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Background: Lysosomal diseases (LDs) are progressive life-threatening disorders that are usually asymptomatic at birth. Specific treatments are available for several LDs, and early intervention improves patient's outcomes. Thus, these diseases benefit from newborn screening (NBS). We have performed a pilot study for six LDs in Brazil by tandem mass spectrometry., Methods: Dried blood spot (DBS) samples of unselected newborns were analyzed by the Neo-LSD™ kit (Perkin-Elmer) by MS/MS. Samples with low enzyme activity were submitted to the evaluation of specific biomarkers by ultra-performance liquid chromatography tandem-mass spectrometry as the second-tier, and were analyzed by a next-generation sequencing (NGS) multi-gene panel as the third-tier. All tests were performed in the same DBS sample., Results: In 20,066 newborns analyzed, 15 samples showed activity of one enzyme below the cutoff. Two newborns had biochemical and molecular results compatible with Fabry disease, and five newborns had biochemical results and pathogenic variants or variants of unknown significance (VUS) in GAA., Conclusions: This study indicates that the use of enzyme assay as the first-tier test gives an acceptably low number of positive results that requires second/third tier testing. The possibility to run all tests in a DBS sample makes this protocol applicable to large-scale NBS programs., Competing Interests: Declaration of Competing Interest The authors declare no confliefhe writing of the manuscript, or in the decision to publish the results., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Fabry disease is a rare, multisystemic disorder caused by GLA gene variants that lead to alpha galactosidase A deficiency, resulting in accumulation of glycosphingolipids and cellular dysfunction. Fabry-associated clinical events (FACEs) cause significant morbidity and mortality, yet the long-term effect of Fabry therapies on FACE incidence remains unclear., Methods: This posthoc analysis evaluated incidence of FACEs (as a composite outcome and separately for renal, cardiac and cerebrovascular events) in 97 enzyme replacement therapy (ERT)-naïve and ERT-experienced adults with Fabry disease and amenable GLA variants who were treated with migalastat for up to 8.6 years (median: 5 years) in Phase III clinical trials of migalastat. Associations between baseline characteristics and incidence of FACEs were also evaluated., Results: During long-term migalastat treatment, 17 patients (17.5%) experienced 22 FACEs and there were no deaths. The incidence rate of FACEs was 48.3 events per 1000 patient-years overall. Numerically higher incidence rates were observed in men versus women, patients aged >40 years versus younger patients, ERT-naïve versus ERT-experienced patients and men with the classic phenotype versus men and women with all other phenotypes. There was no statistically significant difference in time to first FACE when analysed by patient sex, phenotype, prior treatment status or age. Lower baseline estimated glomerular filtration rate (eGFR) was associated with an increased risk of FACEs across patient populations., Conclusions: The overall incidence of FACEs for patients during long-term treatment with migalastat compared favourably with historic reports involving ERT. Lower baseline eGFR was a significant predictor of FACEs., Competing Interests: Competing interests: DAH reports advisory board participation, consulting fees and honoraria for Takeda, Sanofi, Amicus Therapeutics, Inc., Idorsia, Freeline and Protalix. DGB reports advisory board participation, consulting fees, speakers’ bureau fees and honoraria from Amicus Therapeutics, Inc. and Sanofi/Genzyme. RG reports consulting fees from Abeona, Amicus Therapeutics, Inc., Chiesi, Denali, Inventiva, JCR, Novartis, PTC, Protalix, RegenxBio and Sobi; speakers’ bureau fees from BioMarin, Amicus Therapeutics, Inc., Chiesi, Idorsia, Janssen, Novartis, Pfizer, PTC, Sanofi and Takeda; research funding from Allievex, Avrobio, Azafaros, JCR, Lysogene, Paradigm, PassageBio, RegenxBio, Sanofi, Sigilon, Takeda and Ultragenyx. RJH reports consulting fees from Alexion, Amicus Therapeutics, Inc., Avrobio, Chiesi, Sangamo, Sanofi/Genzyme and Takeda; advisory fees from Alexion, Amicus Therapeutics, Inc. and Sanofi/Genzyme; speakers’ bureau fees from Alexion and Sanofi/Genzyme and grants/research funding from Alexion, Amicus Therapeutics, Inc., Idorsia, Protalix, Sangamo, Sanofi/Genzyme and Takeda. EK reports consulting fees from Amicus Therapeutics, Inc. KN reports advisory board participation for Amicus Therapeutics, Inc., Takeda and Sanofi/Genzyme; consulting fees from Amicus Therapeutics, Inc. and Takeda and research funding from Amicus Therapeutics, Inc., Takeda, Sanofi/Genzyme, Idorsia and Avrobio. IO reports advisory board participation for Amicus Therapeutics, Inc., Bristol Myers Squibb, Bayer, Astra Zeneca and Cytokinetics; contracted research for Amicus Therapeutics, Inc., Menarini International, Shire-Takeda, Bristol Myers Squibb, Boston Scientific and Sanofi/Genzyme and speaker’s bureau fees from Boston Scientific, Bristol Myers Squibb and Sanofi/Genzyme. UF-R reports advisory board participation from Amicus Therapeutics, Inc., Freeline, Sanofi/Genzyme and Takeda; speakers’ fees and travel support from Amicus Therapeutics, Inc., Sanofi/Genzyme and Takeda and research funding from Sanofi/Genzyme and Takeda. NSa reports speakers’ bureau fees from Amicus Therapeutics, Inc., Takeda, JCR and Sanofi and research funding from JCR and Sanofi. NSk was an employee and stockholder in Amicus Therapeutics, Inc. at the time of drafting this manuscript and determining the analysis plan. GS-P reports advisory board participation for Amicus Therapeutics, Inc. and Sanofi, research grants/funding from Amicus Therapeutics, Takeda, Idorsia and Freeline and honoraria from Amicus Therapeutics, Inc. and Sanofi. RT reports advisory board participation, consulting fees and honoraria for Takeda, Sanofi, Amicus Therapeutics, Inc. and Chiesi. WRW reports advisory board participation for Sanofi/Genzyme, Takeda, Chiesi, Alexion/Astra Zeneca and BioMarin; research funding from Amicus Therapeutics, Inc. and Takeda; consulting fees from Amicus Therapeutics, Inc. and Spark; contracted clinical study research from Amicus Therapeutics, Inc., Alexion/Astra Zeneca, BioMarin, Chiesi, Freeline, Orphazyme, Pfizer, Protalix, Sangamo, Sanofi/Genzyme, Takeda and 4D Molecular Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of affected patients. Here, we review the history of FOS and the analyses and publications disseminated from the registry, and we discuss the contributions FOS studies have made in understanding FD., Results: FOS was initiated in April 2001 and, as of January 2021, 4484 patients with a confirmed diagnosis and patient informed consent have been enrolled from 144 centers across 26 countries. Data from FOS have been published in nearly 60 manuscripts on a wide variety of topics relevant to FD. Analyses of FOS data have investigated the long-term effectiveness and safety of enzyme replacement therapy (ERT) with agalsidase alfa and its effects on morbidity and mortality, as well as the benefits of prompt and early treatment with agalsidase alfa on the progression of cardiomyopathy and the decline in renal function associated with FD. Based on analyses of FOS data, ERT with agalsidase alfa has also been shown to improve additional signs and symptoms of FD experienced by patients. FOS data analyses have provided a better understanding of the natural history of FD and the specific populations of women, children, and the elderly, and have provided practical tools for the study of FD. FOS has also provided methodology and criteria for assessing disease severity which contributed to the continuous development of medical practice in FD and has largely improved our understanding of the challenges and needs of long-term data collection in rare diseases, aiding in future rare disease real-world evidence studies., Conclusion: FOS over the last 20 years has substantially increased the scientific knowledge around improved patient management of FD and continues to expand our understanding of this rare disease., (© 2022. The Author(s).)

Background: Lysosomal storage disorders (LSDs) are rare genetic disorders, with heterogeneous clinical manifestations and severity. Treatment options, such as enzyme replacement therapy (ERT), substrate replacement therapy, and pharmacological chaperone therapy, are available for several LSDs, including Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (mucopolysaccharidosis type II [MPS II]). However, patients in some countries face challenges accessing treatments owing to limited availability of locally licensed, approved drugs., Methods: The Takeda LSD Charitable access program aims to meet the needs of individuals with GD, FD or MPS II with the greatest overall likelihood of benefit, in selected countries, through donation of ERT to nonprofit organizations, and support for medical capacity-building as well as family support via independent grants. Long-term aims of the program are to establish sustainable healthcare services delivered by local healthcare providers for patients with rare metabolic diseases. Patients receiving treatment through the program are monitored regularly, and their clinical data and progress are reviewed annually by an independent medical expert committee (MEC). The MEC also selects patients for enrollment completely independent from the sponsoring company., Results: As of 31 August, 2019, 199 patients from 13 countries were enrolled in the program; 142 with GD, 41 with MPS II, and 16 with FD. Physicians reported improvements in clinical condition for 147 (95%) of 155 patients with follow-up data at 1 year., Conclusions: The response rate for follow-up data at 1 year was high, with data collected for > 90% of patients who received ERT through the program showing clinical improvements in the majority of patients. These findings suggest that the program can benefit selected patients previously unable to access disease-specific treatments. Further innovative solutions and efforts are needed to address the challenges and unmet needs of patients with LSDs and other rare diseases around the world.

Purpose: Following the publication of 5-year agalsidase alfa enzyme replacement therapy (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed., Patients and Methods: FOS (ClinicalTrials.gov identifier: NCT03289065) data (April 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment start (baseline) for patients with ≥3 measurements, including baseline and year 10., Results: Median (range) age (years) of the evaluable treated renal cohort at treatment start was 48.8 (17.9-67.3) for females (n=62), 34.4 (18.0-66.8) for males (n=90). With eGFR ≥60 mL/min/1.73 m 2 at baseline, mean (95% CI) rate of eGFR change (eGFR/year) over 10 years was relatively stable in females (n=52; -0.55 [-1.12, +0.01]) and slightly declined in males (n=79; -1.99 [-2.45, -1.54]). With impaired kidney function (eGFR <60 mL/min/1.73 m 2 ) at baseline, mean (95% CI) eGFR/year was stable in females (n=10; -0.14 [-1.43, +1.15]) and slightly declined in males (n=11; -2.79 [-4.01, -1.56]) over 10 years. Median (range) age (years) of the evaluable treated cardiac cohort at treatment start was 46.7 (3.7-67.3) for females (n=34), 28.2 (4.0-54.2) for males (n=35). With left ventricular hypertrophy (LVH; LVMI >48 g/m 2.7 in females, >50 g/m 2.7 in males) at baseline, mean (95% CI) LVMI/year slightly increased over 10 years in females (n=18; +1.51 [+0.91, +2.12]) and males (n=14; +0.87 (+0.19, +1.55). Without LVH at baseline, mean (95% CI) LVMI/year was stable in females (n=16; +0.52 [-0.13, +1.17]) and males (n=21; +0.57 [+0.02, +1.13]) over 10 years., Conclusion: Agalsidase alfa-treated patients with 10-year FOS data and preserved kidney function and/or normal LVMI at baseline remained largely stable; those with decreased kidney function or LVH at baseline experienced modest declines in renal function and/or increases in LVMI., Competing Interests: Uma Ramaswami has received travel and research grants and honoraria for lectures and advisory boards from Amicus, Chiesi, Genzyme, and Shire (now a member of the Takeda group of companies). She is also a member of the steering committee (SC) of FOS, a registry of Fabry disease sponsored by Shire/Takeda, and has received honoraria for compensation of the time spent on SC meetings. Michael Beck has received consulting fees from Genzyme and Shire. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Derralynn Hughes has received travel and research grants and honoraria for speaking and advisory boards from Amicus, Genzyme, Protalix, and Shire. She also reports personal fees from Takeda, Sanofi, and Amicus, outside the submitted work. She is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Christoph Kampmann has received consulting fees from Amicus, BioMarin, Gore, and Shire and honoraria for lectures and travel and research grants from BioMarin, Shire, and Gore. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Jaco Botha is an employee of Takeda and a Takeda stock owner. Guillem Pintos-Morell has received consulting fees, honoraria for lectures, and travel grants from Alexion, Amicus, BioMarin, and Shire, during the conduct of the study. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Michael West has received consulting fees from GlaxoSmithKline, AvroBio and Shire; has performed contract research for Alexion, Genzyme, Idorsia and Shire; has received speaker honoraria from Excelsior, Genzyme, Shire, and Sumitomo; honoraria for serving on a data and safety monitoring board for Amicus; and honoraria for advisory boards from Actelion, Genzyme, and Shire. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Dau-Ming Niu has received travel and research grants and speaker honoraria from Genzyme and Shire. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Kathy Nicholls reports grants from Melbourne Health, during the conduct of the study and has received research support from Amicus, Genzyme, and Shire, outside the submitted work. She is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. Roberto Giugliani has received consulting fees, fees for non-CME/CE services, investigator fees, and support for travel expenses to attend scientific meetings from Actelion, Amicus, Armagen, BioMarin, GC Pharma, Inventiva, JCR Pharmaceuticals, Lysogene, RegenxBio, Sanofi-Genzyme, Shire, Sobi and Ultragenyx. He is also a member of the SC of FOS and has received honoraria for compensation of the time spent on SC meetings. The authors report no other conflicts of interest in this work., (© 2019 Ramaswami et al.)

