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Fabry disease (FD, α-galactosidase A deficiency) is a rare, progressive, complex lysosomal storage disorder affecting multiple organ systems with a diverse spectrum of clinical phenotypes, particularly among female patients. Knowledge of its clinical course was still limited in 2001 when FD-specific therapies first became available and the Fabry Registry (NCT00196742; sponsor: Sanofi) was initiated as a global observational study. The Fabry Registry has now been operational for over 20 years, overseen by expert Boards of Advisors, and has collected real-world demographic and longitudinal clinical data from more than 8000 individuals with FD. Leveraging the accumulating evidence base, multidisciplinary collaborations have resulted in the creation of 32 peer-reviewed scientific publications, which have contributed to the greatly expanded knowledge on the onset and progression of FD, its clinical management, the role of sex and genetics, the outcomes of enzyme replacement therapy with agalsidase beta, and prognostic factors. We review how the Fabry Registry has evolved from its inception to become the largest global source of real-world FD patient data, and how the generated scientific evidence has helped to better inform the medical community, individuals living with FD, patient organizations, and other stakeholders. The patient-centered Fabry Registry fosters collaborative research partnerships with the overarching goal of optimizing the clinical management of patients with FD and is well positioned to add to its past achievements., Competing Interests: Declaration of Competing Interest C.W. has received honoraria for board meetings and lecturing from Amicus Therapeutics, Chiesi Pharmaceuticals, Idorsia Pharmaceuticals, Sanofi, and Takeda. A.O. has received grants from Sanofi and consultancy, speaker fees or travel support from Advicenne, Alexion, Amgen, Amicus Therapeutics, Astellas, AstraZeneca, Bayer, Chiesi Pharmaceuticals, Fresenius Medical Care, GlaxoSmithKline, Idorsia Pharmaceuticals, Kyowa Kirin, Menarini, Novo-Nordisk, Otsuka, and Vifor Fresenius Medical Care Renal Pharma, and is Director of the Cátedra Mundipharma-UAM of diabetic kidney disease and the Cátedra AstraZeneca-UAM of chronic kidney disease and electrolytes. W.R.W. is a member of the Fabry Registry Board of Advisors, has consulted for Amicus Therapeutics, Sanofi, Spark, Takeda, and UniQure, and has been an investigator in clinical studies for Fabry disease sponsored by Amicus Therapeutics, Chiesi Pharmaceuticals, Freeline Therapeutics, Idorsia Pharmaceuticals, 4D Molecular Therapeutics, Protalix Biotherapeutics, Sangamo Therapeutics, and Sanofi. These activities are monitored and are in compliance with the conflict-of-interest policies at Emory University School of Medicine. R.J.H. is a member of the Fabry Registry Advisory Board, consults with Amicus Therapeutics and Sanofi, and has been an investigator in clinical trials sponsored by Amicus Therapeutics, Idorsia Pharmaceuticals, Protalix Biotherapeutics, Sangamo Therapeutics, Sanofi, and Takeda. These activities have been monitored and found to be in compliance with the conflict-of-interest policies at Cincinnati Children's Hospital Medical Center. J.J. has received honoraria from Sanofi, and travel support from Amicus Therapeutics and Sanofi. E.P., J.T.E., J.L.B., and Ma.M. are full-time employees of Sanofi and may hold/have held stock and/or stock options in that company. J.M.P. has received honoraria from Amicus Therapeutics, Sanofi, and Takeda, and consulting fees from Sanofi and Takeda. A.M.M. has received Advisory Board honoraria from Astra Zeneca-Alexion Pharmaceuticals, BioMarin Pharmaceutical, JCR Pharmaceuticals, and Sanofi, and speaker honoraria and travel support from Astra Zeneca-Alexion Pharmaceuticals, BioMarin Pharmaceutical, Chiesi Pharmaceuticals, JCR Pharmaceuticals, and Sanofi. M.B. is a member of the Fabry Registry Advisory Board and has received honoraria for consultancies, honoraria for disease registry advisory board meetngs, honoraria for lecturing and support for research from Sanofi. She also has received consulting and/or lecturing honoraria from Amicus Therapeutics and Chiesi Pharmaceuticals. A.L. has received consulting honoraria from Amicus Therapeutics, Sanofi Genzyme, and Takeda, and speaker honoraria and travel support from Sanofi Genzyme and Takeda. Mi.M. is a member of the Fabry Registry Board, has an investigator-initiated research grant from Sanofi, performs laboratory work and is a consultant to Sanofi for clinical trial design, received speaker fees and travel support from Sanofi for non-promotional presentations (these interests have been reviewed and managed by the University of Minnesota in accordance with its conflict-of-interest policies), is a consultant and performs laboratory work for Amicus Therapeutics, and is a consultant to Acelink Therapeutics, Avrobio, Freeline Therapeutics, and Sangamo Therapeutics. J.P.O. is member of the European Advisory Board of the Fabry Registry and has received honoraria for consultancies, honoraria for disease registry advisory board, honoraria for lecturing and support for research from Sanofi. He also has received consulting and/or lecturing honoraria from Amicus Therapeutics, Chiesi Pharmaceuticals and Takeda, and support for travel and accommodation from Amicus Therapeutics, Sanofi, and Takeda. F.W. has received research grants from Sanofi and Takeda and speaker honoraria from Amicus Therapeutics, Sanofi, and Takeda. D.P.G. has received grants and consultancy fees from Chiesi Pharmaceuticals, Idorsia Pharmaceuticals, Sanofi, and Takeda, and travel support from Sanofi., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Fabry disease is an X-linked lysosomal multisystem storage disorder induced by a mutation in the alpha-galactosidase A (GLA) gene. Reduced activity or deficiency of alpha-galactosidase A (AGAL) leads to escalating storage of intracellular globotriaosylceramide (GL-3) in numerous organs, including the kidneys, heart and nerve system. The established treatment for 20 years is intravenous enzyme replacement therapy. Lately, oral chaperone therapy was introduced and is a therapeutic alternative in patients with amenable mutations. Early starting of therapy is essential for long-term improvement. This review describes chaperone therapy in Fabry disease.

Aims: Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes., Methods and Results: Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9-1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95% confidence interval (CI)] = -0.41 [-0.68, -0.15] mm/year, P pre-post difference  <0.01; IVST: n = 38, slope difference = -0.32 [-0.67, 0.02] mm/year, P pre-post difference  = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95% CI: -0.13 [-1.15, 0.89] mL/min/1.73m 2 /year, P pre-post difference  = 0.80)., Conclusions: Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objective: To investigate A-delta fiber conduction in mild to moderate Fabry disease (FD) patients using pain-related evoked potentials (PREP)., Methods: In this case-control study we prospectively investigated 58 patients with mild to moderate FD and compared data with those of healthy controls. Small fiber function (quantitative sensory testing, QST and sympathetic skin response, SSR), morphology (intraepidermal nerve fiber density, IENFD), and electrical conduction (PREP) were assessed and correlated with sweating as major autonomic function disturbed in FD. Patients were further stratified for gender, disease severity as reflected by renal and cardiac function, and genetics., Results: An- or hypohidrosis (i.e. dyshidrosis) was reported by 7/32 (22%) women and 15/26 (58%) men with FD (p < 0.01). QST showed small fiber impairment in female and male patients regardless of clinical symptoms, while SSR was obtained in all patients except one man with hypohidrosis. IENFD was reduced in 50% of FD patients, with no differences between groups with and without autonomic symptoms. However, PREP amplitudes were reduced independent of the stimulation site only in female patients with dyshidrosis (p < 0.01). Genetics had no influence on PREP parameters., Conclusion: A-delta fiber conduction investigated using PREP is impaired in mild to moderately affected female FD patients with clinical signs of hypohidrosis., Significance: Small fiber assessment in FD is of diagnostic value already in mild to moderate stages of disease., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients., Methods: A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type., Results: Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease., Conclusions: This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Initiation of enzyme replacement therapy (ERT) early in the Fabry disease course may facilitate better outcomes than in patients with advanced disease. Early diagnosis is often hindered by the heterogeneous nature of signs and symptoms, and by the presentation of atypical phenotypes., Methods: The Sophisticated Assessment of Disease Burden in Patients with Fabry Disease study (SOPHIA; ClinicalTrials.gov, NCT01210196) evaluated clinical and diagnostic assessments for early detection of Fabry-related organ pathology in ERT-naïve patients with mild FD symptoms. Assessments included cardiac magnetic resonance imaging with late gadolinium enhancement (LGE-CMR), echocardiography, 24-h Holter electrocardiography, and biomarkers of FD and fibrosis., Results: 35 patients with mean (SD) baseline age of 45.0 (10.2) years were included and assessed at baseline, 12 months, and (optionally) at 24 months. At baseline, LGE-CMR and elevated procollagen III N-terminal propeptide, sphingosine-1-phosphate, and globotriaosylsphingosine were the most prevalent indicators of early Fabry-related pathology. LGE was already present in 58.8% of patients with normal left ventricular mass index. 15.2% of patients showed grade 1 diastolic dysfunction. QRS duration increased from baseline to last observation, particularly in patients with severe baseline fibrosis. Fibrosis progressed from baseline to last observation, especially in patients with baseline LGE ≥ 2.50 mL (3.65 [1.14] mL vs 6.74 [1.10] mL). Statistically significant correlations were found between LGE volume and high-sensitivity troponin T, and between LGE volume and fragments of urinary collagen alpha-1 (I), (III), and (VII), and collagen alpha-3 (V)., Conclusions: Fibrosis may become apparent before left ventricular hypertrophy occurs. LGE-CMR imaging is superior to conventional echocardiography for detecting early cardiomyopathy in FD and, in conjunction with biomarker tests, may help detect early organ involvement in mild FD., (Copyright © 2019 Shire International GmbH, The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate potential risk factors for stroke or transient ischemic attacks (TIA) and to test the feasibility and efficacy of a Fabry-specific stroke risk score in Fabry disease (FD) patients without atrial fibrillation (AF)., Background: FD patients often experience cerebrovascular events (stroke/TIA) at young age., Methods: 159 genetically confirmed FD patients without AF (aged 40 ± 14 years, 42.1% male) were included, and risk factors for stroke/TIA events were determined. All patients were followed up over a median period of 60 (quartiles 35-90) months. The pre-defined primary outcomes included new-onset or recurrent stroke/TIA and all-cause death., Results: Prior stroke/TIA (HR 19.97, P < .001), angiokeratoma (HR 4.06, P = .010), elevated creatinine (HR 3.74, P = .011), significant left ventricular hypertrophy (HR 4.07, P = .017), and reduced global systolic strain (GLS, HR 5.19, P = .002) remained as independent risk predictors of new-onset or recurrent stroke/TIA in FD patients without AF. A Fabry-specific score was established based on above defined risk factors, proving somehow superior to the CHA 2 DS 2 -VASc score in predicting new-onset or recurrent stroke/TIA in this cohort (AUC 0.87 vs. 0.75, P = .199)., Conclusions: Prior stroke/TIA, angiokeratoma, renal dysfunction, left ventricular hypertrophy, and global systolic dysfunction are independent risk factors for new-onset or recurrent stroke/TIA in FD patients without AF. It is feasible to predict new or recurrent cerebral events with the Fabry-specific score based on the above defined risk factors. Future studies are warranted to test if FD patients with high risk for new-onset or recurrent stroke/TIA, as defined by the Fabry-specific score (≥ 2 points), might benefit from antithrombotic therapy. Clinical trial registration HEAL-FABRY (evaluation of HEArt invoLvement in patients with FABRY disease, NCT03362164).

Background: Fabry patients on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in estimated glomerular filtration rate (eGFR) and an increase of the Mainz Severity Score Index., Methods: In this prospective observational study, we assessed end-organ damage and clinical symptoms in 112 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, who were (i) non-randomly assigned to continue this treatment regime (regular-dose group, n = 37); (ii) received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n = 38); or (iii) were re-switched to agalsidase-beta after receiving agalsidase-alfa for at least 12 months (re-switch group, n = 37) with a median follow-up of 53 (38-57) months., Results: eGFR of patients in the regular-dose group remained stable. Patients in the switch group showed an annual eGFR loss of - 4.6  ±  9.1 mL/min/1.73 m2 (P < 0.05). Patients in the re-switch group also had an eGFR loss of - 2.2  ±  4.4 mL/min/1.73 m2 after re-switch to agalsidase-beta, but to a lower degree compared with the switch group (P < 0.05). Patients in the re-switch group suffered less frequently from diarrhoea (relative risk 0.42; 95% confidence interval 0.19-0.93; P = 0.02). Lyso-Gb3 remained stable in the switch (P = 0.97) and the regular-dose (P = 0.48) groups, but decreased in the re-switch group after change of the therapy regimen (P < 0.05)., Conclusions: After switch to agalsidase-alfa, Fabry patients experienced a continuous decline in eGFR, while this decline was attenuated in patients who were re-switched to agalsidase-beta. Decreasing lyso-Gb3 levels may indicate a better treatment response in the latter group.

Background: Fabry disease, an inherited lysosomal storage disorder, causes multi-organ pathology resulting in substantial morbidity and a reduced life expectancy. Although Fabry disease is an X-linked disorder, both genders may be affected, but generally to a lesser extent in females. The disease spectrum ranges from classic early-onset disease to non-classic later-onset phenotypes, with complications occurring in multiple organs or being confined to a single organ system depending on the stage of the disease. The impact of therapy depends upon patient- and disease-specific factors and timing of initiation., Methods: A European panel of experts collaborated to develop a set of organ-specific therapeutic goals for Fabry disease, based on evidence identified in a recent systematic literature review and consensus opinion., Results: A series of organ-specific treatment goals were developed. For each organ system, optimal treatment strategies accounted for inter-patient differences in disease severity, natural history, and treatment responses as well as the negative burden of therapy and the importance of multidisciplinary care. The consensus therapeutic goals and proposed patient management algorithm take into account the need for early disease-specific therapy to delay or slow the progression of disease as well as non-specific adjunctive therapies that prevent or treat the effects of organ damage on quality of life and long-term prognosis., Conclusions: These consensus recommendations help advance Fabry disease management by considering the balance between anticipated clinical benefits and potential therapy-related challenges in order to facilitate individualized treatment, optimize patient care and improve quality of life., (Copyright © 2018. Published by Elsevier Inc.)

Single nucleotide polymorphisms (SNPs) in the alpha-galactosidase A gene region (GLA) have been discussed as potential cause of symptoms and organ manifestations similarly to those seen in Fabry disease (FD). However, due to scarce data, clinical implications remain limited. The aim of the present study was to investigate the clinical impact of -10C>T SNP in the GLA.Prospective single-center observational study to determine the natural history and outcome of FD.Subjects initially referred to the Fabry Center for Interdisciplinary Therapy Würzburg (FAZIT) for management of suspected FD (11 women, 2 men, mean age 42 ± 10 years) who were tested negative for coding GLA mutations but positive for the noncoding -10C>T SNP underwent comprehensive characterization for therapy recommendation.All subjects reported at least 1 neurological, but no cardiac or renal symptoms. In 7 patients, pain of unknown etiology was reported and 3 patients had a history of cryptogenic stroke. In all patients, α-GAL activity was at a lower limit, ranging between 0.27 and 0.45 nmol/min per mg protein (reference: 0.4-1.0), while plasma Lyso-Gb3 levels remained normal (range 0.39 ± 0.33; reference: ≤0.9 ng/mL). For both hemizygous subjects investigated, brain magnetic resonance imaging revealed unspecific white matter lesions. One of these subjects had suffered from severe early-onset stroke, the other showed mild hypertrophic cardiomyopathy.Presence of isolated heterozygous -10C >T SNP is not associated with clinically relevant symptoms or organ manifestations as seen in FD. Respective polymorphisms might, however, play a role in modifying disease severity in FD. Great care has to be taken in respective subjects suspected to suffer from nonclassical FD in order to prevent unnecessary Fabry-specific therapy.

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications. Phenotypes vary from the "classic" phenotype, with pediatric onset and multi-organ involvement, to later-onset, a predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Enzyme replacement therapy (ERT) and adjunctive treatments can provide significant clinical benefit. However, much of the current literature reports outcomes after late initiation of ERT, once substantial organ damage has already occurred. Updated monitoring and treatment guidelines for pediatric patients with Fabry disease have recently been published. Expert physician panels were convened to develop updated, specific guidelines for adult patients. Management of adult patients depends on 1) a personalized approach to care, reflecting the natural history of the specific disease phenotype; 2) comprehensive evaluation of disease involvement prior to ERT initiation; 3) early ERT initiation; 4) thorough routine monitoring for evidence of organ involvement in non-classic asymptomatic patients and response to therapy in treated patients; 5) use of adjuvant treatments for specific disease manifestations; and 6) management by an experienced multidisciplinary team., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fabry disease is an X-linked lysosomal storage disorder caused by deficient activity of α -galactosidase A which leads to progressive intracellular accumulation of globotriaosylceramide in tissues and organs including heart, kidney, vascular endothelium, the nervous system, the eyes and the skin. Cardiac involvement is common, leads to fatal complications and is mainly responsible for reduced life expectancy in Fabry disease. The exact staging of disease progression and timely initiation of treatment is essential in Fabry disease. Therefore, it is essential to use the possibilities of specific biomarkers for early detection of organ involvement or early diagnosis., Methods: By the use of Pubmed all relevant papers for biomarkers in Fabry disease were screened. The quality of retrieved papers was appraised using standard tools. Finally, 70 peer reviewed paper were included., Results: In the past biomarkers for Fabry disease biomarkers did not have clinical relevance. Nowadays, a lot of research is focusing on identification of new biomarkers and their clinical relevance. Only two biomarkers reached clinical applicability. Lyso-GB3 for identification of atypical FD variants and hsTNT for identification of cardiac involvement, which should indicate further diagnostics. Treatment response to ERT can be monitored by lyso-GB3 but data for long-time outcome are missing. A lot of GB3-related analogs are identified in urine and plasma, some of which might play an important role for managing Fabry disease in future., Conclusion: In conclusion, we suggest to measure lyso-GB3 and hsTNT at least once a year. The routine measurement of these two biomarkers will help now for the staging of every individual patient and in addition, will help for a better general understanding of Fabry disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Anderson-Fabry disease (AFD) is an X-linked recessive, multisystem disease of lysosomal storage. A mutation in the gene encoding the hydrolase enzyme α-galactosidase A results in its deficiency, or complete absence of activity. Subsequent progressive intracellular accumulation of glycosphingolipids, predominantly globotriaosylceramide, in various tissues, results in progressive organ dysfunction and failure, most commonly affecting the kidneys, nervous system, skin, eyes, vascular endothelium, and the heart. Cardiac involvement in AFD represents a leading cause of morbidity and mortality. Globotriaosylceramide accumulation affects cardiomyocytes, smooth muscle cells, vascular endothelial cells, and fibroblasts leading to various pathologies including valvular regurgitation, conduction disease and arrhythmias, coronary microvascular dysfunction, and right and left ventricular hypertrophy (LVH) leading to early diastolic dysfunction and late-stage systolic impairment. Diagnosis is on the basis of decreased plasma α-galactosidase activity in men and positive genetic testing in women. Contemporary large-scale screening studies have revealed a prevalence of 1%-5% in patients with unexplained LVH in multiple cohorts. Cardiac magnetic resonance imaging, with its unique tissue characterization capabilities, is the most important imaging modality to assess for cardiomyopathy in patients with AFD. Enzyme replacement therapy is indicated in AFD patients with significant organ involvement, and has been shown to clear sphingolipids from endothelial cells in other organs, as well as to reduce left ventricular mass as early as 6 months after starting treatment. There is increasing evidence that enzyme replacement therapy might be more effective if given at earlier stages of disease, before the development of LVH and myocardial fibrosis., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The progressive cardiomyopathy in patients with Fabry disease is often accompanied by angina pectoris and elevated levels of high-sensitive troponin T (hs-TnT), potentially mimicking acute coronary syndrome. Here, we present to representative cases with focus on clinical, diagnostic and therapeutic settings. An overview on the cardiomyopathy associated with Fabry disease and its role as differential diagnosis of acute coronary syndrome is provided. Fabry cardiomyopathy might exhibit similar clinical and biochemical constellations as seen in acute coronary syndrome. Thus, Fabry cardiomyopathy should be considered a differential diagnosis in acute coronary syndrome, particularly in patients demonstrating left ventricular hypertrophy of unknown origin., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Purpose: A patent foramen ovale (PFO) is disproportionately prevalent in patients with cryptogenic stroke. Without alternative explanations, it is frequently considered to be causative. A detailed stratification of these patients may improve the identification of incidental PFO., Methods: We investigated the PFO prevalence in 3497 transient ischemic attack and ischemic stroke patients aged 18 to 55 years in the prospective multicenter SIFAP1 study (Stroke in Young Fabry Patients 1) using the ASCO classification. Patients without an obvious cause for transient ischemic attack/stroke (ASCO 0) were divided into subgroups with and without vascular risk factors (ASCO 0+ and 0-). In addition, we looked for PFO-related magnetic resonance imaging lesion patterns., Results: PFO was identified in 25% of patients. Twenty percent of patients with a definite or probable cause of transient ischemic attack/stroke (≥1 grade 1 or 2 ASCO criterion; n=1769) had a PFO compared with 29% of cryptogenic stroke patients (ASCO 0 and 3; n=1728; P<0,001); subdivision of cryptogenic strokes revealed a PFO in 24% of 978 ASCO 3 patients (n.s. versus ASCO 1 and 2) and a higher prevalence of 36% in 750 ASCO 0 cases (P<0.001 versus ASCO 3 and versus ASCO 1 and 2). PFO was more commonly observed in ASCO 0- (n=271) than in ASCO 0+ patients (n=479; 48 versus 29%; P<0.001). There was no PFO-associated magnetic resonance imaging lesion pattern., Conclusions: Cryptogenic stroke patients demonstrate a heterogeneous PFO prevalence. Even in case of less conclusive diseases like nonstenotic arteriosclerosis, patients should preferentially be considered to have a non-PFO-mediated stroke., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583., (© 2016 American Heart Association, Inc.)

