{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:40:23Z","timestamp":1792521623432,"version":"4.5.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      PPA2 (pyrophosphatase 2) deficiency is a relatively newly recognized condition caused by biallelic variants in the\n                      <jats:italic toggle=\"yes\">PPA2<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Case records from published and unpublished affected individuals diagnosed with PPA2 deficiency were compiled in a retrospective cohort study of genotypes, phenotypes and clinical management protocols in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\n                      <jats:italic toggle=\"yes\">PPA2<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">PPA2<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>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\u2019 clinical management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.125.005673","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T09:00:15Z","timestamp":1792400415000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Pyrophosphatase 2 Deficiency: Clinical Presentation, Diagnosis and Management"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4956-7778","authenticated-orcid":true,"given":"Hayley","family":"Nehoff","sequence":"first","affiliation":[{"name":"Department of Cardiology, Christchurch Hospital, Waitaha, Te Whatu Ora, Aotearoa, New Zealand (H.N., I.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4652-7791","authenticated-orcid":true,"given":"Ian","family":"Crozier","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Christchurch Hospital, Waitaha, Te Whatu Ora, Aotearoa, New Zealand (H.N., I.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9940-9866","authenticated-orcid":true,"given":"Hilary","family":"Vernon","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology, Johns Hopkins Hospital, Baltimore, MD (H.V., W.R.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5737-2624","authenticated-orcid":true,"given":"Christine","family":"James","sequence":"additional","affiliation":[{"name":"Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo (C.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1509-5191","authenticated-orcid":true,"given":"Ana I.","family":"Fern\u00e1ndez-\u00c1vila","sequence":"additional","affiliation":[{"name":"Cardiology Department, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, IiSGM (A.I.F.-A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9830-9517","authenticated-orcid":true,"given":"Michael","family":"Bowes","sequence":"additional","affiliation":[{"name":"Alder Hey Children\u2019s NHS Foundation Trust, Liverpool, United Kingdom (M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4175-1487","authenticated-orcid":true,"given":"Esther","family":"Gomez-Gonzalez","sequence":"additional","affiliation":[{"name":"Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain (E.G.-G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0956-071X","authenticated-orcid":true,"given":"Colin","family":"Phoon","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Hassenfeld Children\u2019s Hospital at NYU Langone (C.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9189-6408","authenticated-orcid":true,"given":"Kristy","family":"DiLoreto","sequence":"additional","affiliation":[{"name":"Department of Genomic Health, Geisinger Health System, Danville, PA (K. DiLoreto)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9303-0978","authenticated-orcid":true,"given":"Martin E.","family":"Matsumura","sequence":"additional","affiliation":[{"name":"Heart and Vascular Institute, Geisinger Health System, Danville, PA (M.E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5598-8840","authenticated-orcid":true,"given":"D\u00e9sir\u00e9e Y.","family":"van Haaften-Visser","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Lysosomal &amp; Metabolic Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands (D.Y.v.H.-V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6367-0752","authenticated-orcid":true,"given":"Cameron","family":"Seaman","sequence":"additional","affiliation":[{"name":"Division Pediatric Cardiology, Perth Children\u2019s Hospital, Nedlands, WA, Australia (C.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8477-530X","authenticated-orcid":true,"given":"Matthew R.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Clinical Genetics &amp; Genomics Laboratory, Royal Brompton Hospital, Guy\u2019s and St Thomas\u2019 NHS Foundation Trust (M.R.E., D.J.M.-R.)."},{"name":"Royal Brompton Hospital, Guy\u2019s and St Thomas\u2019 NHS Foundation Trust, London, United Kingdom (M.R.E., D.J.M.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7780-4707","authenticated-orcid":true,"given":"Deborah J.","family":"Morris-Rosendahl","sequence":"additional","affiliation":[{"name":"Clinical Genetics &amp; Genomics Laboratory, Royal Brompton Hospital, Guy\u2019s and St Thomas\u2019 NHS Foundation Trust (M.R.E., D.J.M.-R.)."},{"name":"Royal Brompton Hospital, Guy\u2019s and St Thomas\u2019 NHS Foundation Trust, London, United Kingdom (M.R.E., D.J.M.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8834-6781","authenticated-orcid":true,"given":"Kathleen","family":"Simonetti","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology, Columbia University (K.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4735-5223","authenticated-orcid":true,"given":"Alyssa L.","family":"Rippert","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora (A.L.R., R.C.A.-N., C.T., E.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8243-7123","authenticated-orcid":true,"given":"Rebecca C.","family":"Ahrens-Nicklas","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora (A.L.R., R.C.A.-N., C.T., E.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra","family":"Tormey","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora (A.L.R., R.C.A.-N., C.T., E.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Bogush","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora (A.L.R., R.C.A.-N., C.T., E.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6353-1170","authenticated-orcid":true,"given":"Aaina","family":"Kochhar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Section of Clinical Genetics &amp; 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