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      Twenty years of the Fabry Outcome Survey (FOS): insights, achievements, and lessons learned from a global patient registry


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          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.


          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.


          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.

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          Most cited references97

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          The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies

          The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that underlie, or are closely associated with human inherited disease. At the time of writing (March 2017), the database contained in excess of 203,000 different gene lesions identified in over 8000 genes manually curated from over 2600 journals. With new mutation entries currently accumulating at a rate exceeding 17,000 per annum, HGMD represents de facto the central unified gene/disease-oriented repository of heritable mutations causing human genetic disease used worldwide by researchers, clinicians, diagnostic laboratories and genetic counsellors, and is an essential tool for the annotation of next-generation sequencing data. The public version of HGMD (http://www.hgmd.org) is freely available to registered users from academic institutions and non-profit organisations whilst the subscription version (HGMD Professional) is available to academic, clinical and commercial users under license via QIAGEN Inc.
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            Prevalence of lysosomal storage disorders.

            Lysosomal storage disorders represent a group of at least 41 genetically distinct, biochemically related, inherited diseases. Individually, these disorders are considered rare, although high prevalence values have been reported in some populations. These disorders are devastating for individuals and their families and result in considerable use of resources from health care systems; however, the magnitude of the problem is not well defined. To date, no comprehensive study has been performed on the prevalence of these disorders as a group. To determine the prevalence of lysosomal storage disorders individually and as a group in the Australian population. Retrospective case studies. Australia, from January 1, 1980, through December 31, 1996. Enzymatic diagnosis of a lysosomal storage disorder. Twenty-seven different lysosomal storage disorders were diagnosed in 545 individuals. The prevalence ranged from 1 per 57000 live births for Gaucher disease to 1 per 4.2 million live births for sialidosis. Eighteen of 27 disorders had more than 10 diagnosed cases. As a group of disorders, the combined prevalence was 1 per 7700 live births. There was no significant increase in the rate of either clinical diagnoses or prenatal diagnoses of lysosomal storage disorders during the study period. Individually, lysosomal storage disorders are rare genetic diseases. However, as a group, they are relatively common and represent an important health problem in Australia.
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              Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey.

              Fabry disease is a rare X-linked lysosomal storage disorder characterised by severe multisystemic involvement that leads to major organ failure and premature death in affected men and women. Over the past 7 years, the Fabry Outcome Survey (FOS) has collected data on the natural history of Fabry disease, and the long-term efficacy and safety of enzyme-replacement therapy. This paper provides an update on the first analysis of FOS data. Baseline data on clinical manifestations and causes of death in a cohort of 1453 patients (699 male, 754 female) from 19 countries worldwide were analysed. Causes of death of affected relatives were analysed separately. The most frequently reported signs and symptoms of Fabry disease were neurological. Cardiac, ocular, gastrointestinal, dermatological, auditory and renal manifestations were also common. The principal causes of death among 181 affected relatives of patients in FOS (most of whom had died before 2001) were renal failure in males (42%) and cerebrovascular disease in females (25%). In contrast, of the 42 patients enrolled in FOS whose deaths were reported between 2001 and 2007, cardiac disease was the main cause of death in both male (34%) and female (57%) patients. These data suggest that the importance of renal disease as a cause of death in patients with Fabry disease is decreasing while the importance of cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease.

                Author and article information

                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central (London )
                20 June 2022
                20 June 2022
                : 17
                : 238
                [1 ]SphinCS GmbH, Institute Clinical Science LSD, Hochheim, Germany
                [2 ]GRID grid.83440.3b, ISNI 0000000121901201, Lysosomal Disorders Unit, Institute of Immunity and Transplantation, Royal Free London NHS Foundation Trust, , University College London, ; London, UK
                [3 ]Late Phase Solutions Europe AB, Täby, Sweden
                [4 ]GRID grid.5802.f, ISNI 0000 0001 1941 7111, Johannes Gutenberg School of Medicine, , University of Mainz, ; Mainz, Germany
                [5 ]GRID grid.83440.3b, ISNI 0000000121901201, Department of Haematology, , University College London, ; London, UK
                [6 ]The Royal Melbourne Hospital, University of Melbourne, Parkville, VIC Australia
                [7 ]GRID grid.278247.c, ISNI 0000 0004 0604 5314, Taipei Veterans General Hospital, ; Taipei, Taiwan
                [8 ]GRID grid.411083.f, ISNI 0000 0001 0675 8654, Reference Centre for Hereditary Metabolic Disorders (MetabERN), , Vall d’Hebron University Hospital, ; Barcelona, Spain
                [9 ]GRID grid.414382.8, ISNI 0000 0001 2337 0926, Hospital Británico de Buenos Aires, ; Buenos Aires, Argentina
                [10 ]GRID grid.55602.34, ISNI 0000 0004 1936 8200, Department of Medicine, , Dalhousie University, ; Halifax, NS Canada
                [11 ]Takeda Pharmaceuticals International AG, Zurich, Switzerland
                [12 ]GRID grid.8532.c, ISNI 0000 0001 2200 7498, Department of Genetics, , UFRGS, Medical Genetics Service, HCPA, ; Porto Alegre, Brazil
                Author information
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                : 15 February 2022
                : 6 June 2022
                Funded by: Shire, a Takeda company
                Funded by: Takeda Development Center Americas, Inc.
                Custom metadata
                © The Author(s) 2022

                Infectious disease & Microbiology
                agalsidase alfa,enzyme replacement therapy,fabry disease,cardiovascular outcomes,renal outcomes


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