presentation involved lactic acidosis, seizures, hypotonia, and
        cardiac arrhythmia within the first months of life. Myocyte loss,
        disarray, or fibrosis was present in all individuals.
      explanation: >-
        Links severe PPA2 deficiency in early infancy directly to systemic
        lactic acidosis alongside neurological and cardiac manifestations.
  - target: Seizure
    description: >-
      Severe neonatal mitochondrial bioenergetic failure and lactic acidosis
      impair neuronal energy homeostasis, causing early-infantile seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
        clinical presentation involved lactic acidosis, seizures, hypotonia, and
        cardiac arrhythmia within the first months of life. Myocyte loss,
        disarray, or fibrosis was present in all individuals.
      explanation: >-
        Links severe neonatal PPA2 bioenergetic failure to seizures in the first
        months of life.
  - target: Hypotonia
    description: >-
      Impaired ATP availability in skeletal muscle and central motor pathways
      causes muscular hypotonia in severely affected neonates and infants.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
        clinical presentation involved lactic acidosis, seizures, hypotonia, and
        cardiac arrhythmia within the first months of life. Myocyte loss,
        disarray, or fibrosis was present in all individuals.
      explanation: >-
        Links severe infantile PPA2 deficiency to muscular hypotonia in the
        first months of life.
  - target: Peripheral axonal neuropathy
    description: >-
      Chronic mitochondrial dysfunction and suboptimal ATP availability in
      long peripheral axons cause progressive distal axonal degeneration and
      peripheral axonal neuropathy in surviving patients.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These observations are consistent with mitochondrial depletion or
        dysfunction affecting tissues requiring optimal levels of ATP
        availability such as muscle and nerve cells.
      explanation: >-
        Attributes the peripheral nerve and muscle manifestations in
        surviving PPA2 patients to mitochondrial dysfunction in tissues
        requiring optimal ATP availability.
  - target: External ophthalmoplegia
    description: >-
      Chronic mitochondrial bioenergetic insufficiency in extraocular muscles
      causes progressive external ophthalmoplegia in adult survivors.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These observations are consistent with mitochondrial depletion or
        dysfunction affecting tissues requiring optimal levels of ATP
        availability such as muscle and nerve cells.
      explanation: >-
        Connects mitochondrial dysfunction and impaired ATP availability in
        muscle and nerve cells to extraocular muscle paresis in adult survivors.
  - target: Ptosis
    description: >-
      Mitochondrial ATP deficiency in levator palpebrae superioris muscle fibers
      produces eyelid ptosis in surviving adults with multisystemic PPA2
      deficiency.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These observations are consistent with mitochondrial depletion or
        dysfunction affecting tissues requiring optimal levels of ATP
        availability such as muscle and nerve cells.
      explanation: >-
        Links mitochondrial dysfunction in high-ATP-demand muscle and nerve
        tissues to ptosis and ophthalmoplegia in adult PPA2 survivors.
  - target: Progressive cerebellar ataxia
    description: >-
      Chronic mitochondrial bioenergetic dysfunction in high-ATP-demand
      cerebellar and spinocerebellar neurons leads to adolescent- or adult-onset
      progressive spastic cerebellar ataxia in surviving individuals.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These observations are consistent with mitochondrial depletion or
        dysfunction affecting tissues requiring optimal levels of ATP
        availability such as muscle and nerve cells.
      explanation: >-
        Explains progressive cerebellar and neuromuscular involvement in
        surviving patients via chronic mitochondrial dysfunction in nerve and
        muscle cells.
- name: Cardiomyocyte loss and myofibrillar disarray
  description: >-
    Acute or recurrent bioenergetic collapse in PPA2-deficient cardiomyocytes
    causes focal or patchy cardiomyocyte dropout (myocyte loss) and
    myofibrillar disarray across the ventricular myocardium,
    initiating reparative replacement fibrosis and impairing ventricular
    contractility.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
      clinical presentation involved lactic acidosis, seizures, hypotonia, and
      cardiac arrhythmia within the first months of life. Myocyte loss,
      disarray, or fibrosis was present in all individuals.
    explanation: >-
      Documents universal myocyte loss, disarray, or fibrosis on cardiac
      histopathology in affected individuals.
  downstream:
  - target: Focal myocardial replacement fibrosis
    description: >-
      Necrotic loss of energy-depleted cardiomyocytes triggers cardiac
      fibroblast activation and extracellular matrix deposition, producing focal
      and mid-myocardial replacement fibrosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
        clinical presentation involved lactic acidosis, seizures, hypotonia, and
        cardiac arrhythmia within the first months of life. Myocyte loss,
        disarray, or fibrosis was present in all individuals.
      explanation: >-
        Links cardiomyocyte loss and disarray directly to replacement myocardial
        fibrosis on histopathology.
  - target: Acute myocardial contractile failure
    description: >-
      Loss of functional cardiomyocytes and myofibrillar disarray directly
      reduce ventricular systolic force generation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
        clinical presentation involved lactic acidosis, seizures, hypotonia, and
        cardiac arrhythmia within the first months of life. Myocyte loss,
        disarray, or fibrosis was present in all individuals.
      explanation: >-
        Connects cardiomyocyte loss and disarray to myocardial contractile
        failure in affected infants.
- name: Focal myocardial replacement fibrosis
  description: >-
    Following cardiomyocyte loss, cardiac fibroblasts deposit collagen-rich
    extracellular matrix, producing prominent focal, patchy, or circumferential
    mid-myocardial and subepicardial replacement fibrosis (occasionally
    accompanied by mild secondary inflammatory infiltrates). Myocardial fibrosis
    is the histopathological and cardiac MRI hallmark of biallelic PPA2
    deficiency, observed in nearly all examined hearts (15 of 17 evaluated cases
    in the 2021 international cohort) and often detectable on cardiac MRI even
    in clinically asymptomatic siblings prior to arrhythmic or heart-failure
    decompensation.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: fibroblast of cardiac tissue
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Focal myocardial fibrosis upon histology and/or cardiac MRI was reported
      in 15 of 17 cases for which data were available. Such an observation
      should alert physicians to possible PPA2 dysfunction regardless of the
      clinical presentation and even in asymptomatic individuals.
    explanation: >-
      Establishes focal myocardial fibrosis as the consistent tissue-level
      hallmark across 15 of 17 evaluated patients on histology and/or cardiac
      MRI.
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4
      shown in Figure 2). They subsequently each received an implantable
      defibrillator for primary prophylaxis of sudden arrhythmic cardiac death,
      although no events have occurred to date.
    explanation: >-
      Demonstrates marked mid-myocardial fibrosis on cardiac MRI in surviving
      biallelic siblings.
  downstream:
  - target: Myocardial fibrosis
    description: >-
      Focal and mid-myocardial collagen deposition manifests clinically and
      radiologically as myocardial fibrosis on late gadolinium enhancement
      cardiac MRI and autopsy histology.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Focal myocardial fibrosis upon histology and/or cardiac MRI was reported
        in 15 of 17 cases for which data were available. Such an observation
        should alert physicians to possible PPA2 dysfunction regardless of the
        clinical presentation and even in asymptomatic individuals.
      explanation: >-
        Directly connects histological and MRI-detected focal myocardial
        fibrosis to the clinical phenotype.
  - target: Ventricular arrhythmia and electrical instability
    description: >-
      Patchy mid-myocardial fibrosis creates conduction heterogeneity and
      re-entrant circuits that, together with acute bioenergetic crisis, trigger
      malignant ventricular tachyarrhythmias and sudden cardiac arrest.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4
        shown in Figure 2). They subsequently each received an implantable
        defibrillator for primary prophylaxis of sudden arrhythmic cardiac
        death, although no events have occurred to date.
      explanation: >-
        Links marked mid-myocardial fibrosis directly to the risk of sudden
        arrhythmic cardiac death, motivating prophylactic ICD implantation.
  - target: Acute myocardial contractile failure
    description: >-
      Extensive mid-myocardial replacement fibrosis stiffens and weakens the
      ventricular walls, contributing to dilated cardiomyopathy, acute heart
      failure, and cardiogenic shock.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most common clinical presentation remains sudden unexpected cardiac
        arrest, reported in all of the deceased teenagers and half of the
        children who died before their teens, while the other half presented
        with dilated cardiomyopathy, cardiogenic shock, or arrhythmia before
        death.
      explanation: >-
        Demonstrates that half of affected children progress to dilated
        cardiomyopathy and cardiogenic shock before death.
- name: Ventricular arrhythmia and electrical instability
  description: >-
    Combined acute bioenergetic failure and focal mid-myocardial fibrosis
    destabilize cardiomyocyte action potential propagation and repolarization,
    producing malignant ventricular arrhythmias including ventricular
    tachycardia, torsades de pointes, ventricular fibrillation, bradycardia, or
    pulseless electrical activity, culminating in sudden unexpected cardiac
    arrest and sudden cardiac death.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the latter group of 13 individuals, dilated cardiomyopathy or
      ventricular dysfunction was usually diagnosed by echocardiography, rapidly
      followed by multiorgan failure and/or ventricular fibrillation (VF,
      reported for six cases).
    explanation: >-
      Documents rapid progression to malignant ventricular fibrillation in six
      patients with ventricular dysfunction, alongside primary sudden cardiac
      arrest in 15 patients.
  - reference: PMID:33028643
    reference_title: "Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The underlying rhythm was primarily pulseless electrical activity (PEA),
      with one incidence of pulseless ventricular tachycardia, for which the
      patient was unsuccessfully defibrillated.
    explanation: >-
      Documents lethal pulseless electrical activity and pulseless ventricular
      tachycardia in a neonate with biallelic PPA2 variants.
  downstream:
  - target: Ventricular fibrillation
    description: >-
      Electrical instability in the fibrotic, energy-depleted myocardium
      degenerates into lethal ventricular fibrillation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In the latter group of 13 individuals, dilated cardiomyopathy or
        ventricular dysfunction was usually diagnosed by echocardiography,
        rapidly followed by multiorgan failure and/or ventricular fibrillation
        (VF, reported for six cases).
      explanation: >-
        Directly documents ventricular fibrillation as a recurrent terminal
        rhythm in affected children.
  - target: Ventricular tachycardia
    description: >-
      Myocardial electrical instability manifests as pulseless or sustained
      ventricular tachycardia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33028643
      reference_title: "Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The underlying rhythm was primarily pulseless electrical activity (PEA),
        with one incidence of pulseless ventricular tachycardia, for which the
        patient was unsuccessfully defibrillated.
      explanation: >-
        Directly documents pulseless ventricular tachycardia during fatal
        cardiac decompensation.
  - target: Cardiac arrest
    description: >-
      Malignant ventricular arrhythmias and pulseless electrical activity cause
      abrupt cessation of effective cardiac mechanical output.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27523598
      reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we report seven individuals from three families affected by sudden
        and unexpected cardiac arrest between 4 and 20 months of age.
        Whole-exome sequencing revealed compound heterozygous missense mutations
        in PPA2 in affected infants of each family.
      explanation: >-
        Establishes sudden unexpected cardiac arrest in infancy as the hallmark
        clinical outcome of biallelic PPA2 mutations.
  - target: Sudden cardiac death
    description: >-
      Refractory ventricular fibrillation, pulseless ventricular tachycardia, or
      asystole/PEA frequently resists resuscitation and results in sudden
