Explore the vast range of titles available.

BackgroundFabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.MethodsThe main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.ResultsFifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (−6.6 g/m2 (−11.0 to −2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.ConclusionsMigalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.Trial registration number:NCT00925301; Pre-results.

BackgroundFabry disease is a progressive, X-linked lysosomal disorder caused by reduced or absent α-galactosidase A activity due to GLA variants. Females with Fabry disease often experience diagnostic delays and an underappreciated disease burden owing to their variable disease presentation and progression.MethodsWe conducted a post hoc analysis of all females from the clinical studies FACETS (NCT00925301) and ATTRACT (NCT01218659) and their open-label extensions, assessing baseline characteristics and long-term efficacy of migalastat regarding cardiac and renal function and Fabry-associated clinical events (FACEs).ResultsOverall, 60 females had a median migalastat exposure of 5.1 years. At baseline, the median age was 47 years with multiorgan involvement in 70.0% of females (≥2 organ systems: renal, cardiac, central nervous system, peripheral nervous system and gastrointestinal). At baseline, 21.7% of females had left ventricular hypertrophy (LVH). In multiorgan involvement and LVH subgroups, the median baseline estimated glomerular filtration rate (eGFR) was in chronic kidney disease stage 2. Annualised rate of change in left ventricular mass index remained below 1 g/m2/year regardless of LVH or eGFR category at baseline. Mean (SD) eGFR annualised change was −1.1 (2.8) mL/min/1.73 m2 overall. Ten FACEs were reported in eight females, seven of whom had prior events. Seven FACEs were cardiac; the remaining three were cerebrovascular (all transient ischaemic attacks). The incidence of renal, cardiac and cerebrovascular events was 0, 24.9 and 10.7 events per 1000 patient-years, respectively.ConclusionThese data show that females with Fabry disease experience considerable disease severity and burden and support the long-term efficacy of migalastat for the treatment of females.

Outcomes in patients with Fabry disease receiving migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. Data were evaluated in two subgroups of patients with migalastat-amenable GLA variants: “classic phenotype” (n=14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and “other patients” (n=36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb3). Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFRCKD-EPI with migalastat was −0.3 (3.76) mL/min/1.73m2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb3 were −16.7 (18.64) g/m2, −0.9 (1.66), and −36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with migalastat (−0.8) and increased with placebo (0.3); switching from placebo to migalastat, PTC inclusions decreased by −0.7. Numerically smaller changes in these endpoints were observed in the other patients. Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial. Males aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine). Plasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m(2) (range 90.4-161.0 mL/min/1.73 m(2)) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0-27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients. These data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome. ClinicalTrials.gov NCT00701415.

Migalastat stabilizes mutant α-galactosidase in Fabry's disease, reducing globotriaosylceramide deposition. In this study, the percentage of patients with a decrease of 50% or more in kidney interstitial capillary deposition at 6 months was similar in the migalastat and placebo groups. Fabry’s disease is a rare, progressive, and devastating X-linked disorder caused by the functional deficiency of lysosomal α-galactosidase. 1 The resultant accumulation of glycosphingolipids, predominantly globotriaosylceramide (GL-3), can lead to multisystem disease and early death. 2 Binding of the pharmacologic chaperone migalastat to the active site of α-galactosidase stabilizes certain mutant enzymes, thus facilitating proper trafficking to lysosomes, where dissociation of migalastat allows α-galactosidase to catabolize accumulated substrates. 3 – 7 In patients with mutant enzymes that are identified with the validated assay, orally administered migalastat may be an alternative treatment option for addressing certain unmet medical needs associated with enzyme-replacement therapy — for . . .

Vestibular and oculomotor abnormalities have been widely identified in Fabry disease (FD), with inflammation potentially playing an important role. We aim to investigate the expression of inflammatory cytokines (ICs) in FD patients and their relationship with the vestibular/oculomotor dysfunctions. This prospective observational study enrolled 40 FD patients. All 40 patients underwent the visuo-oculomotor examination, and 22 of them received the vestibulo-oculomotor examination. Plasma concentrations of 14 ICs were detected, including interferon-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-17F, IL-22, tumor necrosis factor (TNF)-α, and TNF-β. Statistical analyses were made between different subgroups of patients. (1) In the visuo-oculomotor examination, TNF-β was significantly higher in patients with prolonged saccade latency (1.61 ± 0.38 VS 1.14 ± 0.39, p=0.001) and hypometria (1.46 ± 0.39 VS 1.18 ± 0.48, p=0.043) than in patients without those abnormalities. The average saccade latency was positively correlated with the level of TNF-β (r=0.378, p=0.021), while the average saccadic accuracy was negatively correlated with the level of TNF-β (r=-0.333, p=0.044). IL-12p70 was significantly elevated in patients with defective pursuit compared to patients with normal pursuit (1.63 ± 0.20 VS 1.21 ± 0.54, p=0.040). (2) In the patients with vestibulo-oculomotor dysfunction, the plasma levels of IL-2 (3.40 ± 1.00 VS 2.13 ± 0.91, p=0.007), IL-17A (6.42 ± 3.59 VS 3.05 ± 2.13, p=0.021) and TNF-β (1.55 ± 0.41 VS 1.21 ± 0.37, p=0.030) were significantly elevated compared to the patients with normal vestibulo-oculomotor function. Inflammation-mediated pathological mechanism, especially TNF-β-related pathways, is associated to both central and peripheral vestibular dysfunction in FD patients.

BackgroundTwo recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes.MethodsIn this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex.Results387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (β: −18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar.ConclusionsTreatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta.

Anderson-Fabry disease (AFD), a genetic disorder caused by mutations in the α-galactosidase-A (GLA) gene, disrupts lysosomal function, leading to vascular complications. The accumulation of globotriaosylceramide (Gb3) in arterial walls triggers upregulation of adhesion molecules, decreases endothelial nitric oxide synthesis, and induces reactive oxygen species production. This cascade results in fibrotic thickening, endothelial dysfunction, hypercontractility, vasospasm, and a pro-thrombotic phenotype. AFD patients display increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating heightened cardiovascular risk. Nailfold capillaroscopy (NFC) shows promise in diagnosing and monitoring microcirculatory disorders in AFD, though it remains underexplored. Morphological evidence of AFD as a storage disorder can be demonstrated through electron microscopy and immunodetection of Gb3. Secondary pathophysiological disturbances at cellular, tissue, and organ levels contribute to the clinical manifestations, with prominent lysosomal inclusions observed in vascular, cardiac, renal, and neuronal cells. Chronic accumulation of Gb3 represents a state of ongoing toxicity, leading to increased cell turnover, particularly in vascular endothelial cells. AFD-related vascular pathology includes increased renin-angiotensin system activation, endothelial dysfunction, and smooth muscle cell proliferation, resulting in IMT increase. Furthermore, microvascular alterations, such as atypical capillaries observed through NFC, suggest early microvascular involvement. This review aims to unravel the complex interplay between inflammation, oxidative stress, and endothelial dysfunction in AFD, highlighting the potential connections between metabolic disturbances, oxidative stress, inflammation, and fibrosis in vascular and cardiac complications. By exploring novel cardiovascular risk factors and potential diagnostic tools, we can advance our understanding of these mechanisms, which extend beyond sphingolipid accumulation to include other significant contributors to disease pathogenesis. This comprehensive approach can pave the way for innovative therapeutic strategies and improved patient outcomes.