Heterogeneous Biochemical Responses to Migalastat in Real-World Cases of Fabry Disease

Fabry disease (FD), an X-linked lysosomal disorder with deficient α-galactosidase A (GLA) activity, leads to the systemic globotriaosylceramide (Gb3) accumulation. Therapeutic options include enzyme replacement therapy and migalastat, which stabilizes amenable GLA variants identified with an in vitro GLA enzymatic activity assay. The real-world efficacy of migalastat on GLA activity remains unclear. This study evaluated enzymatic and biochemical responses to migalastat therapy in patients with FD.

This retrospective study included seven patients with FD, including four male and three female patients, treated with migalastat between 2017 and 2026. Changes in leukocyte GLA activity and plasma globotriaosylsphingosine (lyso-Gb3) levels after migalastat initiation; clinical data on kidney, cardiac involvement; serum brain natriuretic peptide and troponin I levels, left ventricular ejection fraction, and left ventricular mass index; estimated glomerular filtration rate and urinary albumin/creatinine ratio, were evaluated.

Two male and one female patient had classic FD, whereas two male and two female patients had late-onset FD. Baseline GLA activity was nearly absent in two male patients with classic FD but exceeded 50% of the normal in all female patients and two male patients with late-onset FD. In one male patient with classic FD, GLA activity increased 12-fold but remained only 2.4% of the normal level, and in all female patients and one male patient with late-onset FD, GLA activity increased less than twofold but reached >90% of the normal. GLA activity increased significantly after migalastat initiation (P = 0.03), with female patients showing a significantly greater increase (P = 0.02). Plasma lyso-Gb3 increased in two male patients after switching from enzyme replacement therapy but remained unchanged or decreased in female patients. Kidney and cardiac parameters remained largely stable during follow-up.

Migalastat was associated with heterogeneous biochemical responses across GLA genotypes and clinical phenotypes. Assessment of both genetic and biochemical characteristics may help identify patients most likely to benefit from migalastat, although larger studies with longer follow-up are required.