Only one beer can be mortal: a case report of two sisters with cardiac arrest due to a homozygous mutation in PPA2 gene

Abstract

We report the long way to the correct diagnosis in two teenage sisters who developed a cardiac arrest after consuming minimal amounts of alcohol. The older girl dramatically survived two cardiac arrests at the age of 14 and 15 years. She underwent an extensive examination that revealed isolated cardiac abnormalities including fibrosis, dilated cardiomyopathy and inflammation. The younger girl also had a cardiac arrest at the age of 15 and died suddenly after consuming 1–2 beers, 3 years after her sister´s first incident. Autopsy of the heart revealed acute myocarditis without structural alterations. Multigene panel analysis (not including PPA2) showed SCN5A and CACNA1D variants in both sisters and their healthy mother. Six years later duo exome allowed the diagnosis of an autosomal recessive PPA2-related mitochondriopathy. We discuss the molecular results and clinical picture of our patients compared to other PPA2-related cases. We highlight the diagnostic contribution of multigene panels and exome analysis. The genetic diagnosis is important for medical care and for everyday life, specifically because alcohol intake can result in cardiac arrest and should be strictly avoided. Conclusion: Duo exome sequencing clarified the diagnosis of PPA2-related mitochondriopathy in two sisters with isolated cardiac features and sudden cardiac arrest triggered by minimal amounts of alcohol. What is Known:• Multigene-Panel or exome analysis is a valuable tool to identify genetic causes of hereditary cardiac arrhythmias.• Variants of unknown significance can lead to misinterpretation. PPA2-related mitochondriopathy is a very rare autosomal recessive condition that is normally fatal in infancy. What is New:• Duo exome analysis in two teeenage sisters with cardiac arrest revealed a homozygous mild PPA2 mutation as the underlying pathology restricted to the heart muscle

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

“…Max LOD = 2.8 (estimated) 87 LV traits – PPA2 Inorganic pyrophosphatase DCM/SCD 7 (refs. 7 , 8 , 89 – 93 ) 32 53 Missense Exome (21 trio, 3 proband). Panel (8 trio) – – PPP1R13L NF-κB and p53 inhibitor DCM 6 (refs.…”

PPA2 Deficiency in 2 Sisters

“…The paternally inherited variant, PPA2 c.683 C>T (p.P228L), has been described in 14 individuals with PPA2 deficiency and has an estimated population frequency of 0.0043% (gnomAD: 66/152018, no homozygotes). 2 , 7 , 8 , 9 , 11 In vitro analysis has shown that this variant retains 24% to 28% residual PPA2 activity. 2 Of the 14 individuals reported with this variant, 4 died in infancy, 5 died following alcohol consumption, and 5 are currently living with hypersensitivity to alcohol ( Table 2 ).…”

“… 2 Of the 14 individuals reported with this variant, 4 died in infancy, 5 died following alcohol consumption, and 5 are currently living with hypersensitivity to alcohol ( Table 2 ). 2 , 7 , 8 , 9 Three living individuals have myocardial fibrosis, and 1 has a purely neurologic presentation of progressive cerebellar ataxia. 7 The maternally inherited variant, c.987 G>A (p.W329∗), is a novel nonsense sequence variant resulting in truncation of the last 6 amino acids of the PPA2 protein.…”

“…Biallelic loss-of-function variants in the inorganic pyrophosphatase 2 gene ( PPA2 ) have been reported in individuals with sudden cardiac death (SCD), often triggered by viral infection in infancy or by alcohol consumption in adolescence. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 The PPA2 protein hydrolyzes pyrophosphate (PPi) into inorganic phosphate, an essential substrate for oxidative phosphorylation of adenosine triphosphate (ATP). 1 , 2 , 7 A total of 59 individuals with PPA2 deficiency have been identified in the literature, but only 10 are living (mean age 19.8 years; range 3-40 years).…”

“… 1 , 2 , 7 A total of 59 individuals with PPA2 deficiency have been identified in the literature, but only 10 are living (mean age 19.8 years; range 3-40 years). 2 , 7 , 9 Nine of the survivors have ongoing cardiovascular and/or neurologic manifestations, including cardiomyopathy, cerebellar ataxia, and peripheral neuropathy ( Table 1 ). Here we describe lethal and nonlethal cardiac presentations of PPA2 deficiency in 2 adolescent sisters, following alcohol exposure, that resulted from a novel pathogenic PPA2 variant.…”