알파갈락토시다제

PURPOSE: To evaluate the disease biomarker response of venglustat in patients with Fabry disease (FD), utilizing data from a single-arm phase 2 study of venglustat and a placebo-controlled phase 3 study of agalsidase beta through historical control and case-matched analyses. METHODS: Eleven venglustat-treated male patients with classic FD in the phase 2 study were matched with placebo- or agalsidase beta-treated patients from the phase 3 study based on propensity scores at baseline. Changes from baseline in plasma globotriaosylceramide (GL-3 or Gb3) concentrations were analyzed at approximately 6-36 months. RESULTS: Venglustat treatment resulted in greater significant reductions in plasma GL-3 concentrations at 6 months from baseline vs. placebo (mean difference -2.56 μg/mL, p < 0.001), and at 24 and 36 months from baseline vs. agalsidase beta (mean difference -1.8 μg/mL, p < 0.05 and -2.35 μg/mL, p < 0.01, respectively). GL-3 concentrations continued to decline with venglustat for up to 3 years without plateauing. CONCLUSIONS: Venglustat showed significantly greater reductions in plasma GL-3 concentrations than placebo after 6 months and agalsidase beta after 24 and 36 months. These findings support the potential of long-term venglustat treatment to reduce GL-3 accumulation in patients with classic FD. Further studies are needed to confirm clinical benefit. © 2025 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

BACKGROUND: Fabry 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. METHODS: We 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). RESULTS: Overall, 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. CONCLUSION: These 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. © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676. © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BACKGROUND: Postprandial symptoms presumably related to intestinal gas production are common in patients with irritable bowel syndrome (IBS). The aim of the study was to assess if oral α-galactosidase is superior to placebo in reducing gastrointestinal (GI) symptoms and intestinal gas production after ingestion of carbohydrate-rich meals in adult patients with IBS. METHODS: We studied the effect of 1200 GaIU/meal α-galactosidase (Nogasin® ) or placebo capsules on GI symptoms in patients with IBS after three standardized, meals high in oligosaccharides, in a randomized, double-blind, crossover study. The intensity of eight GI symptoms was rated, and breath hydrogen and methane were measured every 30 min during 7.5 h. The severity of GI symptoms the following morning was assessed and compared with baseline. S KEY RESULTS: Twenty adult patients with IBS (19 females), mean age 49 years (range 22-75 years), were included. All test meals were well tolerated but induced a gradual increase in GI symptom severity. Neither GI symptom ratings over time, nor hydrogen and methane concentrations differed between the days with α-galactosidase or placebo. The severity of abdominal pain and bloating was lower the following morning, but with no differences between α-galactosidase and placebo. CONCLUSIONS & INFERENCES: The use of α-galactosidase together with meals high in oligosaccharides was in this pilot study not superior to placebo in reducing postprandial GI symptoms or the concentration of hydrogen and methane in expired air in IBS. © 2021 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.