Purpose: Outcomes in patients with Fabry disease receiving migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype., Methods: 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-Gb 3 )., Results: Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFR CKD-EPI with migalastat was -0.3 (3.76) mL/min/1.73 m 2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb 3 were -16.7 (18.64) g/m 2 , -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., Conclusion: Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

Background: Fabry disease is frequently characterized by gastrointestinal symptoms, including diarrhea. Migalastat is an orally-administered small molecule approved to treat the symptoms of Fabry disease in patients with amenable mutations., Methods: We evaluated minimal clinically important differences (MCID) in diarrhea based on the corresponding domain of the patient-reported Gastrointestinal Symptom Rating Scale (GSRS) in patients with Fabry disease and amenable mutations (N = 50) treated with migalastat 150 mg every other day or placebo during the phase 3 FACETS trial (NCT00925301)., Results: After 6 months, significantly more patients receiving migalastat versus placebo experienced improvement in diarrhea based on a MCID of 0.33 (43% vs 11%; p = .02), including the subset with baseline diarrhea (71% vs 20%; p = .02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031)., Conclusions: Migalastat was associated with a clinically meaningful improvement in diarrhea in patients with Fabry disease and amenable mutations. Reductions in kidney globotriaosylceramide may be a useful surrogate endpoint to predict clinical benefit with migalastat in patients with Fabry disease., Trial Registration: NCT00925301 ; June 19, 2009.

Fabry disease (FD) is a disorder that results from mutations of hydrolase α-galactosidase A. The enzymatic defect leads to accumulation of globotriaosylceramide (Gb3) in the kidney. Substrate deposition is related to tissue damage in FD, but the relation of urinary Gb3 levels in patients and the renal function markers remain not completely understood. Once nephropathy is one of the main features of FD and is marked by an insidious development, we investigated a possible correlation of Gb3 with biochemical markers of nephropathy including albuminuria, estimated glomerular filtration rate (eGFR), serum creatinine and urea, and proteinuria in male and female patients under or not enzyme replacement therapy (ERT).Gb3, proteinuria and albuminuria were increased in male and female FD patients. We found no correlation between urinary Gb3 levels and all renal function parameters evaluated in Fabry patients (in both sexes and using or not ERT). On the other hand, albuminuria showed negative correlation with eGFR only in male under or not ERT, demonstrating that albuminuria seems to be an early marker of renal function alteration. In conclusion, the results suggest that urinary Gb3 level does not reflect the renal function and that albuminuria is an important biomarker in male FD patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Fabry disease (FD [MIM: 301500]) is a disorder caused by mutations in the alpha-galactosidase gene (GLA), which presents great allelic heterogeneity. The development of fast screening methods may reduce costs and length of diagnosis, being particularly important for screening programs of high-risk female patients. Therefore, the purpose of this study was to develop a pre-sequencing genetic screening method based on high resolution melting (HRM) analysis., Methods: We performed HRM analysis in one hundred and three individuals, 79 females and 24 males, with a total of 27 different variants in 30 different genotypes. We standardized a protocol using EvaGreen, a release-on-demand dye specific for HRM, added to the PCR reaction. Amplification was performed in a conventional real-time system with HRM capability., Results: All genotypes in all amplicons were distinguishable from wild type. In most amplicons it was even possible to differentiate each genotype from the others., Conclusion: We developed a simple, fast and highly sensitive HRM based protocol that may facilitate genetic screening of FD., (Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Purpose: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity., Methods: A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in α-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies., Results: Comparison of the GLP HEK assay results in in vivo white blood cell α-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (≥0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay., Conclusion: The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.Genet Med 19 4, 430-438.

