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Background: The prognostic value of different grades of left ventricular hypertrophy (LVH) and left ventricular (LV) mechanical function in Fabry disease is unclear. We aimed to evaluate the association between the severity of LVH, LV mechanical function, and clinical outcomes in Fabry disease., Methods: We conducted a retrospective cohort study from a single-center registry of adult patients with Fabry disease. Left ventricular mass index (LVMI) was measured by echocardiography. The severity of LVH was categorized by LVMI using the sex-specific cutoff values. Left ventricular mechanical function was measured as LV global longitudinal strain (GLS) by speckle-tracking analysis. The primary outcome was a composite of major adverse cardiovascular events (MACE) at 5 years, including heart failure hospitalization, sustained ventricular tachycardia, acute ischemic stroke, and all-cause mortality., Results: The study included 268 patients (age 50.4 ± 15.4 years, men 46.6%) with Fabry disease (83.2% IVS4+919G > A mutation), and 106 patients (39.6%) had LVH. Patients with mild, moderate, or severe LVH had 5-year MACE rates of 7.4%, 10%, and 30.5%, respectively (P < .001). Moreover, patients with impaired LV GLS (<14.1%) had a higher 5-year MACE rate than those with preserved LV GLS (32.1% vs 2.4%, P < .001). Severe LVH was an independent predictor of MACE compared with absence of LVH (adjusted hazard ratio, 12.73; 95% CI, 1.3-124.71; P = .03), after adjusting for age, sex, hypertension, hyperlipidemia, atrial fibrillation, renal function, average E/e', enzyme replacement therapy, and LV GLS. Patients with severe LVH and impaired LV GLS had the highest incidence for MACE (log-rank P < .05), irrespective of sex, genotypes, and whether receiving enzyme replacement therapy or not., Conclusions: Sex-specific grading of LVH by LVMI is practical for risk stratification in patients with Fabry disease, and impaired LV GLS further refines the prognostication., (Copyright © 2024 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background A previously underrecognized phenotype of left ventricular apical aneurysm (LVAA) has been increasingly identified in Fabry disease. This study explored LVAA's clinical prevalence and its prognostic implications over a long-term follow-up. Methods and Results We retrospectively analyzed 268 consecutive patients with Fabry disease at a tertiary medical center. Patients with increased left ventricular mass index were recognized as having left ventricular hypertrophy (LVH). LVAA was identified using either echocardiography or cardiovascular magnetic resonance imaging. Two patients with ischemic LVAA were excluded. The primary end point was a composite of cardiovascular events, including heart failure hospitalization, sustained ventricular tachycardia, ischemic stroke, and all-cause mortality. Of 266 enrolled patients, 105 (39.5%) had LVH (age 58.5±11.9 years, 48.6% men), and 11 (10.5%) had LVAA. Over 49.3±34.8 months of follow-up, 25 patients with LVH experienced composite events, including 9 heart failure hospitalizations, 4 sustained ventricular tachycardia, 6 ischemic strokes, and 15 mortalities. In patients with LVH, those with LVAA had a significantly higher risk of composite events and lower event-free survival than those without LVAA (8 [72.7%] versus 17 [18.1%], log-rank P <0.001). LVAA was independently associated with an increased risk of composite events (hazard ratio, 3.59 [95% CI, 1.30-9.91]; P =0.01) after adjusting for age, sex, advanced heart failure, renal function, dyslipidemia, atrial fibrillation, left ventricular ejection fraction, left ventricular diastolic function, and left ventricular mass index. Conclusions LVAA is present in approximately 10% of patients with Fabry disease and LVH. It is associated with an increased risk of adverse cardiovascular events and may necessitate aggressive treatment.

