Abstract
Introduction: This study has focussed upon a relatively recent cause of sudden cardiac death; related to mutations in the pyrophosphatase 2 gene. This gene encodes mitochondrial protein crucial for cellular energy production in the form of ATP. Understanding this rare mechanism of sudden cardiac death is important for both clinicians and families affected by this rare disorder.
Aim: To understand the pathophysiology underlying pyrophosphatase 2's role in causing sudden cardiac death.
Methodology: To capture data from the literature, an integrative review was undertaken, using Whittemore and Knaffl's established five step process, and then synthesis of results was carried out using a constant comparative approach.
Results: Database searches with keywords designed to identify relevant research in this field, yielded 865 articles, which were eventually systematically reduced to 9 articles for data extraction. By this process, 32 families were found to be affected by PPA2 associated sudden cardiac death. This included 58 affected individuals harbouring two recessively inherited mutations (one from each parent) and one patient with a homozygous inherited mutation and a de-novo mutation. Forty-seven of these individuals died, and 12 survived. In total, 22 pathogenic variants (mutations) were identified within the PPA2 gene, located on chromosome 4. These variants were found to seriously impact the function PPA2 protein function, resulting in a spectrum of protein dysfunction from mild muscle pain and impaired neurological signs to sudden cardiac death. Two triggers of sudden cardiac failure were identified - viral infections before the age of two years, and alcohol in adolescents.
Discussion: PPA2 dysfunction in mitochondria is hypothesised to cause a reduction in ATP production and an increased concentration of its substrate, PPi. The effect of disturbance to the balance of these molecules' concentrations in mitochondria remains unknown, but several possibilities have been presented as a cause of cellular death via these problems, including mitochondrial swelling (and disintegration), leading to cell death and myocardial tissue fibrosis. Fibrosis and in particular mid-myocardial scarring are common presentations, either prior to death or detected in post-mortem analyses. The exact biochemical mechanisms for this crisis in cardiac function when individuals are presented with viral or ethanol triggers remain unknown.
Conclusion: Inheritance of two dysfunctional PPA2 genes or one inherited plus a de novo mutation can cause a wide range of illness from muscle pain to death. Adding the PPA2 gene into gene panels for screening siblings of sudden unexplained cardiac death in infants, or for unexpected development of cardiomyopathies, may assist decision making around implanting cardioverter/defibrillators and advising the total abstinence from alcohol.