Recently, a new mechanism of drug-drug interaction (DDI) was reported between agalsidase, a therapeutic protein, and migalastat, a small molecule, both of which are treatment options of Fabry disease. Migalastat is a pharmacological chaperone that stabilizes the native form of both endogenous and exogenous agalsidase. In Fabry patients co-administrated with agalsidase and migalastat, the increase in active agalsidase exposure is considered a pharmacokinetic effect of agalsidase infusion but a pharmacodynamic effect of migalastat administration, which makes this new DDI mechanism even more interesting. To quantitatively characterize the interaction between agalsidase and migalastat in human, a pharmacometric DDI model was developed using literature reported concentration-time data. The final model includes three components: a 1-compartment linear model component for migalastat; a 2-compartment linear model component for agalsidase; and a DDI component where the agalsidase-migalastat complex is formed via second order association constant kon, dissociated with first order dissociation constant koff, and distributed/eliminated with same rates as agalsidase alone, albeit the complex (i.e., bound agalsidase) has higher enzyme activity compared to free agalsidase. The final model adequately captured several key features of the unique interaction between agalsidase and migalastat, and successfully characterized the kinetics of migalastat as well as the kinetics and activities of agalsidase when both drugs were used alone or in combination following different doses. Most parameters were reasonably estimated with good precision. Because the model includes mechanistic basis of therapeutic protein and small molecule pharmacological chaperone interaction, it can potentially serve as a foundational work for DDIs with similar mechanism. © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Migalastat HCl is an investigational, pharmacological chaperone for mutant α-galactosidase A, which is responsible for Fabry disease, an X-linked, lysosomal storage disorder. Two Phase I studies evaluated relative bioavailability, effect of meal type and timing on pharmacokinetics, safety, and tolerability of migalastat HCl in healthy volunteers. Study 1 (N = 15, 19-55 years): single 100-mg doses of migalastat HCl capsule and solution formulations were bioequivalent. The ratios of LSM (90% CIs) for Cmax were 97.1% (86.8-109) and AUC0-inf 97.9% (88.8-108) under fasted conditions. Single 100-mg doses of migalastat HCl capsules administered with a high-fat meal decreased Cmax by 40% and AUC0-inf by 37%. A high-fat meal delayed tmax by approximately 1 hour. Study 2 (N = 20, 18-65 years): A high-fat or light meal up to 1 hour before or after administration of single 150 mg doses of migalastat HCl capsules decreased Cmax and AUC0-inf up to 40%, but had no apparent effect on tmax (range of medians with food: 1.5-3 hours, median fasted: 3 hours). A 50-g glucose drink co-administered with migalastat HCL did not result in clinically significant changes in migalastat absorption. No serious safety or tolerability issues were identified. © 2014, The American College of Clinical Pharmacology.

Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease.

Since the melanocortin MC3 and melanocortin MC4 receptors are the main melanocortin receptor subtypes expressed in rat brain, we characterized the activity and affinity of nine melanocortin receptor ligands using these receptors in vitro, as well as their activity in a well-defined melanocortin-induced behavior in the rat: grooming behavior. We report here that [D-Tyr4]melanotan-II and RMI-2001 (Ac-cyclo-[Cys4, Gly5, D-Phe7, Cys10]alpha-MSH-NH2) have significantly higher affinity and potency on the rat melanocortin MC4 receptor as compared to the rat melanocortin MC3 receptor. Nle-gamma-MSH (melanocyte-stimulating hormone) was the only ligand with higher affinity and potency on the rat melanocortin MC3 receptor. The potency order of melanocortin MC4 receptor agonists, but not that of melanocortin MC3 receptor agonists, fitted with the potency of these ligands to stimulate grooming behavior, when administered intracerebroventricularly. SHU9119 (Ac-cyclo-[Nle4, Asp5, D-Nal(2)7, Lys10]alpha-MSH-(4-10)-NH2) and RMI-2005 (Ac-cyclo-[Cys4, Gly5, D-Na](2)7, Nal(2)9, Cys10]alpha-MSH-(4-10)-NH2) were able to inhibit alpha-MSH-induced melanocortin receptor activity in vitro, as well as alpha-MSH-induced grooming behavior. Melanotan-II, [Nle4-D-Phe7]alpha-MSH and RMI-2001 were also effective in inducing grooming behavior when administered intravenously. In the absence of purely selective melanocortin MC(3/4) receptor ligands, we demonstrated that careful comparison of ligand potencies in vitro with ligand potencies in vivo, could identify which melanocortin receptor subtype mediated alpha-MSH-induced grooming behavior. Furthermore, blockade of novelty-induced grooming behavior by SHU9119 demonstrated that this physiological stress response is mediated via activation of the melanocortin system.