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: Fabry disease is an inherited lysosomal storage disease affecting multiple organs with complications, including cardiomyopathy such as left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) has been the main treatment for Fabry patients since 2001. However, the indications of ERT are not clearly defined. We performed a meta-analysis according to previous studies to review the benefit of ERT for LVH improvement in Fabry patients. Methods: We performed a literature search from the National Center for Biotechnology Information (NCBI) and PubMed database without restriction of years for systematic review purposes. We performed a systematic review of clinical cohort studies and trials using a pooled analysis of proportions. We calculated the pooled proportions and the confidence intervals (CI) for left ventricular mass index (LVMI) for both ERT treatment and ERT treatment-naïve groups. The results for before ERT treatment and after ERT treatment are also investigated. Results: A total of 5 cohort studies and 2 randomized controlled trials (RCTs), involving a total of 552 participants (267 on ERT treatment versus 285 on naïve treatment), met the inclusion criteria. The pooled proportions analysis showed that the difference in means of LVMI between the ERT treatment group and the ERT treatment-naïve group was -0.149 [95% CI: -0.431, 0.132]. Effect differences favored the ERT treatment group over the ERT treatment-naïve group ( p = 0.034). Another analysis included 3 cohort studies and 1 RCT with 442 participants (228 on before ERT and 214 on 4 years after ERT). The pooled proportions analysis showed that the difference in means of LVMI between the before ERT treatment group and the after ERT treatment group was -0.448 [95% CI: -0.787, -0.108]. It favored the 4 years after ERT group over the before ERT group ( p = 0.037). Conclusions: Based on the currently available data, our meta-analysis showed that there are beneficial effects on LVH improvement with ERT in Fabry disease patients. It is better to start ERT as soon as we have diagnoses in female carriers and atypically affected males. Further research is needed to investigate the role of ERT in LVH improvement., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease-specific therapies when available. Fabry disease, an X-linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end-stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non-specificity of early symptoms. Newborn screening and screening of at-risk populations, (e.g., patients with hypertrophic cardiomyopathy or undiagnosed nephropathies) can identify individuals with Fabry disease. Subsequent cascade genotyping of family members may disclose a greater number of affected individuals, often at younger age than they would have been diagnosed otherwise., Methods: We conducted a literature search to identify all published data on family genetic testing for Fabry disease, and discussed these data, experts' own experiences with family genetic testing, and the barriers to this type of screening that are present in their respective countries., Results: There are potential barriers that make implementation of family genetic testing challenging in some countries. These include associated costs and low awareness of its importance, and cultural and societal issues. Regionally, there are barriers associated with population educational levels, national geography and infrastructures, and a lack of medical geneticists., Conclusion: In this review, the worldwide experience of an international group of experts of Fabry disease highlights the issues faced in the family genetic testing of patients affected with rare genetic diseases., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Objectives: The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation., Design and Setting: Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed., Results: A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages., Conclusions: PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised., Competing Interests: Competing interests: DAH: advisory boards for Amicus, Sanofi, Shire (now part of Takeda); consulting fees from Amicus, Idorsia, Sanofi and Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire (now part of Takeda). PA: research grant and honoraria from Shire (now part of Takeda); honoraria from Amicus, Biomarin, Sanofi and Ultragenyx. PBD: speaker honoraria from and advisory boards for Takeda and Sanofi; consultancy for Sanofi. FE: travel grants and speaker honoraria from Pfizer, Sanofi Genzyme and Takeda. AF: research grants from Amicus and Shire. OL: travel grants and speaker honoraria from Amicus, Sanofi Genzyme and Shire HGT. AL: speaker’s honoraria or consultation fees from Amicus, Sanofi Genzyme and Takeda. J-CL: speaker’s honoraria and consultation fees from Shire. JCM: research grant and speaker honoraria from Sanofi Genzyme; advisory board for, and honoraria from ST; consulting fees from 4DMT. KN: research support and/or honoraria from Amicus, Idorsia, Protalix, Sanofi and Shire (now part of Takeda); advisory boards for Amicus, Sanofi and Shire (now part of Takeda). D-MN: research funding from Shire (now part of Takeda) and Sanofi. AN: honoraria and research support from Sanofi Genzyme and Shire (now part of Takeda). UR: advisory boards for Amicus, Chiesi, Idorsia and Shire; travel grants and honoraria from Amicus, Genzyme and Shire. RR: travel grants and speaker honoraria from Amicus and Shire HGT (now part of Takeda). PR: advisory board, consulting fees and research grant from Shire (now part of Takeda). RS: advisory boards for Amicus, Sanofi, Shire (now part of Takeda); honoraria from Amicus and Shire; research funding from Idorisia, Protalix, Sanofi Genzyme and Takeda. ES: speaker’s fees and travel support from Amicus, Sanofi Genzyme and Shire; advisory board honoraria from Amicus and Sanofi Genzyme. MT: advisory boards for Amicus, Sanofi and Shire (now part of Takeda); travel grants and speaker’s honoraria from Amicus, Sanofi and Shire; research funding from Amicus, AVROBIO and Idorsia. RT: travel grants, speaker’s honoraria or consultation fees from Amicus, Sanofi Genzyme and Takeda. BV: speaker’s fees and travel support from Greenovation, Sanofi Genzyme and Shire/Takeda; advisory board honoraria from Sanofi Genzyme. DGW: advisory boards for Amicus, Avrobio, Freeline Therapeutics, 4D-MT Technology, Idorsia and Protalix; honoraria and travel expenses from Amicus, Protalix and Sanofi; and equity interest in Reata Pharmaceuticals. MLW: advisory boards for Amicus, Sanofi and Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire; research funding from Amicus, Idorisia, Protalix and Shire. JJ: honoraria from Sanofi; travel expenses from Amicus and Sanofi. MJR is an employee of Oxford PharmaGenesis (Oxford, UK). SF: advisory boards for Amicus; consulting fees from Shire (now part of Takeda); contracted research from Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire (now part of Takeda); speaker’s bureau for Amicus, Sanofi and Shire (now part of Takeda); travel expenses from Amicus, Sanofi and Shire (now part of Takeda)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder engendered by a deficiency of the enzyme α-galactosidase A, leading to systemic accumulation of glycolipids. Studies have reported that the cardiac subtype of FD has a later onset and minimal extracardiac involvement. However, whether the severity of cardiac involvement differs between the classic and cardiac subtypes of FD remains unclear., Methods: We enrolled consecutive patients with classic FD (n = 22; median age [25th-75th percentile], 47.0 [32.75-56.25] years; men, 72.7%) as well as age- and sex-matched patients with a later-onset cardiac subtype of FD who were selected from our cohort of patients with IVS4 919G>A mutation. FD was diagnosed on the basis of clinical symptoms/signs and pedigree screening of index case, plasma α-galactosidase activity, and molecular analysis. Data on clinical manifestations, laboratory findings, and echocardiogram findings were collected before enzyme replacement treatment. Disease severity was evaluated using the Mainz Severity Score Index score., Results: All female patients demonstrated heterozygous mutations, with five, one, and four of them showing normal α-galactosidase activity, classic FD, and cardiac subtype of FD, respectively. The distributions of left ventricular performance indices and comorbidities, including hypertension, diabetes mellitus, and dyslipidemia, were similar between the two groups. Moreover, MSSI cardiovascular scores did not differ significantly between the groups (classic vs cardiac subtype, 10.0 [2.0-12.5] vs 10.5 [9.0-15.25]; p = 0.277)., Conclusion: Cardiac manifestations are similar between patients with classic and cardiac subtype of FD.

The Fabry disease-causing mutation, the GLA IVS4+919G>A (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919G>A mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919G>A mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.

