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Case Reports
. 2025 Aug 20;30(24):104676.
doi: 10.1016/j.jaccas.2025.104676.

Nonischemic Cardiomyopathy in Adult-Onset PPA2-Deficient Mitochondrial Disease

Emilie Théberge  1 , Jillianne Code  2 , John K Khoo  3 , Chi Lai  4 , Andrew Ignaszewski  5 , Sean Virani  5 , Mustafa Toma  5 , Thomas M Roston  5 , Tara Sedlak  5 , Anna Lehman  6
Affiliations
Case Reports

Nonischemic Cardiomyopathy in Adult-Onset PPA2-Deficient Mitochondrial Disease

Emilie Théberge et al. JACC Case Rep. .

Abstract

Background: Nonischemic cardiomyopathy (NICM) can be caused by single-gene mutations, including genes such as inorganic pyrophosphatase 2 (PPA2) with multisystem effects.

Case summary: A 28-year-old woman presenting with respiratory symptoms was discharged with a diagnosis of decompensated idiopathic NICM. Her NICM progressively worsened, and the patient underwent a heart transplant at the age of 38 and again at the age of 42. At age 47, genetic testing confirmed 2 mutations in the PPA2 gene that had caused her NICM.

Discussion: This patient is to our knowledge the oldest published to date (48 years) presenting with cardiac symptoms who has PPA2 deficiency, a mitochondrial disease characterized by sudden cardiac death in infancy.

Take-home message: This case exemplifies the utility of employing genetic testing early in the diagnostic workup of NICM before applying the designation "idiopathic."

Keywords: PPA2; cardiomyopathy; mitochondrial disease; monogenic.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Roston has received honoraria from Cardurion Pharma and Solid Biosciences (advisory board). Dr Sedlak has received honoraria for speaking engagements and advisory boards from Eli-Lilly, Novo Nordisk, Novartis, KYE Pharmaceuticals, Amgen, Sanofi, Pfizer, Bayer, Pendopharm, CCRN, and CPD Network. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Visual Summary
Visual Summary
Timeline Summary of the Key Events in the Patient's Clinical Course cMRI = cardiac magnetic resonance imaging; EF = ejection fraction; ICD = implantable cardioverter-defibrillator; LVAD = left ventricular assist device.
Figure 1
Figure 1
Right Ventricle Endomyocardial Biopsy (Age 29 Years) Endomyocardial biopsy of the right ventricle (H&E stain; 100× magnification) shows focal interstitial fibrosis (asterisks) and hypertrophic cardiomyocytes with hyperchromatic and dysmorphic nuclei (arrows). Very little fat is present in the biopsy (not shown in this photomicrograph). There was no convincing histologic evidence of acute myocarditis, granulomatous inflammation, vasculitis, ischemia or thrombosis, glycogen storage disease, amyloid, or microorganisms/viral inclusions. A rare collection of mature adipocytes was identified; however, the extent of “marbling” was considered insufficient for a diagnosis of arrhythmogenic right ventricular cardiomyopathy. These findings are compatible with a cardiomyopathic process. H&E = hematoxylin and eosin.
Figure 2
Figure 2
Delayed-Enhancement Cardiac Magnetic Resonance Imaging Scans Delayed-enhancement cardiac magnetic resonance imaging scans from 2006 when the patient was age 29 (A to C) and 2010 when she was age 33 (D to H). The red arrows indicate late gadolinium enhancement. (A and D) Short-axis basal slice; (B and E) short-axis mid slice; (C and F) short-axis apical slice; (G) long-axis 2-chamber slice; (H) long-axis 4-chamber slice.
See this image and copyright information in PMC

References

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