Fabry disease (FD) is caused by deficient activity of the lysosomal enzyme α-galactosidase A. Its substrates, mainly globotriaosylceramide (Gb3), accumulate and seem to induce other pathophysiological findings of FD. Once enzyme replacement therapy (ERT) is not completely efficient on preventing disease progress in FD patients, elucidating the underlying mechanisms in FD pathophysiology is essential to the development of additional therapeutic strategies. We investigated 58 Fabry patients (23 male and 35 female) subdivided into two groups (at diagnosis and during long-term ERT) and compared them to healthy individuals. Fabry patients at diagnosis presented altered glutathione (GSH) metabolism (higher GSH levels, lower glutathione peroxidase - GPx - and normal glutathione reductase - GR - activities), higher lipid peroxidation levels (thiobarbituric acid reactive species - TBARS - and malondialdehyde - MDA), nitric oxide (NO(.)) equivalents and urinary Gb3. Fabry patients on ERT presented GSH metabolism similar to controls, although lipid peroxidation and urinary levels of NO(.) equivalents remained higher whereas Gb3 levels were lower than at diagnosis but still higher than controls. These data demonstrated that redox impairment occurs in Fabry patients before and after ERT, probably as a consequence of Gb3 accumulation, providing targets to future therapy approaches using antioxidants in combination with ERT in FD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes., Methods: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes., Results: The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased., Conclusions: Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

Fabry Disease (FD) is an X-linked inborn error of glycosphingolipid catabolism, caused by a deficiency of the lisosomal α-galactosidase A (AGAL). The disorder leads to a vascular disease secondary to the involvement of kidney, heart and the central nervous system. The mutation analysis is a valuable tool for diagnosis and genetic counseling. Although more than 600 mutations have been identified, most mutations are private. Our objective was to describe the analysis of nine Colombian patients with Fabry disease by automated sequencing of the seven exons of the GLA gene. Two novel mutations were identified in two patients affected with the classical subtype of FD, in addition to other 6 mutations previously reported. The present study confirms the heterogeneity of mutations in Fabry disease and the importance of molecular analysis for genetic counseling, female heterozygotes detection as well as therapeutic decisions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Fabry disease (FD) is a lysosomal storage disorder associated with loss of activity of the enzyme α-galactosidase A. In addition to accumulation of α-galactosidase A substrates, other mechanisms may be involved in FD pathophysiology, such as inflammation and oxidative stress. Higher levels of oxidative damage to proteins and lipids in Fabry patients were previously reported. However, DNA damage by oxidative species in FD has not yet been studied. We investigated basal DNA damage, oxidative DNA damage, DNA repair capacity, and reactive species generation in Fabry patients and controls. To measure oxidative damage to purines and pyrimidines, the alkaline version of the comet assay was used with two endonucleases, formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (EndoIII). To evaluate DNA repair, a challenge assay with hydrogen peroxide was performed. Patients presented significantly higher levels of basal DNA damage and oxidative damage to purines. Oxidative DNA damage was induced in both DNA bases by H2O2 in patients. Fabry patients presented efficient DNA repair in both assays (with and without endonucleases) as well as significantly higher levels of oxidative species (measured by dichlorofluorescein content). Even if DNA repair be induced in Fabry patients (as a consequence of continuous exposure to oxidative species), the repair is not sufficient to reduce DNA damage to control levels., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Fabry disease (FD) is a rare X-linked inborn error of metabolism caused by deficient activity of lysosomal α-galactosidase A (α-GAL). Due to random X inactivation, α-GAL activity in heterozygous females ranges from very low to overlapping normal values. Determining this specific range and altering assays cutoffs could become a valuable tool for minimizing the need in DNA sequencing for screening of all potential carriers. Therefore, the aim of this study was to establish the range of enzyme in dried blood spots (DBS), plasma and leukocytes that suggests carrier status for FD., Design and Methods: α-GAL gene was sequenced in 453 women with clinical suspicion and/or positive family history of FD. This data was compared to the α-GAL activity measured in DBS (dried blood spots) and/or plasma and/or leukocytes., Results: About 12% of the samples had pathogenic mutations (c.30&#95;32delG, c.718&#95;719delAA, p.R118C, p.S126G, p.Y152X, p.A156D, p.C202Y, p.N215S, p.P259R, p.D264Y, p.V269M, p.R342Q and p.R356W). When compared to genotype, DBS was the least reliable biochemical test for screening, with very low specificity. Plasma and leukocyte activities presented high AUC in ROC curve analysis, both over 84%. When cutoffs were altered to identify all carriers, leukocyte specificity was higher than that of plasma (35.2% and 27.6%, respectively). Moderated correlation and agreement coefficients were found between them, which reinforces the need for using both data combined., Conclusion: A combined approach involving plasma and leukocyte α-GAL activities, with distinct cutoffs for men and women, could represent a more accurate, faster and less expensive tool to screen women for FD in high-risk groups in middle- and low-income countries., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Fabry disease (FD) results from mutations in the gene (GLA) that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of α-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively, generally equal to or greater than observed for GL-3. Furthermore, baseline plasma lyso-Gb3 levels were markedly elevated in six male FD patients enrolled in Phase 2 studies. Oral administration of migalastat HCl (150 mg QOD) reduced urine GL-3 and plasma lyso-Gb3 in three subjects (range: 15% to 46% within 48 weeks of treatment). In contrast, three showed no reductions in either substrate. These results suggest that measurement of tissue and/or plasma lyso-Gb3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD.