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: Evaluation standards and treatment initiation timing have been debated for a long time, particularly for late-onset Fabry disease (FD), because of its slow progression. However, early initiation of enzyme replacement therapy (ERT) for FD could be effective in stabilizing the disease progression and potentially preventing irreversible organ damage. We aimed to examine globotriaosylceramide (Gb3) deposits in patients' endomyocardial biopsies to understand the early pathogenesis of FD cardiomyopathy., Methods: Immunofluorescent (IF) staining of Gb3 and lysosomal-associated membrane protein 1 (LAMP-1) was performed on endomyocardial biopsies of patients suspected of Fabry cardiomyopathy who had negative or only slight Gb3 accumulation determined by toluidine blue staining and electron microscopic examination., Results: The IF staining results revealed that all patients examined had abundant Gb3 accumulation in their cardiomyocytes, including the ones who are negative for inclusion bodies. Furthermore, we found that early Gb3 deposits were mostly confined within lysosomes, while they appeared extralysosomally at a later stage., Conclusion: A significant amount of lysosomal Gb3 deposits could be detected by IF staining in cardiac tissue before the formation of inclusion bodies, suggesting the cardiomyocytes might have been experiencing cellular stress and damage early on, before the appearance of typical pathological changes of FD during the disease progression.

Fabry disease (FD) is an X-linked lysosomal storage disease and is the result of mutation in the α-Galactosidase A gene; such mutations cause a deficiency in α-Galactosidase A enzyme and an accumulation of glycosphingolipid in tissue. Affected males with classic FD have little or no enzyme activity and have an early onset of symptoms and signs, including acroparesthesias, hypohidrosis, angiokeratomas, gastrointestinal dysfunction and/or a characteristic corneal dystrophy during childhood/adolescence. Males with late-onset FD who have residual enzyme activity develop progressive multi-systemic involvement that leads to renal failure and hypertrophic cardiomyopathy, as well as cerebrovascular disease; these events mostly occur during the fourth to seventh decades of life. Heterozygous females can develop vital organ damage that in turn causes severe morbidity and mortality; these symptoms may be as severe as those in affected males. For the treatable disease, this review aims to raise awareness of early recognition and further management of FD based on newborn screening. As newborn screening for FD has been implemented worldwide, it allows the early detection of individuals with Fabry mutations. Based on screening studies, the prevalence of the later-onset type FD is much higher than that of classical type FD. Newborn screening studies have also revealed that patients with FD may develop insidious but ongoing irreversible organ damage. The timing of enzyme replacement therapy, which is able to stabilize the progression of disease, is important in order to prevent irreversible organ damage. Therapies that may become available in the future include pharmacological chaperones and substrate reduction therapy, both of which are still under investigation as ways of improving the health of individuals with FD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Fabry disease is an X-linked disorder resulted from deficiency of α-galactosidase A (GLA) activity. In Taiwan, a total of 792,247 newborns were screened from 2008 to 2014 in two newborn screening centers, and 13 variants of uncertain significance (VOUS) in the GLA gene were identified. To determine whether these variants were pathogenic or not, functional, biochemical, clinical and pedigree analyses were performed. In vitro functional assay was established through site-directed mutagenesis, and four in silico tools were used to predict pathogenesis. The enzyme activity of dried blood spots and plasma metabolite lyso-Gb3 level from subjects with the variants were measured. Additionally, clinical manifestations were evaluated extensively from the subjects and their relatives. Our results revealed that p.G104V, p.I232T, p.D322H, and p.G360C all exhibited relatively low residual enzyme activities and elevated plasma lyso-Gb3 level. These data strongly suggest that these Fabry mutations may cause classical or later-onset phenotypes. In contrast, neither significantly clinical symptoms nor elevated lyso-Gb3 level was found in cases with p.P60S, p.A108T, p.S304T, p.R356Q, and p.P362T variants, which may be non-pathogenic or milder forms of Fabry variants. More data need to be included for the patients with p.N53D, p.P210S, p.M296L, and p.K391T variants. The established system provides us more information to classify these GLA variants., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Many female carriers of Fabry disease are likely to develop severe morbidity and mortality. However, by our own estimation, around 80% of female newborns are missed by our current enzyme-based screening approach. Our team's aim was to develop an improved cost-effective screening method that is able to detect Fabry disease among female newborns. In Taiwan, based on a database of 916,000 newborns, ~98% of Fabry patients carry mutations out of a pool of only 21 pathogenic mutations. An Agena iPLEX platform was designed to detect these 21 pathogenic mutations using only a single-assay panel. A total of 54,791 female infants were screened and 136 female newborns with the IVS4 + 919G > A mutation and one female newborn with the c.656T > C mutation were identified. Using the current enzyme-based newborn screening approach as baseline, around 83% of female newborns are being missed. Through a family study of the IVS4 female newborns, 30 IVS4 adult family members were found to have left ventricular hypertrophy. Ten patients received endomyocardial biopsy and all were found to have significant globotriaosylceramide (Gb3) accumulation in their cardiomyocytes. All of these individuals now receive enzyme replacement therapy. We have demonstrated that the Agena iPLEX assay is a powerful tool for detecting females with Fabry disease. Furthermore, through this screening, we also have been able to identify many disease-onset adult family members who were originally undiagnosed for Fabry disease. This screening helps them to receive treatment in time before severe and irreversible cardiac damage has occurred.

Objectives: The level of 8-hydroxy-2-deoxyguanosise (8-OHdG) is a marker of oxidative stress. The objective of this study was to evaluate the effect of enzyme replacement therapy (ERT) on the level of 8-OHdG in patients with Fabry cardiomyopathy and the clinical evolution of Fabry cardiomyopathy., Methods: We measured the serum levels of 8-OHdG in 20 healthy control and 22 patients with Fabry cardiomyopathy before and after ERT., Results: The mean lysoGb3 and 8-OHdG levels was significantly increased in patients with Fabry cardiomyopathy compared with that of control subjects (lysoGb3, 3.6 ± 1.1 nM vs. 0.4 ± 0.1 nM, p < 0.01; 8-OHdG, 4.5 ± 0.5 ng/mL vs. 3.4 ± 0.4 ng/mL, P < 0.05). The mean lysoGb3 and 8-OHdG levels was significantly reduced after ERT for 14.2 months (lysoGb3, 3.6 ± 1.1 nM vs. 2.9 ± 1.1 nM, P < 0.05; 8-OHdG, 4.5 ± 0.5 ng/mL to 4 ± 0.4 ng/mL, P < 0.05). These changes were accompanied by decreases in LVM and LVMI., Conclusions: We demonstrated that the serum 8-OHdG levels is increased in patients with Fabry cardiomyopathy (FC) and that successful management of FC with ERT is associated with a decrease in this oxidative stress marker. Serum 8-OHdG levels can be used not only as a noninvasive biomarker of oxidative stress in patients with FC but also an objective and quantitative parameter in the follow-up of patients during ERT., (Copyright © 2017. Published by Elsevier Inc.)

