Pyrophosphatase 2 Deficiency: Clinical Presentation, Diagnosis and Management

BACKGROUND: PPA2 (pyrophosphatase 2) deficiency is a relatively newly recognized condition caused by biallelic variants in the PPA2 gene. The gene encodes the mitochondrial enzyme PPA2, involved in the production of orthophosphate in the mitochondrial matrix. Affected individuals typically present with sudden cardiac death or acute heart failure following common viral illnesses in infants and toddlers, or following exposure to small amounts of alcohol as teenagers. The condition has a high mortality rate in these situations. Here, we explore the clinical presentations and current management of these patients with a view to guiding future emergency clinical management of cases. METHODS: Case records from published and unpublished affected individuals diagnosed with PPA2 deficiency were compiled in a retrospective cohort study of genotypes, phenotypes and clinical management protocols in individuals with biallelic (likely) pathogenic PPA2 variants. RESULTS: We collated 93 affected individuals from 53 families, 14 of which have not previously been reported. Patient presentation is invariably acute, often associated with fatigue, vomiting, seizures and collapse. Generally, presenting individuals received standard emergency management with cardiopulmonary resuscitation and appropriate management of arrhythmia, and here we present compiled clinical management protocols for emergency and ongoing treatment of PPA2-deficient patients. A pronounced inheritance rate of pathogenic alleles from carrier parents is noted, and further research is warranted to confirm and investigate any selective advantage for gametes carrying pathogenic PPA2 variants. CONCLUSIONS: PPA2 deficiency has a high mortality rate following exposure to common childhood viruses in children around and under the age of 3 and in teenagers exposed to ethanol. We have presented current therapeutic approaches gathered from a worldwide survey of clinicians treating their patients, possible pathogenic mechanisms and inheritance peculiarities of the condition and provide a comprehensive review of the current recommendations surrounding patients’ clinical management.

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Journal
Circulation Genomic and Precision Medicine
Published
2026-10-19
DOI
https://doi.org/10.1161/circgen.125.005673
Primary Topic
Mitochondrial Function and Pathology
Type
article
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article

Pyrophosphatase 2 Deficiency: Clinical Presentation, Diagnosis and Management

Eric S. Silver, Kristy DiLoreto, Désirée Y. van Haaften–Visser, Colin K. L. Phoon et al.
Circulation Genomic and Precision Medicine
Mitochondrial Function and Pathology
article

Pyrophosphatase 2 Deficiency: Clinical Presentation, Diagnosis and Management

Eric S. Silver, Kristy DiLoreto, Désirée Y. van Haaften–Visser, Colin K. L. Phoon, Martin E. Matsumura, Christine James, Saskia Brigitte Wortmann, Amy C. Goldstein, Kit Doudney, Ian Crozier, Robert Gideon Weintraub, Alicia M. Kamsheh, Michael Bowes, Deborah J. Morris-Rosendahl, Hayley L. Nehoff, Robert McFarland, Cameron S. Seaman, Hilary J. Vernon, Jan A. Till, Alyssa L. Rippert, Aaina Kochhar, Johannes Adalbert Mayr, Johan L.K. Van Hove, Warren A. Zuckerman, Esther González-López, Rebecca C. Ahrens‐Nicklas, John F. Pearson, Kathryn C. Chatfield, Emily Bogush, Ana Isabel Fernández, Matthew Edwards, W. Reid Thompson, Kathleen Simonetti, Cassandra Tormey, Bridget A. Leone
article en

Abstract

BACKGROUND: PPA2 (pyrophosphatase 2) deficiency is a relatively newly recognized condition caused by biallelic variants in the PPA2 gene. The gene encodes the mitochondrial enzyme PPA2, involved in the production of orthophosphate in the mitochondrial matrix. Affected individuals typically present with sudden cardiac death or acute heart failure following common viral illnesses in infants and toddlers, or following exposure to small amounts of alcohol as teenagers. The condition has a high mortality rate in these situations. Here, we explore the clinical presentations and current management of these patients with a view to guiding future emergency clinical management of cases. METHODS: Case records from published and unpublished affected individuals diagnosed with PPA2 deficiency were compiled in a retrospective cohort study of genotypes, phenotypes and clinical management protocols in individuals with biallelic (likely) pathogenic PPA2 variants. RESULTS: We collated 93 affected individuals from 53 families, 14 of which have not previously been reported. Patient presentation is invariably acute, often associated with fatigue, vomiting, seizures and collapse. Generally, presenting individuals received standard emergency management with cardiopulmonary resuscitation and appropriate management of arrhythmia, and here we present compiled clinical management protocols for emergency and ongoing treatment of PPA2-deficient patients. A pronounced inheritance rate of pathogenic alleles from carrier parents is noted, and further research is warranted to confirm and investigate any selective advantage for gametes carrying pathogenic PPA2 variants. CONCLUSIONS: PPA2 deficiency has a high mortality rate following exposure to common childhood viruses in children around and under the age of 3 and in teenagers exposed to ethanol. We have presented current therapeutic approaches gathered from a worldwide survey of clinicians treating their patients, possible pathogenic mechanisms and inheritance peculiarities of the condition and provide a comprehensive review of the current recommendations surrounding patients’ clinical management.

Circulation Genomic and Precision Medicine
Royal Children's Hospital (AU), Children's Hospital of Philadelphia (US), Western Michigan University (US), Washington University in St. Louis (US), Paracelsus Medical University (AT), Princess Margaret Hospital for Children (AU), Erasmus MC (NL), Harefield Hospital (GB), Hospital General Universitario Gregorio Marañón (ES), Alder Hey Children's NHS Foundation Trust (GB), Children's Hospital Colorado (US), Royal Brompton Hospital (GB), Hospital Universitario Puerta de Hierro Majadahonda (ES), Wellcome Centre for Mitochondrial Research (GB), Stony Brook Children's Hospital (US), Johns Hopkins Hospital (US), University of Colorado Anschutz Medical Campus (US), Geisinger Health System (US), University of Otago (NZ), University of Colorado Denver (US)
Openalex Percentile: Top 23%
Mitochondrial Function and Pathology
DOISourceOpenAlex
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