      cardiac death.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Among the 34 individuals, only 6 remain alive. Twenty-three died before
        the age of 2 years while five died between 14 and 16 years. Within these
        28 cases, 15 died of sudden cardiac arrest and 13 of acute heart
        failure.
      explanation: >-
        Confirms that sudden cardiac arrest and acute heart failure cause high
        early mortality in biallelic PPA2 deficiency.
- name: Acute myocardial contractile failure
  description: >-
    Severe cardiomyocyte bioenergetic depletion and replacement fibrosis impair
    left and biventricular systolic contractility, causing rapid-onset dilated
    cardiomyopathy, congestive heart failure, refractory cardiogenic shock, and
    multiorgan failure.
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the latter group of 13 individuals, dilated cardiomyopathy or
      ventricular dysfunction was usually diagnosed by echocardiography, rapidly
      followed by multiorgan failure and/or ventricular fibrillation (VF,
      reported for six cases).
    explanation: >-
      Demonstrates that acute ventricular systolic dysfunction and dilated
      cardiomyopathy rapidly progress to multiorgan failure and death in nearly
      half of affected infants and children.
  downstream:
  - target: Dilated cardiomyopathy
    description: >-
      Impaired myocardial contractility and myocyte loss manifest structurally
      as left ventricular or biventricular dilation and systolic dysfunction on
      echocardiography.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In the latter group of 13 individuals, dilated cardiomyopathy or
        ventricular dysfunction was usually diagnosed by echocardiography,
        rapidly followed by multiorgan failure and/or ventricular fibrillation
        (VF, reported for six cases).
      explanation: >-
        Links ventricular contractile dysfunction directly to
        echocardiographically confirmed dilated cardiomyopathy.
  - target: Congestive heart failure
    description: >-
      Severe ventricular systolic failure leads to acute or rapidly progressive
      heart failure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Among the 34 individuals, only 6 remain alive. Twenty-three died before
        the age of 2 years while five died between 14 and 16 years. Within these
        28 cases, 15 died of sudden cardiac arrest and 13 of acute heart
        failure.
      explanation: >-
        Documents acute heart failure as the primary cause of death in 13 of 28
        deceased individuals in the 2021 cohort.
  - target: Cardiogenic shock
    description: >-
      Fulminant pump failure in infants and young children produces acute
      cardiogenic shock and multiorgan failure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most common clinical presentation remains sudden unexpected cardiac
        arrest, reported in all of the deceased teenagers and half of the
        children who died before their teens, while the other half presented
        with dilated cardiomyopathy, cardiogenic shock, or arrhythmia before
        death.
      explanation: >-
        Directly documents cardiogenic shock as a recurrent presentation of
        acute cardiac decompensation in children with biallelic PPA2 variants.
phenotypes:
- name: Cardiac arrest
  category: Cardiovascular
  diagnostic: true
  frequency: VERY_FREQUENT
  severity: SEVERE
  description: >-
    Sudden unexpected cardiac arrest—often occurring between 4 and 24 months of
    age following a mild viral respiratory or gastrointestinal illness, or in
    adolescence after small amounts of alcohol—is the most frequent clinical
    presentation of biallelic PPA2 deficiency.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:27523598
    reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report seven individuals from three families affected by sudden
      and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome
      sequencing revealed compound heterozygous missense mutations in PPA2 in
      affected infants of each family.
    explanation: >-
      Establishes sudden and unexpected cardiac arrest between 4 and 20 months
      of age as the defining presentation in the original three-family cohort.
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common clinical presentation remains sudden unexpected cardiac
      arrest, reported in all of the deceased teenagers and half of the children
      who died before their teens, while the other half presented with dilated
      cardiomyopathy, cardiogenic shock, or arrhythmia before death.
    explanation: >-
      Confirms across 34 patients that sudden unexpected cardiac arrest is the
      single most common presentation of biallelic PPA2 deficiency.
- name: Sudden cardiac death
  category: Cardiovascular
  diagnostic: true
  frequency: VERY_FREQUENT
  severity: SEVERE
  description: >-
    Mortality exceeds 80% in published cohorts (28 of 34 patients in the 2021
    series), with sudden cardiac death peaking in infancy/early toddlerhood (<2
    years) and again in adolescence (14–16 years).
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 34 individuals, only 6 remain alive. Twenty-three died before
      the age of 2 years while five died between 14 and 16 years. Within these
      28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure.
    explanation: >-
      Quantifies mortality in the 34-patient cohort, showing 28 deaths (82%) in
      infancy or adolescence from sudden cardiac arrest or acute heart failure.
- name: Myocardial fibrosis
  category: Cardiovascular
  diagnostic: true
  frequency: VERY_FREQUENT
  description: >-
    Focal, patchy, or circumferential mid-myocardial and subepicardial fibrosis
    is the signature structural abnormality of PPA2 deficiency, identified on
    autopsy histopathology or late gadolinium enhancement cardiac MRI in 15 of
    17 (88%) evaluated patients in the 2021 cohort and detectable even in
    asymptomatic biallelic siblings.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Focal myocardial fibrosis upon histology and/or cardiac MRI was reported
      in 15 of 17 cases for which data were available. Such an observation
      should alert physicians to possible PPA2 dysfunction regardless of the
      clinical presentation and even in asymptomatic individuals.
    explanation: >-
      Documents focal myocardial fibrosis in 15 of 17 (88%, VERY_FREQUENT)
      evaluated patients on histology and/or cardiac MRI, including asymptomatic
      siblings.
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4
      shown in Figure 2). They subsequently each received an implantable
      defibrillator for primary prophylaxis of sudden arrhythmic cardiac death,
      although no events have occurred to date.
    explanation: >-
      Demonstrates marked mid-myocardial fibrosis on cardiac MRI in surviving
      biallelic siblings.
- name: Dilated cardiomyopathy
  category: Cardiovascular
  diagnostic: true
  frequency: FREQUENT
  severity: SEVERE
  description: >-
    Rapid-onset or chronic dilated cardiomyopathy with left ventricular or
    biventricular systolic dysfunction occurs in approximately half of infants
    and children prior to fatal decompensation, as well as in surviving children
    and adults. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel
    classifies the PPA2–dilated cardiomyopathy gene-disease relationship as
    Strong.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the latter group of 13 individuals, dilated cardiomyopathy or
      ventricular dysfunction was usually diagnosed by echocardiography, rapidly
      followed by multiorgan failure and/or ventricular fibrillation (VF,
      reported for six cases).
    explanation: >-
      Documents dilated cardiomyopathy or ventricular dysfunction diagnosed by
      echocardiography in 13 of 28 deceased patients (plus surviving patients
      who underwent heart transplantation or adult cardiomyopathy management).
  - reference: CGGV:assertion_35b7716c-4c72-4ca2-b176-e732d136ed0d-2025-05-16T160000.000Z
    reference_title: "PPA2 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | PPA2 | HGNC:28883 | dilated cardiomyopathy | MONDO:0005021 | AR | Strong | SOP10 | Dilated Cardiomyopathy Gene Curation Expert Panel | 2025-05-16T16:00:00.000Z |
    explanation: >-
      ClinGen Dilated Cardiomyopathy Gene Curation Expert Panel classifies
      autosomal recessive PPA2 deficiency as a Strong cause of dilated
      cardiomyopathy.
- name: Congestive heart failure
  category: Cardiovascular
  frequency: FREQUENT
  severity: SEVERE
  description: >-
    Acute or subacute heart failure is the second major mode of presentation and
    death in biallelic PPA2 deficiency, accounting for 13 of 28 deaths (46%) in
    the 2021 international cohort.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 34 individuals, only 6 remain alive. Twenty-three died before
      the age of 2 years while five died between 14 and 16 years. Within these
      28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure.
    explanation: >-
      Shows that 13 of 28 fatal cases (46%, FREQUENT) died of acute heart
      failure.
- name: Cardiogenic shock
  category: Cardiovascular
  frequency: FREQUENT
  severity: SEVERE
  description: >-
    Fulminant cardiogenic shock with rapid progression to multiorgan failure
    frequently complicates acute infantile or early-childhood heart failure
    presentations.
  phenotype_term:
    preferred_term: Cardiogenic shock
    term:
      id: HP:0030149
      label: Cardiogenic shock
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common clinical presentation remains sudden unexpected cardiac
      arrest, reported in all of the deceased teenagers and half of the children
      who died before their teens, while the other half presented with dilated
      cardiomyopathy, cardiogenic shock, or arrhythmia before death.
    explanation: >-
      Documents cardiogenic shock among the half of affected children who
      present with acute myocardial failure prior to death.
- name: Ventricular fibrillation
  category: Cardiovascular
  frequency: OCCASIONAL
  severity: SEVERE
  description: >-
    Malignant ventricular fibrillation can supervene during acute
    ventricular decompensation or as the primary rhythm of sudden cardiac arrest.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the latter group of 13 individuals, dilated cardiomyopathy or
      ventricular dysfunction was usually diagnosed by echocardiography, rapidly
      followed by multiorgan failure and/or ventricular fibrillation (VF,
      reported for six cases).
    explanation: >-
      Documents ventricular fibrillation in 6 cases within the 13-patient acute
      ventricular-dysfunction/heart-failure subgroup.
- name: Ventricular tachycardia
  category: Cardiovascular
  frequency: OCCASIONAL
  severity: SEVERE
  description: >-
    Polymorphic or pulseless ventricular tachycardia is observed during acute
    cardiac decompensation and resuscitation attempts.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:33028643
    reference_title: "Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The underlying rhythm was primarily pulseless electrical activity (PEA),
      with one incidence of pulseless ventricular tachycardia, for which the
      patient was unsuccessfully defibrillated.
    explanation: >-
      Documents pulseless ventricular tachycardia during fatal neonatal cardiac
      arrest due to compound heterozygous PPA2 variants.
- name: Lactic acidosis
  category: Metabolic/Laboratory
  frequency: OCCASIONAL
  description: >-
    Elevated blood and CSF lactate occurs particularly in severely affected
    neonates (such as homozygotes for p.Pro167Leu) and during acute metabolic
    or cardiac decompensation, but may be absent at baseline in milder infantile
    or adolescent cases.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
      clinical presentation involved lactic acidosis, seizures, hypotonia, and
      cardiac arrhythmia within the first months of life. Myocyte loss,
      disarray, or fibrosis was present in all individuals.
    explanation: >-
      Documents lactic acidosis in infants with severe biallelic PPA2
      deficiency.
- name: Seizure
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Seizures occur in neonates with severe hypomorphic alleles (such as
    homozygous p.Pro167Leu) or as a manifestation of acute cerebral hypoperfusion
    preceding cardiac arrest.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
      clinical presentation involved lactic acidosis, seizures, hypotonia, and
      cardiac arrhythmia within the first months of life. Myocyte loss,
      disarray, or fibrosis was present in all individuals.
    explanation: >-
      Documents seizures in the first months of life in infants homozygous for
      p.Pro167Leu.
- name: Hypotonia
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Muscular hypotonia is observed in neonatal and early-infantile multisystemic
    presentations of biallelic PPA2 deficiency.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
      clinical presentation involved lactic acidosis, seizures, hypotonia, and
      cardiac arrhythmia within the first months of life. Myocyte loss,
      disarray, or fibrosis was present in all individuals.
    explanation: >-
      Documents hypotonia within the first months of life in severely affected
      infants.
- name: Vomiting
  category: Gastrointestinal
  description: >-
    Prodromal emesis can precede acute cardiac decompensation or sudden
    cardiac arrest in infants during intercurrent viral illnesses.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:31705601
