Fig. 4: Fabry disease diagnostic algorithm.

^aSee Table 1. ^bGenetic analysis must include the study of possible large deletions or a copy number variation not detected by the Sanger technique. ^cThe finding of increased plasma and/or urinary Gb3, or plasma lyso Gb3 and its analogues in the evaluation of male or female patients with a VUS and normal (in female patients) or lowered α-Gal A activity provides additional diagnostic information, but the role of biomarkers in such patients still requires validation. ^dLow native T1 values reinforce or generate suspicion of Fabry disease. Normal native T1 values do not exclude Fabry disease, as they are rarely observed in untreated patients with mild LVH (mostly females), or in advanced disease due to pseudonormalization. ^eAn endomyocardial biopsy is recommended, but could be done in other affected organs such as the kidneys and skin. It should be evaluated by expert pathologists and always include electron microscopy studies to detect lamellar bodies and intracellular inclusions. Of note, some drugs may produce drug-induced phospholipidosis with an intracellular accumulation of phospholipids in different organs that can mimic zebra bodies on electron microscopy. α-Gal A alpha-galactosidase A, AFD Anderson–Fabry disease, CMR cardiac magnetic resonance, Gb3 globotriaosylceramide, HCM hypertrophic cardiomyopathy, LVH left ventricular hypertrophy, lyso Gb3 globotriaosylsphingosine, P/LP pathogenic/likely pathogenic, VUS variant of unknown significance. Reproduced with permission from Arbelo et al.⁹⁶.