Abstract 4344315: When Cardiac Hypertrophy Masks Fabry Disease: A Pathological and Genetic Diagnostic Challenge

Introduction: Fabry disease (FD), an X-linked lysosomal storage disorder, is caused by mutations in the GLA gene, leading to deficient alpha-galactosidase A activity and subsequent accumulation of glycosphingolipids in various organs. The cardiac manifestations can closely resemble those of hypertrophic cardiomyopathy (HCM), making it a diagnostic challenge, particularly when presenting without the hallmark systemic symptoms of FD, such as pain crises or skin lesions. Case Report: A 64-year-old male with a history of decompensated heart failure was initially diagnosed with HCM after presenting with severe concentric left ventricular hypertrophy and a reduced ejection fraction (25%). Despite undergoing cardiac resynchronization therapy, the patient's condition continued to deteriorate, ultimately leading to the need for heart transplantation. In the post-transplantation phase, a first-degree relative was diagnosed with Fabry disease. This prompted a reconsideration of the diagnosis. Enzymatic analysis of the explanted heart tissue revealed a significant reduction in alpha-galactosidase A activity (0.28 µmol/L/h; reference >1.68), and genetic testing confirmed a pathogenic variant (p.N215S) in the GLA gene. Histopathological examination of the explanted heart demonstrated glycosphingolipid deposition, characteristic of Fabry disease. Discussion: The initial diagnosis of HCM was complicated by the absence of classic systemic symptoms of Fabry disease. Histopathological findings of glycosphingolipid accumulation in the myocardium confirmed the diagnosis, shedding light on the overlap between HCM and Fabry disease. This case illustrates that, while enzyme replacement therapy (ERT) can help manage Fabry disease, the key to improving outcomes lies in early detection. Unfortunately, by the time the diagnosis was made in this case, the patient’s disease had progressed to end-stage heart failure, highlighting the crucial need for awareness and early diagnosis. Conclusion: This case emphasizes the diagnostic importance of considering FD in patients with unexplained hypertrophic cardiomyopathy or progressive heart failure. Family history, along with advanced diagnostic tools like genetic testing and enzymatic analysis, should guide clinicians to reconsider initial diagnoses. Early identification could significantly alter the management course, optimizing the benefits of enzyme replacement therapy and preventing the progression to advanced heart failure.