title: Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson's disease cohort.
abstract: OBJECTIVE
  Wide phenotypic and genotypic heterogeneities in Wilson's disease (WD) have been reported, hampering the study of their correlations. The goal of this study was to identify the factors related to these diversities.
  
  
  METHODS
  Clinical courses and molecular genetic characteristics were analysed in 237 unrelated Korean WD families. The average follow-up period was 8.2 ± 5.8 years.
  
  
  RESULTS
  Presenting phenotypes were classified as H1 (12.2%), H2 (42.4%), N1 (21.6%), N2 (0.4%), NX (0.4%), presymptomatic (22.4%) and other (0.4%), modifying the guidelines by Ferenci and colleagues. Age at presentation was youngest and cirrhosis was rarest in the presymptomatic group. Decompensated cirrhosis was the highest in the H1 group. Favourable outcome was rarest in the N1 group. Forty-seven (11 novel) ATP7B mutations were identified in 85% of the 474 alleles. Multiplex ligation-dependent probe amplification assays in ATP7B and analyses of ATOX1 and COMMD1 genes identified no additional mutations. Yeast complementation assays demonstrated functional perturbation of the seven novel missense mutants. Five major mutations, p.Arg778Leu, p.Ala874Val, p.Asn1270Ser, p.Lys838SerfsX35 and p.Leu1083Phe, accounted for 63% of the alleles. H1 was more common, age at presentation was younger and N1+N2+NX tended to be less common in patients with nonsense, frame shifting or splicing mutations than in those with missense mutations alone. Patients with both mutations in the transduction (Td) or the ATP hinge domain showed presymptomatic or hepatic manifestations but no neurological manifestation.
  
  
  CONCLUSIONS
  The presenting phenotype strongly affects the clinical outcome of WD, and is related to the ATP7B mutation type and location, providing an evidence for genotype-phenotype correlations in WD.
authors.affiliation: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Beom H
authors.initials: BH
authors.lastname: Lee
authors.forename: Joo H
authors.initials: JH
authors.lastname: Kim
authors.forename: Sun Y
authors.initials: SY
authors.lastname: Lee
authors.forename: Hye Y
authors.initials: HY
authors.lastname: Jin
authors.forename: Kwi-Joo
authors.initials: KJ
authors.lastname: Kim
authors.forename: Jin-Joo
authors.initials: JJ
authors.lastname: Lee
authors.forename: Jung-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Gu-Hwan
authors.initials: GH
authors.lastname: Kim
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Kyung M
authors.initials: KM
authors.lastname: Kim
authors.forename: Han-Wook
authors.initials: HW
authors.lastname: Yoo
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D027682:Cation Transport Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006527:Hepatolenticular Degeneration / Q000150:complications / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D006801:Humans; D007223:Infant; D008107:Liver Diseases / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009422:Nervous System Diseases / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D010375:Pedigree; D010641:Phenotype; D056910:Republic of Korea; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D027682:Cation Transport Proteins; D018389:Codon, Nonsense; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases