title: Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson's disease.
abstract: OBJECTIVE
  Wilson's disease (WND) is an autosomal recessive disorder of copper (Cu) transport, resulting from pathogenic mutations in the ATP7B gene. The reason for the high variability in phenotypic expressions of WND is unknown. Hepatotoxic and neurotoxic effects of homocysteine (Hcy), as well as interrelationships between Hcy and Cu toxicity, were documented.
  
  
  METHODS
  We genotyped the two 5,10-methylenetetrahydrofolate reductase (one of the key folate/Hcy pathway enzymes) gene (MTHFR) polymorphisms: C677T and A1298C in 245 WND patients. Next, we tested the modulation of WND phenotypes by genotypes of MTHFR.
  
  
  RESULTS
  MTHFR C677T genotype distribution deviated from that expected from a population in Hardy-Weinberg equilibrium (C677T, χ(2) = 12.14, p = 0.0005). Patients with the MTHFR 1298C allele were younger at symptoms' onset than those without this allele (median (IQR) age, 24.9 (14.0) years vs. 28.5 (12.0) years, p = 0.006). Carriers of MTHFR "high activity" diplotype (double wild-type homozygotes 677CC/1298AA) manifested WND at older age, than non-carriers (median (IQR) age, 33.5 (9.0) years vs. 25.0 (13.0) years, p = 0.0009). Patients with the MTHFR 677T allele less frequently exhibited the neurological WND phenotype (31 (29.5%) vs. 36 (48.0%)), and more frequently presented with hepatic WND (44 (41.9%) vs. 22 (29.3%)), compared with subjects MTHFR 677T(-).
  
  
  CONCLUSIONS
  We postulate that MTHFR polymorphism contributes to the phenotypic variability of WND.
authors.affiliation: Institute of Psychiatry and Neurology, Second Department of Neurology, Warsaw, Poland. gromadz@ipin.edu.pl
authors.forename: Grażyna
authors.initials: G
authors.lastname: Gromadzka
authors.forename: Magdalena
authors.initials: M
authors.lastname: Rudnicka
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Chabik
authors.forename: Adam
authors.initials: A
authors.lastname: Przybyłkowski
authors.forename: Anna
authors.initials: A
authors.lastname: Członkowska
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D027682:Cation Transport Proteins / Q000235:genetics; D002648:Child; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006527:Hepatolenticular Degeneration / Q000235:genetics* / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D055815:Young Adult
chemical_list: D027682:Cation Transport Proteins; D006710:Homocysteine; D003300:Copper; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases