Assessment of α-Galactosidase A Activity Following Migalastat Therapy in Real-World Cases of Fabry Disease

Introduction: Fabry disease is an X-linked hereditary disorder characterized by the systemic accumulation of globotriaosylceramide (GL3) due to deficient activity of α-galactosidase A (GLA), leading to a variety of clinical manifestations. Current treatment options include enzyme replacement therapy (ERT) with recombinant agalsidase alfa or beta, and pharmacological chaperone therapy with migalastat. Migalastat stabilizes specific mutant forms of GLA, with responsiveness determined via in vitro HEK cell-based assays. However, its clinical efficacy in real-world settings remains variable and not fully elucidated. This case series aimed to evaluate the enzymatic response to migalastat in Fabry disease patients treated at our institution. Case Description: We retrospectively analyzed five Fabry disease patients (two males and three females) who received migalastat therapy. The identified GLA gene variants included c.928C>T, c.335G>A, c.352C>T, and c.880T>G. Among them, two males and one female exhibited the classic phenotype, while the remaining two females had the late-onset form. All patients underwent renal biopsy, confirming GL3 accumulation in podocytes. Based on established genotype-specific amenability to migalastat, we assessed changes in GLA activity before and after treatment using clinical data. Compared to healthy control, the two males with the classic phenotype showed nearly absent baseline enzyme activity (~0%), while all three female patients retained over 50% of normal activity. In one male patient, GLA activity could not be evaluated after the initiation of migalastat. In contrast, the other male patient showed a 12-fold increase in enzyme activity; however, it only reached 2.4% of the normal level. All three female patients exhibited less than a two-fold increase in enzyme activity, yet each achieved enzyme activity levels exceeding 90% of normal following treatment. Discussion: Although migalastat is approved for Fabry disease patients with amenable mutations, its clinical efficacy appears to vary considerably depending on the specific genotype. Our findings underscore the importance of individualized assessment before initiating migalastat therapy, highlighting that treatment decisions should be based not solely on genetic amenability but also on clinical context and expected therapeutic benefit.