PPA2 deficiency—a rare cause of genetic cardiomyopathy: a case report

Abstract

Background

PPA2 deficiency is a rare mitochondrial disorder associated with non-ischemic cardiomyopathy, recurrent rhabdomyolysis, and sudden cardiac death (SCD). This case attempts to highlight the diagnostic and management challenges and contribute to the growing literature on mitochondrial disorders.

Case summary

A 21-year-old female with lupus presented with chest pain that developed after hospitalisation for rhabdomyolysis during a viral illness. A cardiac MRI showed patchy late gadolinium enhancement suggestive of myocarditis. She was started on colchicine, but her symptoms persisted. Subsequent imaging revealed persistent myocardial inflammation without troponin elevation. She experienced further episodes of muscle aches and chest pain, prompting additional hospitalisations. Her sibling’s diagnosis of non-ischemic cardiomyopathy and need for cardiac transplantation raised suspicion for a genetic aetiology. Genetic testing confirmed compound heterozygosity for pathogenic PPA2 variants (c.380G > T and c.514G > A). She was managed with rhythm monitoring, alcohol avoidance, and genetic counseling.

Discussion

PPA2 deficiency should be suspected in patients with unexplained cardiomyopathy, recurrent muscle involvement, and family history of SCD. Cardiac MRI findings of subepicardial and mid-myocardial fibrosis without troponin elevation are characteristic. Early identification allows for lifestyle modifications and consideration of preventive measures like an implantable cardioverter-defibrillator to mitigate the risk of SCD. This case highlights the importance of recognising PPA2 cardiomyopathy in young patients with recurrent cardiac and muscle symptoms. Comprehensive diagnostic evaluation, including genetic testing, is crucial for identifying this rare but life-threatening condition.

Learning points.

• Beyond Typical Myocarditis: Cardiac MRI findings like LGE and myocardial oedema are not exclusive to myocarditis; their presence without elevated troponin or response to anti-inflammatory therapy should prompt consideration of rare cardiomyopathies, with tissue diagnosis and genetic testing as essential tools.

• Personalized Management Necessity: Conditions like PPA2 deficiency lack established treatment guidelines, highlighting the need for personalized interventions and specific lifestyle modifications, particularly strict alcohol avoidance, to manage these rare cardiomyopathies effectively.

Introduction

Inorganic pyrophosphatase 2 (PPA2) deficiency is an uncommon genetic condition documented in fewer than 70 cases, with only 10 individuals surviving on average until approximately 19.8 years of age. This disorder is linked to sudden cardiac arrest and heart failure, often triggered by stressors like alcohol consumption and viral infections, with most cases being diagnosed post-humously. Autopsy findings have frequently demonstrated myocarditis, cardiac inflammation, and cardiac fibrosis.^1,2 In our case report, we present two sisters harbouring pathogenic PPA2 variants, highlighting the initial diagnostic challenges along with the management of this enigmatic condition.

Summary figure

Case presentation

A 21-year-old female with a history of SLE presented with chest pain to cardiology clinic in December 2020. Two years before this presentation, she had symptoms of polyarthritis and was diagnosed with undifferentiated connective tissue disease with lupus-like features. She was noted to have a positive ANA titre of 1:640 and β2 Glycoprotein IgG. Her arthritis symptoms were initially managed by rheumatology with corticosteroids, and she was later switched to Hydroxychloroquine and Methotrexate. Three months prior to her cardiology evaluation, she was admitted with a sudden onset of severe muscle pain with CK levels of 4000 U/L. She was diagnosed with rhabdomyolysis and improved with intravenous hydration. A viral aetiology was subsequently ruled out. She developed chest pain following discharge, prompting a referral to cardiology.

Chest pain was described as ‘tightness’, with pleuritic features, and was associated with fatigue, dyspnoea and diaphoresis. She had a normal EKG and troponin T (<0.01 ng/mL) and was started empirically on Colchicine for a presumptive diagnosis of pericarditis and referred for a cardiac MRI.

Cardiac MRI (Figure 1) showed patchy late gadolinium enhancement (LGE) in the mid-myocardium and epicardium suggestive of myocarditis, without any pericardial enhancement. Left ventricular systolic function was normal. 14-day Holter monitoring did not show any arrhythmias.

Figure 1.

Cardiac MRI performed on 11/20: Normal left and right ventricular size and function. Left ventricular ejection fraction 58% by 3D assessment. Late gadolinium enhancement was seen in basal and mid-inferolateral epicardial and mid-wall segments with crescentic enhancement. The estimated late gadolinium enhancement burden visually was about 10%–15%. Apical slice showed predominantly epicardial and mid-myocardial enhancement in the anterior, mid-septal, and infero-septal segments. No evidence of endocardial or transmural enhancement. There was no evidence of pericardial inflammation. These areas of enhancement are likely consistent with inflammatory patterns. There was a small infero-basal and apical pericardial effusion. There was no evidence of infiltrative disease or prior infarction based on the late gadolinium enhancement pattern.

In March 2021, she was readmitted with rhabdomyolysis and treated for presumed lupus flare. Colchicine was discontinued due to its rare association with rhabdomyolysis. Follow-up MRI showed persistent patchy LGE and T2 imaging was suggestive of myocardial oedema. A unifying diagnosis of mitochondrial myopathy involving skeletal muscle and myocardium was considered, with intention to pursue skeletal muscle biopsy if symptoms were to recur. Physical examination was normal.

She was readmitted in August 2021 with a recurrence of chest pain. Her admission coincided with sudden onset and rapidly progressive non-ischemic cardiomyopathy in her sibling, necessitating orthotopic cardiac transplantation. Her sibling’s explanted heart pathology revealed mitochondrial necrosis and vacuolisation without inflammatory infiltrates. Genetic testing was ordered.

Investigations performed over multiple admissions are summarized in (Figure 2). Hydroxychloroquine was temporarily discontinued due to concerns for drug-induced cardiomyopathy. Ultimately, the results of genetic testing performed through the Invitae genetic testing panel revealed compound heterozygosity for two pathogenic DNA variants in the PPA2 gene in both siblings: c.380G  >  T (p. Arg127Leu), c.514G  >  A (p. Glu172Lys) (Figure 3).

Figure 2.

Diagnostic evaluations performed over multiple admissions summarized in a tabular format.

Figure 3.

Pedigree chart depicting the patient and her family.

A follow-up cardiac MRI (Figure 4) showed a persistent abnormal LGE pattern, but since the clinical syndrome was not consistent with myocarditis the imaging findings were attributed to PPA2 cardiomyopathy. An exercise treadmill test was performed to further stratify her risk of ventricular arrhythmias, which only showed rare atrial ectopy and normal haemodynamic response to exercise. A 30-day Holter monitor revealed occasional premature atrial contractions without other abnormal rhythms.

Figure 4.

Cardiac MRI performed on 8/21. Normal left and right ventricular size and function. Left ventricular ejection fraction 66% by 3D assessment. Markedly abnormal late gadolinium enhancement showing multifocal myocardial enhancement in a non-coronary distribution: involving mid-wall and epicardial basal inferolateral segment, patchy distribution along the entire septum, mid-wall of the mid and apical anterior segments. The estimated late gadolinium enhancement burden visually was about 10%–15%. These areas of enhancement are likely consistent with inflammatory patterns such as myocarditis. There is also abnormal TIR imaging (T2 weighted imaging) indicative of myocardial inflammation.

Since the genetic variant predisposes to arrhythmias and sudden cardiac death (SCD), she had been monitoring her heart rhythm using AliveCor KardiaMobile® device, with no documented arrhythmias. She was referred to a geneticist and electrophysiologist to discuss the risk of SCD and the need for a primary prevention intracardiac defibrillator (ICD). A loop recorder was considered with the prospect of ICD implantation if non-sustained ventricular arrhythmia was identified. Given the lack of symptoms at the time and preserved EF, she chose to defer this intervention. She was instructed to avoid alcohol use strictly.

In December 2024, she started experiencing symptoms of light-headedness, prompting two emergency department visits. Initial workup including EKG, troponin T, and pro-BNP was unremarkable. A 30-day Holter monitor redemonstrated occasional atrial ectopy but no ventricular arrhythmias. After careful deliberation, she underwent primary prevention ICD implantation (Medtronic™ Extravascular ICD). She has remained asymptomatic since then.

Discussion

We report a case of two sisters with PPA2 deficiency, a rare genetic cardiomyopathy. This case expands the spectrum of documented cases, as our patient initially presented with recurrent rhabdomyolysis and myopericarditis complicating diagnosis.