Background: The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity., Methods: At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data., Results: We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy., Conclusions: Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients., Competing Interests: Competing Interests: N.S., W.K., and D.K. have received travel grants from Genzyme Corp. F.W. and C.W. are members of the Fabry Registry European Board of Advisors and have received travel assistance and speaker honoraria. Research grants were given to the University of Würzburg by Genzyme and Shire Corp. C.S. has received consulting fees and honoraria for educational lectures from Genzyme Corp. N.Ü. has received travel grants and honoraria for lectures from Genzyme Corp. and Shire HGT. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Fabry disease is characterized by a progressive deposition of sphingolipids in different organ systems, whereby cardiac involvement leads to death. We hypothesize that lysosomal storage of sphingolipids in the heart as occurring in Fabry disease does not reflect in higher cardiac lipid concentrations detectable by 1 H magnetic resonance spectroscopy (MRS) at 3 Tesla., Methods: Myocardial lipid content was quantified in vivo by 1 H-MRS in 30 patients (12 male, 18 female; 18 patients treated with enzyme replacement therapy) with genetically proven Fabry disease and in 30 healthy controls. The study protocol combined 1 H-MRS with cardiac cine imaging and LGE MRI in a single examination., Results: Myocardial lipid content was not significantly elevated in Fabry disease (p = 0.225). Left ventricular (LV) mass was significantly higher in patients suffering from Fabry disease compared to controls (p = 0.019). Comparison of patients without signs of myocardial fibrosis in MRI (LGE negative; n = 12) to patients with signs of fibrosis (LGE positive; n = 18) revealed similar myocardial lipid content in both groups (p > 0.05), while the latter showed a trend towards elevated LV mass (p = 0.076)., Conclusions: This study demonstrates the potential of lipid metabolic investigation embedded in a comprehensive examination of cardiac morphology and function in Fabry disease. There was no evidence that lysosomal storage of sphingolipids influences cardiac lipid content as measured by 1 H-MRS. Finally, the authors share the opinion that a comprehensive cardiac examination including three subsections (LGE; 1 H-MRS; T 1 mapping), could hold the highest potential for the final assessment of early and late myocardial changes in Fabry disease.

Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holter electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holter ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 ± 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses ≥3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter-defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holter ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines., Methods: Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed., Results: Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-naïve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-naïve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels., Conclusion: The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females.

Background: High-sensitivity troponin (hs-TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs-TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow-up study to assess longitudinal hs-TNT changes relative to fibrosis and cardiomyopathy progression., Methods and Results: For the prospective analysis, hs-TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry-associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs-TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs-TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95% CI, 3.56-302.59]; P=0.002); patients with elevated baseline hs-TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1-3.3] %; follow-up, 3.2 [2.3-4.9] %; P<0.001) and slightly elevated hs-TNT (baseline, 44.7 [30.1-65.3] ng/L; follow-up, 49.1 [27.6-69.5] ng/L; P=0.116) during follow-up. Left ventricular wall thickness and EF of patients with elevated hs-TNT were decreased during follow-up, indicating potential cardiomyopathy progression., Conclusions: hs-TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs-TNT could be helpful for staging and follow-up of Fabry patients., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma., Methods: To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations., Results: p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed., Conclusions: We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option.

Because of the shortage of agalsidase-β supply between 2009 and 2012, patients with Fabry disease either were treated with reduced doses or were switched to agalsidase-α. In this observational study, we assessed end organ damage and clinical symptoms with special focus on renal outcome after 2 years of dose-reduction and/or switch to agalsidase-α. A total of 89 adult patients with Fabry disease who had received agalsidase-β (1.0 mg/kg body wt) for >1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=24), to receive a reduced dose of 0.3-0.5 mg/kg and a subsequent switch to 0.2 mg/kg agalsidase-α (dose-reduction-switch group, n=28), or to directly switch to 0.2 mg/kg agalsidase-α (switch group, n=37) and were followed-up for 2 years. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD), changes in cardiac and renal function, Fabry-related symptoms (pain, hypohidrosis, diarrhea), and disease severity scores. Determination of renal function by creatinine and cystatin C-based eGFR revealed decreasing eGFRs in the dose-reduction-switch group and the switch group. The Mainz Severity Score Index increased significantly in these two groups (P=0.02 and P<0.001, respectively), and higher frequencies of gastrointestinal pain occurred during follow-up. In conclusion, after 2 years of observation, all groups showed a stable clinical disease course with respect to serious clinical events. However, patients under agalsidase-β dose-reduction and switch or a direct switch to agalsidase-α showed a decline of renal function independent of the eGFR formula used., (Copyright © 2016 by the American Society of Nephrology.)