    reference_title: "Sudden unexpected death in asymptomatic infants due to PPA2 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the 2 days before death, she experienced fever, vomiting, diarrhea, and
      poor appetite.
    explanation: >-
      Documents prodromal vomiting and diarrhea with fever immediately preceding
      sudden cardiac death in an infant with biallelic PPA2 variants.
- name: Diarrhea
  category: Gastrointestinal
  description: >-
    Mild gastrointestinal symptoms including diarrhea can accompany the febrile
    prodrome preceding sudden infantile cardiac arrest.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:31705601
    reference_title: "Sudden unexpected death in asymptomatic infants due to PPA2 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the 2 days before death, she experienced fever, vomiting, diarrhea, and
      poor appetite.
    explanation: >-
      Documents diarrhea as part of the acute febrile prodrome before fatal
      cardiac arrest.
- name: Vocal cord paralysis
  category: Otolaryngological
  frequency: RARE
  description: >-
    Bilateral vocal cord paralysis presenting with neonatal stridor has been
    reported as an early cranial neuropathic feature prior to sudden cardiac
    death in neonatal PPA2 deficiency.
  phenotype_term:
    preferred_term: Vocal cord paralysis
    term:
      id: HP:0001605
      label: Vocal cord paralysis
  evidence:
  - reference: PMID:33028643
    reference_title: "Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a 5-wk-old male with bilateral vocal cord paralysis and
      hypertension who had a sudden unexpected cardiac death. Subsequently,
      molecular autopsy via whole-genome sequencing from newborn dried blood
      spot identified compound heterozygous mutations in PPA2, with a paternally
      inherited, pathogenic missense variant (c.514G > A; p.Glu172Lys) and a
      novel, maternally inherited missense variant of uncertain significance
      (c.442A > T; p.Thr148Ser).
    explanation: >-
      Documents bilateral vocal cord paralysis in a neonate with compound
      heterozygous PPA2 variants who subsequently died of sudden cardiac arrest.
- name: Peripheral axonal neuropathy
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Adult survivors with biallelic PPA2 variants may develop chronic progressive
    distal muscle weakness, bilateral foot drop, and electromyography-confirmed
    peripheral axonal neuropathy.
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual II-1 from family 17 is alive aged 40 years. She was diagnosed
      with multisystemic mitochondrial disease with cardiomyopathy at 17 years
      and has had a history of progressive distal weakness and bilateral foot
      drop with peripheral axonal neuropathy identified by electromyography,
      external ophthalmoplegia, and ptosis since the age of 29 years.
    explanation: >-
      Documents EMG-confirmed peripheral axonal neuropathy with distal weakness
      and bilateral foot drop in an adult survivor with biallelic PPA2
      deficiency.
- name: External ophthalmoplegia
  category: Ophthalmological
  frequency: RARE
  description: >-
    Progressive external ophthalmoplegia and ptosis can develop in adult
    survivors with multisystemic PPA2 mitochondrial disease.
  phenotype_term:
    preferred_term: External ophthalmoplegia
    term:
      id: HP:0000544
      label: External ophthalmoplegia
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual II-1 from family 17 is alive aged 40 years. She was diagnosed
      with multisystemic mitochondrial disease with cardiomyopathy at 17 years
      and has had a history of progressive distal weakness and bilateral foot
      drop with peripheral axonal neuropathy identified by electromyography,
      external ophthalmoplegia, and ptosis since the age of 29 years.
    explanation: >-
      Documents adult-onset external ophthalmoplegia and ptosis in a patient
      with biallelic PPA2 variants.
- name: Ptosis
  category: Ophthalmological
  frequency: RARE
  description: >-
    Eyelid ptosis accompanies external ophthalmoplegia in adult multisystemic
    PPA2 deficiency.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual II-1 from family 17 is alive aged 40 years. She was diagnosed
      with multisystemic mitochondrial disease with cardiomyopathy at 17 years
      and has had a history of progressive distal weakness and bilateral foot
      drop with peripheral axonal neuropathy identified by electromyography,
      external ophthalmoplegia, and ptosis since the age of 29 years.
    explanation: >-
      Documents ptosis as part of the adult neurological spectrum of biallelic
      PPA2 deficiency.
- name: Progressive cerebellar ataxia
  category: Neurological
  frequency: RARE
  description: >-
    Adolescent- or adult-onset progressive spastic cerebellar ataxia has been
    reported in surviving individuals with biallelic PPA2 variants, expanding
    the extra-cardiac neurological phenotype.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual II-4 in family 4 (this report) displayed signs of progressive
      spastic cerebellar ataxia with distal weakness starting from 14 years of
      age.
    explanation: >-
      Documents adolescent-onset progressive spastic cerebellar ataxia in a
      surviving patient with biallelic PPA2 variants.
genetic:
- name: PPA2
  gene_term:
    preferred_term: PPA2
    term:
      id: hgnc:28883
      label: PPA2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: Positive
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:27523598
      reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Altogether these data demonstrate that PPA2 is an essential gene in yeast
        and that biallelic mutations in PPA2 cause a mitochondrial disease leading
        to sudden cardiac arrest in infants.
      explanation: >-
        Establishes autosomal recessive inheritance of biallelic PPA2 mutations
        in infantile sudden cardiac arrest.
  features: >-
    Biallelic pathogenic variants in PPA2 (12 exons, chromosome 4q24) cause
    autosomal recessive infantile sudden cardiac failure and the broader
    PPA2-related sudden cardiac death and cardiomyopathy spectrum. Because
    complete loss of mitochondrial inorganic pyrophosphatase is incompatible with
    cell survival, biallelic null genotypes have not been observed; affected
    individuals carry either two hypomorphic missense variants or one missense
    variant in trans with a nonsense, frameshift, splice-site, or multi-exon
    deletion allele. The most frequent recurrent pathogenic missense allele in
    European-ancestry cohorts is c.514G>A (p.Glu172Lys), identified in 11 of 20
    families in the 2021 international series. Homozygosity for c.500C>T
    (p.Pro167Leu) causes a severe neonatal/early-infantile presentation with
    lactic acidosis, seizures, hypotonia, and lethal arrhythmia, whereas compound
    heterozygosity pairing c.683C>T (p.Pro228Leu; 24%–28% residual activity) with
    c.514G>A (p.Glu172Lys; 5%–10% residual activity) permits survival into
    adolescence or adulthood with extreme sensitivity to alcohol-induced sudden
    cardiac arrest (allelic disorder MONDO:0014974).
  evidence:
  - reference: PMID:27523598
    reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Altogether these data demonstrate that PPA2 is an essential gene in yeast
      and that biallelic mutations in PPA2 cause a mitochondrial disease leading
      to sudden cardiac arrest in infants.
    explanation: >-
      Establishes that biallelic pathogenic mutations in PPA2 cause autosomal
      recessive mitochondrial disease presenting with infantile sudden cardiac
      arrest.
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of note, the most frequent pathogenic PPA2 variant is c.514G>A;
      p.(Glu172Lys), identified in 11 of the 20 families in our cohort, and has
      been reported in several families in previous studies.
    explanation: >-
      Identifies c.514G>A (p.Glu172Lys) as the most frequent recurrent
      pathogenic PPA2 allele across published cohorts.
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two truncating variants: c.250C>T; p.(Arg84*) and c.938C>A;
      p.(Ser313*), lie in exons 3 and 10 respectively (of 12 exons in total)
      and are predicted to induce nonsense-mediated messenger RNA (mRNA) decay.
    explanation: >-
      Documents nonsense loss-of-function alleles occurring in trans with
      hypomorphic missense alleles in affected individuals.
  - reference: PMID:33826954
    reference_title: "Long-read sequencing identified a novel nonsense and a de novo missense of PPA2 in trans in a Chinese patient with autosomal recessive infantile sudden cardiac failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome and Sanger sequencing revealed two variants in PPA2, with one
      novel nonsense variant (c.524C > G; p.Ser175*) inherited from the mother
      and one de novo missense variant (c.379C > T; p.Arg127Cys).
    explanation: >-
      Documents compound heterozygosity for a maternal nonsense variant and a de
      novo missense variant in trans in an infant with sudden cardiac failure.
  variants:
  - name: c.514G>A (p.Glu172Lys)
    description: >-
      Most frequent recurrent pathogenic PPA2 missense allele in European-ancestry
      cohorts (identified in 11 of 20 families in the 2021 international series).
      Recombinant p.Glu172Lys retains 5%–10% residual inorganic pyrophosphatase
      activity; compound heterozygosity with a severe missense or truncating allele
      causes infantile sudden cardiac failure (MONDO:0014973), whereas compound
      heterozygosity with p.Pro228Leu causes adolescent/adult alcohol-induced
      sudden cardiac failure (MONDO:0014974).
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Of note, the most frequent pathogenic PPA2 variant is c.514G>A;
        p.(Glu172Lys), identified in 11 of the 20 families in our cohort, and has
        been reported in several families in previous studies.
      explanation: >-
        Establishes c.514G>A (p.Glu172Lys) as the most frequent recurrent
        pathogenic PPA2 variant.
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Compared to wild-type, the p.Pro167Leu and p.Glu172Lys variants showed
        5%–10% residual activity at PPi substrate concentrations 18–500 μmol/L.
        The p.Pro228Leu variant had a residual activity of 24%–28% in this
        concentration range compared to wild-type (Figure 3D).
      explanation: >-
        Quantifies 5%–10% residual enzymatic activity for recombinant p.Glu172Lys.
  - name: c.500C>T (p.Pro167Leu)
    description: >-
      Severe hypomorphic missense variant retaining 5%–10% residual enzymatic
      activity; homozygosity causes neonatal/early-infantile lactic acidosis,
      seizures, hypotonia, cardiac arrhythmia, and fatal heart failure within
      the first months of life.
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In affected individuals homozygous for c.500C>T (p.Pro167Leu), the
        clinical presentation involved lactic acidosis, seizures, hypotonia, and
        cardiac arrhythmia within the first months of life. Myocyte loss,
        disarray, or fibrosis was present in all individuals.
      explanation: >-
        Documents the severe early-infantile clinical phenotype associated with
        homozygous c.500C>T (p.Pro167Leu).
  - name: c.683C>T (p.Pro228Leu)
    description: >-
      Milder hypomorphic missense allele retaining 24%–28% residual activity in
      recombinant enzyme assays across PPi substrate concentrations of 18–500
      μmol/L.
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Compared to wild-type, the p.Pro167Leu and p.Glu172Lys variants showed
        5%–10% residual activity at PPi substrate concentrations 18–500 μmol/L.
        The p.Pro228Leu variant had a residual activity of 24%–28% in this
        concentration range compared to wild-type (Figure 3D).
      explanation: >-
        Demonstrates 24%–28% residual catalytic activity for recombinant
        p.Pro228Leu.
  - name: c.379C>T (p.Arg127Cys)
    description: >-
      De novo pathogenic missense variant identified in trans with a maternal
      nonsense PPA2 allele (c.524C>G; p.Ser175*) in a patient with infantile
      sudden cardiac failure.
    evidence:
    - reference: PMID:33826954
      reference_title: "Long-read sequencing identified a novel nonsense and a de novo missense of PPA2 in trans in a Chinese patient with autosomal recessive infantile sudden cardiac failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole exome and Sanger sequencing revealed two variants in PPA2, with one
        novel nonsense variant (c.524C > G; p.Ser175*) inherited from the mother
        and one de novo missense variant (c.379C > T; p.Arg127Cys).
      explanation: >-
        Documents de novo c.379C>T (p.Arg127Cys) in trans with maternal nonsense
        c.524C>G (p.Ser175*) in an infant with sudden cardiac failure.
environmental:
- name: Viral infection and febrile illness (hyperthermia)
  disease_effect: TRIGGERS
  causal_role: MODIFIER
  exposure_term:
    preferred_term: exposure to virus
    term:
      id: ECTO:3000001
      label: exposure to virus
  description: >-
    Mild intercurrent viral infections (respiratory or gastrointestinal) and the
    accompanying febrile response (hyperthermia) frequently precipitate acute
    cardiac decompensation or sudden cardiac arrest in infants and young children
    with biallelic PPA2 variants. Elevated body temperature further destabilizes
    thermolabile mutant PPA2 enzymes, causing acute intramitochondrial PPi
    accumulation and myocardial ATP crisis.
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infection induces the cellular response of hyperthermia, which in the case
