title: Later Onset Fabry Disease, Cardiac Damage Progress in Silence: Experience With a Highly Prevalent Mutation.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ting-Rong
authors.initials: TR
authors.lastname: Hsu
authors.affiliation: 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.
authors.forename: Sheng-Che
authors.initials: SC
authors.lastname: Hung
authors.affiliation: Pathology and Laboratory Medicine Department, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Fu-Pang
authors.initials: FP
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University, School of Medicine, Taipei, Taiwan.
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Yu
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University, School of Medicine, Taipei, Taiwan.
authors.forename: Shih-Hsien
authors.initials: SH
authors.lastname: Sung
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Hsu
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dzhagalov
authors.affiliation: Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Environmental and Occupational Health Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Feng
authors.initials: CF
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Tzu-Hung
authors.initials: TH
authors.lastname: Chu
authors.affiliation: Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Han-Jui
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yung-Hsiu
authors.initials: YH
authors.lastname: Lu
authors.affiliation: Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Sheng-Kai
authors.initials: SK
authors.lastname: Chang
authors.affiliation: Neonatal Screening Center, Chinese Foundation of Health, Taipei, Taiwan.
authors.forename: Hsuan-Chieh
authors.initials: HC
authors.lastname: Liao
authors.affiliation: Department of Pediatrics, Mackay Memorial Hospital and Department of Medicine, Mackay Medical College, Taipei, Taiwan.
authors.forename: Hsiang-Yu
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Radiology, Zhongxiao Branch, Taipei City Hospital, Taipei, Taiwan.
authors.forename: Tsan-Chieh
authors.initials: TC
authors.lastname: Liao
authors.affiliation: Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Pi-Chang
authors.initials: PC
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Hsing-Yuan
authors.initials: HY
authors.lastname: Li
authors.affiliation: Pathology and Laboratory Medicine Department, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: An-Hang
authors.initials: AH
authors.lastname: Yang
authors.affiliation: Taipei Institute of Pathology, Taipei, Taiwan.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Ho
authors.affiliation: Neonatal Screening Center, Chinese Foundation of Health, Taipei, Taiwan.
authors.forename: Chuan-Chi
authors.initials: CC
authors.lastname: Chiang
authors.affiliation: College of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Ching-Yuang
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Genetics & Genomic Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: robert.desnick@mssm.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.affiliation: 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.
authors.forename: Dau-Ming
authors.initials: DM
authors.lastname: Niu
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D004452:Echocardiography; D000795:Fabry Disease / Q000150:complications / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000175:diagnosis / Q000209:etiology*; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015997:Neonatal Screening / Q000379:methods*; D010641:Phenotype; D015995:Prevalence; D012189:Retrospective Studies; D013624:Taiwan / Q000453:epidemiology; D055815:Young Adult; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: C576330:GLA protein, human; D000519:alpha-Galactosidase
keywords: IVS4+919G>A; cardiac fibrosis; late gadolinium enhancement; newborn screening