Background: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day., Methods: Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology., Results: Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients' increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated., Conclusions: Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing.

Fabry disease is an X-linked inborn error of glycosphingolipid catabolism due to deficient activity of α-galactosidase A that leads to accumulation of the enzyme substrates, mainly globotriaosylceramide (Gb3), in body fluids and lysosomes of many cell types. Some pathophysiology hypotheses are intimately linked to reactive species production and inflammation, but until this moment there is no in vivo study about it. Hence, the aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokines and Gb3 levels in Fabry patients under treatment with enzyme replacement therapy (ERT) and finally to establish a possible relation between them. We analyzed urine and blood samples of patients under ERT (n=14) and healthy age-matched controls (n=14). Patients presented decreased levels of antioxidant defenses, assessed by reduced glutathione (GSH), glutathione peroxidase (GPx) activity and increased superoxide dismutase/catalase (SOD/CAT) ratio in erythrocytes. Concerning to the damage to biomolecules (lipids and proteins), we found that plasma levels of malondialdehyde (MDA) and protein carbonyl groups and di-tyrosine (di-Tyr) in urine were increased in patients. The pro-inflammatory cytokines IL-6 and TNF-α were also increased in patients. Urinary Gb3 levels were positively correlated with the plasma levels of IL-6, carbonyl groups and MDA. IL-6 levels were directly correlated with di-Tyr and inversely correlated with GPx activity. This data suggest that pro-inflammatory and pro-oxidant states occur, are correlated and seem to be induced by Gb3 in Fabry patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Disease registries are an important source of information on the natural history of rare diseases and the response to new therapies in a real-world setting. The value of the information, however, is directly related to the completeness of the data entered for each patient over the course of time. The Fabry Outcome Survey (FOS) is a Shire Human Genetic Therapies-sponsored, physician-directed registry of patients with Fabry disease, a rare, multisystem, lysosomal storage disorder, established in 2001., Objective and Methods: In 2005, measures were introduced to improve the completeness of data capture, including a focus on centers with 20 or more patients enrolled in the FOS, concentration on a limited number of core variables (i.e., serum creatinine, urinary protein, left ventricular mass [echocardiography], blood pressure [systolic and diastolic], pain, quality of life, and other Fabry disease-related signs and symptoms, as well as height and weight) and the introduction of Clinical Project Associates (CPAs) to facilitate data management by participating treatment centers., Results: An analysis of random samples of approximately 25% of patients in the registry in 2008 showed significant increases in data capture for most of the core variables examined., Conclusions: We conclude that the measures introduced in 2005 significantly improved the value of the information in the registry, which has contributed greatly to our understanding of patients' real-world experience with enzyme replacement therapy for Fabry disease., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Fabry disease (α-galactosidase A deficiency) is an X-linked disorder. Women who are heterozygous for disease-causing mutations often manifest signs and symptoms of Fabry disease, but most studies of the effects of enzyme replacement therapy (ERT) have included only men. To date, no direct comparison has been made of the relative effectiveness of long-term ERT between men and women. The aim of this analysis was to report the effectiveness of agalsidase alfa in a cohort of 78 women treated for 4 years and to compare outcomes with those of 172 men. All data were obtained from the Fabry Outcome Survey--an international database of patients with Fabry disease sponsored by Shire Human Genetic Therapies. Quantifiable clinical parameters were assessed at baseline and the 4-year time point. Measures of pain, health-related quality of life, cardiac structure and function, and renal function changed to a similar extent in women and men during treatment, with the exception of left ventricular mass, which only reduced significantly in women. Changes in the presence of each of 27 clinical features after 4 years of ERT were evaluated in two subpopulations: patients with and patients without clinical features at baseline. It was clear for most types of clinical features that a number of women with a feature at baseline were no longer reported to have it at the 4-year time point, and that clinical features were observed in only a small percentage of women in whom they had been absent at baseline. The percentage of patients who were symptomatic at the 4-year time point was calculated for each type of clinical feature. The results showed no significant differences between men and women for most clinical features evaluated. Overall, both sexes responded to agalsidase alfa in a similar way, suggesting there should be no difference in the criteria for assessment of treatment in women and men., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Prior to the introduction of enzyme replacement therapy (ERT), management of Fabry disease (FD) consisted of symptomatic and palliative measures. ERT has been available for several years using recombinant human agalsidase alfa, an analogue of alpha-galactosidase A (GALA). However, the limitations of ERT in improving kidney function have not been established. This study evaluates the safety and therapeutic effect of agalsidase alfa replacement in terms of kidney function and reduction in 24-hour proteinuria., Methods: During the period between January 1, 2002, and August 1, 2005, nine Fabry patients (7 male, 2 female) were treated according to protocol, receiving 0.2 mg/kg agalsidase alfa IV every two weeks. Kidney function was evaluated by measuring the glomerular filtration rate (GFR) using chromium ethylene diamine tetra-acetate clearance ((51)Cr-EDTA mL/min/ 1.73 m(2)) at baseline, 12, 24, and 36 months. 24-hour proteinuria was measured at baseline, 3, 6, 12, 18, 24, and 36 months of ERT. Kidney disease was classified according to National Kidney Foundation Disease Outcome Quality Initiative (NKF/DOQI) Advisory Board criteria, which define stage I chronic kidney disease (CKD) as GFR >or= 90 mL/min/1.73 m(2), stage II as 60-89 mL/min/1.73 m(2), stage III as 30-59 mL/min/1.73 m(2), stage IV as 15-29 mL/min/1.73 m(2), and stage V as < 15 mL/min/1.73 m(2)., Results: Six patients completed 36 months of therapy, 2 patients completed 18 months, and 1 patient completed 12 months. Mean patient age at baseline was 34.6 +/- 11.3 years. During the study period, kidney function remained stable in patients with stages I, II, or III CKD. One patient, who entered the study with stage IV CKD, progressed to end-stage chronic kidney disease, beginning hemodialysis after 7 months and receiving a kidney transplant after 12 months of ERT. Proteinuria also remained stable in the group of patients with pathologic proteinuria. The use of agalsidase alfa was well tolerated in 99.5% of the infusions administered., Conclusion: Over the course of 36 months of ERT, there was no change in kidney function and 24-hour proteinuria. This suggests that agalsidase alfa may slow or halt the progression of kidney disease when used before extensive kidney damage occurs. No significant side effects were observed with ERT during the course of the study.

Background: Fabry disease (FD) is a lysosomal storage disorder caused by a deficiency of alpha-Galactosidase A (alpha-Gal A). Fabry nephropathy typically progresses throughout the fifth decade to end-stage renal disease (ESRD), requiring hemodialysis and/or kidney transplantation., Objective: To estimate the prevalence of FD among ESRD males on hemodialysis treatment in Rio Grande do Sul, the southernmost state of Brazil., Methods: Screening for alpha-Gal A activity was performed by a dried blood spot (normal reference value: >1.5 nmoles/hour/mL). Positive screening results were confirmed by plasma alpha-Gal A activity assay (reference value: >3.3 nmoles/hour/mL)., Results: Five hundred fifty-eight male patients on hemodialysis were evaluated. Of these, only two had low alpha-Gal A activity and were diagnosed with Fabry disease (0.36%). One of these, age 42, had left ventricular hypertrophy and renal manifestations of Fabry disease without the classic symptoms. The other, age 46, had the classical manifestations of angiokeratomas, acroparesthesias, hypohidrosis, and ocular opacities., Conclusions: Although the prevalence of Fabry disease was very low in our study (0.36%), routine screening of male hemodialysis patients would enable earlier identification of many other affected relatives in their families who might benefit from specific clinical treatment.

