Sudden cardiac death frequently remains unexplained following conventional autopsy, particularly when structural findings are non-specific or absent. Integration of the “molecular autopsy,” or genetic testing for inherited channelopathies and cardiomyopathies, allows for determination of otherwise unascertained deaths, especially in young decedents, and facilitates clinical evaluation of surviving, at-risk family members.

A 17-year-old male reported bilateral leg pain and shortness of breath while attending hockey camp, during which he consumed alcohol. During transport, he suffered a cardiac arrest, and despite resuscitative efforts, died on route to hospital. Aside from a childhood history of Kawasaki disease, he was presumed healthy with no known risk factors for sudden death. Toxicology was negative except for a non-lethal blood alcohol concentration. Autopsy revealed a mildly enlarged heart, considered to be within normal limits for his stature. External and internal examinations were otherwise unremarkable; however, histopathological assessment demonstrated diffuse myocardial injury, necrosis and inflammation. Despite an initial negative genetic panel, extensive testing was undertaken to determine the etiology of this acute coronary mimic, ultimately identifying a pathogenic variant in PPA2, which encodes inorganic pyrophosphatase 2, an essential enzyme in mitochondrial energy metabolism.

This case highlights how common metabolic stressors, including modest alcohol intake, can trigger fatal arrhythmias in individuals with underlying cardiomyopathies, that may go unrecognized in life and death. Among 59 reported individuals with PPA2-deficiency, the mean lifespan is 19.8 years, with survivors experiencing debilitating cardiovascular or neurological deficits. In affected individuals, strict avoidance of metabolic triggers is essential, as is genetic counselling, familial testing, and in many cases, use of an implantable cardioverter-defibrillator to manage such arrhythmias.

This paradigm parallels emerging observations in myocarditis, where individuals initially believed to have died of viral myocarditis, were found to consistently carry pathogenic variants in cardiomyopathy-associated genes, suggesting an inflammation-mediated trigger of an underlying inherited cardiomyopathy. Recognition of this “two-hit” model of sudden cardiac death is critical, as the poorly understood, underlying pathophysiology results in variable severity of clinical manifestations among affected family members. Therefore, a multi-modal approach, informed by evolving knowledge of genetic susceptibilities, is essential for thorough forensic investigation and improved clinical outcomes for surviving relatives. It also highlights the need to expand and improve accessibility to databases of cardiomyopathy-associated genes to advance understanding and classification of sudden death.

Authors

• Darya Ali (Department of Diagnostic and Molecular Pathology, Queen's University, Canada)
• Jeffrey Tanguay (Department of Diagnostic and Molecular Pathology, Queen's University, Canada)
• Kristopher Cunningham (Department of Diagnostic and Molecular Pathology, Queen's University, Canada)