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

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

doi:10.1038/s41436-021-01296-6

Abstract

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.

Highlights

The role of pyrophosphatase 2 (PPA2) in mitochondrial disease has recently emerged with the discovery of biallelic PPA2 variants that cause a partial loss of gene function within families affected by recurrent sudden cardiac death in siblings. [1, 2] These two publications reported eight hypomorphic variants segregating within seven families
Clustal Omega version 1.2.4 multiple sequence alignment analysis was carried out using the following protein sequences: Homo sapiens NP_789845.1 inorganic pyrophosphatase 2; Mus musculus AAH11417.1 pyrophosphatase 2; Gallus gallus XP_004941113.1 inorganic pyrophosphatase 2; Xenopus tropicalis CAJ83623.1 inorganic pyrophosphatase 2; Danio rerio XP_005159941.1 inorganic pyrophosphatase 2; in infants aged between 1 month and 2 years, sudden cardiac Drosophila melanogaster NP_001246494.1 NUF3; Saccharomyces cerevisiae arrest following the ingestion of small amounts of alcohol in teenagers, and adults reporting acute sensitivity to alcohol
We report 34 individuals from 20 previously unreported families (Fig. 1a) with at least one member affected by rapidly progressive cardiac failure or sudden unexplained death and harboring biallelic PPA2 variants

Summary

INTRODUCTION

The role of pyrophosphatase 2 (PPA2) in mitochondrial disease has recently emerged with the discovery of biallelic PPA2 variants that cause a partial loss of gene function (hypomorphs) within families affected by recurrent sudden cardiac death in siblings. [1, 2] These two publications reported eight hypomorphic variants segregating within seven families. The role of pyrophosphatase 2 (PPA2) in mitochondrial disease has recently emerged with the discovery of biallelic PPA2 variants that cause a partial loss of gene function (hypomorphs) within families affected by recurrent sudden cardiac death in siblings. The second study [4] reported two affected sibs who died unexpectedly at 12 and 10 months of age Both were diagnosed as sudden unexpected death in infancy (SUDI), attributed to a possible cardiac arrhythmia. The activities of respiratory chain enzymes were measured for one affected individual spectrophotometrically in tissue supernatants of cardiac and skeletal muscle (Supplementary Table S2), as previously described. We report 34 individuals from 20 previously unreported families (Fig. 1a) with at least one member affected by rapidly progressive cardiac failure or sudden unexplained death and harboring biallelic PPA2 variants.

MATERIALS AND METHODS

Findings

Guimier et al 4