title: Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease.
abstract: BACKGROUND
  Mutations in the gene ATP7B cause Wilson disease, a copper storage disorder with a high phenotypic and genetic heterogeneity. We aimed to evaluate whether 'severe' protein-truncating ATP7B mutations (SMs) are associated with low serum ceruloplasmin oxidase activities and an early age of onset when compared to missense mutations (MMs).
  
  
  METHODS
  The clinical phenotype of 59 genetically confirmed WD patients was analyzed retrospectively. Serum ceruloplasmin was measured by its oxidase activity with o-dianisidine dihydrochloride as substrate and immunologically.
  
  
  RESULTS
  Thirty-nine patients had two MMs, 15 had the genotype SM/MM, and 5 patients had two SMs on their ATP7B alleles. Enzymatic and immunologic serum ceruloplasmin levels differed significantly between the three groups (P < 0.001 and P < 0.01, respectively). The lowest levels were measured in patients with two SMs (0.0 U/L; IQR, 0.0-0.0 U/L and 0.02 g/L; IQR, 0.01-0.02 g/L, respectively) and the highest in patients with two MMs (17.8 U/L; IQR, 5.8-35.1 U/L and 0.11 g/L; IQR,0.10-0.17 g/L, respectively). The age of onset was also significantly different between the three patient groups (P < 0.05), with SM/SM patients showing the earliest onset (13 years; IQR, 9-13 years) and patients with two MMs showing the latest onset (22 years; IQR, 14-27 years). By ROC curve analysis a ceruloplasmin oxidase level <or= 5 U/L can predict the presence of at least one SM with a sensitivity of 80% and a specificity of 79.5%.
  
  
  CONCLUSIONS
  In our German study cohort truncating ATP7B mutations were associated with lower ceruloplasmin serum oxidase levels and an earlier age of onset when compared to MMs. Measurement of serum ceruloplasmin oxidase might help to predict presence of truncating ATP7B mutations and might facilitate the mutation analysis.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, Heidelberg, Germany. uta_merle@med.uni-heidelberg.de
authors.forename: Uta
authors.initials: U
authors.lastname: Merle
authors.forename: Karl Heinz
authors.initials: KH
authors.lastname: Weiss
authors.forename: Christoph
authors.initials: C
authors.lastname: Eisenbach
authors.forename: Sabine
authors.initials: S
authors.lastname: Tuma
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D027682:Cation Transport Proteins / Q000235:genetics*; D002570:Ceruloplasmin / Q000378:metabolism*; D002648:Child; D015331:Cohort Studies; D000073840:Copper-Transporting ATPases; D005260:Female; D005838:Genotype; D006527:Hepatolenticular Degeneration / Q000097:blood / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D012372:ROC Curve; D055815:Young Adult
chemical_list: D027682:Cation Transport Proteins; D002570:Ceruloplasmin; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases