Wilson disease: revision of diagnostic criteria in a clinical series with great genetic homogeneity.

BACKGROUND Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. An early diagnosis is crucial to prevent evolution of the disease, as implantation of early therapeutic measures fully prevents its symptoms. As population genetics data predict a higher than initially expected prevalence, it was important to define the basic diagnostic tools to approach population screening. METHODS A highly genetically homogeneous cohort of 70 patients, belonging to 50 unrelated families, has been selected as a framework to analyze all their clinical, biochemical and genetic characteristics, to define the disease in our population, with an estimated prevalence of 1 in 12,369, and determine the most useful features that reach diagnostic value. RESULTS Serum ceruloplasmin below 11.5 mg/dL and cupremia below 60 μg/mL, were the best analytical predictors of the disease in asymptomatic individuals, while cupruria or hepatic copper determination were less powerful. Genetic analysis reached a conclusive diagnosis in all 65 patients available for complete testing. Of them, 48 were carriers of at least one p.Leu708Pro mutant allele, with 24 homozygotes. Nine patients carried a promoter deletion mutation, revealing that extended sequencing beyond the ATP7B gene-coding region is essential. All mutations caused hepatic damage since early ages, increasing its severity as diagnosis was delayed, and neurological symptoms appear. CONCLUSION Serum ceruloplasmin determination followed by genetic screening would reduce costs and favor the prioritization of non-invasive procedures to reach a definitive diagnosis, even for asymptomatic cases.