30. C R Seances Soc Biol Fil. 1980;173(6):1152-6. [Functional, histological, ultrastructural and biochemical study of rat kidney treated with fosfomycin and gentamycin, administered separately or together]. [Article in French] Viotte G, Morin JP, Bendirdjian JP, Godin M, Fillastre JP. Wistar rats received by intraperitoneal injection for 8 days different doses of Fosfomycin, a new antibiotic. No renal pathological changes are seen under light microscopy after these treatments. Ultrastructural study reveal an intact cellular structure of the proximal tubule. Fosfomycin induces no change in the lysosomal structural latency and enzymatic study show no change in the activities of our hydrolases (alanine-aminopeptidase, alpha-galactosidase, N-acetyl-beta-D-glucosaminidase and sphingomyelinase), after treatment by 100 and 500 mg/kg Fosfomycin. At 1000 mg/kg, Fosfomycin induces an inhibition in enzymatic activities of the four hydrolases. Fosfomycin does not modify the activity of Gentamicin on the proximal tubular cell and induces neither protection nor potentialization of its nephrotoxic effect.

BACKGROUND: This is the first phase 4 study evaluating safety and efficacy of enzyme replacement therapy (ERT) in Chinese patients with Fabry disease, and exploring the impact of COVID-19 infection on the prognosis of Fabry disease under ERT. METHODS AND RESULTS: Eligible patients received an infusion of agalsidase beta (1.0 mg/kg/2w) for up to 48 weeks. The primary endpoint was the safety of agalsidase beta. The endpoints of efficacy included changes in plasma globotriaosylceramide (GL-3), globotriaosylsphingosine (Lyso-GL-3), symptoms and estimated glomerular filtration rate (eGFR) from baseline to week 48. A post-hoc subgroup analysis was conducted by age group (< 30 years and ≥ 30 years) and in patients with or without COVID-19 infection. All 22 patients completed the study and 14 of them were infected by COVID-19. Treatment-related adverse events (AEs) and infusion-associated reactions (IARs) were reported in 8 participants (36.4%). Mean plasma GL-3 (-34.6%) and Lyso-GL-3 (-60.3%) levels decreased from baseline to week 48. Thirteen participants (59.1%) experienced improved specific symptoms at week 48. There were no meaningful changes in eGFR during the study, and the overall population showed an annual eGFR slope of 0.43 mL/min/1.73 m2/year (95% CI: -5.95 to 6.82). In the subgroup analysis, the reductions in plasma GL-3 and Lyso-GL-3 levels, improvement in symptoms, and attenuation of eGFR decline after 48 weeks of treatment were generally greater in patients aged < 30 years (n = 11) than in patients aged ≥ 30 years (n = 11), and less pronounced in the COVID-19 infected group (n = 14) than in the uninfected group (n = 8). CONCLUSIONS: This study demonstrates that agalsidase beta is safe and effective in Chinese patients with Fabry disease, and suggestes that COVID-19 infection may potentially impact the renal prognosis for Fabry disease. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05054387. Registered 09 September 2021, https://clinicaltrials.gov/study/NCT05054387. © 2025. The Author(s).

Fabry disease is a rare X-linked lysosomal disease, in which mutations in the gene encoding α-galactosidase A result in progressive cellular accumulation of globotriaosylceramide (GL-3) in various organs including the skin, kidney, and heart, often leading to life-threatening conditions. Enzyme replacement therapy is currently the standard therapy for the disease, to which two α-galactosidase A formulations have been approved: agalsidase α (Replagal®, Shire) and agalsidase β (Fabrazyme®, Sanofi). We have recently developed a biosimilar of agalsidase β, JR-051, and investigated its pharmacokinetics and pharmacodynamics to assess its bioequivalence to agalsidase β. In a randomized phase I study, healthy adult male volunteers were treated with JR-051 or agalsidase β and the pharmacokinetics of the drugs were compared. The ratio of geometric means (90% confidence interval [CI]) of the AUC0-24 and Cmax for JR-051 over agalsidase β were 0.91 (0.8294, 1.0082) and 0.90 (0.7992, 1.0125), respectively. In a 52-week, single-arm, phase II/III study, patients with Fabry disease switched therapy from agalsidase β to JR-051 to evaluate its pharmacodynamics. The mean (95% CI) plasma GL-3 concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.03 (0.91, 1.15) and 0.96 (0.86, 1.06), respectively, which were within the pre-determined bioequivalence acceptance range (0.70, 1.43). The mean (95% CI) plasma globotriaosylsphingosine (lyso-GL-3) concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.07 (0.92, 1.23) and 1.13 (1.03, 1.22), respectively. Estimated glomerular filtration rate and left ventricular mass index, as renal and cardiac function indicators, showed no notable changes from baseline throughout the study period, and no new safety concerns were identified. In conclusion, these studies demonstrated bioequivalence of JR-051 to agalsidase β in terms of its pharmacokinetics and pharmacodynamics. JR-051 offers a potential new treatment option for patients with Fabry disease.

