ファブリー病

Lucerastat is an iminosugar with the potential to provide substrate reduction therapy for the treatment of Fabry disease (FD), an inherited X-linked lysosomal storage disorder. The aims of this study were to develop a population pharmacokinetic (PK) model describing lucerastat plasma concentration over time, to investigate the relationships between subject-specific characteristics and model parameters, and to assess the influence of these differences between subjects on lucerastat exposure via model-based simulations. Longitudinal nonlinear mixed effects modeling was applied to develop a model based on data from 250 participants in six Phase 1 and two Phase 3 studies. Lucerastat pharmacokinetics were described by a two-compartment model with linear first-order absorption and elimination, including allometric scaling of body weight on clearance and volume parameters. Lucerastat clearance was reduced in subjects with lower estimated glomerular filtration rate (eGFR). Disease status (with/without FD) was found to impact clearance and volumes of distribution to a limited extent. The model described the data well across the dose range from 100 to 4000 mg. Body weight, disease status, and renal function were shown to influence exposure, with dose adaptation only required in patients with renal function impairment, as body weight and disease status had limited impact. Dose adaptation as applied in Phase 3 (i.e., eGFR [mL/min/1.73 m2] ≥60: 1000 mg; ≥45 and <60: 750 mg; ≥30 and <45: 500 mg; ≥15 and <30: 250 mg b.i.d.) resulted in achieving similar exposure in study participants with FD with different levels of renal function impairment.

BACKGROUND: Fabry disease is a lysosomal storage disorder caused by deficient activity of the enzyme α-galactosidase A, resulting in progressive accumulation of globotriaosylceramide (Gb3) and widespread tissue and organ damage. Enzyme replacement therapy (ERT) can slow disease progression but may elicit antidrug antibody (ADA) responses. The impact of ADA status on long-term ERT efficacy and safety remains incompletely understood. OBJECTIVE: We conducted a systematic literature review (SLR) to examine the impact of ADA status on outcomes in patients with Fabry disease receiving ERT. We aimed to evaluate associations between ADA status and specific outcomes, and to identify remaining evidence needs. METHODS: Systematic searches were conducted in MEDLINE and Embase (up to March 4, 2025), supplemented by searches of the Cochrane Library and clinical trial registries. Eligible publications reported data on the relationship between ADA status and Fabry disease-related biomarkers (Gb3, globotriaosylsphingosine [lyso-Gb3]), efficacy (renal and cardiovascular) outcomes, and safety (adverse events [AEs] and infusion-related reactions [IRRs]) outcomes. RESULTS: Of 1763 articles screened, 24 were included (19 reported disease-related biomarkers, 10 renal outcomes, 4 cardiovascular, and 9 AE/IRR data). Most analyses of disease-related biomarkers (17/18) reported statistically significant positive associations (p < 0.05) between ADA positivity and elevated biomarkers: plasma lyso-Gb3 (4/8 studies), plasma Gb3 (1/3 studies), and urine Gb3 (6/6 studies). Some renal data sets (2/9) reported evidence suggesting a potential association between more rapid decline in estimated glomerular filtration rate in ADA-positive (vs ADA-negative) patients. Four out of 9 studies reported statistically significant associations between ADA positivity and IRR occurrence; most studies stratifying IRR rates by ADA status (5/7) reported higher rates among ADA-positive (vs ADA-negative) subgroups. CONCLUSION: This SLR found evidence that ADA positivity may be associated with increased IRR risk and may have a negative effect on some measures of ERT efficacy. Inconsistencies in the identified data were likely driven by study design differences, including prior ERT exposure, follow-up time, and ADA assessment protocols. Additional prospective studies with standardized ADA assessments and accounting for patient baseline characteristics and disease severity, are needed to better understand the clinical implications of ADA formation on ERT outcomes, including an assessment of causality.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by α-galactosidase A (α-GAL) deficiency, resulting in progressive accumulation of globotriaosylceramide and related glycosphingolipids, leading to progressive organ damage (including the heart, kidney, and brain). The GLA variant c.427G > A p.(Ala143Thr) is currently classified as a "variant of uncertain significance" (VUS). There is no consensus about this variant's significance in the literature and it remains controversial in non-classical FD. We generated a human induced pluripotent stem cell (hiPSC) line derived from dermal fibroblasts of a 64-year-old hemizygous man carrying the p.(Ala143Thr) variant, using an RNA-based reprogramming method.

Cardiovascular disease represents the leading cause of death in patients with Anderson-Fabry disease (FD), with sudden cardiac death (SCD) being one of the most frequently reported causes of mortality. However, a significant diagnostic gap persists in identifying patients at risk, as current stratification tools are inadequate for predicting lethal arrhythmic events. This narrative review resumes the existing peer-reviewed literature regarding the pathophysiology of FD arrhythmias and evaluates the diagnostic limitations of the current standard intermittent monitoring tools, such as the 24-hour Holter. Standard monitoring tools, such as the 24-hour Holter often miss paroxysmal, asymptomatic arrhythmias. Recent studies using implantable loop recorders (ILRs) show a significantly higher burden of arrhythmias than previously recognized. Myocardial fibrosis, identified as late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR), is strongly associated with malignant arrhythmias, together with the degree of left ventricular hypertrophy (LVH). Current consensus statements may underestimate the need for continuous monitoring in FD. By providing a comprehensive narrative synthesis of available observational and registry data, this paper proposes an updated, exploratory risk-stratification clinical guide for the extension of countinuous rhythm monitoring in high-risk subgroups of FD.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterized by α-galactosidase A deficiency, marked phenotypic heterogeneity, and frequent diagnostic delay. We report a multigenerational family with Fabry disease caused by a de novo GLA (α-galactosidase A gene) mutation in a female patient, affecting two adult sons and an infant granddaughter. The index patient, a 25-year-old male, experienced neuropathic pain, recurrent unexplained fever, gastrointestinal symptoms, anhidrosis, and cerebrovascular events for more than a decade prior to diagnosis. Cardiac hypertrophy, cornea verticillata, and ischemic cerebral lesions were detected. His mother showed neurological and cardiac involvement and was confirmed to carry a de novo GLA mutation. The younger brother presented a milder phenotype without cardiac or ocular involvement. Early cascade genetic screening enabled diagnosis of an affected infant at 6 months of age. Enzyme replacement therapy (ERT) was initiated in all adult patients, leading to symptomatic improvement, although cerebrovascular events persisted in the index case. This case series highlights the pronounced intrafamilial phenotypic variability of Fabry disease and underscores the need to consider FD even in the absence of a positive family history. Early genetic screening, including prenatal and early postnatal testing, is critical to reduce diagnostic delay and optimize long-term clinical outcomes.