TY - JOUR
T1 - PPA2-associated sudden cardiac death
T2 - extending the clinical and allelic spectrum in 20 new families
AU - Guimier, Anne
AU - Achleitner, Melanie T.
AU - de Bellaing, Anne Moreau
AU - Edwards, Matthew
AU - de Pontual, Loïc
AU - Mittal, Kirti
AU - Dunn, Kyla E.
AU - Grove, Megan E.
AU - Tysoe, Carolyn J.
AU - Dimartino, Clémantine
AU - Cameron, Jessie
AU - Kanthi, Anil
AU - Shukla, Anju
AU - van den Broek, Florence
AU - Chatterjee, Diptendu
AU - Alston, Charlotte L.
AU - Knowles, Charlotte V.
AU - Brett, Laura
AU - Till, Jan A.
AU - Homfray, Tessa
AU - French, Paul
AU - Spentzou, Georgia
AU - Elserafy, Noha A.
AU - Lichkus, Kate S.
AU - Sankaran, Bindu P.
AU - Kennedy, Hannah L.
AU - George, Peter M.
AU - Kidd, Alexa
AU - Wortmann, Saskia B.
AU - Fisk, Dianna G.
AU - Koopmann, Tamara T.
AU - Rafiq, Muhammad A.
AU - Merker, Jason D.
AU - Parikh, Sumith
AU - Ahimaz, Priyanka
AU - Weintraub, Robert G.
AU - Ma, Alan S.
AU - Turner, Christian
AU - Ellaway, Carolyn J.
AU - Phillips, Liza K.
AU - Thorburn, David R.
AU - Chung, Wendy K.
AU - Kana, Sajel L.
AU - Faye-Petersen, Ona M.
AU - Thompson, Michelle L.
AU - Janin, Alexandre
AU - McLeod, Karen
AU - McGowan, Ruth
AU - McFarland, Robert
AU - Girisha, Katta M.
AU - Morris-Rosendahl, Deborah J.
AU - Hurst, Anna C.E.
AU - Turner, Claire L.S.
AU - Hamilton, Robert M.
AU - Taylor, Robert W.
AU - Bajolle, Fanny
AU - Gordon, Christopher T.
AU - Amiel, Jeanne
AU - Mayr, Johannes A.
AU - Doudney, Kit
N1 - Funding Information:
This work was supported by MSD Avenir (Devo-Decode) (JA), the Austrian Science Fund (FWF) [I 4695-B] (JAM) and the ERA PerMed project PerMiM (Austrian Science Fund FWF, I4704-B) (SBW). C.L.A., R.M. and R.W.T. are supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z). R.M. and R.W.T. are supported by the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, Newcastle University Centre for Aging and Vitality (supported by the Biotechnology and Biological Sciences Research Council and Medical Research Council [G016354/1]), the National Institute of Health Research (NIHR) Biomedical Research Centre in Age and Age Related Diseases award to the Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation, the Lily Foundation and the NHS Highly Specialised Service for Rare Mitochondrial Disorders. C.L.A. is supported by the NIHR Post-Doctoral Fellowship (PDF-2018-11-ST2-021). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. We acknowledge the research genome teams at Nicklaus Children’s Hospital, Miami, Florida, USA and at the Rady Children’s hospital, San Diego, California, USA. We thank the Māia Health Foundation (NZ) for experimental reagents and publication support. This research was supported by the Australian Genomics Health Alliance (Australian Genomics) project, funded by an NHMRC Targeted Call for Research grant (GNT1113531; DRT). M.T., O.F.P. and A.H. are supported by the National Human Genome Research Institute (NHGRI; U01HG007301).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41436-021-01296-6
DO - 10.1038/s41436-021-01296-6
M3 - Article
AN - SCOPUS:85111701867
SN - 1098-3600
VL - 23
SP - 2415
EP - 2425
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 12
ER -