FEASIBILITY OF NEONATAL WILSON DISEASE SCREENING BY MUTATION ANALYSIS

Abstract

Wilson disease (WD) is an autosomal recessive disorder caused by a defective function of the copper transporting ATP7B protein. This results in progressive copper overload and consequent liver, brain and kidney damage. The development of an accurate, cost-effective diagnostic test may pave the way to preventing the devastating tissue damage caused by WD. In some isolated populations, such as the Sardinian population and the Greek inhabitants of the island of Kalymnos, WD results from a limited spectrum of mutations. Herein we report an estimation of the incidence of WD in these two populations by molecular analysis. In the past few years mutation analysis of the WD gene in Sardinians has led us to characterize the mutation in 94.3% of the WD chromosomes and to identify 21 disease-causing mutations. The most common of these is the -441/-427 del promoter mutation, which accounts for 60% of the total. Presence of the -441/-427 del was screened for in a random sample of 5290 subjects mainly newborns. The results revealed 122 positive heterozygous samples with a carrier rate of 3.8%. Based on these data and according to the Hardy-Weinberg law we calculated the expected new cases of the disease, which are 5 new cases per 150000 live births per year with an incidence of approximately 1/3000 live births per year. In the island of Kaymnos (Greece), with a population of 20000 inhabitants, mutation analysis of 10 WD families revealed the presence of the compound heterozygous or homozygous state for mutations H1069Q or R969Q. By screening for these mutations in 400 guthrie cards (corresponding to 50% of the newborns in 4 years) we detected one compound heterozygous state for mutations R969Q/H1069Q, 18 heterozygous for mutation H1069Q, and 9 heterozygous for mutation R969Q. According to these results, the carrier frequency was 4.4% for H1069Q and 2.2% for R969Q, while the expected new cases of the disease are 23.1/20000 inhabitants. These preliminary data are important because they suggest that an efficient screening program based on mutations analysis for the early identification and treatment of Wilson disease in a preclinic stage is not only needed, but also feasible in these populations, as it would prevent the severe toxic effect of copper in presymptomatic patients.