Fabry disease (FD) was an X-linked lysosomal storage disorder resulting from a deficiency in glycosphingolipid catabolism caused by mutations in the α-galactosidase A gene GLA. Variant FD patients did not present with classical symptoms during childhood and were undiagnosed or misdiagnosed with other kidney diseases, such as chronic glomerulonephritis (CGN). In this study, we utilized exome sequencing and Sanger sequencing identified the variation p.E66Q of GLA completely co-segregated with the disease phenotype in a Chinese family, which previously been diagnosed as possible CGN. Female patients exhibited preferential X-chromosome inactivation (XCI) of the normal p.E66 allele, as indicated by XCI analysis. By measuring α-Gal A activity, we found that male patients in the pedigree had just little enzymatic activity while female patients had residual enzymatic activity. These patients were diagnosed with renal variant FD in subsequent clinical review. Our results directly implicated the GLA mutation p.E66Q as the genetic etiology of the Chinese renal variant FD pedigree.

Patients that are exposed to biotechnology-derived therapeutics often develop antibodies to the therapeutic, the magnitude of which is assessed by measuring antibody titers. A statistical approach for analyzing antibody titer data conditional on seroconversion is presented. The proposed method is to first transform the antibody titer data based on a geometric series using a common ratio of 2 and a scale factor of 50 and then analyze the exponent using a zero-inflated or hurdle model assuming a Poisson or negative binomial distribution with random effects to account for patient heterogeneity. Patient specific covariates can be used to model the probability of developing an antibody response, i.e., seroconversion, as well as the magnitude of the antibody titer itself. The method was illustrated using antibody titer data from 87 male seroconverted Fabry patients receiving Fabrazyme. Titers from five clinical trials were collected over 276 weeks of therapy with anti-Fabrazyme IgG titers ranging from 100 to 409,600 after exclusion of seronegative patients. The best model to explain seroconversion was a zero-inflated Poisson (ZIP) model where cumulative dose (under a constant dose regimen of dosing every 2 weeks) influenced the probability of seroconversion. There was an 80% chance of seroconversion when the cumulative dose reached 210 mg (90% confidence interval: 194-226 mg). No difference in antibody titers was noted between Japanese or Western patients. Once seroconverted, antibody titers did not remain constant but decreased in an exponential manner from an initial magnitude to a new lower steady-state value. The expected titer after the new steady-state titer had been achieved was 870 (90% CI: 630-1109). The half-life to the new steady-state value after seroconversion was 44 weeks (90% CI: 17-70 weeks). Time to seroconversion did not appear to be correlated with titer at the time of seroconversion. The method can be adequately used to model antibody titer data.