PPA2 loss-of-function mutations are linked to SCD, often triggered by viral infections during infancy or alcohol consumption in adolescence.¹ The enzyme PPA2 hydrolyses inorganic pyrophosphate (PPi) into orthophosphate (Pi), essential for ATP production. Deficiency leads to PPi accumulation, ATP depletion, and mitochondrial dysfunction. Infection-induced hyperthermia or alcohol metabolism may exacerbate this dysfunction, increasing SCD risk. Studies done on S. cerevisiae with PPA2 knockout strains, suggest that diminished antioxidant production, a by-product of respiratory enzyme activity, is a possible reason behind the disruption of cellular metabolism.³

Our patient carried compound heterozygous variants (c.[380G  >  T]; [514G  >  A], p.[Arg127Leu]; [Glu172Lys]), previously reported in a child who died at age two.⁴ However, their clinical presentation was seizures at 10 months, progressing to dilated cardiomyopathy and multiorgan failure by age 1, requiring several weeks of intensive care. Notably, the most prevalent pathogenic PPA2 variant, c.514G  >  A; p. (Glu172Lys), has been reported in multiple previous studies. Recombinant human PPA2 carrying this variant exhibits a 90% reduction in enzyme activity. There are no tests available to directly measure enzyme activity in individuals. Thus, neither genotype nor enzyme activity predicts disease severity, further complicating management.^3,4

PPA2 mutations exhibit an autosomal recessive inheritance pattern, with at least 25 pathogenic variants identified, exhibiting a broad spectrum of clinical severity.⁵ In our patient, AR inheritance was confirmed as both parents were carriers of the mutation. Some variants such as the p.Pro228Leu substitution, allow partial enzyme activity but can still cause life-threatening events when triggered by stressors.³ A study of 34 biallelic variants in 20 families revealed significant phenotypic variability, ranging from sudden cardiac arrest and progressive dilated cardiomyopathy to arrhythmias and neurological symptoms such as peripheral neuropathy and cerebellar ataxia.⁴ With an estimated prevalence of 1 in 171 000 according to gnomAD data, PPA2 deficiency is now included in cardiomyopathy and arrhythmia genetic panels.^1,6

The presence of cardiac fibrosis on cardiac MRI alongside strong clinical suspicion warrants PPA2 testing. Additionally, ICD implantation may mitigate SCD in individuals with biallelic PPA2 mutations. These patients should undergo regular neurological evaluation, and measures such as abstaining from alcohol and vinegar consumption and promptly treating fevers are essential for averting lethal arrhythmias. Cardiac MRI can aid in identifying subclinical disease.^1,3,4,5

In summary, the concomitant occurrence of skeletal muscle and cardiac symptoms should trigger the possibility of mitochondrial myopathy in the differential diagnosis. PPA2 cardiomyopathy is one such condition and appears to consistently have MRI findings of subepicardial and mid-myocardial fibrosis^1,3 without troponin elevation (ruling out active myocarditis).

Conclusion

Cardiac MRI findings of LGE and myocardial oedema, while classically seen in myocarditis, can also occur in mitochondrial cardiomyopathies. Lack of troponin elevation despite imaging suggestive of myopericarditis and lack of response to anti-inflammatory therapies should suggest alternate aetiologies. Tissue diagnosis and genetic testing can aid in establishing rare but pivotal diagnoses such as the above. Data on the management of PPA2 deficiency is lacking and needs personalized interventions along with strict avoidance of alcohol.

Lead author biography

I am an Internal Medicine resident at Allegheny General Hospital with a deep passion for cardiology, driven by a fascination with the field's complex physiology and the challenge of solving intricate diagnostic puzzles. My research interests centre on quality improvement, women's health, and healthcare equity. I hope to bridge the existing gaps in care and advocate for better outcomes for underserved populations through my work. I aim to contribute to the advancement of patient-centered cardiovascular care and research.

Author contributions

Sanchaya Khetrapal (Conceptualization, Writing—original draft), Aakash Tuli (Writing—review & editing), Yochitha Pulipati (Visualization), Victor Farah (Resources, Supervision), and Indu Poornima (Project administration, Supervision, Validation).

Consent: The authors confirm that consent for submission and publication of case report including images and associated text was obtained from the patient in line with COPE guidelines.

Funding: All the authors did not receive any kind of financial support or grant.

Data availability

The available data are presented within the manuscript.