Acute heart failure in adulthood as the first manifestation of a homozygous pyrophosphatase 2 variant, expanding the phenotypic spectrum: a case report

Abstract

Background

PPA2 encodes the mitochondrial inorganic pyrophosphatase 2 enzyme, essential for energy metabolism. Biallelic loss-of-function variants have been associated with early-onset sudden cardiac death and cardiomyopathy, typically in infants or adolescents following minimal alcohol intake. Adult-onset presentations are extremely rare.

Case summary

We report a 58-year-old woman presenting with acute heart failure following a febrile viral infection. Echocardiography revealed severe left ventricular systolic dysfunction. Cardiac MRI showed diffuse myocardial fibrosis. Genetic testing identified a homozygous pathogenic variant in PPA2 (p.Arg127Leu). Family history included two brothers who died suddenly in adolescence, one after minimal alcohol intake. Our patient, after 6 months of follow-up with treatment for heart failure, had her systolic function normalized. However, an implantable cardioverter-defibrillator was placed due to extensive fibrosis and non-sustained ventricular tachycardia and the high risk of sudden death associated with the disease.

Conclusion

This is the first known case of PPA2-related cardiomyopathy presenting with reversible heart failure in adulthood, highlighting an expanded phenotypic spectrum. Recognizing adult-onset cases is crucial, as it provides an opportunity to manage these patients in a personalized manner and to prevent complications, decompensation, or fatal outcomes.

Learning points.

• Cardiomyopathy related to PPA2 deficiency can present in adulthood and should be systematically included in cardiomyopathy gene panels currently available.

• A family history of sudden death related to alcohol consumption should raise the possibility of mitochondrial cardiomyopathy due to PPA2 deficiency.

• Identifying PPA2 deficiency enables the implementation of specific preventive strategies, such as avoiding alcohol intake, managing infections, and implanting a defibrillator.

Introduction

Inorganic pyrophosphatase 2 (PPA2) is an enzyme encoded by nuclear DNA and is crucial in mitochondrial maintenance and function. It hydrolyzes inorganic pyrophosphate (PPi) into two phosphate (Pi) molecules essential for energy metabolism and provides a substrate for adenosine triphosphate (ATP) synthesis.^1,2 PPA2 is involved in numerous cellular reactions, such as the synthesis of DNA, RNA, proteins, polysaccharides, and lipids.²  PPA2 mutations have significant consequences, particularly in energy-demanding organs, such as the heart.³ A literature review has identified 69 cases^1–13 (Table 1). Sudden death during childhood or in adolescence after consuming minimal amounts of alcohol is the most common phenotypic manifestation. In some cases, it manifests as heart failure, cardiogenic shock, dilated cardiomyopathy, arrhythmia, or alcohol intolerance. No deaths have been reported during adulthood. An adulthood onset is rare. This enzyme is found in all kingdoms of life, and its deficiency manifests in the first years of life.

Table 1.

Summary of the relevant characteristics of the published cases

	Kennedy et al.1	Guimier et al.2	Guimier et al.3	Phoon et al.4	Graham et al.5	Gómez et al.6	Genthe et al.7	Zhao et al.8	Manzanilla et al.9	Vasilescu et al.10	Sanford et al.11	Harris et al.12	Khetrapal et al.13	Total
Cases	10	7	34	2	1	4	2	1	2	2	1	1	2	69
Families	4	3	20	1	1	2	1	1	1	1	1	1	1	38
Median age at onset (range)	10.95 years (3 days–38 years)	14 months (4–20 months)	4.57 years (2 days–19 years)	11 months (10–12 months)	19 years	15.75 years (13–17 years)	15 years (14–16 years)	11 months	14.5 years (14–15 years)	6.5 months (8–5 months)	42 days	8 years	21 years	7.95 years (2 days–38 years)
Deceased/alive	8/2	7/0	28/6	2/0	1/0	3/1	1/1	0/1	2/0	2/0	1/0	0/1	0/2	55/14
Virus	3	2	14	1	ND	ND	ND	1	1	2	1	1	ND	26
Alcohol intolerance	4	ND	7	ND	1	4	1	ND	2	ND	ND	ND	ND	19
Fibrosis/analysed	5/10	3/6	15/17	0/1	1/1	3/4	1/2	1/1	1/1	2/2	0/1	0	1/2	33/48
Sudden cardiac arrest	3	6	15	2	1	3	1	0	2	0	1	1	0	35
Heart failure	6	2	13	0	0	0	0	1	0	2	0	0	1	25

ND, not determined.