BACKGROUND: Cryptogenic stroke (CS) is an ischemic stroke with no identifiable cause after extensive evaluation and is particularly concerning in young adults. Among potential etiologies, Fabry disease (FD), a rare X-linked lysosomal storage disorder caused by GLA mutations, has been implicated. FD leads to α-galactosidase A deficiency and accumulation of globotriaosylceramide in endothelial cells, contributing to cerebrovascular events. However, the prevalence and clinical features of FD in CS remain uncertain. To determine the prevalence of FD in CS and characterize its classical manifestations. METHODS: We performed a systematic review and meta-analysis (PROSPERO: CRD420251003865) in accordance with PRISMA 2020. PubMed, Embase, Web of Science, and Scopus were searched through January 2025. Eligible studies assessed FD among adult CS patients using enzymatic and/or genetic testing. A random-effects model was used to calculate pooled prevalence estimates. Heterogeneity was evaluated via I2, and meta-regression was used to explore variability. RESULTS: Sixteen studies (n = 7048) were included. The pooled prevalence of FD in CS was 1.3% (95% CI 0.75-2.32%; I2 = 56.4%). Among FD-positive patients, the pooled prevalence of hypohidrosis was 15.9%, acroparesthesia 8.9%, pain crises 6.0%, angiokeratoma 3.7%, and cornea verticillata 1.9%. Meta-regression identified male sex as a significant predictor. CONCLUSION: FD accounts for a small but clinically relevant proportion of cryptogenic strokes. Selective screening, especially in young males with systemic redflags, may improve early detection. Future research should adopt standardized diagnostic algorithms to enhance cost-effective identification and management. LEVEL OF EVIDENCE: III. © 2025. Springer-Verlag GmbH Germany, part of Springer Nature.

Fabry disease or Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (GLA), leading to systemic accumulation of globotriaosyl-ceramide (Gb3). Initially described in 1898 as a dermatological condition, Fabry disease is now recognized as a progressive multisystem disorder with significant cardiac involvement. Cardiomyopathy in Fabry disease arises from Gb3 accumulation in cardiac tissue, resulting in fibrosis, left ventricular hypertrophy (LVH), diastolic dysfunction, and heart failure. The deacylated derivative, lysoGb3, serves as a biomarker of cardiac involvement. Diagnosis relies on enzyme assays, genetic testing, and advanced cardiac imaging modalities like echocardiography and cardiac MRI. Management strategies are centered around enzyme replacement therapy, and prognosis varies due to phenotypic heterogeneity and severity of disease progression. Psychological and social burdens further complicate patient care. However, underdiagnosis remains a concerning issue, particularly in individuals with unexplained cardiomyopathies. Early recognition through increased clinical awareness and genetic screening is crucial for timely intervention. Ongoing research is essential to develop new therapies targeting the genetic and metabolic roots of the disease. This systematic review comprehensively examines current evidence regarding the mechanisms, diagnosis, treatment, and prognosis of cardiomyopathy associated with Fabry disease, providing insights that may enhance clinical practice and guide future research initiatives.

BACKGROUND: Fabry disease (FD) is a rare, X-linked lysosomal storage disorder in which a lack of alpha-galactosidase (α-Gal A) enzyme activity leads to intracellular accumulation of deacylated globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), and their analogs. Lyso-Gb3, present in the blood and urine of affected patients, has been extensively investigated as a biomarker for FD. This systematic literature review (SLR) aimed to comprehensively assess the use of lyso-Gb3 as a biomarker for screening, monitoring, and diagnosis of FD in both real-world and clinical trial settings. METHODS: An SLR was performed to identify the following outcomes in adult and pediatric patients with FD: lyso-Gb3 testing patterns, lyso-Gb3 levels in subpopulations, performance and accuracy of lyso-Gb3 testing for diagnosis, and lyso-Gb3 testing for monitoring of disease progression or treatment efficacy/effectiveness. Interventional and non-interventional studies published between 1 January 2017 and 3 November 2022 were included. Searches were primarily conducted in MEDLINE and Embase; pragmatic or hand searches were also performed. The methodological quality of included full-text studies was assessed using validated appraisal tools. Extracted data were synthesized qualitatively. RESULTS: The SLR included 83 eligible publications, comprising 71 observational studies and 12 clinical trials. Differences in lyso-Gb3 levels were identified across subpopulations, with several studies reporting higher levels in males versus females. Lyso-Gb3 demonstrated good diagnostic performance in newborns and high-risk patients when used in combination with other markers (α-Gal A activity or GLA variants) but failed to diagnose females with late-onset FD. Reliability and stability across different methods used to measure lyso-Gb3 was high, with a coefficient of variation <10 % for inter- and intra-assay measurements. Several studies identified moderate to strong correlation between plasma lyso-Gb3 levels and cardiac measures, but association with renal measures needs further investigation. CONCLUSIONS: Lyso-Gb3 testing demonstrated accuracy in screening, diagnosis, and monitoring of F