While a base substitution in intron 4 of GLA (IVS4+919G>A) that causes aberrant alternative splicing resulting in Fabry disease has been reported, its molecular mechanism remains unclear. Here we reported that upon IVS4+919G>A transversion, H3K36me3 was enriched across the alternatively spliced region. PSIP1, an adapter of H3K36me3, together with Hsp70 and NONO were recruited and formed a complex with SF2/ASF and SRp20, which further promoted GLA splicing. Amiloride, a splicing regulator in cancer cells, could reverse aberrant histone modification patterns and disrupt the association of splicing complex with GLA. It could also reverse aberrant GLA splicing in a PP1-dependant manner. Our findings revealed the alternative splicing mechanism of GLA (IVS4+919G>A), and a potential treatment for this specific genetic type of Fabry disease by amiloride in the future.

Background: Fabry disease (FD) is a lysosomal storage disease in which glycosphingolipids (GB3) accumulate in organs of the human body, leading to idiopathic hypertrophic cardiomyopathy and target organ damage. Its pathophysiology is still poorly understood., Objectives: We aimed to generate patient-specific induced pluripotent stem cells (iPSC) from FD patients presenting cardiomyopathy to determine whether the model could recapitulate key features of the disease phenotype and to investigate the energy metabolism in Fabry disease., Methods: Peripheral blood mononuclear cells from a 30-year-old Chinese man with a diagnosis of Fabry disease, GLA gene (IVS4+919G>A) mutation were reprogrammed into iPSCs and differentiated into iPSC-CMs and energy metabolism was analyzed in iPSC-CMs., Results: The FD-iPSC-CMs recapitulated numerous aspects of the FD phenotype including reduced GLA activity, cellular hypertrophy, GB3 accumulation and impaired contractility. Decreased energy metabolism with energy utilization shift to glycolysis was observed, but the decreased energy metabolism was not modified by enzyme rescue replacement (ERT) in FD-iPSCs-CMs., Conclusion: This model provided a promising in vitro model for the investigation of the underlying disease mechanism and development of novel therapeutic strategies for FD. This potential remedy for enhancing the energetic network and utility efficiency warrants further study to identify novel therapies for the disease., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Fabry disease is a lysosomal storage disorder with an incidence of 1:1600 for the late-onset IVS4+919G>A cardiac variant mutation in Taiwan. Signs and symptoms of this cardiac variant include left ventricular hypertrophy, mitral insufficiency and/or arrhythmias. The search for biomarkers that might predict the clinical outcomes and guide treatment options is important. We thus investigated relationships between Fabry disease biomarkers (such as globotriaosylceramide (Gb 3 ), globotriaosylsphingosine (lyso-Gb 3 )/related analogues) and age, gender, enzyme activity, clinical manifestations and severity of the disease in these patients., Method: Urine and plasma biomarkers were analyzed using tandem mass spectrometry. A large cohort of 191 adult and pediatric Fabry patients carrying the IVS4+919G>A mutation was studied. Some patients were members of the same family., Results: Our results show that the plasma lyso-Gb 3 level, and urinary analogue levels of lyso-Gb 3 at m/z (+16), (+34), and (+50) adjusted for gender and age had a positive association with the left ventricular mass index, and/or the Mainz Severity Score Index., Conclusions: It might thus be of particular interest to monitor children with high levels of these biomarkers, as part of a longitudinal study in order to determine if the excretion profile at a young age is predictive of the outcomes of disease severity in adulthood., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Patients with the later-onset IVS4+919G>A (IVS4) Fabry mutation are known to have positive central nervous system involvement compared with age- and sex-matched controls. This study compares central nervous system manifestations in patients with the IVS4 mutation or classical Fabry mutations., Methods: This was a retrospective analysis of magnetic resonance imaging (MRI) data from Taiwanese patients enrolled in the Fabry Outcome Survey (sponsored by Shire; data extracted March 2015)., Results: Twenty-five IVS4 (19 males) and 12 (four males) classical Fabry patients underwent MRI at a median (range) age of 60.7 (45.0-70.4) and 43.0 (18.0-61.4) years, respectively. All patients received agalsidase alfa enzyme replacement therapy; two (16.7%) classical Fabry patients underwent MRI before treatment start. The pulvinar sign occurred in eight (32.0%; seven males) IVS4 and six (50.0%; three males) classical Fabry patients. Infarction occurred in eight (32.0%) IVS4 and four (33.3%) classical Fabry patients. Fazekas scores of 0, 1, 2, and 3 were found for 15 (60.0%), seven (28.0%), two (8.0%), and one (4.0%) of the IVS4 patients and for six (50.0%), four (33.3%), two (16.7%), and 0 classical Fabry patients, respectively. Abnormal height bifurcation of the basilar artery was observed in 40.0% of IVS4 and 58.3% of classical Fabry patients; abnormal laterality was observed in 4.0% of IVS4 and 16.7% of classical Fabry patients. Median (range) basilar artery diameter was 2.7 (1.4-4.0) mm in IVS4 and 3.2 (2.3-4.7) mm in classical Fabry patients (P = 0.0293); vascular stenosis was noted in 8.3% of IVS4 patients but in no classical Fabry patients., Conclusions: A similar range of MRI findings was found for both IVS4 and classical Fabry patients. Notably, basilar artery diameter was larger in classical Fabry patients than IVS4 patients.