      of PPA2-deficient individuals may mean a further reduction in residual
      PPA2 enzyme function. We propose that this may be the mechanism that
      affects their cardiac tissue, ultimately resulting in sudden death.
    explanation: >-
      Proposes how infection-induced hyperthermia further reduces residual mutant
      PPA2 activity and triggers acute cardiac decompensation and sudden death.
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose that viral infections in affected individuals may tip the
      cardiac muscle into ATP deficit, due to a build-up of PPi following the
      effects of temperature increase on the already deficient PPA2 enzyme of
      these individuals.
    explanation: >-
      Links viral infection and fever to PPi buildup and myocardial ATP
      deficit in PPA2-deficient patients.
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      For 11 variants, recombinant PPA2 enzyme activities were significantly
      decreased and sensitive to temperature, compared to wild-type PPA2 enzyme
      activity.
    explanation: >-
      Demonstrates experimentally that pathogenic recombinant PPA2 variants are
      temperature-sensitive in vitro.
  influences_mechanisms:
  - target: Mitochondrial inorganic pyrophosphatase 2 (PPA2) enzymatic deficiency
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Fever/hyperthermia during viral infection further reduces the residual
      catalytic activity of temperature-sensitive mutant PPA2 enzymes.
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        For 11 variants, recombinant PPA2 enzyme activities were significantly
        decreased and sensitive to temperature, compared to wild-type PPA2 enzyme
        activity.
      explanation: >-
        Directly demonstrates in vitro temperature sensitivity of mutant
        recombinant PPA2 enzymes.
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Infection induces the cellular response of hyperthermia, which in the
        case of PPA2-deficient individuals may mean a further reduction in
        residual PPA2 enzyme function. We propose that this may be the mechanism
        that affects their cardiac tissue, ultimately resulting in sudden death.
      explanation: >-
        Supports thermal exacerbation of residual PPA2 enzymatic deficiency
        during febrile viral illness.
- name: Ethanol (alcohol) and acetic acid / vinegar exposure
  disease_effect: TRIGGERS
  causal_role: MODIFIER
  exposure_term:
    preferred_term: exposure to ethanol
    term:
      id: ECTO:9000027
      label: exposure to ethanol
  chemicals:
  - Ethanol
  - Acetic acid
  description: >-
    Shared metabolic trigger across the PPA2 deficiency spectrum: in older
    surviving individuals and those carrying milder hypomorphic genotypes
    (corresponding to the allelic presentation sudden cardiac failure,
    alcohol-induced; MONDO:0014974), ingestion of even small amounts of ethanol
    (alcohol) or acetic acid/vinegar-containing foods can precipitate acute
    cardiac arrest. Ethanol is oxidized via acetaldehyde to acetic acid, which
    is activated to acetyl-CoA in cardiac mitochondria by short-chain acyl-CoA
    synthetases (such as ACSS1), generating equimolar intramitochondrial
    inorganic pyrophosphate (PPi) that overwhelms deficient PPA2 activity.
  evidence:
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ethanol is oxidized to acetaldehyde and further to acetic acid.13
      Resulting acetic acid has to be activated to acetyl-coenzyme A, which is
      accompanied by the formation of equimolar amounts of PPi (Figure S7). This
      esterification reaction is catalyzed by short-chain acyl-CoA synthetases
      encoded, for example, by ACSS1 (MIM: 614355), an enzyme with high
      expression in heart mitochondria.14
    explanation: >-
      Defines the biochemical mechanism by which ethanol oxidation and
      ACSS1-mediated acetate activation generate intramitochondrial PPi in
      cardiomyocytes, precipitating acute decompensation in PPA2 deficiency.
  influences_mechanisms:
  - target: Mitochondrial matrix inorganic pyrophosphate accumulation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      ACSS1-mediated esterification of ethanol-derived acetic acid generates an
      acute intramitochondrial PPi surge that cannot be hydrolyzed by deficient
      PPA2, directly exacerbating mitochondrial matrix PPi accumulation.
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ethanol is oxidized to acetaldehyde and further to acetic acid.13
        Resulting acetic acid has to be activated to acetyl-coenzyme A, which is
        accompanied by the formation of equimolar amounts of PPi (Figure S7).
        This esterification reaction is catalyzed by short-chain acyl-CoA
        synthetases encoded, for example, by ACSS1 (MIM: 614355), an enzyme with
        high expression in heart mitochondria.14
      explanation: >-
        Establishes that ethanol-derived acetic acid activation generates
        equimolar PPi in heart mitochondria, directly overloading the
        PPi-dependent mitochondrial energy-transducing system.
diagnosis:
- name: Molecular genetic testing of PPA2
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Identification of biallelic (homozygous or compound heterozygous) pathogenic
    variants in PPA2 by multigene cardiomyopathy/arrhythmia panel, exome or
    genome sequencing (including postmortem molecular autopsy from dried blood
    spots), or long-read sequencing to phase de novo or structural variants.
  description: >-
    Definitive diagnosis requires identification of biallelic pathogenic variants
    in PPA2. Because respiratory chain enzyme activities in skeletal muscle and
    skin fibroblasts are typically normal, molecular genetic testing and cascade
    carrier/sibling screening are essential for diagnosis, including postmortem
    molecular autopsy in unexplained infantile sudden death or suspected viral
    myocarditis.
  evidence:
  - reference: PMID:27523598
    reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report seven individuals from three families affected by sudden
      and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome
      sequencing revealed compound heterozygous missense mutations in PPA2 in
      affected infants of each family.
    explanation: >-
      Demonstrates that whole-exome sequencing establishes the molecular
      diagnosis by identifying biallelic PPA2 mutations in affected infants.
  - reference: PMID:33028643
    reference_title: "Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsequently, molecular autopsy via whole-genome sequencing from newborn
      dried blood spot identified compound heterozygous mutations in PPA2, with
      a paternally inherited, pathogenic missense variant (c.514G > A;
      p.Glu172Lys) and a novel, maternally inherited missense variant of
      uncertain significance (c.442A > T; p.Thr148Ser).
    explanation: >-
      Demonstrates postmortem diagnosis of biallelic PPA2 deficiency by
      whole-genome sequencing from archived newborn dried blood spots.
- name: Cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging of the Heart
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  results: >-
    Demonstrates focal, patchy, or circumferential mid-myocardial and
    subepicardial late gadolinium enhancement (myocardial fibrosis), frequently
    present even in clinically asymptomatic individuals with biallelic PPA2
    variants.
  description: >-
    Cardiac MRI is the most sensitive non-invasive modality to detect subclinical
    or overt myocardial fibrosis in PPA2 deficiency and is recommended for
    evaluation and longitudinal surveillance of at-risk or biallelic siblings.
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Focal myocardial fibrosis upon histology and/or cardiac MRI was reported
      in 15 of 17 cases for which data were available. Such an observation
      should alert physicians to possible PPA2 dysfunction regardless of the
      clinical presentation and even in asymptomatic individuals.
    explanation: >-
      Establishes cardiac MRI detection of focal myocardial fibrosis as a key
      diagnostic clue to PPA2 dysfunction, even in asymptomatic individuals.
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4
      shown in Figure 2). They subsequently each received an implantable
      defibrillator for primary prophylaxis of sudden arrhythmic cardiac death,
      although no events have occurred to date.
    explanation: >-
      Demonstrates that cardiac MRI detects marked mid-myocardial fibrosis in
      asymptomatic biallelic siblings, guiding prophylactic ICD placement.
- name: Transthoracic echocardiography
  diagnosis_term:
    preferred_term: Echocardiography Test
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  results: >-
    May show acute or chronic left ventricular dilation and systolic dysfunction
    (dilated cardiomyopathy) during decompensation, or may be entirely normal
    prior to sudden arrhythmic cardiac arrest despite underlying mid-myocardial
    fibrosis on cardiac MRI.
  description: >-
    Echocardiography diagnoses dilated cardiomyopathy and ventricular systolic
    dysfunction in patients presenting with acute heart failure, though a normal
    echocardiogram does not exclude PPA2 deficiency or myocardial fibrosis.
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the latter group of 13 individuals, dilated cardiomyopathy or
      ventricular dysfunction was usually diagnosed by echocardiography, rapidly
      followed by multiorgan failure and/or ventricular fibrillation (VF,
      reported for six cases).
    explanation: >-
      Documents echocardiography as the primary modality diagnosing dilated
      cardiomyopathy and ventricular dysfunction in patients presenting with
      acute heart failure.
differential_diagnoses:
- name: Viral myocarditis
  disease_term:
    preferred_term: viral myocarditis
    term:
      id: MONDO:0023161
      label: viral myocarditis
  description: >-
    Infants and young children with biallelic PPA2 deficiency frequently present
    with acute heart failure, cardiogenic shock, or sudden cardiac arrest
    shortly after a febrile viral respiratory or gastrointestinal illness, and
    a subset show mild myocardial inflammatory infiltrates on autopsy or biopsy,
    closely mimicking acute viral myocarditis.
  distinguishing_features:
  - >-
    Prominent focal or mid-myocardial collagen fibrosis (present in ~88% of
    evaluated PPA2 cases and always accompanying any inflammatory infiltrate)
    on cardiac MRI or histology
  - >-
    Familial recurrence of sudden unexpected cardiac arrest or acute heart
    failure in siblings
  - >-
    Identification of biallelic pathogenic variants in PPA2 on molecular
    genetic testing
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Irrespective of the main clinical presentation, myocardial fibrosis was
      reported in 15 cases in our cohort, either at necropsy or on cardiac MRI,
      whereas an inflammatory infiltrate was noted in only 6 cases and always in
      combination with fibrosis. Thus, fibrosis may help discriminate between
      PPA2-related cardiomyopathy and viral myocarditis when individuals present
      with acute heart failure.
    explanation: >-
      Highlights viral myocarditis as the principal clinical differential
      diagnosis during acute heart failure and identifies prominent myocardial
      fibrosis and PPA2 genetic testing as the key discriminating features.
- name: Sudden cardiac failure, alcohol-induced
  disease_term:
    preferred_term: sudden cardiac failure, alcohol-induced
    term:
      id: MONDO:0014974
      label: sudden cardiac failure, alcohol-induced
  description: >-
    Sudden cardiac failure, alcohol-induced (SCFAI; OMIM:617223; MONDO:0014974)
    is an allelic autosomal recessive disorder caused by biallelic hypomorphic
    variants in PPA2—classically compound heterozygosity pairing the milder
    hypomorphic allele p.Pro228Leu (24%–28% residual enzymatic activity) in
    trans with a lower-activity allele such as p.Glu172Lys (5%–10% residual
    activity)—in which sudden cardiac arrest is triggered in adolescence or
    adulthood by ingestion of small amounts of alcohol.
  distinguishing_features:
  - >-
    SCFI (MONDO:0014973) typically presents in the neonatal, infantile, or
    early-childhood period (often triggered by febrile viral illness) in
    individuals whose biallelic PPA2 genotypes confer lower total residual
    enzymatic activity (e.g., 5%–10% for p.Pro167Leu and p.Glu172Lys)
  - >-
    SCFAI (MONDO:0014974) typically presents in adolescence or adulthood with
    sudden cardiac arrest precipitated by small amounts of alcohol in
    individuals carrying at least one milder hypomorphic allele with higher
    residual PPA2 activity (~24%–28% for p.Pro228Leu, often in compound
    heterozygosity with p.Glu172Lys)
  evidence:
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Compared to wild-type, the p.Pro167Leu and p.Glu172Lys variants showed
      5%–10% residual activity at PPi substrate concentrations 18–500 μmol/L.
      The p.Pro228Leu variant had a residual activity of 24%–28% in this
      concentration range compared to wild-type (Figure 3D).
    explanation: >-
      Demonstrates that the infantile-onset (MONDO:0014973) and adolescent
      alcohol-induced (MONDO:0014974) forms of PPA2 deficiency are stratified by
      the residual mitochondrial pyrophosphatase activity of the underlying
      missense alleles (5%–10% for p.Pro167Leu and p.Glu172Lys versus 24%–28%
      for p.Pro228Leu).
treatments:
- name: Implantable cardioverter-defibrillator (ICD) placement
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Implantable Cardioverter-Defibrillator Placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  description: >-
