title: Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Internal Medicine I.
authors.forename: Markus
authors.initials: M
authors.lastname: Niemann
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.forename: Stefan
authors.initials: S
authors.lastname: Störk
authors.forename: Bart
authors.initials: B
authors.lastname: Bijnens
authors.forename: Frank
authors.initials: F
authors.lastname: Breunig
authors.forename: Meinrad
authors.initials: M
authors.lastname: Beer
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.forename: Frank
authors.initials: F
authors.lastname: Weidemann
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D015331:Cohort Studies; D000795:Fabry Disease / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics; D005260:Female; D005838:Genotype; D006017:Glycolipids / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013107:Sphingolipids / Q000032:analysis* / Q000378:metabolism; D055815:Young Adult; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D015415:Biomarkers; D006017:Glycolipids; D013107:Sphingolipids; C063288:globotriaosyl lysosphingolipid; D000519:alpha-Galactosidase
keywords: Fabry disease; biological markers; cardiomyopathies; mutation