Summary figure

We present a previously undescribed manifestation of the disease with adult onset, characterized by cardiomyopathy with severe left ventricular (LV) systolic dysfunction and functional recovery during follow-up.

Case presentation

A 58-year-old woman presented with acute heart failure, progressive dyspnoea, orthopnea, and lower limb oedema following a viral infection. Initial assessment revealed a nondilated left ventricle with severe left ventricular (LV) dysfunction on echocardiogram (Figure 1B; Supplementary material online, Video S1). Laboratory tests showed N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels of 8925 (normal, <150) pg/ml. Cardiac magnetic resonance imaging (MRI) revealed extensive late gadolinium enhancement at meso- and epicardial levels, affecting all LV segments. T1 mapping values were >1200 ms in virtually all segments (normal, 950–1050) ms. T2 mapping values were 52.4 ms (normal, 52.5 ± 2.5 ms), not indicative of myocardial oedema; thus, acute myocarditis was ruled out (Figure 2A–2D). Upon admission, an episode of non-sustained monomorphic ventricular tachycardia (NSMVT) was identified on monitoring.

Figure 1.

(A) Electrocardiography shows sinus tachycardia with T wave inversion on leads V5 and V6. (B) Echocardiogram at admission. The apical two-chamber view shows an ejection fraction of 33% using the Simpson’s biplane method.

Figure 2.

Cardiac magnetic resonance images: (A) Corresponding late gadolinium enhancement (LGE) at the short axis shows diffuse subepicardial and midwall enhancement. (B) LGE in a horizontal long-axis image shows diffuse subepicardial and midwall enhancement. (C) T1 mapping of a short-axis image of the mid-left ventricle shows elevated values (>1200 ms; normal range 950–1050 ms). (D) T2 mapping of the mid-left ventricle in a short-axis image shows normal values (52.4 ms; normal range 52.5 ± 2.5 ms).

Given the severe heart failure, she was prescribed sacubitril-valsartan, spironolactone, empagliflozin, and bisoprolol. A genetic panel for cardiomyopathy analysed 227 genes and detected a homozygous pathogenic p.Arg127Leu variant in the PPA2 gene. Six months after the symptom onset, she was asymptomatic, with normal NT-proBNP levels (90 pg/ml). An echocardiogram confirmed the recovery of LV systolic function (Figure 3; Supplementary material online, Video S2).

Figure 3.

Follow-up echocardiogram: the apical four-chamber view shows an ejection fraction of 58% using the Simpson’s biplane method.

Her parents were not consanguineous. Her father died at the age of 83 from pneumonia. Her 80-year-old mother has no medical history. She had two brothers who died suddenly. The first brother, who had no previous medical history, died at the age of 17 after consuming a small amount of alcohol and experiencing cardiorespiratory arrest. An autopsy was not performed. Several years later, her other brother, aged 19 years with no medical history, died following cardiorespiratory arrest. The autopsy revealed dilated cardiomyopathy. He never consumed alcohol (Figure 4). She stopped drinking alcohol in her teens after experiencing intense precordial pain and paresthaesia following her first exposure to alcohol. As an adult, she has resumed drinking small amounts without discomfort.

Figure 4.

The patient’s pedigree is presented. The individual indicated by an arrow represents the patient.

Understanding the pathological substrate led to recommendations, such as avoiding alcohol intake, vinegar, and certain medical drugs that could negatively affect mitochondrial function. Febrile processes should be actively treated. Treatment to preserve mitochondrial function should be started, involving vitamin B complex, vitamin C, and coenzyme Q10.

She was referred for neurological evaluation to rule out neurological involvement and receive follow-up care. She received genetic counselling, and genetic testing for the variant was recommended for her first-degree relatives. Given the cardiac MRI findings of extensive fibrosis, the NSMVT episode, and the high prevalence of sudden death in documented cases, a defibrillator was implanted for the primary prevention of sudden death.