    Primary or secondary prophylactic placement of an implantable
    cardioverter-defibrillator is used in surviving children, adolescents, and
    adults with biallelic PPA2 variants (especially those with mid-myocardial
    fibrosis on cardiac MRI) to prevent sudden arrhythmic death from ventricular
    tachycardia or ventricular fibrillation.
  target_phenotypes:
  - preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  - preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  - preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  target_mechanisms:
  - target: Ventricular arrhythmia and electrical instability
    treatment_effect: MODULATES
    description: >-
      Detects and terminates malignant ventricular tachyarrhythmias via
      defibrillation or antitachycardia pacing, preventing progression to fatal
      cardiac arrest.
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4
        shown in Figure 2). They subsequently each received an implantable
        defibrillator for primary prophylaxis of sudden arrhythmic cardiac
        death, although no events have occurred to date.
      explanation: >-
        Documents prophylactic ICD implantation in surviving biallelic PPA2
        siblings with mid-myocardial fibrosis to prevent sudden arrhythmic
        cardiac death.
  evidence:
  - reference: PMID:27523597
    reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac MRI showed marked mid-myocardial fibrosis in both siblings (P4
      shown in Figure 2). They subsequently each received an implantable
      defibrillator for primary prophylaxis of sudden arrhythmic cardiac death,
      although no events have occurred to date.
    explanation: >-
      Supports primary prophylactic ICD placement in surviving patients with
      PPA2-related myocardial fibrosis.
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At-risk patients may benefit from cardiac MRI monitoring, treatment of
      fever, exclusion of alcohol consumption, avoidance of vinegar and
      vinegar-containing foods, repeated neurological evaluation, and
      consideration for early heart transplantation or implantation of a
      cardioverter defibrillator.
    explanation: >-
      Recommends consideration of cardioverter-defibrillator implantation as a
      core management strategy for at-risk biallelic PPA2 patients.
- name: Orthotopic heart transplantation
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  description: >-
    Early orthotopic heart transplantation is a life-saving intervention for
    children with severe, rapid-onset dilated cardiomyopathy and refractory
    heart failure due to biallelic PPA2 deficiency, correcting the primary
    cardiac bioenergetic defect while requiring ongoing surveillance for
    potential late-onset extra-cardiac neurological manifestations.
  target_phenotypes:
  - preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  target_mechanisms:
  - target: Acute myocardial contractile failure
    treatment_effect: RESTORES
    description: >-
      Replaces the PPA2-deficient, fibrotic myocardium with a donor heart that
      has normal mitochondrial inorganic pyrophosphatase activity and contractile
      function.
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Individual II-1 from family 12 is noteworthy having received a heart
        transplant for severe and rapid-onset dilated cardiomyopathy leading to
        heart failure at 3 years 9 months. He remains alive and well 20 months
        post-transplantation.
      explanation: >-
        Demonstrates successful orthotopic heart transplantation with sustained
        survival in a young child with severe PPA2-related dilated
        cardiomyopathy and heart failure.
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual II-1 from family 12 is noteworthy having received a heart
      transplant for severe and rapid-onset dilated cardiomyopathy leading to
      heart failure at 3 years 9 months. He remains alive and well 20 months
      post-transplantation.
    explanation: >-
      Provides clinical evidence of durable survival following heart
      transplantation for severe PPA2-related dilated cardiomyopathy.
- name: Strict avoidance of alcohol and vinegar/acetic acid-containing foods and prompt antipyretic management of fever
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Lifestyle Counseling
    term:
      id: NCIT:C180632
      label: Lifestyle Counseling
  description: >-
    Patients with biallelic PPA2 deficiency must strictly avoid alcohol
    (including alcohol-containing medications) and vinegar/acetic
    acid-containing foods to prevent ACSS1-driven intramitochondrial PPi surges,
    and should receive prompt antipyretic treatment during febrile illnesses to
    prevent thermal inactivation of residual mutant PPA2 enzyme activity.
  target_phenotypes:
  - preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  - preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  target_mechanisms:
  - target: Mitochondrial inorganic pyrophosphatase 2 (PPA2) enzymatic deficiency
    treatment_effect: MODULATES
    description: >-
      Controlling fever prevents thermal denaturation of residual mutant PPA2,
      while excluding ethanol and acetic acid prevents acute ACSS1-mediated PPi
      overload in cardiac mitochondria.
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        At-risk patients may benefit from cardiac MRI monitoring, treatment of
        fever, exclusion of alcohol consumption, avoidance of vinegar and
        vinegar-containing foods, repeated neurological evaluation, and
        consideration for early heart transplantation or implantation of a
        cardioverter defibrillator.
      explanation: >-
        Recommends fever control, exclusion of alcohol consumption, and
        avoidance of vinegar-containing foods to prevent acute metabolic
        overload of residual PPA2 activity.
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At-risk patients may benefit from cardiac MRI monitoring, treatment of
      fever, exclusion of alcohol consumption, avoidance of vinegar and
      vinegar-containing foods, repeated neurological evaluation, and
      consideration for early heart transplantation or implantation of a
      cardioverter defibrillator.
    explanation: >-
      Establishes trigger avoidance (alcohol and vinegar exclusion, prompt
      treatment of fever) as standard preventive management in biallelic PPA2
      deficiency.
- name: Longitudinal cardiac MRI and neurological surveillance
  action_category: MONITORING
  treatment_term:
    preferred_term: Longitudinal cardiac MRI and neurological monitoring
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  description: >-
    Regular cardiac MRI monitoring to detect or track myocardial fibrosis and
    repeated neurological evaluations for peripheral axonal neuropathy,
    ophthalmoplegia, or cerebellar ataxia are recommended for all diagnosed and
    at-risk biallelic PPA2 individuals, alongside cascade genetic counseling and
    testing of siblings.
  evidence:
  - reference: PMID:34400813
    reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At-risk patients may benefit from cardiac MRI monitoring, treatment of
      fever, exclusion of alcohol consumption, avoidance of vinegar and
      vinegar-containing foods, repeated neurological evaluation, and
      consideration for early heart transplantation or implantation of a
      cardioverter defibrillator.
    explanation: >-
      Supports longitudinal cardiac MRI monitoring and repeated neurological
      evaluations for individuals with biallelic PPA2 deficiency.
notes: >-
  Nosological relationship to MONDO:0014974 (sudden cardiac failure,
  alcohol-induced): OMIM and MONDO maintain two distinct autosomal recessive
  PPA2-related entries based on clinical presentation and onset—sudden cardiac
  failure, infantile (SCFI; OMIM:617222; MONDO:0014973; Guimier et al.,
  PMID:27523598) and sudden cardiac failure, alcohol-induced (SCFAI;
  OMIM:617223; MONDO:0014974; Kennedy et al., PMID:27523597). Functional and
  clinical cohort studies (PMID:27523597; PMID:34400813) show that these two
  allelic disorders reflect different levels of residual mitochondrial inorganic
  pyrophosphatase 2 (PPA2) activity and distinct acute metabolic triggers:
  lower-activity genotypes (such as homozygous p.Pro167Leu or compound
  heterozygous p.Glu172Lys paired with a severe or truncating allele) present in
  the neonatal period, infancy, or early childhood (frequently precipitated by
  febrile viral illness, corresponding to MONDO:0014973), whereas compound
  heterozygous genotypes retaining higher residual activity (classically pairing
  p.Pro228Leu with a lower-activity allele such as p.Glu172Lys) permit survival
  into adolescence or adulthood with sudden cardiac arrest triggered by modest
  ethanol/acetic acid intake (corresponding to MONDO:0014974).
references:
- reference: PMID:27523598
  title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
  findings:
  - statement: >-
      Compound heterozygous missense variants in PPA2 cause sudden unexpected
      cardiac arrest between 4 and 20 months of age, and pathogenic PPA2
      variants rapidly collapse the mitochondrial inner membrane electrical
      potential in yeast complementation models.
    supporting_text: >-
      Using a regulatable (doxycycline-repressible) gene expression system, we
      found that the pathogenic PPA2 mutations rapidly inactivate the
      mitochondrial energy transducing system and prevent the maintenance of a
      sufficient electrical potential across the inner membrane, which explains
      the subsequent disappearance of mitochondria from the mutant yeast cells.
    evidence:
    - reference: PMID:27523598
      reference_title: "Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Using a regulatable (doxycycline-repressible) gene expression system, we
        found that the pathogenic PPA2 mutations rapidly inactivate the
        mitochondrial energy transducing system and prevent the maintenance of a
        sufficient electrical potential across the inner membrane, which
        explains the subsequent disappearance of mitochondria from the mutant
        yeast cells.
      explanation: >-
        Demonstrates the mechanistic link between pathogenic PPA2 variants and
        collapse of the inner mitochondrial membrane potential.
- reference: PMID:27523597
  title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
  findings:
  - statement: >-
      Biallelic hypomorphic variants in PPA2 reduce mitochondrial inorganic
      pyrophosphatase activity in correlation with clinical severity (5%–10%
      residual activity in infantile-lethal p.Pro167Leu and p.Glu172Lys versus
      24%–28% in p.Pro228Leu), cause mid-myocardial fibrosis, and sensitize the
      myocardium to ACSS1-mediated PPi generation from ethanol/acetic acid.
    supporting_text: >-
      Comparison of normal and mutant PPA2-containing mitochondria from
      fibroblasts showed that the activity of inorganic pyrophosphatase was
      significantly reduced in affected individuals. Recombinant PPA2 enzymes
      modeling hypomorphic missense mutations had decreased activity that
      correlated with disease severity.
    evidence:
    - reference: PMID:27523597
      reference_title: "Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Comparison of normal and mutant PPA2-containing mitochondria from
        fibroblasts showed that the activity of inorganic pyrophosphatase was
        significantly reduced in affected individuals. Recombinant PPA2 enzymes
        modeling hypomorphic missense mutations had decreased activity that
        correlated with disease severity.
      explanation: >-
        Establishes that residual PPA2 enzymatic activity correlates with
        clinical severity across infantile and adolescent presentations.
- reference: PMID:34400813
  title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
  findings:
  - statement: >-
      In a cohort of 34 individuals from 20 families (expanding the world total
      to 56 patients from 30 families), 28 died (15 of sudden cardiac arrest, 13
      of acute heart failure), focal myocardial fibrosis was present in 15 of 17
      evaluated cases, and adult survivors developed progressive peripheral
      axonal neuropathy, external ophthalmoplegia, ptosis, or spastic cerebellar
      ataxia.
    supporting_text: >-
      Among the 34 individuals, only 6 remain alive. Twenty-three died before
      the age of 2 years while five died between 14 and 16 years. Within these
      28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure.
    evidence:
    - reference: PMID:34400813
      reference_title: "PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Among the 34 individuals, only 6 remain alive. Twenty-three died before
        the age of 2 years while five died between 14 and 16 years. Within these
        28 cases, 15 died of sudden cardiac arrest and 13 of acute heart
        failure.
      explanation: >-
        Summarizes the natural history and mortality of biallelic PPA2
        deficiency in the largest published cohort.
- reference: PMID:31705601
  title: "Sudden unexpected death in asymptomatic infants due to PPA2 variants."
  findings: []
- reference: PMID:33028643
  title: "Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis."
  findings: []
- reference: PMID:33826954
  title: "Long-read sequencing identified a novel nonsense and a de novo missense of PPA2 in trans in a Chinese patient with autosomal recessive infantile sudden cardiac failure."
  findings: []
- reference: CGGV:assertion_35b7716c-4c72-4ca2-b176-e732d136ed0d-2025-05-16T160000.000Z
  title: "PPA2 / dilated cardiomyopathy (Strong)"
  findings: []