We retrospectively evaluated correlations between cardiac manifestations and globotriaosylceramide (Gb3) accumulation in cardiomyocytes from Taiwanese patients with Fabry disease and the IVS4+919G>A (IVS4) mutation who underwent endomyocardial biopsy (Shire; Fabry Outcome Survey data; extracted January 2015). Of 24 males and six females (median age [Q1; Q3] at biopsy 60.4 [57.4; 64.1] and 61.3 [60.4; 65.1] years, respectively), 13 males (54.2%) and five females (83.3%) received agalsidase alfa enzyme replacement therapy (ERT) before biopsy. Median left ventricular mass indexed to height (LVMI) within ±6 months of biopsy was 65.3 (52.7; 93.1) in males and 53.2 (42.0; 55.0) g/m 2.7 in females. A moderate, positive, statistically significant correlation was found between the percentage area Gb3 accumulation in cardiomyocytes and LVMI (Spearman's ρ, 0.45; p = 0.014); a smaller, positive, non-statistically significant correlation was observed between cardiomyocyte diameter and LVMI (Spearman's ρ 0.16, p = 0.394). Moderate, statistically significant, negative correlations were found between Gb3 accumulation and ERT duration (Spearman's ρ, -0.49, p = 0.007) and between cardiomyocyte size and ERT duration (Spearman's ρ, -0.37, p = 0.048). Longer ERT duration was associated with smaller amounts of Gb3 accumulation and smaller cardiomyocyte size. Further follow-up is recommended to confirm these trends in a larger sample size., Competing Interests: Ting-Rong Hsu has received travel support from Genzyme and Shire. Svetlana Bizjajeva is an employee of, and holds stock options in, Shire. Wen-Chung Yu has received travel support from Genzyme and Shire. Dau-Ming Niu has received research and travel support from Genzyme and Shire. Fu-Pang Chang, Tzu-Hung Chu, and Shih-Hsien Sung declare no conflicts of interest.

Background: Recently, several studies revealed a much higher prevalence of later onset Fabry disease (FD) than previously expected. It suggested that later onset FD might present as an important hidden health issue in certain ethnic or demographic populations in the world. However, the natural history of its phenotype has not been systemically investigated, especially the cardiac involvement., Objectives: The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD., Methods: To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919G>A (IVS4) mutation. Echocardiography was performed in 620 adults with the IVS4 mutation to analyze the prevalence of left ventricular hypertrophy (LVH), and gadolinium-enhanced cardiac magnetic resonance imaging was performed in 129 patients with FD, including 100 IVS4 adults., Results: LVH was observed in 67% of men and 32% of women older than 40 years. Imaging evidenced significant late gadolinium enhancement in 38.1% of IVS4 men and 16.7% of IVS4 women with the IVS4 mutation but without LVH. Seventeen patients underwent endomyocardial biopsies, which revealed significant globotriaosylceramide substrate accumulation in their cardiomyocytes., Conclusions: Significant cardiomyocyte substrate accumulation in IVS4 patients led to severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations. Thus, it might be too late to start enzyme replacement therapy after the occurrence of LVH or other significant cardiac manifestations in patients with later onset FD. This study also indicated the importance of newborn screening for early detection of the insidious, ongoing, irreversible cardiac damage in patients with later onset FD., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Fabry disease (FD) causes progressive glycosphingolipid accumulation and damage in various organs, and several proinflammatory processes may be involved in this disease. Enzyme replacement therapy (ERT) can reduce the severity of Fabry cardiomyopathy (FC), but whether ERT could attenuate proinflammatory cytokines in FC remains unclear. In this study, we attempted to evaluate the efficacy of ERT on proinflammatory cytokines and vascular cell adhesion biomarkers., Methods: We enrolled 25 patients with FC and administered ERT to them according to the present clinical guideline. We analyzed and compared echocardiographic and blood examination results between 25 patients with FD without left ventricular hypertrophy (LVH), 25 patients with FC with LVH who were receiving ERT, and 25 healthy age- and sex-matched controls. The parameters of cardiac function at baseline and 12 months after ERT were assessed through echocardiography, and the expression profiles of proinflammatory biomarkers were determined., Results: Left ventricular mass (LVM), LVM index (LVMI), interventricular septal thickness at diastole, and serum levels of globotriaosylsphingosine (Gb3) were elevated in patients with FC. Meanwhile, several proinflammatory cytokines, including interleukin (IL)-6, IL-2, IL-1b, tumor necrosis factor-α, intercellular adhesion molecule, soluble vascular cell adhesion molecule, and monocyte chemoattractant protein-1 (MCP-1) were concomitantly increased. ERT significantly reduced these transthoracic echocardiographic parameters and lyso-Gb3 and proinflammatory cytokine levels. The changes in IL-6, MCP-1, and lyso-Gb3 levels were positively correlated with the change in LVMI., Conclusions: Our study has revealed that proinflammatory biomarkers, particularly IL-6 and MCP-1, may represent effective biomarkers for evaluating ERT outcomes in patients with FC., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Baseline demographic and phenotypic characteristics of patients aged ≥50years in the Fabry Outcome Survey (Shire; data extracted June 2014) were compared with younger adults to investigate potential factors influencing treatment decisions in later life. Age groups were defined using age at treatment initiation or at FOS entry for untreated patients: 18-49 (n=1344; 49.5% male; 64.6% received agalsidase alfa enzyme replacement therapy [ERT]); 50-64 (n=537; 35.4% male; 74.3% treated); 65-74 (n=137; 32.1% male; 68.6% treated); and ≥75years (n=26; 26.9% male; 50.0% treated). Successive age groups showed higher median age at first symptom and diagnosis. Median alpha-galactosidase A activity, measured as percentage activity of the midpoint of the normal range, was much greater in females than males of all groups except ≥75years (33.4% in females; 27.8% in males). Patients aged ≥75years showed greater values than patients aged 18-49years for median left ventricular mass indexed to height (62.7 vs 42.4g/m(2.7)), mean ventricular wall thickness (15.0 vs 10.0mm) and prevalence of hypertension (57.7% vs 21.8%), and lower median estimated glomerular filtration rate (Modification of Diet in Renal Disease: 65.6 vs 98.5mL/min/1.73m(2)). Larger proportions in the groups aged ≥50 exhibited cardiac and/or cerebrovascular manifestations compared with patients aged 18-49years. The smaller proportion of patients receiving ERT aged ≥75years compared with the younger groups might reflect relatively milder disease burden or physician/patient reluctance to initiate/continue ERT at this age. Further studies are needed to increase knowledge of Fabry disease and ERT in later life., (Copyright © 2016 Shire Human Genetic Therapies. Published by Elsevier Inc. All rights reserved.)

