Anderson–Fabry Disease: Red Flags for Early Diagnosis of Cardiac Involvement

Abstract

Anderson–Fabry disease (AFD) is a lysosome storage disorder resulting from an X-linked inheritance of a mutation in the galactosidase A (GLA) gene encoding for the enzyme alpha-galactosidase A (α-GAL A). This mutation results in a deficiency or absence of α-GAL A activity, with a progressive intracellular deposition of glycosphingolipids leading to organ dysfunction and failure. Cardiac damage starts early in life, often occurring sub-clinically before overt cardiac symptoms. Left ventricular hypertrophy represents a common cardiac manifestation, albeit conduction system impairment, arrhythmias, and valvular abnormalities may also characterize AFD. Even in consideration of pleiotropic manifestation, diagnosis is often challenging. Thus, knowledge of cardiac and extracardiac diagnostic “red flags” is needed to guide a timely diagnosis. Indeed, considering its systemic involvement, a multidisciplinary approach may be helpful in discerning AFD-related cardiac disease. Beyond clinical pearls, a practical approach to assist clinicians in diagnosing AFD includes optimal management of biochemical tests, genetic tests, and cardiac biopsy. We extensively reviewed the current literature on AFD cardiomyopathy, focusing on cardiac “red flags” that may represent key diagnostic tools to establish a timely diagnosis. Furthermore, clinical findings to identify patients at higher risk of sudden death are also highlighted.

Heart Failure with Preserved Ejection Fraction: How to Deal with This Chameleon

“…Firstly, clinical features should be well investigated and distinguished from those conditions that may mimic this syndrome or contribute to its development, such as deconditioning, anemia, lung disease, and obesity. HFpEF is more likely to affect women and elderly people (aged > 60 years) with comorbidities, including arterial hypertension (AH), atrial fibrillation (AF) [ 13 , 14 ], diabetes mellitus (DM), and chronic kidney disease (CKD) [ 15 , 16 ]. Moreover, due to the wide variability in etiopathogenetic causes and presentation modalities, diagnosis and management are challenging, requiring a targeted and highly specific treatment [ 8 ].…”

“…Echocardiography plays a pivotal role in diagnosing HFpEF and almost all aspects of its management [ 8 ]. Moreover, the majority of score-based algorithms to help clinicians in the diagnosis of HFpEF (such as H2FPEF and HFA-PEFF) [ 15 , 18 ] are based on echocardiographic parameters (left atrialLA size, mitral E velocity, septal e′ velocity, and E/e′ ratio) and can be obtained only by means of an accurate echocardiographic evaluation. Moreover, an echocardiographic exam is useful to monitor the status of LVEF in the case of a new onset of symptoms in subjects with already known HFpEF, although, in most cases, LVEF is likely to remain stable over the years.…”

“…Indeed, NPs’ release is strictly linked to left ventricular (LV) wall stress. For this reason, NP dosage is more accurate in evaluating HFrEF than HFpEF [ 15 ].…”

“…Therefore, NPs are not ideal biomarkers in HFpEF assessment [ 6 ], especially in the chronic subset of patients, although they have an important prognostic significance [ 23 ]. Recently, new algorithms have been proposed to diagnose HFpEF [ 24 ], such as the H2FPEF score (without NPs) [ 18 ] or the HFA-PEFF score (including NPs and other criteria) [ 15 ].…”

Are Endomyocardial Ventricular Biopsies Useful for Assessing Myocardial Fibrosis?

“…When interpreting GLA mutations or initiating therapy is contentious, an EMB may be necessary, thus providing definitive evidence of AFD by demonstrating fine granular vacuolization via Sudan black staining, concentric lamellar bodies formed by Gb3, and typical lysosomal inclusions or “zebra” bodies under electron microscopy. The vacuolization and presence of lamellar bodies identified through light and electron microscopy, respectively, are considered histological hallmark findings [ 7 ]. Beyond its diagnostic value, virus detection through immunohistochemistry, PCR, reverse transcription PCR (RT-PCR), and the direct sequencing of heart samples have therapeutic implications, such as evaluating potential candidates for immunosuppressive therapy.…”