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

2021; Elsevier BV; Volume: 23; Issue: 12 Linguagem: Inglês

10.1038/s41436-021-01296-6

1530-0366

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

Endoplasmic Reticulum Stress and Disease

PurposeBiallelic 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.MethodsSynthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized.ResultsAmong 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.ConclusionWe 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.