Background: In spite of several research studies help to describe the heart in Fabry disease (FD), the cardiomyopathy is not entirely understood. In addition, the impact of blood pressure and alterations in geometry have not been systematically evaluated., Methods: In 74 FD patients (mean age 36±12 years; 45 females) the extent of myocardial fibrosis and its progression were quantified using cardiac magnetic-resonance-imaging with late enhancement technique (LE). Results were compared to standard echocardiography complemented by 2D-speckle-tracking, 3D-sphericity-index (SI) and standardized blood pressure measurement. At baseline, no patient received enzyme replacement therapy (ERT). After 51±24 months, a follow-up examination was performed., Results: Systolic blood pressure (SBP) was higher in patients with vs. without LE: 123±17 mmHg vs. 115±13 mmHg; P = 0.04. A positive correlation was found between SI and the amount of LE-positive myocardium (r = 0.51; P<0.001) indicating an association of higher SI in more advanced stages of the cardiomyopathy. SI at baseline was positively associated with the increase of LE-positive myocardium during follow-up. The highest SBP (125±19 mmHg) and also the highest SI (0.32±0.05) was found in the subgroup with a rapidly increasing LE (ie, ≥0.2% per year; n = 16; P = 0.04). Multivariate logistic regression analysis including SI, SBP, EF, left ventricular volumes, wall thickness and NT-proBNP adjusted for age and sex showed SI as the most powerful parameter to detect rapid progression of LE (AUC = 0.785; P<0.05)., Conclusions: LV geometry as assessed by the sphericity index is altered in relation to the stage of the Fabry cardiomyopathy. Although patients with FD are not hypertensive, the SBP has a clear impact on the progression of the cardiomyopathy.

Introduction: Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD., Methods: A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement., Results: For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m(2)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped., Conclusion: The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.

Fabry disease is induced by a mutation in the alpha-galactosidase A gene, causing a deficiency of the enzyme alpha-galactosidase A. (1) The enzyme defect leads to progressive intracellular accumulation of globotriaosylceramide in lysosomes of various tissues and organs, including heart, kidney and nerve system. Cardiac involvement is common and is presenting as concentric left ventricular hypertrophy. Myocardial replacement fibrosis is a typical feature of more advanced stages of Fabry cardiomyopathy, first limited to the mid-myocardial layers of the basal postero-lateral wall, then spreading to transmural fibrosis. Since 2001, enzyme replacement therapy is available. If therapy is started early, before myocardial fibrosis has developed, a long-term improvement of myocardial morphology, function and exercise capacity can be achieved. In end-stage cardiomyopathy enzyme replacement therapy might prevent further progression of the disease. This review provides an overview of Fabry disease, with a focus on cardiac involvement with its characteristic features, clinical presentation and possible treatment., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency. The intracellular storage of globotriaosylceramides in different tissues and organs leads to a multisystemic disease affecting kidneys, nervous system and the heart. Fabry cardiomyopathy is frequent and leads to concentric left-ventricular hypertrophy. Typical pattern in advanced stages is myocardial replacement fibrosis, first localized to mid myocardial layers of postero-lateral basal myocardium and then spreading to transmural fibrosis.Long term prognosis is dependent on timely initiation of specific and concomitant therapies, while therapy in advanced stages is only able to stabilize the organ affection. This review describes the characteristics of Fabry cardiomyopathy, shows the clinical assessment of cardiac involvement and highlights therapeutic issues aiming at the best outcome for patients with Fabry disease.

Background: Screening in subjects with left ventricular hypertrophy (LVH) reveals a high prevalence of Fabry disease (FD). Often, a diagnosis is uncertain because characteristic clinical features are absent and genetic variants of unknown significance (GVUS) in the α-galactosidase A (GLA) gene are identified. This carries a risk of misdiagnosis, inappropriate counselling and extremely expensive treatment. We developed a diagnostic algorithm for adults with LVH (maximal wall thickness (MWT) of >12 mm), GLA GVUS and an uncertain diagnosis of FD., Methods: A Delphi method was used to reach a consensus between FD experts. We performed a systematic review selecting criteria on electrocardiogram, MRI and echocardiography to confirm or exclude FD. Criteria for a definite or uncertain diagnosis and a gold standard were defined., Results: A definite diagnosis of FD was defined as follows: a GLA mutation with ≤ 5% GLA activity (leucocytes, mean of reference value, males only) with ≥ 1 characteristic FD symptom or sign (neuropathic pain, cornea verticillata, angiokeratoma) or increased plasma (lyso)Gb3 (classical male range) or family members with definite FD. Subjects with LVH failing these criteria have a GVUS and an uncertain diagnosis. The gold standard was defined as characteristic storage in an endomyocardial biopsy on electron microscopy. Abnormally low voltages on ECG and severe LVH (MWT>15 mm) <20 years exclude FD. Other criteria were rejected due to insufficient evidence., Conclusions: In adults with unexplained LVH and a GLA GVUS, severe LVH at young age and low voltages on ECG exclude FD. If absent, an endomyocardial biopsy with electron microscopy should be performed., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Impairments of health related quality of life (HRQoL) are frequently observed in Fabry disease (FD) and are known to be related to neuropathic pain and cardiovascular events. This study aimed to explore the role of chronic kidney disease (CKD) in a large cohort of patients with FD., Methods: In 96 patients (53% female; age 40±12 yrs) with genetically proven FD, HRQoL was assessed by the Medical Outcomes Study (SF-36) questionnaire. All patients were naïve to enzyme replacement therapy. Three categories for kidney dysfunction were chosen, eGFR≥/<60 ml/min/1.73 m2 or need of renal replacement therapy (RRT). Minor (e.g. arrhythmia, angina pectoris, etc.) and major (e.g. myocardial infarction, coronary artery bypass, stroke or implantable cardioverter-defibrillator) vascular events as well as pain and pain therapy were considered in linear regression analyses with the dimensions of HRQoL., Results: Ten patients (10%) had impaired kidney function and a further nine were on RRT (9.4%). Kidney function and pain emerged as the main factors associated with lower scores on the SF 36, in particular on physical components (PCS beta-coefficients for CKD -6.2, for RRT -11.8, for pain -9.1, p<0.05, respectively), while controlling for gender, vascular event and pain-therapy. Relationships were found for mental aspects of HRQoL. Age and history of vascular events were not related to HRQoL., Conclusion: Cardiovascular events and pain are important factors related to HRQoL, social functioning and depression. Our study highlights impaired chronic kidney disease, in particular after initiation of RRT, as a strong determinant of reduced HRQoL in FD.

