Fabry disease is a lysosomal storage disorder with multiple organ involvement. Renal and cardiac symptoms can lead to dialysis and myocardial hypertrophy with fibrosis, responsible for heart failure with preserved ejection fraction (HFpEF). Enzyme replacement therapy (ERT) is available for all patients with Fabry disease since 2001, requiring infusions every other week. Since May 2016, the chaperone migalastat represents a novel form of specific therapy as the first oral therapy available for certain Fabry patients. Through this molecule the function of the mutated enzyme α-galactosidase A can be restored. Recent trials have shown positive cardiac effects of chaperone therapy using echocardiography; however, MRI investigations further evaluating these findings are not available yet. To evaluate cardiac effects of migalastat therapy in patients with amenable α-galactosidase A mutations in the prospective monocentric HEAL-FABRY registry (NCT03362164). Comprehensive clinical investigations including serial MRI were conducted at baseline before initiation of migalastat therapy and at least one year thereafter in all patients without contraindications such as pacemakers or ICDs. Out of 29 patients included in the study (mean age at start of therapy 52.8±14 years, total range 20–74 years), until then 12 patients with MRI data completed the 1-year follow-up. At 1 year, enzyme activity in leucocytes increased from 0.06 to 0.21 nmol/min/mg protein (p=0.001). Distinctive changes over time were observed not only in diastolic but also systolic parameters. The systolic myocardial mass index was reduced by 2.39% (p=0.10). In the AHA segment number 5, most important for classification of severe myocardial damage in Fabry patients, late gadolinium enhancement was reduced by 8.58% in all 5 patients with verified progressive fibrosis (p=0.14). One patient stopped migalastat therapy due to personal reasons. No significant side effects were observed. Analysis of LGE (systolic phase) These preliminary MRI data show positive effects of migalastat therapy in patients with Fabry disease and cardiac involvement. Compared to echocardiography, MRI has the potential to allow for comprehensive additional analyses regarding both cardiac morphology and function.

Conclusions: Long-term ERT can effectively prevent LVH in Fabry patients.ERT strongly inhibits the progression of LVH in female patients without LVH, suggesting that early treatment of ERT might improve the prognosis of female Fabry patients.

Cardiomyopathy in Fabry disease 231With several additional patients anticipated to be initiated for this drug therapy, related follow-up visits over the next months at FAZiT will be included in further study analyses.Conclusion: These first data suggest that oral chaperone therapy in Fabry disease can be a well-tolerated feasible alternative to enzyme replacement therapy in Fabry disease.In addition to direct therapeutic effects, patients with amenable α-galactosidase A gene mutations potentially benefit through increased quality of life by oral therapy instead of biweekly intravenous therapy.

Background. Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD.Methods. In this retrospective study, we investigated the effect of long-term immunosuppression on ERT inhibition in male patients with FD (n = 26) receiving immunosuppressive therapy due to kidney (n = 24) or heart (n = 2) transplantation.Results. No ERT-native transplanted patient (n = 8) developed antibodies within follow-up (80 +/- 72 months) after ERT initiation. Seven (26.9%) patients were tested ERT inhibition positive prior to transplantation. No de novo ERT inhibition was observed after transplantation (n = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate-mofetil/mycophenolate acid, ERT inhibition decreased after transplantation (n = 12; P = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re-increase ERT inhibition (n = 4, median [range]: 16.6 [6.9; 36.9] %; P = 0.0972) over time. One ERT inhibition-positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered ERT inhibition.Conclusion. We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent de novo ERT inhibition in ERT-native patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased ERT inhibition in affected patients, but did not result in long-term protection. Future studies are needed to establish ERT inhibition-specific immunosuppressive protocols with long-term modulating properties to warrant an improved disease course in ERT inhibition-positive males.