📚

References & Deep Research

References

7

PMID:27523598

Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy.

1 finding

Compound heterozygous missense variants in PPA2 cause sudden unexpected cardiac arrest between 4 and 20 months of age, and pathogenic PPA2 variants rapidly collapse the mitochondrial inner membrane electrical potential in yeast complementation models.

"Using a regulatable (doxycycline-repressible) gene expression system, we found that the pathogenic PPA2 mutations rapidly inactivate the mitochondrial energy transducing system and prevent the maintenance of a sufficient electrical potential across the inner membrane, which explains the..."

Show evidence (1 reference)

PMID:27523598 SUPPORT Model Organism

"Using a regulatable (doxycycline-repressible) gene expression system, we found that the pathogenic PPA2 mutations rapidly inactivate the mitochondrial energy transducing system and prevent the maintenance of a sufficient electrical potential across the inner membrane, which explains the..."

Demonstrates the mechanistic link between pathogenic PPA2 variants and collapse of the inner mitochondrial membrane potential.

PMID:27523597

Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2.

1 finding

Biallelic hypomorphic variants in PPA2 reduce mitochondrial inorganic pyrophosphatase activity in correlation with clinical severity (5%–10% residual activity in infantile-lethal p.Pro167Leu and p.Glu172Lys versus 24%–28% in p.Pro228Leu), cause mid-myocardial fibrosis, and sensitize the myocardium to ACSS1-mediated PPi generation from ethanol/acetic acid.

"Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with..."

Show evidence (1 reference)

PMID:27523597 SUPPORT In Vitro

"Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with..."

Establishes that residual PPA2 enzymatic activity correlates with clinical severity across infantile and adolescent presentations.

PMID:34400813

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.

1 finding

In a cohort of 34 individuals from 20 families (expanding the world total to 56 patients from 30 families), 28 died (15 of sudden cardiac arrest, 13 of acute heart failure), focal myocardial fibrosis was present in 15 of 17 evaluated cases, and adult survivors developed progressive peripheral axonal neuropathy, external ophthalmoplegia, ptosis, or spastic cerebellar ataxia.

"Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure."

Show evidence (1 reference)

PMID:34400813 SUPPORT Human Clinical

"Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure."

Summarizes the natural history and mortality of biallelic PPA2 deficiency in the largest published cohort.

PMID:31705601

Sudden unexpected death in asymptomatic infants due to PPA2 variants.

No top-level findings curated for this source.

PMID:33028643

Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis.

No top-level findings curated for this source.

PMID:33826954

Long-read sequencing identified a novel nonsense and a de novo missense of PPA2 in trans in a Chinese patient with autosomal recessive infantile sudden cardiac failure.

No top-level findings curated for this source.

CGGV:assertion_35b7716c-4c72-4ca2-b176-e732d136ed0d-2025-05-16T160000.000Z

PPA2 / dilated cardiomyopathy (Strong)

No top-level findings curated for this source.

Deep Research

1

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

Claude Code ▸

Research report: Sudden cardiac failure, infantile (SCFI; MONDO:0014973)

claude-haiku-4-5-20251001, claude-opus-5-5 6 citations 2026-10-14T15:54:19.548640

I'm pulling the cached PPA2 abstracts now. Next I'll search for newer papers on models and survivors, then write the report.

Pulling full abstracts for the 2023–2026 case reports and the mitochondrial-fission paper, so I can quote them exactly.

Pulling key sentences from the cached full text of the 2021 cohort paper. After that I'll write the report.

Research report: Sudden cardiac failure, infantile (SCFI; MONDO:0014973)

Method. Abstracts and full texts for the key papers were read from this repository's references_cache/: PMID:27523597 (full text), PMID:27523598, PMID:34400813 (full text), PMID:31705601, PMID:33028643 and PMID:33826954. Case reports from 2023–2026 were found through a PubMed search on PPA2 and read through NCBI E-utilities and the Europe PMC API.

Two kinds of citation in this report: - Exact quotes from cached files. Quotes marked (cached) were copied from those files and can be used as snippets. - Quotes from summaries of web pages. Quotes from uncached PMIDs came through a tool that summarises pages, so some are partial. Run just fetch-reference on each one and re-quote it from the cache before using it as a snippet.

Ontology IDs. The labels shown were checked against this repository's cache/*/terms.csv. IDs marked [verify] were not in the cache. Look them up before you bind them.

Unavailable tools. The claude.ai PubMed and OLS connectors were not authorized in this session, so they were not used. They can be enabled in the claude.ai connector settings.

1. Disease information

Overview. SCFI is an autosomal recessive mitochondrial disease. It is caused by biallelic hypomorphic variants in PPA2 (hgnc:28883), which encodes the mitochondrial inorganic pyrophosphatase. Affected children who seemed healthy die suddenly of cardiac arrest or acute heart failure, usually before age 2. Death often follows a viral illness. Guimier et al. 2016 reported "seven individuals from three families affected by sudden and unexpected cardiac arrest between 4 and 20 months of age" and found "compound heterozygous missense mutations in PPA2" (PMID:27523598, cached).

Identifiers

System	ID
MONDO	MONDO:0014973, "sudden cardiac failure, infantile"
OMIM (disease)	#617222 (named in PMID:33028643 and PMID:33826954)
OMIM (gene)	PPA2 *609988 (PMID:31705601)
Allelic disorder	Sudden cardiac failure, alcohol-induced (SCFAI): OMIM #617223, MONDO:0014974
HGNC	hgnc:28883 (PPA2)
LOVD	disease #06623 (LOVD)
Orphanet	No dedicated ORPHA code was found; no `ORPHA_.md` cache mentions PPA2 [verify]*
ICD-10/11, MeSH	No disease-specific codes. The closest MeSH headings are Death, Sudden, Cardiac and Mitochondrial Diseases (MeSH terms on PMID:27523597)

Synonyms: SCFI; PPA2 deficiency; inorganic pyrophosphatase 2 deficiency; PPA2-associated sudden cardiac death (PMID:34400813); PPA2-related mitochondriopathy (PMID:37269378).

Source of the data. All knowledge comes from aggregated case reports and case series. About 45 individuals in roughly 25 families had been reported by 2021, with further single reports in 2023–2026. There are no registry or EHR cohorts.

Lump/split note. SCFI and SCFAI are separate in both OMIM and MONDO. They are, however, one genotype–activity continuum. Guimier 2021 describes "inter- and intrafamilial phenotypic variability" (PMID:34400813, cached). Kennedy's index family (p.[Glu172Lys];[Pro228Leu]) presented in the teens with alcohol sensitivity, while other genotypes caused death in infancy (PMID:27523597).

2. Etiology

Cause. Biallelic PPA2 variants that partly lose function. "Biallelic hypomorphic variants in PPA2 … have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection" (PMID:34400813, cached).

Genetic risk factors - Commonest variant: c.514G>A p.(Glu172Lys). It is "the most frequent pathogenic PPA2 variant … identified in 11 of the 20 families in our cohort". It has a "gnomAD allele frequency of 0.00053, and has never been seen in the homozygous state" (PMID:34400813, cached). Its absence as a homozygote suggests it is close to null and is only tolerated in trans with a milder allele. - Other recurrent alleles: p.Pro228Leu (milder), p.Arg127Leu, p.Pro167Leu, p.Met94Val, p.Ser61Phe, p.Arg127Cys, p.Ser175* (nonsense), and p.Gln327fs (frameshift).

Environmental triggers (gene × environment) - Febrile viral illness. "Both individuals from family 3 and the affected individual from family 4 had viral infections at the time of hospital admission". Rotavirus and norovirus were confirmed in stool (PMID:27523597, cached). Guimier 2021: "a viral test was positive in five cases" (cached). - Alcohol, even small amounts. "Four teenagers drank alcohol before sudden cardiac arrest" (PMID:34400813, cached). Also reported in PMID:37249496, PMID:37269378 and PMID:38582264: "Two brothers from family 1 suffered sudden death after a small first intake of alcohol". - Temperature. Mutant enzymes "were significantly decreased and sensitive to temperature" (PMID:34400813, cached). This gives a plausible molecular basis for fever as a trigger: thermolabile enzyme activity falls below a critical threshold. This link is inferred, not demonstrated in patients. - Protective factors. None known. Avoiding alcohol and preventing or treating fever are the only modifiable factors.

3. Phenotypes

Cardiac phenotypes

Phenotype	HPO	Frequency / evidence	Onset and course
Sudden cardiac death	HP:0001645 Sudden cardiac death	28/34 died; 15 by sudden arrest (PMID:34400813)	Infancy (median under 2 y); a second peak at 14–16 y
Cardiac arrest	HP:0001695 Cardiac arrest	Core feature	Acute
Acute heart failure / cardiogenic shock	HP:0001635 Congestive heart failure; HP:0030149 Cardiogenic shock	13/28 deaths were from acute heart failure (PMID:34400813)	Acute, often with infection
Myocardial fibrosis	HP:0001685 Myocardial fibrosis	"myocardial fibrosis was reported in 15 cases" (PMID:34400813); "marked mid-myocardial fibrosis" on MRI (PMID:27523597)	Chronic, accumulates over time
Dilated cardiomyopathy	HP:0001644 Dilated cardiomyopathy	Necropsy: "dilation of the left ventricle, focal fibrosis, and inflammatory infiltrates with acute myocyte loss" (PMID:34400813)	Progressive; one prenatal case
Ventricular fibrillation / VT	HP:0001663 Ventricular fibrillation; HP:0004756 Ventricular tachycardia	Two children with "multiple VF arrests starting at 20 months and 18 months" (PMID:34400813)	Episodic
Myocarditis-like inflammatory infiltrate	HP:0012819 Myocarditis	6/34, always with fibrosis (PMID:34400813)	—
Hypertrophic cardiomyopathy	HP:0001639 Hypertrophic cardiomyopathy	Listed only in aggregator summaries; no primary source found [verify]	—

Metabolic, neurological and other phenotypes

Phenotype	HPO	Frequency / evidence	Onset and course
Lactic acidosis	HP:0003128 Lactic acidosis	5/34 (PMID:34400813); severe in neonates (PMID:27523597)	Neonatal or during crises
Seizures	HP:0001250 Seizure	In the severe neonatal and infantile forms (PMID:27523597)	Neonatal to infancy
Hypotonia	HP:0001252 Hypotonia	Severe forms	—
Vomiting / diarrhea	HP:0002013 Vomiting; HP:0002014 Diarrhea	Before decompensation (PMID:27523597)	Prodrome
Vocal cord paralysis	HP:0001605 Vocal cord paralysis	Single case, with hypertension (PMID:33028643)	5 weeks
Peripheral axonal neuropathy, external ophthalmoplegia, ptosis	HP:0003477 Peripheral axonal neuropathy; HP:0000544 External ophthalmoplegia; HP:0000508 Ptosis	One survivor, from age 29 (PMID:34400813)	Progressive
Ataxia, spasticity, dysarthria	HP:0002073 Progressive cerebellar ataxia	One survivor, from about age 14 (PMID:34400813); "Progressive neurological signs were observed in 2/6 surviving individuals"	Progressive
Alcohol sensitivity	No precise HPO term found [verify]	Index family and teenagers	Lifelong

Quality of life. No formal QoL studies exist. In survivors, the burden comes from a defibrillator, lifelong restrictions on alcohol and medicines, and progressive neurological disability.

4. Genetic and molecular information

Gene. PPA2, located at 4q24 (location from aggregator sources). It is nuclear-encoded and imported into the mitochondrial matrix. Its catalytic function is inorganic diphosphatase activity: GO:0004427 [verify label]. The parent term GO:0016462 "pyrophosphatase activity" is cached.
Variant classes. Mostly missense. LoF alleles (nonsense, frameshift) occur only in trans with a hypomorph. The authors took "the absence of common or homozygous LoF variants within gnomAD … as evidence to support LoF as a mechanism for pathogenicity" (PMID:34400813, cached). Complete loss is presumed lethal, consistent with yeast ppa2Δ inviability.
Variant effects on enzyme activity (PMID:27523597, cached):
p.Pro167Leu and p.Glu172Lys: "5%–10% residual activity".
p.Pro228Leu: "residual activity of 24%–28%".
Residual activity tracks severity: "Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity".
Germline vs somatic. All variants are germline. A de novo missense in trans with an inherited nonsense variant was phased by long-read sequencing (PMID:33826954).
Population frequency. "The cumulative heterozygous carrier frequency … is 0.0024, which would result in a calculated prevalence … of 0.58 per 100,000 (1 in 170,000)" (PMID:27523597, cached).
ClinGen. PPA2–dilated cardiomyopathy (MONDO:0005021) is classified Strong, AR by the DCM gene curation expert panel (2025-05-16). That classification is for DCM, not for SCFI itself.
Updated DCM gene evidence. PPA2 is among the AR genes rated "high evidence" for DCM (Jordan et al., Circulation 2026, PMID:42708185).
Modifier genes, epigenetics, chromosomal abnormalities. None reported.

5. Environmental information

Ethanol (CHEBI:16236 [verify]). A trigger at very low doses. Avoid ethanol in medicines (PMID:39882621).
Viral infections. These are triggers, not causes. Rotavirus and norovirus have been documented (PMID:27523597). Fever is the likely link (see Section 2).
Toxins and lifestyle. Nothing else reported. Maternal smoking was noted in one case without causal inference (PMID:31705601).