Background: In Taiwan, DNA-based newborn screening showed a surprisingly high incidence (1/875 in males and 1/399 in females) of a cardiac Fabry mutation (IVS4 + 919G > A). However, the natural course, long-term treatment outcomes and suitable biomarkers for monitoring the therapeutic outcomes of these patients are largely unknown., Methods: Fabry disease (FD) patients who had received enzyme replacement therapy (ERT) for more than 1 year were enrolled in this study from December 2008 to April 2013. Periodic echocardiography and serum globotriaosylsphingosine (lyso-Gb3) analysis were carried out. Before and after ERT, left ventricular mass index (LVMI) and serum lyso-Gb3 level were compared and the correlation between the change of LVMI and the change of serum lyso-Gb3 were also analyzed., Results: Thirty-six patients, in four patient groups, were enrolled: (1) 16 males with IVS4 + 919G > A mutation; (2) 7 females with IVS4 + 919G > A mutation; (3) 2 males with classical mutations; and (4) 11 females with classical mutations. The follow-up period was 13-46 months. There were significant LVMI reductions after ERT in all four groups after excluding confounding factors. However, interestingly, serum lyso-Gb3 decreased significantly in the early period after ERT in all groups, but increased gradually after an average of 11.1 months after ERT in late-onset male and female Fabry groups, even when their LVMI still decreased or remained stable. Furthermore, there was no correlation between the change of serum lyso-Gb3 and the change of LVMI in both classical and IVS4 + 919G > A FD patients., Conclusion: Although lyso-Gb3 has a high diagnostic sensitivity in late-onset Fabry patients and has a good response to ERT during the early stages, it might not be a reliable marker for monitoring the long-term therapeutic outcomes of ERT for late-onset Fabry patients with the Chinese hotspot mutation (IVS4 + 919G > A).

Background: In Taiwan, DNA-based newborn screening showed a surprisingly high incidence of a cardiac Fabry mutation (IVS4 + 919G > A). The prevalence of this mutation is too high to be believed that it is a real pathogenic mutation. The purpose of this study is to identify the cardiac pathologic characteristics in patients with left ventricular hypertrophy and this mutation, Methods and Results: Endomyocardial biopsies were obtained in 22 patients (Median age: 61, males: 17; females: 5) with left ventricular hypertrophy and the IVS4 + 919G > A mutation; five patients had not received enzyme replacement therapy (ERT) before biopsy, while the other 17 patients had received ERT from 8 months to 51 months. Except for three patients who had received ERT for more than 3 years, all other patients showed significant pathological change and globotriaosylceramide (Gb3) accumulation in their cardiomyocytes. In contrast to classical Fabry patients, no Gb3 accumulation was found in the capillary endothelial cells of any of our patients. Fourteen patients (63.6%) were found to have myofibrillolysis., Conclusions: All of the untreated and most of the treated IVS4 + 919G > A patients showed typical pathological changes of Fabry disease in their cardiomyocytes. No endothelial accumulation of Gb3 was found, which is similar to the findings of several previous reports regarding later-onset Fabry disease. This result highly suggests that the IVS4 + 919G > A is a real pathogenic later-onset Fabry mutation.

Background: Fabry disease is an X-linked inherited lysosomal storage disease that can be treated with the enzymes of agalsidase beta (Fabrazyme) and agalsidase alfa (Replagal). Since June 2009, viral contamination of Genzyme's production facility has resulted in a worldwide shortage of agalsidase beta, leading to the switch to agalsidase alfa for patients with Fabry disease in Taiwan., Methods: The medical records were retrospectively reviewed for nine male patients with Fabry disease from the start of agalsidase beta treatment until the switch to agalsidase alfa for at least 1 year., Results: After 12-112 months of enzyme replacement therapy (ERT), decreased plasma globotriaosylsphingosine (lyso-Gb3) was found in five out of seven patients, indicating improvement in disease severity. Among the six patients with available echocardiographic data at baseline and after ERT, all six experienced reductions of left ventricular mass index. Renal function, including microalbuminuria and estimated glomerular filtration rate, showed stability after ERT. Mainz Severity Score Index scores revealed that all nine patients remained stable at 12 months after switching to agalsidase alfa. ERT improved or stabilized cardiac status and stabilized renal function, while reducing plasma lyso-Gb3. ERT was well tolerated, even among the three patients who had hypersensitivity reactions., Conclusion: The switch of ERT from agalsidase beta to agalsidase alfa appears to be safe after 1 year of follow-up for Taiwanese patients with Fabry disease., (Copyright © 2013. Published by Elsevier B.V.)

