Background:Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficient α-galactosidase A (α-Gal) activity, leading to progressive renal, cardiac, and cerebrovascular involvement. Migalastat, an oral pharmacological chaperone, is indicated for patients with amenable GLA variants. Although efficacy has been demonstrated in clinical trials, long-term real-world data remain necessary, particularly in mixed groups of treatment-naïve and ERT-switch patients and genotype-phenotype subgroups. Methods:Eighty-seven adults with FD (55 males, 32 females) carrying GLA variants were retrospectively analysed at a single regional centre. Patients received migalastat as treatment naïve (TN) (n = 48) or treatment switch (TS) (n = 39). Demographic, genotypic, biochemical, renal, and cardiac parameters, and clinical outcomes were evaluated. Results:Variants were predominantly late-onset (67%), most commonly c.644 A > G (p.Asn215Ser)/p.N215S; 14% were classical and 19% unclassified. Plasma globotriaosylsphingosine (lyso-Gb3) declined in both groups (TN: 5.1 (3.7-7.9) to 2.2 (1.3-3.6) ng/mL; TS: 7.2 (3.8-13.0) to 3.3 (1.4-6.7) ng/mL). Renal function remained above clinically relevant thresholds in most patients, with a modest reduction in the proportion maintaining eGFR >90 mL/min/1.73 m2. Blood pressure, and echocardiographic measurements were largely stable; however, a significant reduction (P = 0.009) in left ventricular mass index (LVMI) was observed in TS patients when restricting analysis to variants classified as amenable according to the Galafold® amenability table (United Kingdom (UK), 2024 version). In TS patients, QTc increased significantly (P < 0.001) but remained within normal or only mildly prolonged limits. Sex-stratified analyses showed higher LVMI in males than females at baseline, with non-significant reductions in both groups over time. The incidence of non-fatal cardiovascular events was 81 and 43.5 per 1000 person-years in TN and TS groups, respectively. Six male patients (6.9%) experienced adverse events; five discontinued treatment, and one Fabry-related death occurred in the TN group. Conclusion:Migalastat was well tolerated and maintained stable renal and cardiac parameters with plasma lyso-Gb3 improvement. However, a subset of patients showed progression or intolerance, underscoring that variant amenability alone may not predict clinical benefit.

Abstract Background The cardiovascular manifestations of Fabry disease are common and represent the leading cause of death. Myocardial T1 dispersion has recently emerged as a robust predictor of adverse cardiac outcome in Fabry disease but the relationship between T1 dispersion and other cardiovascular manifestations has not been studied. Objective To evaluate the relationship between myocardial T1 dispersion and other cardiovascular manifestations of Fabry disease, and identify its determinants. Methods Prospective longitudinal cohort study including 181 participants with Fabry disease and 30 controls undergoing clinical cardiovascular magnetic resonance. T1 dispersion was assessed in relation to other structural and functional cardiovascular biomarkers and examined in Pre-hypertrophic, Hypertrophic and Fibrotic phenotypic sub-groups. Determinates of T1 dispersion were investigated using multivariable linear regression. Results T1 dispersion was similar in the Control, Pre-hypertrophic and Hypertrophic sub-groups, but was significantly elevated in the Fibrotic sub-group. Independent determinates of T1 dispersion were age, body surface area-indexed left ventricular mass, indexed left ventricular end diastolic volume, global longitudinal strain, native myocardial T1, non-ischaemic late gadolinium enhancement, and extracellular volume fraction (R2 0.414). T1 dispersion was consistently higher in females than males. Conclusions Myocardial T1 dispersion appears sensitive to both the T1 shortening effect of globotriaosylceramide accumulation and T1 lengthening effect of fibrosis, and accordingly increases as Fabry disease progresses. In conjunction with recent data showing it to be a robust predictor of adverse cardiac outcome, myocardial T1 dispersion is advocated as a key cardiovascular biomarker in Fabry disease.Figure 1Figure 2

Introduction Fabry disease (FD) is an X linked deficiency of α-galactosidase A which leads to an accumulation of globotriaosylceramide (GL-3) throughout the body, particularly in the heart, brain and kidneys. Although left ventricular hypertrophy (LVH) in FD can improve with enzyme-replacement therapy (ERT), the response is difficult to predict. Furthermore, the response of other cardiac features such as aortic dilatation and ECG changes are poorly understood. Methods A local registry of 66 patients with FD was studied. ECG, echocardiogram and Fabry Outcome Survey-Mainz Severity Score Index (FOS-MSSI) data were compared between baseline and after long-term ERT (median 36 months). Results In patients with LVH (n=42), left ventricular mass index (LVMI), maximal wall thickness (MWT), left ventricular end-diastolic diameter (LVEDD) and ejection fraction (EF) were all seen to improve after ERT (LVMI: 135±13 vs 133±13 g/m2, MWT: 17±6 vs 16±5 mm, LVEDD: 55±6 vs 54±6 mm; EF: 62±5 vs 64±3%; p<0.05) (Abstract 070 figure 1). In the entire patient group, PQ interval and P wave duration significantly increased with ERT (PQ: 131±13 vs 144±13 ms, P: 76±5 vs 90±6 ms; p values <0.001); QTc interval significantly decreased (418±18 vs 410±15 ms; p<0.001); and median FOS-MSSI score fell from 16 to 14 (p<0.001) (Abstract 070 figure 2). On logistic-regression analysis, none of the recorded baseline features (age, gender, LVMI, MWT, LVEDD, aortic diameter, EF, PQ interval, P wave duration, QRS duration, QT interval, Romhilt-Estes score or FOS-MSSI) predicted improvements in LVH or FOS-MSSI with ERT (p>0.05).Abstract 070 Figure 1 Effect of enzyme replacement therapy (ERT) on LV morphology and function in patients with LVH at baseline. Left ventricular mass index (LVMI), maximal wall thickness (MWT), LV end-diastolic diameter (LVEDD) and ejection fraction all showed significant improvements (all p values <0.05) at the end of follow-up (median 3 years). [Values shown are mean±SD].Abstract 070 Figure 2 Effect of enzyme replacement (ERT) on the conduction system. There was a significant increase in P wave duration and PQ interval from baseline; there was a significant decrease in QRS width and QTc interval from baseline at the end of follow-up (median 3 years). [Values shown are mean±SD]. Conclusions ERT improved LV morphology and function in patients with LVH- but there was no relationship between age, gender, FOS-MSSI or baseline ECG/TTE features and the response. ERT also normalised long QTc intervals, short PQ intervals and short P waves; and reduced disease burden (FOS-MSSI).