6. Mechanism and pathophysiology

Causal chain

Biallelic hypomorphic PPA2 variants lead to reduced, thermolabile inorganic pyrophosphatase activity in the mitochondrial matrix (GO:0005759). Shown directly with recombinant enzymes and patient-fibroblast mitochondria (PMID:27523597, PMID:34400813).
Reduced PPi hydrolysis results in PPi accumulation and loss of the thermodynamic pull on PPi-producing matrix reactions such as mtDNA, RNA and protein synthesis and fatty-acyl-CoA activation. Inferred from enzymology; matrix PPi has not been measured in patients.
Leads to failure of energy transduction and inability to maintain inner-membrane potential (GO:0051881 "regulation of mitochondrial membrane potential"; GO:0005743). Shown in yeast: "pathogenic PPA2 mutations rapidly inactivate the mitochondrial energy transducing system and prevent the maintenance of a sufficient electrical potential across the inner membrane, which explains the subsequent disappearance of mitochondria" (PMID:27523598, cached).
Results in reduced ATP supply (GO:0006754 "ATP biosynthetic process"; GO:0042775) in cardiomyocytes (CL:0000746 "cardiac muscle cell"). Kennedy et al. propose that hearts "were consistently deprived of adequate ATP resulting in fibrosis" (PMID:27523597, cached). This is a hypothesis, not measured in human heart.
Branch A (chronic): cardiomyocyte loss leads to replacement fibrosis by cardiac fibroblasts (CL:0002548; GO:0030198), mainly mid-myocardial in the left ventricle (UBERON:0002084, UBERON:0002349). This leads to dilated cardiomyopathy and an arrhythmogenic substrate.
Branch B (acute): a stressor such as fever (thermolabile enzyme) or alcohol (unknown mechanism, perhaps extra redox or acetaldehyde load on already-limited mitochondria) pushes activity below a critical threshold. This results in acute myocyte loss, ventricular fibrillation (impaired GO:0086001 "cardiac muscle cell action potential" and GO:0060048 "cardiac muscle contraction"), cardiogenic shock and sudden death. The trigger effect is observed clinically; its molecular mechanism is inferred.
Systemic branch: the same deficit in brain, nerve and skeletal muscle leads to lactic acidosis, seizures and hypotonia in severe neonatal forms, and to progressive neuropathy and ataxia in long-term survivors.

Supporting detail - Mitochondrial dynamics. PPA2 "activates mitochondrial fission signaling through MTFP1-DNM1L … leading to mitochondrial proliferation or mitophagy" (Mishra et al., Autophagy 2026, PMID:40873007, HeLa cells; in vitro). This could explain mitochondrial loss, but it is not shown in patient cells. - Proposed further roles (from a review, PMID:31705601): "mtDNA maintenance; oxidative phosphorylation and generation of ATP; reactive oxygen species homeostasis; mitochondrial membrane potential regulation". - Structure. An animal-specific "W-loop" is proposed as a site for small-molecule effectors (PMID:40513929). The yeast mitochondrial PPase crystal structure is PMID:39178581. - Immune involvement. Inflammatory infiltrates are secondary. "Fibrosis may help discriminate between PPA2-related cardiomyopathy and viral myocarditis" (PMID:34400813, cached). - Omics, single-cell and functional genomics. No patient datasets were found.

7. Anatomical structures affected

Primary: heart (UBERON:0000948), myocardium (UBERON:0002349), left ventricle (UBERON:0002084). Right-ventricle (UBERON:0002080) involvement has not been documented specifically.
Secondary: brain (seizures), peripheral nerve, extraocular muscles, larynx (vocal cord paralysis; one case).
Cells: cardiac muscle cell (CL:0000746); fibroblast of cardiac tissue (CL:0002548); patient skin fibroblasts (CL:0000057) were used for diagnosis.
Subcellular: mitochondrial matrix (GO:0005759) and mitochondrial inner membrane (GO:0005743).
Laterality: fibrosis is focal or patchy and mid-myocardial (PMID:27523597, PMID:40703559).

8. Temporal development

Onset. Neonatal to about 20 months for classic SCFI. Fetal onset has been seen ("One case was diagnosed prenatally with cardiomyopathy", PMID:34400813). Milder genotypes present at school age (PMID:40486711), in adolescence (alcohol), or in adulthood:
acute heart failure after a viral illness at 58 years with homozygous p.Arg127Leu, "reversible" (PMID:41080696);
non-ischemic cardiomyopathy from age 28 needing two heart transplants (PMID:40846385).
Pattern. Often silent until an acute catastrophic event: "Two healthy and asymptomatic sisters died unexpectedly at ages 12 and 10 months" (PMID:31705601, cached). Fibrosis builds up chronically underneath, and survivors show progressive neurological disease.
Critical periods. Infancy, during febrile illness, and adolescence, at first exposure to alcohol.

9. Inheritance and population

Inheritance. Autosomal recessive (HP:0000007 "Autosomal recessive inheritance"). Expressivity is variable, within and between families. Penetrance of severe genotypes appears high; long-term penetrance of mild genotypes is unknown.
Prevalence. The estimate is 1 in 170,000, or 0.58 per 100,000, calculated from ExAC carrier frequencies (PMID:27523597). This is a calculated genotype prevalence, not observed disease prevalence. Use measure_type: UNKNOWN or record it as a carrier-frequency–derived estimate, with the cumulative carrier frequency of 0.0024.
Populations. Reported in Europeans (UK, New Zealand, France, Spain), US, Chinese (PMID:33826954), Pakistani (homozygous, PMID:41743516), and a series from Queensland, Australia (PMID:41640115). No founder effect has been established.
Consanguinity and sex ratio. Homozygous cases suggest consanguinity in some families. No sex bias has been reported.

10. Diagnostics

Genetic testing is the cornerstone.
Exome or genome sequencing, including molecular autopsy.
Diagnosis after death from a newborn dried blood spot: "highlights the utility of dried blood spots for postmortem molecular diagnosis" (PMID:33028643, cached).
PPA2 is on Genomics England PanelApp panels for sudden cardiac death, dilated/arrhythmogenic cardiomyopathy and mitochondrial disease (PanelApp).
Long-read sequencing can establish phase when one variant is de novo (PMID:33826954).
Functional test. Pyrophosphatase activity in fibroblast mitochondria is reduced (PMID:27523597).
Imaging. Cardiac MRI shows mid-myocardial or patchy late gadolinium enhancement (PMID:27523597, PMID:40703559).
Laboratory. Lactate (lactic acidosis) and troponin/BNP during crises.
ECG and Holter. VT/VF.
Histopathology. "Myocyte loss, disarray, or fibrosis was present in all individuals" (PMID:27523597, cached).
Differential diagnosis:
viral myocarditis (fibrosis favours PPA2);
channelopathies (LQTS, CPVT);
other mitochondrial cardiomyopathies (TAZ, AARS2, MRPL44, DNAJC19; see the cohort in PMID:30384889);
fatty-acid oxidation defects;
LPIN1 deficiency (also a cause of sudden death in young children, PMID:41640115);
SIDS/SUDC.
Screening. Cascade testing of siblings is recommended after an index death (PMID:41743516). No newborn screening exists.

11. Outcome and prognosis

Mortality. "Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years" (PMID:34400813, cached).
Survivors. Some survive with a defibrillator. A 13-month-old had "excellent neurological recovery" after prolonged resuscitation (PMID:39882621). Others live into their 40s with fibrosis (PMID:27523597) or reach transplant (PMID:40846385).
Prognostic factors. Residual enzyme activity, genotype, alcohol exposure, febrile illness, and the extent of fibrosis.

12. Treatment

There is no disease-modifying therapy.

Implantable cardioverter-defibrillator for primary or secondary prevention (PMID:27523597, PMID:34400813, PMID:39882621). PMID:38582264 suggests "early defibrillator implantation might prevent lethal arrhythmias". NCIT term [verify]; no cached NCIT ICD term was found. Bind NCIT:C15329 "Surgical Procedure" if the specific term is not admissible, and carry the device as a qualifier per the CLAUDE.md device pattern.
Strict alcohol avoidance, including alcohol in medicines (PMID:34400813, PMID:39882621). Recorded as counselling or behavioural modality.
Heart failure pharmacotherapy and heart transplantation. Transplant was done twice in PMID:40846385. NCIT:C15986 "Pharmacotherapy"; NCIT:C15289 for organ transplantation (taken from CLAUDE.md; confirm in the cache).
Acute care. Supportive care (NCIT:C15747 "Supportive Care"), ECMO, and correction of lactic acidosis. Aggressive treatment of fever is reasonable but unproven.
Genetic counselling. NCIT:C15240 "Genetic Counseling".
Experimental. No clinical trials found. Mitochondrial "cocktails" are unproven.

13. Prevention

Primary prevention. Carrier and cascade testing, and prenatal or preimplantation diagnosis for known familial variants.
Secondary prevention. Genetic screening of siblings, cardiac MRI and Holter, and an ICD for at-risk biallelic relatives.
Tertiary prevention. Lifelong avoidance of alcohol, fever management, and vaccination to limit viral triggers (a reasonable inference; no data).

14. Other species

No naturally occurring PPA2 disease in animals was found; OMIA was not searched directly [verify]. Mitochondrial pyrophosphatases are conserved from yeast (S. cerevisiae PPA2) to human: "Yeast PPA2 gene encodes a mitochondrial inorganic pyrophosphatase that is essential for mitochondrial function" (PMID:1648084).

15. Model organisms

Yeast (S. cerevisiae, NCBITaxon:4932 [verify]).
ppa2Δ "compromises cell viability due to the loss of mitochondria". Human wild-type PPA2 rescues it; patient alleles do not (PMID:27523598, cached).
This recapitulates the molecular and organelle defect but has no cardiac readout. Relationship to the mechanism nodes: RECAPITULATES the membrane-potential and energy-transduction nodes; FAILS_TO_RECAPITULATE fibrosis and arrhythmia.
Ageing context: PMID:31082499.
Recombinant enzyme assays (in vitro). Show thermolability and residual activity (PMID:27523597, PMID:34400813, PMID:40513929).
Patient fibroblasts (in vitro). Show reduced activity (PMID:27523597).
HeLa knockdown (in vitro). Fission and mitophagy signalling (PMID:40873007).
Mouse, zebrafish, iPSC-cardiomyocytes. No published PPA2 disease model was found. This is a knowledge gap and a strong candidate for a HUMAN_MODEL_MISMATCH / KNOWLEDGE_GAP discussion. A zebrafish search result concerned PP2Cm, an unrelated phosphatase, and should not be used.

Key sources

Cached, quotable:

PMID	Paper
27523597	Kennedy et al., AJHG 2016
27523598	Guimier et al., AJHG 2016
34400813	Guimier et al., Genet Med 2021 (PMID:35394429 is a duplicate record of the same title)
31705601	Phoon et al. 2020
33028643	Sanford et al. 2020
33826954	Zhao et al. 2021

Uncached; fetch before citing: 37249496, 37269378, 37869221, 38582264, 39882621, 40486711, 40703559, 40846385, 41080696, 41743516, 41640115, 40873007, 40513929, 42708185, 30384889, 1648084, 16300924. PMID:16300924 is negative: no PPA2 mutations were found in mtDNA depletion syndrome patients.

Web sources: - Kennedy et al. 2016 (PMC) - PubMed search: PPA2 - LOVD disease #06623 - GenCC PPA2 - PanelApp PPA2 - MalaCards SCFI

Sudden cardiac failure, infantile

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Research report: Sudden cardiac failure, infantile (SCFI; MONDO:0014973)

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species

15. Model organisms

Key sources