Sudden unexpected death in asymptomatic infants due to PPA2 variants

Abstract

Background: Sudden death in children is a tragic event that often remains unexplained after comprehensive investigation. We report two asymptomatic siblings who died unexpectedly at approximately 1 year of age found to have biallelic (compound heterozygous) variants in PPA2.

Methods: The index case, parents, and sister were enrolled in the Sudden Unexplained Death in Childhood Registry and Research Collaborative, which included next-generation genetic screening. Prior published cases of PPA2 variants, along with the known biology of PPA2, were also summarized.

Results: Whole exome sequencing in both siblings revealed biallelic rare missense variants in PPA2: c.182C > T (p.Ser61Phe) and c.380G > T (p.Arg127Leu). PPA2 encodes a mitochondrially located inorganic pyrophosphatase implicated in progressive and lethal cardiomyopathies. As a regulator and supplier of inorganic phosphate, PPA2 is central to phosphate metabolism. Biological roles include the following: mtDNA maintenance; oxidative phosphorylation and generation of ATP; reactive oxygen species homeostasis; mitochondrial membrane potential regulation; and possibly, retrograde signaling between mitochondria and nucleus.

Conclusions: Two healthy and asymptomatic sisters died unexpectedly at ages 12 and 10 months, and were diagnosed by molecular autopsy to carry biallelic variants in PPA2. Our cases add additional details to those reported thus far, and broaden the spectrum of clinical and molecular features of PPA2 variants.

Keywords: PPA2; cardiomyopathy; mitochondrial disease; myocarditis; sudden death.

Figure 1

(a) Schematic of PPA2's biological functions, as a pyrophosphatase located in the mitochondrial matrix and inner membrane. Pyrophosphate is generated by nucleotide‐dependent reactions, including DNA and RNA synthesis (including tRNA aminoacylation reactions and cAMP/cGMP synthesis), protein and lipid synthesis, and activation of fatty acids and amino acids. With Mg2+ as a cofactor, PPA2 hydrolyzes inorganic pyrophosphate (PPi) to inorganic phosphate (Pi); this reaction is inhibited by calcium. This reaction energetically favors ongoing nucleotide‐dependent reactions, and inorganic phosphate is used for phosphate metabolism. Biological roles served by PPA2 include the following: mtDNA maintenance; oxidative phosphorylation and generation of ATP; ROS (reactive oxygen species) homeostasis; mitochondrial membrane potential (ΔΨ) regulation; and possibly, communication between mitochondria and nucleus (retrograde signaling pathway). (b) BioGRID showed 49 total interactors (nodes) and 63 interactions (edges), with 48 unique interactors representing diverse mitochondrial and cellular processes (https://thebiogrid.org/117979, accessed 06/30/19)