Biallelic variants in gene cause a rare but lethal mitochondrial disorder. We describe the first four cases reported in Spain of PPA2 disease in two unrelated families. We have conducted a revision of the clinical history, necropsies, and postmortem genetic testing from probands, and clinical evaluation, genetic testing and blood transcript analysis in family members. All the cases harbored biallelic variants in compound heterozygous status. Two brothers from family 1 suffered sudden death after a small first intake of alcohol in 2013 and 2022. The sister remains alive but affected with cardiomyopathy, extensive scar on cardiac imaging, and high sensitivity to alcohol intake. The three siblings carried c.290A > G (p.Glu97Gly) novel missense variant and c.513C > T (p.Cys171 = ) altering splicing site variant, both probably leading to mRNA degradation based on in-silico and transcript analyses. A teenager from family 2 suffered sudden death after a small intake of alcohol in 2018 and carried c.683C > T (p.Pro228Leu) missense and c.980_983del (p.Gln327fs) novel frameshift variant, both probably leading to abnormal protein structure. All cases were asymptomatic until adolescence. Furthermore, the sister in family 1 has survived as an asymptomatic adult. disease can manifest as cardiac arrest in the young, especially after alcohol exposure. Our results show that deficiency can be related to different pathogenicity mechanisms such as abnormal protein structure but also mRNA decay caused by synonymous or missense variants. Strict avoidance of alcohol consumption and early defibrillator implantation might prevent lethal arrhythmias in patients at risk.

中文翻译：

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两个不相关家庭在新的 PPA2 突变背景下因少量饮酒引发心源性猝死

基因的双等位基因变异会导致一种罕见但致命的线粒体疾病。我们描述了西班牙报告的前四例 PPA2 疾病，发生在两个不相关的家庭中。我们对先证者的临床病史、尸检和死后基因检测进行了修订，并对家庭成员进行了临床评估、基因检测和血液转录本分析。所有病例均含有复合杂合状态的双等位基因变异。家庭 1 的两个兄弟在 2013 年和 2022 年首次少量饮酒后突然死亡。妹妹仍然活着，但患有心肌病、心脏影像上有广泛的疤痕，并且对酒精摄入高度敏感。这三个兄弟姐妹携带 c.290A > G (p.Glu97Gly) 新型错义变体和 c.513C > T (p.Cys171 = ) 剪接位点变体，根据计算机模拟和转录本分析，这两种变体都可能导致 mRNA 降解。家庭2的一名青少年在2018年少量饮酒后猝死，携带c.683C > T (p.Pro228Leu)错义和c.980_983del (p.Gln327fs)新移码变异，这两种变异都可能导致蛋白质结构异常。所有病例直到青春期都没有症状。此外，1号家庭的妹妹作为无症状成年人幸存下来。这种疾病在年轻人中可能表现为心脏骤停，尤其是在接触酒精后。我们的结果表明，缺陷可能与不同的致病机制有关，例如异常的蛋白质结构，以及由同义或错义变异引起的 mRNA 衰减。严格避免饮酒和早期植入除颤器可能会预防高危患者发生致命性心律失常。