PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families

Anne Guimier, Melanie T. Achleitner, Anne Moreau de Bellaing, Matthew Edwards, Loïc de Pontual, Kirti Mittal, Kyla E. Dunn, Megan E. Grove, Carolyn J. Tysoe, Clémantine Dimartino, Jessie Cameron, Anil Kanthi, Anju Shukla, Florence van den Broek, Diptendu Chatterjee, Charlotte L. Alston, Charlotte V. Knowles, Laura Brett, Jan A. Till, Tessa HomfrayPaul French, Georgia Spentzou, Noha A. Elserafy, Kate S. Lichkus, Bindu P. Sankaran, Hannah L. Kennedy, Peter M. George, Alexa Kidd, Saskia B. Wortmann, Dianna G. Fisk, Tamara T. Koopmann, Muhammad A. Rafiq, Jason D. Merker, Sumith Parikh, Priyanka Ahimaz, Robert G. Weintraub, Alan S. Ma, Christian Turner, Carolyn J. Ellaway, Liza K. Phillips, David R. Thorburn, Wendy K. Chung, Sajel L. Kana, Ona M. Faye-Petersen, Michelle L. Thompson, Alexandre Janin, Karen McLeod, Ruth McGowan, Robert McFarland, Katta M. Girisha, Deborah J. Morris-Rosendahl, Anna C.E. Hurst, Claire L.S. Turner, Robert M. Hamilton, Robert W. Taylor, Fanny Bajolle, Christopher T. Gordon, Jeanne Amiel, Johannes A. Mayr, Kit Doudney

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Purpose: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. Methods: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. Results: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. Conclusion: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

Original languageEnglish
Pages (from-to)2415-2425
Number of pages11
JournalGenetics in Medicine
Issue number12
Publication statusPublished - 12-2021

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)


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