title: The Dutch Fabry cohort: diversity of clinical manifestations and Gb3 levels.
abstract: BACKGROUND
  Fabry disease (OMIM 301500) is an X-linked lysosomal storage disorder with characteristic vascular, renal, cardiac and cerebral complications. Globotriaosylceramide (Gb(3)) accumulates in Fabry patients as a result of alpha-galactosidase A deficiency. The phenotypic variability is high, but the relationship between clinical symptoms in individual Fabry patients has not been uniformly documented. Also, the relation between the most prominent biochemical abnormalities, elevated Gb(3) levels in plasma and urine, and clinical symptoms is not firmly established.
  
  
  METHODS
  Clinical and biochemical characteristics of 96 (25 deceased) Dutch Fabry patients were collected retrospectively and before the initiation of enzyme therapy.
  
  
  RESULTS
  Clinical assessment revealed that median life expectancy was 57 years for male and 72 years for female patients. Cerebral complications, acroparaesthesias and gastrointestinal complications, but not cardiac and auditory complications, were all seen more frequently in male than female patients. Glomerular filtration rate (GFR) was highly variable in male patients, including 2 patients with GFR < 30 ml/min, but median GFR did not differ between males and females (103 and 101 ml/min, respectively). Hyperfiltration was more frequently observed in the female patient group. Microalbuminuria was present in 60% of males and 45% of females. No specific pattern of combined symptoms existed except for a relationship between left ventricular hypertrophy (LVH) and cerebral complications (males 36%, females 32%), or proteinuria (males 35%, females 31%). Gb(3) was found to be more elevated in plasma samples from male (n = 26; median 6.27 micromol/L (1.39-9.74)) than female Fabry patients (n = 37; median 2.16 (0.77-4.18)). This was also observed for urinary Gb(3): males (n = 22) median 1851 nmol/24 h (40-3724); females (n = 29) median 672 (86-2052). Plasma and urinary Gb(3) levels correlated with each other in both males (r = 0.4, p = 0.05) and females (r = 0.4, p = 0.03), but no correlation between elevated Gb(3) levels and clinical symptoms could be detected.
  
  
  CONCLUSIONS
  Analysis of the characteristics of the Dutch Fabry cohort has revealed that a limited relationship between various disease manifestations exists and that individual symptoms do not correlate with elevated urinary or plasma Gb(3) levels, limiting their value as surrogate disease markers.
authors.affiliation: Department of Internal Medicine/Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: A C
authors.initials: AC
authors.lastname: Vedder
authors.forename: G E
authors.initials: GE
authors.lastname: Linthorst
authors.forename: M J
authors.initials: MJ
authors.lastname: van Breemen
authors.forename: J E M
authors.initials: JE
authors.lastname: Groener
authors.forename: F J
authors.initials: FJ
authors.lastname: Bemelman
authors.forename: A
authors.initials: A
authors.lastname: Strijland
authors.forename: M M A M
authors.initials: MM
authors.lastname: Mannens
authors.forename: J M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: C E M
authors.initials: CE
authors.lastname: Hollak
mesh_terms: D000293:Adolescent; D000368:Aged; D015331:Cohort Studies; D000795:Fabry Disease / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010641:Phenotype; D011788:Quality of Life; D012189:Retrospective Studies; D012737:Sex Factors; D011795:Surveys and Questionnaires; D014281:Trihexosylceramides / Q000097:blood* / Q000652:urine*
chemical_list: D014281:Trihexosylceramides; C018549:globotriaosylceramide