Wilson Disease: an Update

Seo, Jeong Kee

Abstract

Wilson disease (WD) is an autosomal recessive disorder of copper transport that results in accumulation of copper primarily in the liver, the brain and the cornea. WD is the most common inherited liver disease with the prevalence of 1: 37,000 in the pediatric population in Korea. Mutations in the ATP7B gene cause failure of copper excretion into the bile and a defective incorporation of copper into ceruloplasmin. More than 300 mutations in the ATP7B gene have been described so far. Mutations differ between ethnic groups. The p.R778L (an allele frequency of 37%), p.A874V (13%), p.L1083F (8%) and p.N1270S (6%) are the common major mutations in Korea. Conflicting results on genotype/phenotype correlations of the most common mutations have been reported in various countries. There seems to be no correlation between the R778L mutation and age of onset or clinical manifestations in Korean patients. None of the laboratory parameters alone allows a definite diagnosis of WD. In a nation-wide survey of WD, low serum ceruloplasmin (<20 mg/dL), high 24 hour urine copper (>100 microgram), high hepatic copper content (>250 microgram/g of dry liver) and Kayser-Fleischer rings were found in 96%, 86%, 88%, and 73% of the 550 Korean patients respectively. A combination of any two of the above 4 laboratory findings is strong support for a diagnosis of WD. For the last couple of years, genetic testing has been playing an increasingly important role in diagnosing WD. Direct DNA sequencing did confirm WD in 98% of the Korean patients. Two mutations were detected in 70% and one mutation in 28% of the patients who showed characteristic biochemical and clinical findings of WD. Genetic testing, either by haplotype analysis or by mutation analysis, is the only reliable tool for differentiating heterozygote carriers from affected asymptomatic patients. The agents of the first choice among chelators and zinc in specific clinical situations of WD is still a matter of debate. Because of frequent side effects and initial neurologic deterioration of penicillamine therapy, less toxic trientine or zinc has gradually replaced penicillamine over the past few years. Trientine or tetrathiomolybdate has been increasingly recommended as the first-line treatment for neurologic WD. Currently, liver transplantation is not recommended as primary treatment for neurologic WD. Recently published data show that initial zinc therapy for asymptomatic/presymptomatic patients and maintenance zinc therapy in patients after long term chelation are safe and effective. Further researches and the new guidelines on the proper management of patients with WD are needed.