OBJECTIVES: Fabry disease (FD) is a rare metabolic disorder which presents with considerable heterogeneity in disease characteristics. Given the absence of interventional studies comparing all available treatments, it is important for indirect treatment comparisons (ITCs) to account for potential treatment effect modifiers (TEMs). This systematic literature review (SLR) aimed to identify patient characteristics that may impact clinical outcomes by analyzing real-world evidence (RWE) in FD. METHODS: An SLR was conducted according to PRISMA guidelines, with searches performed in the EMBASE, MEDLINE, and Cochrane databases (1946-2022; with a recent update in April 2023). Full-text articles reporting clinical outcomes from RWE studies of pharmacological therapies for the treatment of FD were included. RESULTS: Including studies from the recent SLR update, a total of 119 original studies met the PICOS criteria and 25 studies provided insights into TEMS. Potential TEMs in FD were identified: sex, age, timing of treatment initiation (early/delayed), left ventricular hypertrophy (LVH), estimated glomerular filtration rate (eGFR), proteinuria, presence of anti-drug-antibodies (ADAs) at baseline, and previous enzyme replacement therapy (ERT). In three studies (two including ERT-treated patients and one study of migalastat-treated patients) males showed worse renal outcomes than females. Five studies found that younger patients and those who received initial ERT before the age of 25 years had greater reductions in plasma-lysoGb3, as well as more favorable renal, cardiac, and biochemical outcomes. Seven studies identified associations between LVH and reduced eGFR at baseline, along with an increased risk of cardiovascular, renal, and neurological events. In four studies, lower baseline eGFR and proteinuria were associated with faster annual eGFR decline despite ERT; high baseline proteinuria was a significant predictor of renal disease progression. Baseline ADAs were linked to lower eGFR, increased left ventricular mass, and reduced treatment impact on plasma/urine-lysoGb3. Migalastat was effective in treatment-naïve patients, while those previously treated with ERT experie

INTRODUCTION: Fabry's disease (FD) is a genetic lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) lost/reduced activity. We aim to systematically assess the safety and efficacy of Migalastat, an oral pharmacological chaperone, that has been approved for the treatment of FD in patients with amenable mutations. METHODS: We conducted literature search following the PRISMA guidelines in major databases up to 4 February 2024, for studies that assessed the clinical outcomes of migalastat in patients with FD. The New Castle Ottawa Scale was used to evaluate the quality of the included studies. RESULTS: A total of 2141 records were identified through database searches and register searches, amongst which 26 records were screened, and 12 of these were excluded. The remaining 14 reports were sought for retrieval. The 12 retrieved articles were assessed for eligibility and their quality was assessed after their inclusion. Amongst the included studies, 5 were of high quality, 6 were of medium quality, and 1 was of low quality. CONCLUSION: Migalastat showed varied effects on enzyme activity and substrate levels, with gender-specific differences noted in GL-3 substrate activity and eGFR. Overall, it improved cardiac and renal outcomes similarly to enzyme replacement therapy, with a comparable safety profile.