Background: In view of the therapeutic benefits resulting from early intervention for Fabry disease, our team has implemented an enzyme-based newborn screening in Taiwan since 2008. However, we found that most heterozygous females cannot be detected. To improve the screening efficiency, a more effective method for GLA gene genotyping is necessary., Methods: As the suspected mutations are limited to only 29 different spots in Taiwanese, a panel of Sequenom iPLEX assay was designed for rapid screening of GLA variations. To determine the accuracy and sensitivity of this assay, previously diagnosed and undiagnosed DNA samples were analyzed by this genotyping assay and Sanger sequencing. In addition, DNA extracted from dried blood spots was also tested., Results: Sequenom iPLEX assay is accurate and cost-effective, identifying the sequence variations, which were designated in the panel. It identified common GLA variants in DNA samples extracted from whole blood or dried blood spots with 100% accuracy and sensitivity., Conclusions: Sequenom iPLEX assay is suitable for Fabry newborn screening when hotspot mutations and common variations are known in a well-studied population. In addition, this assay can also be applied for first-line determination of GLA variant sequences in suspected subjects of high-risk patients, or newborns., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Previous studies revealed a high incidence of late-onset Fabry disease mutation, IVS4+919G>A, in Taiwan. However, the natural course is largely unclear and suitable biomarkers for monitoring disease progress are unavailable., Methods and Results: Patients carrying IVS4+919G>A or classical Fabry mutations were enrolled in this study. The subjects ranged from newborn to eighty year old adults. Plasma globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) were measured by LC-MS/MS in subjects to evaluate the sensitivity of these two biomarkers. All adult males and symptomatic females could be distinguished from healthy controls by an elevated plasma lysoGb3 level. The lysoGb3 level was also related to the left ventricular mass considering gender and age (p<0.01). Moreover, approximately 70% of male and 45% of female newborns already had an elevated plasma lysoGb3 level which increased gradually as the subjects got older (p<0.01)., Conclusions: Plasma lysoGb3 is a more sensitive and reliable biomarker than plasma Gb3. LysoGb3 also correlated with age and left ventricular mass index in Fabry patients with IVS4+919G>A mutation. Because lots of infants with the IVS4+919G>A mutation already had elevated lysoGb3 levels at birth, that indicates that the development of hypertrophic cardiomyopathy may require a long and insidious course after lysoGb3 accumulation., (© 2013. Published by Elsevier B.V. All rights reserved.)

Background: As an X-linked genetic disorder, Fabry disease was first thought to affect males only, and females were generally considered to be asymptomatic carriers. However, recent research suggests that female carriers of Fabry disease may still develop vital organ damage causing severe morbidity and mortality. In the previous newborn screening, from 299,007 newborns, we identified a total of 20 different Fabry mutations and 121 newborns with Fabry mutations. However, we found that most female carriers are not detected by enzyme assays., Methods: A streamlined method for high resolution melting (HRM) analysis was designed to screen for GLA gene mutations using a same PCR and melting program. Primer sets were designed to cover the 7 exons and the Chinese common intronic mutation, IVS4+919G>A of GLA gene., Results: The HRM analysis was successful in identifying heterozygous and hemizygous patients with the 20 surveyed mutations. We were also successful in using this method to test dry blood spots of newborns afflicted with Fabry mutations without having to determine DNA concentration before PCR amplification., Conclusion: The results of this study show that HRM could be a reliable and sensitive method for use in the rapid screening of females for GLA mutations., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Newborn screening for Fabry disease in Taiwan Chinese has revealed a high incidence of the late-onset GLA mutation IVS4 + 919G→A (∼1 in 1,500-1,600 males). We studied 94 adults with this mutation [22 men, 72 women; mean age: men 57.8 ± 6.0 (range 42-68), women 39.1 ± 14.1 years (range 19-82)]. Plasma α-galactosidase A activity assay was 10.4 ± 11.2% of normal in the men and 48.6 ± 19.5% of normal in the women. Echocardiography in 90 of the adults revealed left ventricular hypertrophy (LVH) in 19 (21%), including 14 of 21 men (67%) and 5 of 69 women (7%). Microalbuminuria, based on the urine albumin-to-creatinine ratio measured on at least two occasions, was present in 17 of 86 subjects (20%) (men: 5/20, 25%; women 12/66, 18%). At least one ocular manifestation consistent with Fabry disease was present in 41 of 52 subjects (79%) who underwent ophthalmologic examination, including 8 (15%) with conjunctival vessel tortuosity, 15 (29%) with cornea verticillata, 10 (19%) with Fabry cataract, and 34 (65%) with retinal vessel tortuosity. Among subjects over 40 years of age, men were more likely than women to have LVH [14/21 (67%) vs 5/25 (20%), p < 0.001]. Cardiovascular, renal and ocular abnormalities are highly prevalent in adult Taiwan Chinese subjects with the Fabry mutation IVS4 + 919G→A. Our findings contribute to the limited understanding of the course of this late-onset disease variant and underscore the need for close follow up in such patients.

Background: Fabry disease is a treatable lysosomal storage disorder, which is often misdiagnosed or belatedly diagnosed., Methods and Results: To determine the disease incidence in the Taiwan Chinese population, a Fabry disease newborn screening study was initiated. A total of 110 027 newborns were screened by assaying the alpha-galactosidase A (alpha-Gal A) activity using dry blood spots. Low plasma alpha-Gal A activity and presence of a Fabry mutation was demonstrated in 45 neonates (3 females). Eight different mutations were identified, including 3 known missense mutations (R112H, A143T, and R356W), 4 novel missense mutations (G104V, M296L, G360C, and K391T), and one known intronic mutation (IVS4+919G-->A). The IVS4+919G-->A mutation was most common (82% of patients). A total of 20 maternal grandparents of infants harboring this intronic mutation were evaluated by echocardiography, mutation analysis and alpha-Gal A activity assay. The intronic mutation was found in 9 grandfathers and 11 grandmothers. Of these grandparents, 3 grandfathers (33%) but none of the grandmothers had hypertrophic cardiomyopathy. Additionally, 16 males who had been diagnosed with idiopathic hypertrophic cardiomyopathy were screened by mutation analysis and alpha-Gal A activity; 4 (25%) showed deficient plasma alpha-Gal A activity in combination with the intronic mutation., Conclusions: We found an unexpected high prevalence of the cardiac variant Fabry mutation IVS4+919G-->A among both newborns (approximately 1 in 1600 males) and patients with idiopathic hypertrophic cardiomyopathy in the Taiwan Chinese population. The early identification of undiagnosed patients allows timely therapeutic intervention providing a better clinical outcome.