Purpose: To report the clinical and neuroimaging, central nervous system (CNS) findings of patients with Fabry disease (FD) during 24 months of enzyme replacement therapy (ERT) with agalsidase-alpha., Method: Eight patients were included. Six completed 24 months of ERT. Clinical and magnetic resonance imaging (MRI) data were obtained at 0, 12 and 24 months of ERT. White matter lesions (WML) were evaluated as well as their relation to age, symptoms and neurological examination (CNS score)., Results: MRI was stable in 3 patients. WML and CNS score worsened in one patient, fluctuated in another, and improved in the sixth patient. In the whole series, there were 15 WML at baseline, and 19 at the 24th month. In two years, 4 lesions disappeared, whereas 8 appeared., Conclusion: A widespread pattern of silent WML in FD was seen. In two years, some WML appeared, and some disappeared. If these phenomena were related to the natural history, remains to be demonstrated.

We prospectively performed neurophysiologic studies in nine Fabry's Disease (FD) patients (8 male and 1 female) in order to describe the results of nerve conduction studies (NCS) and electromyography (EMG) and to verify whether the sympathetic skin response (SSR) is impaired in these patients. The investigation protocol included SSR, sensory and motor NCS and EMG. SSR was performed not only in FD patients, but also in 18 normal controls. All FD patients had normal nerve conduction studies and electromyography. SSR was present in all controls with a mean amplitude of 1453.6+/-682.3 microV. However, the SSR was absent in six and lower than 500 microV in the remaining FD patients. All patients had normal sensory and motor NCS and EMG. SSR, on the other hand, was significantly altered in all patients and this test could, therefore, be useful in the diagnostic evaluation of FD patients.

Fabry disease (FD) is a lysosomal disorder caused by mutations leading to a deficient activity α-galactosidase A with progressive and systemic accumulation of its substrates. Substrates deposition is related to tissue damage in FD, but the underlying molecular mechanisms remain not completely understood. DNA damage has been associated with disease progression in chronic diseases and was recently described in high levels in Fabry patients. Once renal complications are major morbidity causes in FD, we investigated the effects of the latest biomarker for FD - globotriaosylsphingosine (lyso-Gb3) in a cultured renal lineage - human embryonic kidney cells (HEK-293 T) - on DNA damage. In concentrations found in Fabry patients, lyso-Gb3 induced DNA damage (by alkaline comet assay) with oxidative origin in purines and pyrimidines (by comet assay with endonucleases). These data provide new information about a deleterious effect of lyso-Gb3 and could be useful to studies looking for new therapeutic strategies to FD. [ABSTRACT FROM AUTHOR]

Introduction: Venous thromboembolism (VTE) is a multifactorial genetic disorder that occurs in approximately one in a thousand adults per year. Because there is no laboratory test or clinical marker useful for predicting which patients with Fabry disease may develop thrombotic events, this study aimed to determine whether there is a hereditary predisposition to hypercoagulation in these patients. Methods: The prevalence of p.R506Q mutation in the factor V gene and of c.G20210A mutation in Factor II (prothrombin) gene was evaluated in 39 patients with Fabry disease from Southern Brazil and correlated with clinical findings. The DNA analysis was performed by real-time polymerase chain reaction on genomic DNA using TaqMan probes. Results: In this group of patients, the frequency of mutation in the prothrombin gene was 1.28%, whereas no patient showed mutation in the factor V gene; additionally, there was no correlation between these mutations and the incidence of thrombotic events. Conclusion: Hereditary thrombophilia due to mutations in factor V and prothrombin genes does not seem to be related to thrombotic events in Fabry patients in our cohort, although studies in larger cohorts and the inclusion of additional factors may be required to determine if a correlation exists. [ABSTRACT FROM AUTHOR]

Background: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme á-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day. Methods: Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. Results: Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients' increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated. Conclusions: Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing. Trial registration: Clinicaltrial.gov: NCT00283959 and NCT00283933 [ABSTRACT FROM AUTHOR]