OBJECTIVE: Fabry disease is caused by enzymatic defects in alpha-galactosidase A that leads to the accumulation of glycosphingolipids throughout the body, resulting in a multisystemic disorder. The most common neurological manifestations are neuropathic pain, autonomic nervous system dysfunction and strokes, but some rarer neurological manifestations exist. Among these, aseptic meningitis is a possible complication. Our objectives were to measure the prevalence of this complication in a cohort of patients with Fabry disease, and to describe its clinical features. METHODS: We conducted a retrospective review of Fabry disease patients followed at our tertiary referral center between 1995 and September 2023 with at least one episode of meningitis, and performed a systematic review to identify similar published cases. RESULTS: Four patients out of 107 (3.7%) had at least one episode of aseptic meningitis. Our systematic review identified 25 other observations. The median age of these 29 patients was 29.0 years, the median cerebrospinal fluid leukocyte count was 24 cells/mm3 with a predominance of lymphocytes in 64.7% of cases. In 82.8% of the patients, the diagnosis of Fabry disease was unknown before the meningitis. Large artery stenosis was present in 17.2% of patients and 57.1% of patients had a recent stroke concomitant with the meningitis. Several differential diagnoses were evoked, such as multiple sclerosis or central nervous system vasculitis. INTERPRETATION: Our study suggests that Fabry disease should be considered as a cause of aseptic meningitis. The pathophysiological mechanisms underlying meningeal inflammation remain largely unknown but may reflect the dysregulation of pro-inflammatory signaling pathways. © 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Fabry disease (FD) results from a lack of activity of the lysosomal enzyme α-Galactosidase A (α-Gal A), leading to the accumulation of glycosphingolipids in several different cell types. Protein supplementation by pDNA or mRNA delivery presents a promising strategy to tackle the underlying genetic defect in FD. Protein-coding nucleic acids in FD can be either delivered to the most affected sites by the disease, including heart, kidney and brain, or to specialized organs that can act as a production factory of the enzyme, such as the liver. Lipid-based systems are currently at the top of the ranking of non-viral nucleic acid delivery systems, and their versatility allows the linking to the surface of a wide range of molecules to control their biodistribution after intravenous administration. This systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines and provides an overview and discussion of the targeting ligands that have been employed so far to actively vectorize intravenously administered non-viral vectors based on lipid carriers to clinically relevant organs in the treatment of FD, for protein-coding nucleic acid (pDNA and mRNA) supplementation. Among the thirty-two studies included, the majority focus on targeting the liver and brain. The targeting of the heart has been reported to a lesser degree, whereas no articles addressing kidney-targeting have been recorded. Although a great effort has been made to develop organ-specific nucleic acid delivery systems, the design of active-targeted carriers with high quality, good clinical translation, and large-scale manufacturing capacity is still challenging. © 2024. The Author(s).

BACKGROUND: The diagnosis of Fabry disease (FD) has relevant implications related to the management. Thus, a clear assignment of GLA variant pathogenicity is crucial. This systematic review and meta-analysis aimed to investigate the prevalence of FD in high-risk populations and newborns and evaluate the impact of different GLA variant classifications on the estimated prevalence of FD. METHODS: We searched the EMBASE and PubMed databases on February 21, 2023. Observational studies evaluating the prevalence of FD and reporting the identified GLA variants were included. GLA variants were re-evaluated for their pathogenicity significance using the American College of Medical Genetics and Genomics criteria and the ClinVar database. The pooled prevalence of FD among different settings was calculated. The study was registered on PROSPERO (CRD42023401663) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RESULTS: Of the 3941 studies identified, 110 met the inclusion criteria. The pooled prevalence of FD was significantly different according to the clinical setting and criteria used for the pathogenicity assessment. Using the American College of Medical Genetics and Genomics criteria, the pooled prevalence was 1.2% in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy (26 studies; 10 080 patients screened), 0.3% in end-stage renal disease/chronic kidney disease (38 studies; 62 050 patients screened), 0.7% in stroke (25 studies; 15 295 patients screened), 0.7% in cardiac conduction disturbance requiring pacemaker (3 studies; 1033 patients screened), 1.0% in small-fiber neuropathy (3 studies; 904 patients screened), and 0.01% in newborns (15 studies; 11 108 793 newborns screened). The pooled prevalence was different if the GLA variants were assessed using the ClinVar database, and most patients with a discrepancy in the pathogenicity assignment carried 1 of the following variants: p.A143T, p.D313Y, and p.E66Q. CONCLUSIONS: This systematic review and meta-analysis describe the prevalence of FD among newborns and high-risk populations, highlighting the need for a periodic reassessment of the GLA variants in th