The aim of this study was to investigate the impact of myocardial fibrosis in Fabry disease. Seventy-three patients with genetically confirmed Fabry disease were followed for 4.8 ± 2.4 years. In accordance with current guidelines, 57 patients received enzyme replacement therapy (ERT) after study inclusion, whereas 16 did not. At baseline and latest possible follow-up, myocardial fibrosis was assessed noninvasively by cardiac magnetic resonance, and biomarkers of collagen metabolism were determined. Holter electrocardiography and clinical follow-up at yearly intervals were used to monitor malignant ventricular arrhythmias (MVAs; nonsustained and sustained ventricular tachycardia and sudden cardiac death). In total, 48 patients (66%) showed fibrosis assessed by late enhancement (LE) at baseline, and 4 patients developed new LE during follow-up, 2 of them despite ERT. The 2 patients receiving ERT (1.4 ± 1.9% vs 2.5 ± 2.6%, p <0.001) and the patients not receiving ERT (0.5 ± 0.8% vs 0.7 ± 1.0%, p = 0.035) showed a progression of LE during follow-up. None of the patients displayed reductions of LE during follow-up. Collagen biomarkers were elevated in patients with and without LE but did not correlate with LE amount. Thirteen LE-positive patients at the baseline examination had documented MVAs (including 5 sudden cardiac deaths), whereas none of the patients without LE had MVAs. The yearly increase in fibrosis was 0.9 ± 0.6% in patients with MVAs and 0.2 ± 0.3% in patients without MVAs (p <0.001). Logistic multivariate regression analysis revealed that the annual increase in fibrosis during follow-up was the only independent predictor of MVAs. In conclusion, myocardial fibrosis in Fabry disease is progressive, apparently not modified by ERT, and a crucial outcome determinant., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Because of the shortage of agalsidase-beta in 2009, many patients with Fabry disease were treated with lower doses or were switched to agalsidase-alfa. This observational study assessed end-organ damage and clinical symptoms during dose reduction or switch to agalsidase-alfa. A total of 105 adult patients with Fabry disease who had received agalsidase-beta (1.0 mg/kg body weight) for ≥1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=38), receive a reduced dose of 0.3-0.5 mg/kg (dose-reduction group, n=29), or switch to 0.2 mg/kg agalsidase-alfa (switch group) and were followed prospectively for 1 year. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD); changes in cardiac, renal, and neurologic function; and Fabry-related symptoms (neuropathic pain, hypohidrosis, diarrhea, and disease severity scores). Organ function and Fabry-related symptoms remained stable in the regular-dose group. In contrast, estimated GFR decreased by about 3 ml/min per 1.73 m(2) (P=0.01) in the dose-reduction group, and the median albumin-to-creatinine ratio increased from 114 (0-606) mg/g to 216 (0-2062) mg/g (P=0.03) in the switch group. Furthermore, mean Mainz Severity Score Index scores and frequencies of pain attacks, chronic pain, gastrointestinal pain, and diarrhea increased significantly in the dose-reduction and switch groups. In conclusion, patients receiving regular agalsidase-beta dose had a stable disease course, but dose reduction led to worsening of renal function and symptoms. Switching to agalsidase-alfa is safe, but microalbuminuria may progress and Fabry-related symptoms may deteriorate.

Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 ± 13 years (42% males), and a mean 25(OH)D of 23.5 ± 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D ≤ 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 ± 75 g in deficient, 154 ± 60 g in moderately deficient and 128 ± 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial.

Background: Currently, no method is available to identify α-galactosidase A (agalA) mutations determining clinically relevant Fabry disease. In our largest European Fabry cohort, we investigated whether a biomarker, specific for the defect, could stratify persons at risk., Methods and Results: A total of 124 individuals with agalA mutations were investigated with a comprehensive clinical workup, genetic analysis, and laboratory testing, including measurements of agalA activity and lyso-Gb3 (degradation product of the accumulating Gb3). Additionally, an extensive family screening with a clinical workup of relatives was performed. The patient population was divided into 2 samples: previously described mutations (n=72) and novel mutations (n=52). The patients with previously described mutations were subdivided into 2 groups: classical mutations, which were known to cause the classic type of Fabry disease with specific symptoms and a high risk for major events in all 3 main organs (heart, kidney, and central nervous system), and atypical mutations without the typical presentation. All patients with atypical mutations (n=17) had lower lyso-Gb3 levels than any of the patients with classical Fabry disease (n=55). A cutoff value of 2.7 ng/mL separated the 2 groups. Six out of 52 patients with novel mutations showed a lyso-Gb3 level <2.7 ng/mL. Clinical investigation, blinded to lyso-Gb3 results, revealed no classic organ involvement in these patients or their relatives. In contrast, the characterization of patients with lyso-Gb3≥2.7 ng/mL suggested classical Fabry mutations in most of the patients (93%)., Conclusions: Our data show that the biomarker lyso-Gb3 may identify the clinically relevant agalA mutations leading to Fabry disease.

A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males-females; normal-impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13%) and 5/57 (9%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87%, specificity: 86%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity.

Purpose: The aim of this study was to evaluate the progression of left ventricular hypertrophy in untreated men with Fabry disease and to assess the effects of agalsidase-β (recombinant human α-galactosidase A) on left ventricular hypertrophy., Methods: Longitudinal Fabry Registry data were analyzed from 115 men treated with agalsidase-β (1 mg/kg/2 weeks) and 48 untreated men. Measurements included baseline left-ventricular mass and at least one additional left-ventricular mass assessment over ≥ 2 years. Patients were grouped into quartiles, based on left-ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression., Results: For men in whom treatment was initiated at the age of 18 to <30 years, mean left ventricular mass slope was -3.6 g/year (n = 31) compared with +9.5 g/year in untreated men of that age (n = 15) (P < 0.0001). Untreated men had a 3.4-fold higher risk of having faster increases in left-ventricular mass compared with treated men (odds ratio: 3.43; 95% confidence interval: 1.05-11.22; P = 0.0415). A baseline age of ≥ 40 years was also associated with left--ventricular hypertrophy progression (odds ratio: 5.03; 95% confidence interval: 1.03-24.49; P = 0.0457) compared with men younger than 30 years., Conclusion: Agalsidase-β treatment for ≥2 years may improve or stabilize left-ventricular mass in men with Fabry disease. Further investigations may determine whether early intervention and stabilization of LVM are correlated with clinical outcomes.

Objective: The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease., Methods: A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain., Results: During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry., Conclusion: Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease., (© 2013 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine.)

