Pitfalls in the Diagnosis of Wilson Disease

Wilson disease (WD), an uncommon autosomal recessive (AR) hereditary disorder characterized by abnormal accumulation of copper primarily in the liver and secondarily in other organs like the brain, is caused by a deficiency in the ATP7B transporter gene. The key to successful therapy is early diagnosis.

Mutant genes need to be inherited from both parents for phenotypic expression. The ATP7B gene located on chromosome 13q14.3 comprises 20 introns and 21 exons, encodes a protein of 165 amino acids, and this helps in incorporation of copper into ceruloplasmin, the copper binding protein. So far, more than 800 mutations have been reported, of which 380 have confirmed involvement in the pathogenesis of WD. The most common mutations are H1069Q and R778L in European and Asian populations respectively. Approximately 90%-98% of WD subjects are heterozygous, showing different mutations in each of the alleles encoding the ATP7B. Conversely, the phenotype and the penetrance of WD can be extremely variable. Even patients carrying two disease-causing mutations do not necessarily have a demonstrable alteration of copper metabolism. Considering the possibility of late-onset disease, asymptomatic cases, and phenotypic variability, it is crucial to evaluate previous and future generations of the index case. WD ranges from being asymptomatic in some patients to result in acute liver failure and/or a variety of neuropsychiatric disorders among others. Although WD may be present at any age, is more common between the ages of 5 and 35 years. However, it should be investigated in patients with liver failure of unknown cause and those with liver disease associated with neuropsychiatric symptomatology. Diagnosis requires a combination of clinical signs and symptoms, as well as relevant diagnostic tests such as measurement of serum ceruloplasmin, urinary excretion of copper, liver biopsy or genetic testing. Treatment is lifelong and includes chelating agents (penicillamine and trientine) and inhibitors of copper absorption (zinc salts). Liver transplant is an option for patients with end-stage liver disease. The key to successful therapy is early diagnosis.