Ting-Rong Hsu1, Sheng-Che Hung2, Fu-Pang Chang3, Wen-Chung Yu4, Shih-Hsien Sung4, Chia-Lin Hsu5, Ivan Dzhagalov5, Chia-Feng Yang6, Tzu-Hung Chu7, Han-Jui Lee8, Yung-Hsiu Lu7, Sheng-Kai Chang7, Hsuan-Chieh Liao9, Hsiang-Yu Lin10, Tsan-Chieh Liao11, Pi-Chang Lee7, Hsing-Yuan Li7, An-Hang Yang3, Hui-Chen Ho12, Chuan-Chi Chiang9, Ching-Yuang Lin13, Robert J Desnick14, Dau-Ming Niu15. 1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan. 2. Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming University, Taipei, Taiwan; Department of Biomedical Imaging and Radiological Sciences, National Yang Ming University, Taipei, Taiwan. 3. Pathology and Laboratory Medicine Department, Taipei Veterans General Hospital, Taipei, Taiwan. 4. Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University, School of Medicine, Taipei, Taiwan. 5. Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. 6. Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Environmental and Occupational Health Sciences, National Yang-Ming University, Taipei, Taiwan. 7. Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan. 8. Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan. 9. Neonatal Screening Center, Chinese Foundation of Health, Taipei, Taiwan. 10. Department of Pediatrics, Mackay Memorial Hospital and Department of Medicine, Mackay Medical College, Taipei, Taiwan. 11. Department of Radiology, Zhongxiao Branch, Taipei City Hospital, Taipei, Taiwan. 12. Taipei Institute of Pathology, Taipei, Taiwan. 13. College of Medicine, China Medical University, Taichung, Taiwan. 14. Department of Genetics & Genomic Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: robert.desnick@mssm.edu. 15. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan; Taiwan Clinical Trial Consortium in Fabry Disease, Taipei, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: dmniu1111@yahoo.com.tw.
Abstract
BACKGROUND: Recently, several studies revealed a much higher prevalence of later onset Fabry disease (FD) than previously expected. It suggested that later onset FD might present as an important hidden health issue in certain ethnic or demographic populations in the world. However, the natural history of its phenotype has not been systemically investigated, especially the cardiac involvement. OBJECTIVES: The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD. METHODS: To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919G>A (IVS4) mutation. Echocardiography was performed in 620 adults with the IVS4 mutation to analyze the prevalence of left ventricular hypertrophy (LVH), and gadolinium-enhanced cardiac magnetic resonance imaging was performed in 129 patients with FD, including 100 IVS4 adults. RESULTS: LVH was observed in 67% of men and 32% of women older than 40 years. Imaging evidenced significant late gadolinium enhancement in 38.1% of IVS4 men and 16.7% of IVS4 women with the IVS4 mutation but without LVH. Seventeen patients underwent endomyocardial biopsies, which revealed significant globotriaosylceramide substrate accumulation in their cardiomyocytes. CONCLUSIONS: Significant cardiomyocyte substrate accumulation in IVS4 patients led to severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations. Thus, it might be too late to start enzyme replacement therapy after the occurrence of LVH or other significant cardiac manifestations in patients with later onset FD. This study also indicated the importance of newborn screening for early detection of the insidious, ongoing, irreversible cardiac damage in patients with later onset FD. Copyright Â
BACKGROUND: Recently, several studies revealed a much higher prevalence of later onset Fabry disease (FD) than previously expected. It suggested that later onset FD might present as an important hidden health issue in certain ethnic or demographic populations in the world. However, the natural history of its phenotype has not been systemically investigated, especially the cardiac involvement. OBJECTIVES: The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD. METHODS: To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919G>A (IVS4) mutation. Echocardiography was performed in 620 adults with the IVS4 mutation to analyze the prevalence of left ventricular hypertrophy (LVH), and gadolinium-enhanced cardiac magnetic resonance imaging was performed in 129 patients with FD, including 100 IVS4 adults. RESULTS: LVH was observed in 67% of men and 32% of women older than 40 years. Imaging evidenced significant late gadolinium enhancement in 38.1% of IVS4 men and 16.7% of IVS4 women with the IVS4 mutation but without LVH. Seventeen patients underwent endomyocardial biopsies, which revealed significant globotriaosylceramide substrate accumulation in their cardiomyocytes. CONCLUSIONS: Significant cardiomyocyte substrate accumulation in IVS4 patients led to severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations. Thus, it might be too late to start enzyme replacement therapy after the occurrence of LVH or other significant cardiac manifestations in patients with later onset FD. This study also indicated the importance of newborn screening for early detection of the insidious, ongoing, irreversible cardiac damage in patients with later onset FD. Copyright Â
Authors: Yiting Fan; Tsz-Ngai Chan; Josie T Y Chow; Kevin K H Kam; Wai-Kin Chi; Joseph Y S Chan; Erik Fung; Mabel M P Tong; Jeffery K T Wong; Paul C L Choi; David K H Chan; Bun Sheng; Alex Pui-Wai Lee Journal: J Clin Med Date: 2021-05-17 Impact factor: 4.241