Background: Morphology and function of Fabry cardiomyopathy has been previously studied by echocardiography and cardiac magnetic resonance (CMR). However, the value of electrocardiography (ECG) in relation to these two techniques remains largely unknown., Methods: One hundred fifty genetically confirmed Fabry patients were investigated using a comprehensive clinical workup comprising 12-lead ECG, echocardiography, and CMR., Results: ECG parameters at rest [PR, P wave, QT, QTc, QT dispersion and time interval from the peak to the end of the T wave (Tpeak to Tend)] were normal in the entire cohort and did not distinguish between males and females or stages of cardiomyopathy. A significant positive correlation was found between left ventricular (LV) mass on CMR and both the QRS duration and the LV Sokolow index, with the highest values in male patients with an advanced cardiomyopathy stage. No prediction of late enhancement on CMR (a sign for replacement fibrosis) was possible by a single ECG parameter. However, the absence of ST or T alterations (in 37 of 38 patients) specifically excluded late enhancement on CMR., Conclusion: Our data in a large cohort of Fabry patients, including all cardiomyopathy stages, show, in contrast to former assumptions, that ECG parameters are not suitable to stage Fabry cardiomoypathy. Most ECG parameters were normal in the complete cohort. However, the absence of ST or T alterations seems to almost exclude late enhancement on CMR in these patients.

Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.

Aims: This cross-sectional study aimed to analyse myocardial deformation in patients with Fabry disease (FD) in order to evaluate speckle tracking as a method for non-invasive determination of myocardial fibrosis. Myocardial fibrosis is common in Fabry cardiomyopathy and is associated with disease progression and severe prognosis., Methods and Results: In 101 consecutive Fabry patients (39.8 ± 12.9 years; 42 males), the quantitative measurement of myocardial fibrosis with magnetic resonance imaging was compared with regional myocardial deformation assessed by speckle-tracking imaging. Patients were analysed in relation to per cent of late-enhancement (LE)-positive areas of left-ventricular (LV) mass. Fifty-two patients (51%) displayed LE with a mean volume of 1.2 ± 1.8% of total LV mass. Predominantly basal lateral and posterior segments were affected. Patients with LE had lower global systolic longitudinal strain than those without (LE -14.8 ± 3.5% and -18.9 ± 2.1%, respectively; P < 0.001). Loss of global deformation, quantified by speckle tracking, was predominantly caused by basal posterior (P = 0.049) and lateral (P = 0.005) segments and global systolic strain correlated with the amount of LE (r = 0.543; P < 0.001). Patients with severe LE (>2%, n = 22) showed the lowest deformation values (-5.9 ± 8.4%) in basal postero-lateral segments when compared with those with mild (<2%; n = 30, -7.1 ± 7.5%) or no LE (n = 49, -16.3 ± 3.3%). These changes were accompanied by thinning of the posterior wall and a decrease in diastolic function, whereas ejection fraction and LV end-diastolic diameter were not different. Receiver operating characteristic analysis revealed that the systolic strain of basal postero-lateral segments was the most powerful predictor to distinguish between patients with and without LE (sensitivity = 90%; specificity = 97%, area under the curve = 0.913; P < 0.001)., Conclusions: Late enhancement is associated with lower longitudinal strain in the fibrotic wall segments. Speckle tracking can be used as a tool for the indirect evaluation of LE in FD.

Background: Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP)., Methods: In this case-control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function., Results: All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients., Conclusion: Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction.

Fabry disease is an X-chromosomal recessive deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal). This results in an accumulation of globotriaosylceramide (GL-3) in a variety of cells often with subsequent functional impairment. Here, the impact of Fabry disease on the biology of circulating angiogenic cells (CACs) and the endothelial response to transient ischemia was investigated. Untreated patients with Fabry disease (n = 26), patients after initiation of alpha-Gal enzyme replacement therapy (ERT) (n = 16) and healthy controls (n = 26) were investigated. Endothelial function was assessed by the EndoPAT2000 device. CAC numbers were assessed by flow-cytometry, CAC function by a modified Boyden chamber assay. Fabry patients showed a pathologic endothelial response, which normalized after ERT. CACs were increased in number, but functionally impaired. Immunofluorescence and electron microscopy identified an accumulation of GL-3 in Fabry CACs. ERT attenuated CAC dysfunction and improved markers of oxidative stress response in Fabry patients via a reduction in GL-3 accumulation in vitro and in vivo. Silencing of alpha-Gal in healthy CACs impaired their migratory capacity underlining a key role of this enzyme for CAC function. CAC supernatant as well as CACs from Fabry patients impaired angiogenesis and migratory capacity of HUVECs providing a mechanistic link between CAC and endothelial dysfunction. CAC adhesion to TNF-α pre-stimulated HUVECs and tube formation was impaired by alpha-Gal knockdown. Fabry patients show a dysfunction of CAC and a pathologic endothelial response. ERT improves CAC and endothelial function and thus may attenuate development of cardiovascular disease in the long term in this patient population.

Fabry's disease is an X-chromosome linked lysosomal storage disorder with α-galactosidase A deficiency and subsequent multiple organ involvement. An early and common symptom also in later stages of the disease is pain. This pain depends on various precipitating factors and can severely compromise the quality of life. So-called Fabry crises can lead to the necessity for intensive care treatment. The pain can be classified as predominantly neuropathic and is difficult to treat. In addition, medication has to be adjusted to concomitant cardiac and renal involvement in Fabry's disease. This review gives guidance for pain therapy in Fabry's disease based on the available evidence and on experience.

