Mol Genet Metab Rep. 2026 May 11;47:101316. doi: 10.1016/j.ymgmr.2026.101316. eCollection 2026 Jun.
ABSTRACT
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.
PMID:42181773 | PMC:PMC13191641 | DOI:10.1016/j.ymgmr.2026.101316