Fabry disease (FD) is an X-linked lysosomal storage disease caused by pathogenic variants in the GLA gene. It has a wide range of clinical manifestations, typically related to the specific underlying GLA variant. One of the main features of FD is kidney involvement; therefore, several studies have addressed the prevalence of FD in all types of patients with chronic kidney disease. We performed a systematic review and meta-analysis of screening studies in chronic kidney disease patients, including those on dialysis, had undergone a kidney transplantation, and those who did not receive kidney replacement therapy, and assessed the prevalence of pathogenic variants in these cohorts. Fifty-five studies were included, involving a total of 84,062 individuals. Of these, 251 cases were positive for FD; a third of the reported GLA variants were of a benign phenotype (37.8%), followed by classical phenotype (31.7%), late onset (15.5%), and of uncertain significance (14.7%). The overall prevalence among dialysis patients was 0.10% (CI95%, 0.06-0.15), 0.28% (CI95%, 0.06-0.15) among patients with kidney transplantation, and 0.17% (CI95%, 0.11-0.39) among those without kidney replacement therapy. Although the overall prevalence of FD is low in patients with kidney involvement, screening, especially in patients who have not yet undergone kidney replacement therapy, is important, in order to provide timely and effective treatment interventions, including disease modifying therapies. The prevalence of kidney involvement in females with Fabry Disease is lower but this should not lead to inadequate follow up. Further research is also needed on the impact of genetic variants of uncertain significance to elucidate their role in Fabry disease.

Comment in Neurology. 2023 May 30;100(22):1074. doi: 10.1212/WNL.0000000000207414. Neurology. 2023 May 30;100(22):1074-1075. doi: 10.1212/WNL.0000000000207415. Neurology. 2023 May 30;100(22):1075. doi: 10.1212/WNL.0000000000207416. Neurology. 2023 Sep 5;101(10):457-458. doi: 10.1212/WNL.0000000000207781. Neurology. 2023 Sep 5;101(10):456-457. doi: 10.1212/WNL.0000000000207789. BACKGROUND AND OBJECTIVES: There is accumulating evidence in the literature indicating a strong correlation between Fabry disease (FD) phenotypes and specific sequence variations in the Galactosidase Alpha (GLA) gene. Among them, the potential pathogenicity and clinical relevance of D313Y variation in patients with FD remain debated. METHODS: We performed a systematic review and meta-analysis of studies reporting D313Y as single occurring variant in the GLA gene and sought to evaluate (1) the prevalence of D313Y variation in different populations with or without clinical manifestations of FD, (2) the clinical FD phenotype in D313Y-positive patients, and (3) the proportion of D313Y-positive patients presenting abnormal laboratory findings (alpha-galactosidase-A deficiency or globotriaosylceramide accumulation). RESULTS: Forty cohorts comprising 211 individuals with D313Y variation among 42,723 participants with available GLA gene-sequencing data were included. Patients highly suspected for FD had a higher prevalence of D313Y variation (4.9%, 95% CI 1.6%-9.9%; I2 = 95.5%) compared with the general population (0%, 95% CI 0%-0.1%; I2 = 1.9%; p = 0.004). The prevalence of D313Y variation was 0.6% (95% CI 0.3%-1%; I2 = 74.1%), 0.4% (95% CI 0.2%-0.7%; I2 = 0%), and 0.3% (95% CI 0.2%-0.4%; I2 = 0%) in patients presenting with neurologic, cardiac, or renal manifestations, respectively. D313Y was associated with a milder, late-onset FD phenotype, as indicated by the mean patient age of 51 years (95% CI 44-59; I2 = 94%) and the evidence of alpha-galactosidase A deficiency and globotriaosylceramide accumulation in 26.7% (95% CI 15.3%-40%; I2 = 34%) and 16.2% (95% CI 8%-26.4%; I2 = 35%) of cases, respectively. D313Y-positive patients displayed predominantly neurologic FD manifestations (58.1%, 95% CI