Discussion

In 2016, biallelic loss-of-function variants in PPA2 were initially reported in children and adolescents who died suddenly.^1,2 This condition is known for having high mortality.^3–11 Its clinical spectrum ranges from sudden death or rapidly progressive heart failure in children to sudden death triggered by minimal alcohol intake in adolescents.^3–12 Among all the documented cases, >85% have resulted in sudden death or fatal acute heart failure. Most cases occurred before the age of 2 years, and some cases in adolescents have been linked to alcohol consumption.^5–7,9 In other cases, viral infections have also been recognized as potential triggers.^1–3,10,12

Mitochondria play a central role in the immune system’s defence against viral infections. Viruses can cause deterioration or decompensation in mitochondrial disorders, as in our patient. However, the role of alcohol in patients with PPA2 deficiency is still unclear.^1,3 Alcohol metabolism generates PPi, a molecule existing in high concentrations in these patients owing to PPA2 deficiency. The increase in PPi concentration contributes to reaching a threshold concentration at which it acts as a competitive inhibitor of adenosine diphosphate/ATP translocase. Consequently, energy intake is reduced, promoting cell death.^1,2

Sudden death is the most common clinical manifestation. Among the published cases, only 14 patients are still alive (Table 1), exhibiting various phenotypes, ranging from alcohol intolerance to fulminant heart failure requiring transplantation.^2,3,6,13 Only a few patients exhibited additional features of mitochondrial disease, some of which appeared after adulthood.³ External factors may influence disease progression.³ Moreover, no relationship has been established between lower enzyme activity levels and severe phenotypes.⁶ The p.Arg127Leu variant has very low enzyme activity level and is not invariably associated with more severe clinical presentations.³ In this patient, the disease manifested in adulthood. She presented severe acute heart failure, LV dysfunction, extensive fibrosis, and NSMVT. However, the outcome was favourable, with recovery of LV systolic function. Homozygous variants with relatively high residual activity (p.Gly229Val) have been reported in sudden death cases as early as 3 months of age.³ Unfortunately, no tests can directly measure enzyme activity in patients. Likewise, other unknown factors may influence the penetrance or expressivity of the disease, which would help us understand its different clinical manifestations.⁷

Histological studies have revealed myocarditis, necrosis, or fibrosis.^1,2 Fibrosis is the most frequent histological or cardiac MRI finding.³ Of the 48 reported cases, 33 had myocardial fibrosis (Table 1). However, whether fibrosis serves as the substrate for arrhythmias remains unclear. Some patients with extensive fibrosis had no arrhythmias, whereas cardiac arrest occurred in others with normal histological findings.⁶

Implementing the genetic testing and counselling recommendations outlined in the 2022 ESC Guidelines for managing patients with ventricular arrhythmias and preventing sudden cardiac death¹⁴ and the 2023 ESC Guidelines for managing cardiomyopathies¹⁵ was essential for the diagnosis and management of our patient, who presented symptoms in adulthood. Given the family history of sudden death, suggesting a genetic origin, and the risk of sudden death or ventricular arrhythmias associated with ventricular dysfunction and NSMVT, a genetic test was requested. The results facilitated the diagnosis and supported the recommendation of cascade testing for first-degree relatives.

Conclusion

This report presents three siblings with different phenotypic expressions. Two of them died suddenly in adolescence, and the present case shows additional aspects, broadening the phenotypic spectrum described to date. This case manifests cardiomyopathy and reversible heart failure in adulthood. Thus, this case emphasizes the importance of identifying the precise molecular defect, which enabled us to provide specific recommendations to improve prognosis and prevent sudden death.

Lead author biography

Dr. Natalia Marrero is a specialist in cardiology at Hospital Universitario Materno Infantil de Gran Canaria, Spain. She completed her training in endocrinology at Hospital Universitario Marqués de Valdecilla, Cantabria, Spain, and her training in cardiology at Hospital Universitario Insular Materno Infantil de Gran Canaria, Spain. Her main interest is in inherited cardiovascular diseases, and she currently works in the Inherited Cardiac Disease Unit and Heart Failure Unit at Hospital Universitario Insular Materno Infantil de Gran Canaria, Spain.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

Consent: The author/s confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidelines.

Funding: None declared.

Data availability

The data that support the findings of this case report are available in the article and in its online Supplementary material.