Purpose: In Fabry disease (FD), a progressive deposition of sphingolipids is reported in different organs. The present study applied 1H magnetic resonance spectroscopy (MRS) to investigate the myocardial lipid content in FD., Materials and Methods: In patients (PTS, n = 15) with genetically proven FD, 1H MRS of the heart was acquired in the same examination as routine cardiac cine and late enhancement MR imaging. Healthy volunteers (n = 11) without history of cardiac disease served as control (CTL). Myocardial triglycerides in vivo were quantified in 1H MRS. Left ventricular (LV) ejection fraction (EF) and late enhancement were assessed for the determination of LV systolic function, and onset or absence of myocardial fibrosis., Results: All 1H MRS revealed resonances for intramyocardial triglycerides. Clinical parameters, e.g. EF (PTS 64 ± 2 % vs. CTL 61 ± 1 %) were similar in PTS and CTL or showed a non-significant trend (LV mass). Apart from a single patient with elevated myocardial triglycerides, no significant impact of Fabry disease on the triglyceride/water resonance ratio (PTS 0.47 ± 0.11 vs. CTL 0.52 ± 0.11 %) was observed in our patient cohort., Conclusion: A comprehensive cardiac evaluation of morphology, function as well as metabolism in Fabry PTS with suspected cardiac involvement is feasible in a single examination. No significant effect of myocardial triglyceride deposition could be observed in patients. The remarkably high myocardial triglyceride content in one patient with advanced FD warrants further studies in PTS with an extended history of the disease., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Fabry cardiomyopathy is characterized by left ventricular (LV) hypertrophy and regional fibrosis. Recent high-end echocardiography studies of selected LV sections suggest an interrelation between regional fibrosis, impaired function, and hypertrophy possibly changing under specific enzyme replacement therapy (ERT)., Methods: Magnetic resonance imaging (MRI) was used for a region dependent study of cardiac function, morphology and late enhancement (LE) in 25 Fabry patients before and after 12 months of ERT in comparison to 43 healthy volunteers., Results: Fabry patients presented with LV increased wall thickness (EDWT) and reduced wall thickening (WT) with a focus on basal and midventricular regions corresponding to areas of LE. The degree of hypertrophy and hypokinesia were the highest if LE was detectable. A significant decrease of the EDWT under ERT was observed in LE negative patients accompanied by a decline of hypokinesia with regional differences., Conclusions: Regional differences of LV hypertrophy and wall motion were detected corresponding to the distribution of myocardial fibrosis (LE). Functional impairment was closely restricted to fibrotic regions while morphologic changes slightly exceeded the areas of fibrosis. ERT resulted in regional improvements whereby absence of fibrosis was connected to a better outcome., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder leading to an accumulation of globotriaosylceramides in the lysosomes of various organs., Design: Being X-chromosomal-linked, most studies in the past have focused on involvement in male patients. However, it has been elucidated recently that female patients can present typical organ involvement and thus need to be treated, respectively., Conclusions: This review wants to give a systematical overview of the typical organ involvement in female patients with FD. Moreover, therapy recommendations especially for female patients are discussed., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Purpose: According to echocardiography reports, Fabry cardiomyopathy not only affects the left ventricle (LV) but also the right ventricle (RV). Until now no MRI studies about the effect of enzyme replacement therapy (ERT) on the RV are available. We evaluated the effect of ERT on the RV., Materials and Methods: In this prospective trial 14 patients with genetically proven Fabry's disease were examined using a 1.5 T MR scanner before ERT and after 13 ± 1 months of ERT. All patients underwent cardiac MR imaging and the RV/LV cardiac morphology and function were analyzed., Results: At baseline examination the values were as follows: RV mass 31 ± 6 g/m (2), end-diastolic volume (EDV) 88 ± 13 ml/m (2), end-systolic volume (ESV) 39 ± 9 ml/m (2), stroke volume (SV) 49 ± 7 ml/m (2) and ejection fraction (EF) 56 ± 5 %. The RV mass and EDV decreased significantly after 13 ± 1 months on ERT (mass 27 ± 7 g/m (2), p < 0.05, EDV 76 ± 24 ml/m (2), p < 0.05), with no significant change of ESV (33 ± 13 ml/m (2)), SV (43 ± 12 ml/m (2)) and EF (57 ± 7 %). The LV mass (102 ± 26 g/m (2) vs. 94 ± 27 g/m (2), p < 0.05), EDV (76 ± 13 ml/m (2) vs. 66 ± 22 ml/m (2), p < 0.05) and ESV (29 ± 9 ml/m (2) vs. 23 ± 9 ml/m (2), p < 0.05) decreased significantly while the EF (64 ± 7 % vs. 66 ± 5 %; p < 0.05) increased significantly., Conclusion: Besides the known beneficial effect on the LV, ERT improves RV mass and EDV., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Systolic and diastolic dysfunction of the left ventricle are present in patients with cardiac involvement in Fabry disease. The aim of this study was to investigate the diagnostic value of the Tei index, a marker for combined diastolic and systolic function, in patients with Fabry disease., Methods: A total of 66 consecutive patients with genetically confirmed Fabry disease were included in this study. Standard echocardiography, including the Tei index, and magnetic resonance imaging were performed. Patients were followed for 2.9 ± 1.9 years; 56 patients received enzyme replacement therapy, and 10 patients had natural history follow-up. Patients were subdivided into three groups: (1) those without cardiac involvement, (2) those with left ventricular (LV) hypertrophy and without late enhancement on magnetic resonance imaging, and (3) those with late enhancement on magnetic resonance imaging., Results: The Tei index was significantly higher in the groups 2 (0.56 ± 0.10) and 3 (0.60 ± 0.16) compared with patients without cardiac involvement (0.44 ± 0.10) (P < .001). All patients with Tei indexes > 0.64 showed signs of cardiomyopathy. In contrast, ejection fractions were normal in all three patient groups and therefore not useful for the detection of cardiac involvement. A significant positive correlation was observed between LV wall thickness and the Tei index in the complete patient cohort. Moreover, receiver operating characteristic analysis revealed a large area under the curve for Tei index and hypertrophy, while the area under the curve for fibrosis was small. The Tei index remained unchanged in the natural history and enzyme replacement therapy groups during follow-up., Conclusions: In this cohort, the Tei index was of limited value to detect myocardial fibrosis and monitor enzyme replacement therapy. However, the progression of cardiomyopathy toward LV hypertrophy seems to be paralleled by global functional impairment, which can be assessed by the Tei index but not by ejection fraction. Thus, the Tei index seems to be a global parameter that can detect LV functional reduction in patients with Fabry disease., (Copyright © 2011 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Objectives: We hypothesized that Fabry cardiomyopathy in female patients might differ substantially from that in male patients and sought to prove this hypothesis in a large cohort consisting of 104 patients with Fabry disease., Background: Fabry cardiomyopathy in male patients is characterized by left ventricular (LV) hypertrophy, impaired myocardial function, and subsequent progressive myocardial fibrosis. In contrast, the occurrence of these 3 cardiomyopathic hallmarks in female patients remains unknown., Methods: In 104 patients (58 females, age 42 ± 16 years; 46 males, age 42 ± 13 years) with genetically proven Fabry disease, LV hypertrophy, regional myocardial deformation and myocardial fibrosis were assessed by standard echocardiography, strain rate imaging, and cardiac magnetic resonance (CMR) imaging-guided late enhancement (LE)., Results: In men, end-diastolic left ventricular wall thickness (LVWT) ranged from 6 to 19.5 mm (LV mass CMR 55 to 200 g/m(2)), and LE was never seen with LVWT <12 mm (LV mass <99 g/m(2)). In contrast in female patients, LVWT ranged from 5 to 15.5 mm, LV mass ranged from 39 to 146 g/m(2), and LE was already detectable with an LVWT of 9 mm (LV mass 56 g/m(2)). When LV mass was examined in CMR, LE was detected in 23% of the female patients without hypertrophy (n=9), whereas LE was never seen in male patients with normal LV mass. LE was always associated with low systolic strain rate, but the severity of impairment was independent of LVWT in female patients (lateral strain rate in patients with LV hypertrophy with LE -0.7 ± 0.2 s(-1); patients without LV hypertrophy with LE -0.8 ± 0.2 s(-1); p=0.45)., Conclusions: In contrast to male patients, the loss of myocardial function and the development of fibrosis do not necessarily require myocardial hypertrophy in female patients with Fabry disease. Thus, in contrast to actual recommendations, initial cardiac staging and monitoring should be based on LV hypertrophy and on replacement fibrosis in female patients with Fabry disease., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)