Hearing loss and the related otologic manifestations are receiving increased scrutiny as significant causes of morbidity in Fabry disease. However, the relative risks of auditory deficits among patients with Fabry disease relative to the general population without a diagnosis of Fabry disease have not been studied. This study aims to explore the associations between Fabry disease and hearing-related manifestations using a nationwide population-based dataset. We identified study patients for this cross-sectional study from the 2015–2017 claims databases of the Taiwan Longitudinal Health Insurance Database 2005. We first identified 2312 patients aged over 20 years with a diagnosis of Fabry disease. We used propensity score matching to select five comparison patients per patient with Fabry disease and 11,560 comparison patients without Fabry disease. We used multivariable logistic regressions to estimate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for tinnitus, hearing loss, and sudden deafness among Fabry disease patients vs. comparison patients. Chi-square tests showed statistically significant differences between patients with and without Fabry disease in the prevalence rates of tinnitus (16.7% vs. 11.7%, p < 0.001), hearing loss (7.5% vs. 6.2%, p = 0.014) and sudden deafness (1.7% vs. 1.0%, p = 0.005). Multiple logistic regression revealed that patients with Fabry disease were more likely to suffer from tinnitus, hearing loss and sudden deafness, with adjusted odds ratios of 1.513 (95% CI = 1.336–1.713), 1.246 (95% CI = 1.047–1.483), and 1.681 (95% CI = 1.166–2.423), respectively. We found that Fabry disease is significantly associated with certain auditory manifestations, including hearing loss, sudden deafness, and tinnitus. [ABSTRACT FROM AUTHOR]

Aims Fabry cardiomyopathy (FC) is characterized by progressive left ventricular hypertrophy (LVH). Conventional echocardiography is not sensitive in detecting preclinical FC before the development of LVH. We aim to investigate whether myocardial deformation analysis is useful to detect preclinical FC before LVH. Methods and results One hundred and sixty patients carrying mutated gene were prospectively enrolled, including 86 patients without LVH and 74 patients with LVH. Another 33 healthy individuals were also included for comparison. Standard transthoracic two-dimensional, Doppler, tissue Doppler echocardiography and deformation analysis were performed. The mean age of the overall 193 subjects was 48 ± 15 years, with 51% men. Fabry patients with LVH were older, more often to be men. They also had the worst diastolic function as evidenced by the largest left atrium, lowest E/A, and highest E/e′ ratio. The global longitudinal strain (GLS) deteriorated with the development of LVH (control vs. LVH− patients vs. LVH+ patients = −21.2 ± 2.7 vs. −19.0 ± 2.9 vs. −16.5 ± 4.2%, P  < 0.001). Despite similar LV systolic, diastolic function, and LV mass, LVH− Fabry patients still had a reduced GLS as well as regional longitudinal strains at mid-to-apical, anterior, and inferolateral wall when compared to healthy subjects. The basal longitudinal strain was consistently worse in male patients than in female patients, irrespective of LVH. Conclusion Reduced GLS could be a marker of early FC before the development of LVH. [ABSTRACT FROM AUTHOR]

The rapid spread of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has raised questions about Fabry disease (FD) as an independent risk factor for severe COVID-19 symptoms. Available real-world data on 22 patients from an international group of healthcare providers reveals that most patients with FD experience mild-to-moderate COVID-19 symptoms with an additional complication of Fabry pain crises and transient worsening of kidney function in some cases; however, two patients over the age of 55 years with renal or cardiac disease experienced critical COVID-19 complications. These outcomes support the theory that pre-existent tissue injury and inflammation may predispose patients with more advanced FD to a more severe course of COVID-19, while less advanced FD patients do not appear to be more susceptible than the general population. Given these observed risk factors, it is best to reinforce all recommended safety precautions for individuals with advanced FD. Diagnosis of FD should not preclude providing full therapeutic and organ support as needed for patients with FD and severe or critical COVID-19, although a FD-specific safety profile review should always be conducted prior to initiating COVID-19-specific therapies. Continued specific FD therapy with enzyme replacement therapy, chaperone therapy, dialysis, renin–angiotensin blockers or participation to clinical trials during the pandemic is recommended as FD progression will only increase susceptibility to infection. In order to compile outcome data and inform best practices, an international registry for patients affected by Fabry and infected by COVID-19 should be established. [ABSTRACT FROM AUTHOR]

Abstract: Background: Interest in lysosomal storage diseases in newborn screening programs has increased in recent years. Two techniques, fluorescence (4-MU) and tandem mass spectrometry (MS/MS) methods are frequently used. We report a pilot study of large scale newborn screening for Fabry, Pompe, Gaucher, and MPS I diseases by using the MS/MS method in Taiwan and compared the performance of the MS/MS with 4-MU methods. Methods: More than 100,000 dried blood spots (DBSs) were collected consecutively as part of the national Taiwan newborn screening programs. The enzyme activities were detected by the MS/MS method from a DBS punch. Mutation analysis was further performed for newborns with detected enzyme deficiency. Results: The DNA sequence analysis for suspected cases revealed 64 newborns with confirmed Fabry mutations, 16 were classified as infantile or late-onset Pompe disease, and 1 was characterized as Gaucher disease. The positive predict value increased from 4.0% to 7.1% in the Pompe study, and from 61.0% to 95.5% in the Fabry study by the MS/MS method compared to 4-MU assay. Conclusions: The MS/MS method has been validated as a more specific, powerful and efficient tool than the 4-MU assay. It also provided a multiplex solution of newborn screening for lysosomal storage diseases. [Copyright &y& Elsevier]