Fabry disease screening in patients with idiopathic HCM or idiopathic LVH: preliminary data from the multicentric nationwide F-CHECK study

Background Fabry disease (FD) is a rare lysosomal storage disorder caused by mutations in an X-linked gene that encodes the alpha-galactosidase A enzyme. The most common cardiac manifestation of FD is hypertrophic cardiomyopathy (HCM). Because the clinical presentation of FD can be non-specific, the best way to improve diagnosis rates is to systematically screen patients exhibiting compatible phenotypes, especially those with HCM. Purpose In this multicenter registry, we aim to report the findings from a nationwide FD screening initiative (F-CHECK) conducted in Portugal, to gather more data on the incidence of this rare disease. Methods Participant centers were primarily located in the northern region of Portugal, excluding the area known for having a founder-effect mutation F113L. The inclusion criteria consisted of patients diagnosed with idiopathic HCM, with a left ventricular wall thickness ≥ 15 mm (group A), idiopathic left ventricular hypertrophy, with a wall thickness ≥ 13 mm (group B), dilated phase of HCM (group C), and dilated cardiomyopathy of unknown etiology, with evidence of late gadolinium enhancement (LGE) on cardiac MRI involving the inferolateral segment (group D). These patients had to have undergone either Dried Blood Spot (DBS) or DBS along with or only genetic testing between January 2021 and December 2024. Results The study included 283 patients, 174 males (62%), with a median age of 65 years [range:18-93]. Group A included 197 patients (70%), group B 62 patients (22%), group C 19 patients (6.7%) and group D 5 patients (1.8%). A total of 11 patients were diagnosed with FD (3.9%), with 6 distinct pathogenic mutations of the GLA gene, 4 with the p.F113L mutation, 2 with p.N215S, another 2 with p. M290I and 3 patients with other variants. Among 135 patients who underwent DBS, enzyme activity was reduced in 18 patients (13%), with further genetic FD confirmation obtained in 7 (5.0%) cases. In FD patients, cardiovascular (CV) symptoms/signs were present in 9 patients (82%), and 5 had previous CV events (46%). Additionally, 10 FD patients (91%) had at least one comorbidity, with cerebrovascular disease being significantly more common in these patients, when compared to non-FD (36 vs 8.8%, p=0.016) . FD patients compared to non-FD had larger QRS duration (156 vs 104ms, p=0.001), and higher prevalence of right bundle branch block (60 vs 9.6%, p<0.001), fascicular block (30 vs 5.9%, p=0.021) and LGE inferolateral (70 vs 19%, p<0.001). Although there were no significant differences found in the interventricular septum (IVS) thickness, FD patients had a lower prevalence of IVS hypertrophy (60 vs 90%, p=0.019). Conclusion In this screening study including centers in the Northern region of Portugal with distinct cardiac phenotypes, FD was diagnosed in a significant percentage of patients, 64% with non-F113L mutation, highlighting the importance of FD screening in patients with HCM or idiopathic LVH.