{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:16:42Z","timestamp":1793740602111,"version":"4.6.1"},"reference-count":6,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2023,6,3]],"date-time":"2023-06-03T00:00:00Z","timestamp":1685750400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,6,3]],"date-time":"2023-06-03T00:00:00Z","timestamp":1685750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"University of Innsbruck and Medical University of Innsbruck"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Pediatr"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We report the long way to the correct diagnosis in two teenage sisters who developed a cardiac arrest after consuming minimal amounts of alcohol. The older girl dramatically survived two cardiac arrests at the age of 14 and 15\u00a0years. She underwent an extensive examination that revealed isolated cardiac abnormalities including fibrosis, dilated cardiomyopathy and inflammation. The younger girl also had a cardiac arrest at the age of 15 and died suddenly after consuming 1\u20132 beers, 3\u00a0years after her sister\u00b4s first incident. Autopsy of the heart revealed acute myocarditis without structural alterations. Multigene panel analysis (not including <jats:italic>PPA2<\/jats:italic>) showed <jats:italic>SCN5A<\/jats:italic> and <jats:italic>CACNA1D<\/jats:italic> variants in both sisters and their healthy mother. Six years later duo exome allowed the diagnosis of an autosomal recessive PPA2-related mitochondriopathy. We discuss the molecular results and clinical picture of our patients compared to other PPA2-related cases. We highlight the diagnostic contribution of multigene panels and exome analysis. The genetic diagnosis is important for medical care and for everyday life, specifically because alcohol intake can result in cardiac arrest and should be strictly avoided.<\/jats:p><jats:p>\u00a0 \u00a0<jats:italic>Conclusion<\/jats:italic>: Duo exome sequencing clarified the diagnosis of PPA2-related mitochondriopathy in two sisters with isolated cardiac features and sudden cardiac arrest triggered by minimal amounts of alcohol.\n<jats:table-wrap><jats:table><jats:tbody>\n                    <jats:tr>\n                      <jats:td colspan=\"2\"><jats:bold>What is Known:<\/jats:bold><jats:italic>\u2022 Multigene-Panel or exome analysis is a valuable tool to identify genetic causes of hereditary cardiac arrhythmias.<\/jats:italic><jats:italic>\u2022 Variants of unknown significance can lead to misinterpretation.\u00a0PPA2-related mitochondriopathy is a very rare autosomal recessive condition that is normally fatal in infancy.<\/jats:italic><\/jats:td>\n                    <\/jats:tr>\n                    <jats:tr>\n                      <jats:td colspan=\"2\"><jats:bold>What is New:<\/jats:bold><jats:italic>\u2022\u00a0Duo exome analysis in two teeenage sisters with cardiac arrest revealed a homozygous mild PPA2 mutation as the underlying pathology restricted to the heart muscle<\/jats:italic><\/jats:td>\n                    <\/jats:tr>\n                  <\/jats:tbody><\/jats:table><\/jats:table-wrap><\/jats:p>","DOI":"10.1007\/s00431-023-05034-9","type":"journal-article","created":{"date-parts":[[2023,6,3]],"date-time":"2023-06-03T11:01:35Z","timestamp":1685790095000},"page":"3785-3788","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Only one beer can be mortal: a case report of two sisters with cardiac arrest due to a homozygous mutation in PPA2 gene"],"prefix":"10.1007","volume":"182","author":[{"given":"H\u00e9ctor Hugo","family":"Manzanilla-Romero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Schermer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Mayr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Rudnik-Sch\u00f6neborn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,6,3]]},"reference":[{"issue":"7","key":"5034_CR1","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1016\/j.hrthm.2022.03.1225","volume":"19","author":"AAM Wilde","year":"2022","unstructured":"Wilde AAM, Semsarian C, M\u00e1rquez MF et al (2022) European Heart Rhythm Association (EHRA)\/Heart Rhythm Society (HRS)\/Asia Pacific Heart Rhythm Society (APHRS)\/Latin American Heart Rhythm Society (LAHRS) expert consensus statement on the state of genetic testing for cardiac diseases. Heart Rhythm 19(7):e1\u2013e60. https:\/\/doi.org\/10.1016\/j.hrthm.2022.03.1225","journal-title":"Heart Rhythm"},{"issue":"3","key":"5034_CR2","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1016\/j.ajhg.2016.06.027","volume":"99","author":"H Kennedy","year":"2016","unstructured":"Kennedy H, Haack TB, Hartill V et al (2016) Sudden cardiac death due to deficiency of the mitochondrial inorganic pyrophosphatase PPA2. Am J Hum Genet 99(3):674\u2013682. https:\/\/doi.org\/10.1016\/j.ajhg.2016.06.027","journal-title":"Am J Hum Genet"},{"issue":"3","key":"5034_CR3","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.ajhg.2016.06.021","volume":"99","author":"A Guimier","year":"2016","unstructured":"Guimier A, Gordon CT, Godard F et al (2016) Biallelic PPA2 mutations cause sudden unexpected cardiac arrest in infancy. Am J Hum Genet 99(3):666\u2013673. https:\/\/doi.org\/10.1016\/j.ajhg.2016.06.021","journal-title":"Am J Hum Genet"},{"key":"5034_CR4","doi-asserted-by":"publisher","unstructured":"Guimier A, Achleitner MT, Moreau de Bellaing A (2021) PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families. Genet Med 23(12):2415\u20132425.\u00a0https:\/\/doi.org\/10.1038\/s41436-021-01296-6","DOI":"10.1038\/s41436-021-01296-6"},{"key":"5034_CR5","doi-asserted-by":"publisher","unstructured":"Phoon CKL, Halvorsen M, Goldstein DB et al (2020) Sudden unexpected death in asymptomatic infants due to PPA2 variants. Mol Genet Genomic Med 8(1):e1008.\u00a0https:\/\/doi.org\/10.1002\/mgg3.1008","DOI":"10.1002\/mgg3.1008"},{"issue":"19","key":"5034_CR6","doi-asserted-by":"publisher","first-page":"12168","DOI":"10.1016\/S0021-9258(18)98875-7","volume":"266","author":"M Lundin","year":"1991","unstructured":"Lundin M, Baltscheffsky H, Ronne H (1991) Yeast PPA2 gene encodes a mitochondrial inorganic pyrophosphatase that is essential for mitochondrial function. J Biol Chem 266(19):12168\u201312172","journal-title":"J Biol Chem"}],"container-title":["European Journal of Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-023-05034-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00431-023-05034-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-023-05034-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,26]],"date-time":"2023-08-26T10:04:52Z","timestamp":1693044292000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00431-023-05034-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,3]]},"references-count":6,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["5034"],"URL":"https:\/\/doi.org\/10.1007\/s00431-023-05034-9","relation":{},"ISSN":["1432-1076"],"issn-type":[{"value":"1432-1076","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,3]]},"assertion":[{"value":"31 March 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2023","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2023","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2023","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}