Wilson Disease: High Prevalence in a Mountaineous Area of Crete

Abstract

SummaryWilson disease (WD) is an autosomal recessive disorder of copper metabolism. The disorder is caused by mutations in the ATP7B gene, encoding a copper transporting P-type ATPase. The worldwide incidence is in the order of 30 cases per million, with a gene frequency of 0.56% and a carrier frequency of 1 in 90. The increased number of Wilson disease patients in the island of Crete led us to study the spectrum of mutations in a small village close to the city of Heraklion, from where many patients have been referred during the last 25 years. In order to estimate the frequency of the disease, we firstly investigated the number of births and the number of WD patients in the village since 1978. Six out of 90 births were diagnosed as WD patients, presenting the highest prevalence of WD reported so far. Analysis of the whole gene in three Wilson disease patients, and relatives of a boy who died from WD, led to the detection of 4 different point mutations. Two of them were missense (p.I1148T and p.G1176R) and cosegregated in cis in the same patient; the other allele of this patient carried a nonsense mutation (p.Q289X). This is the first report in the literature of three mutations co-segregating in the same WD patient. The fourth mutation identified was a novel frameshift mutation (c.398delT) with documented cosegregation. When screening 200 inhabitants originating from the same area, 18 were found to be carriers of one of these mutations. These findings indicate the need for health education intervention, genetic counselling and newborn screening for the Wilson disease.

Hypoceruloplasminemia‐related movement disorder without Kayser‐Fleischer rings is different from Wilson disease and not involved in ATP7B mutation

“…Our data showed that 8.1% of patients with idiopathic movement disorders exhibited lower serum CP and accorded with diagnostic criteria of HCMD. This percentage is obviously high compared with 1% of frequency of WD gene carrier in general population [16], which indicates that HCMD is independent of WD gene carrier frequency. To HCMD, lower serum CP is not merely a phenomenon which WD gene carrier produces, but possibly has the etiology relation.…”

Diagnosis of Wilson's Disease: A Comprehensive Review

“…The authors had also noted several differences between published primer sequences and the genomic sequence currently in the National Center for Biotechnology Information (NCBI) human genome database (Table 3). Compound heterozygotes bearing three mutations in the same WD patients have been reported by Dedoussis et al 20 p.I1148T and p.G1176R cosegregated in cis in the same patient, and the other allele harbored p.Q289X. Mak et al also found four patients who carried both p.Q1142H and p.I1148T on the same allele and another mutation on the trans allele (p.A874V, p.T1178A, 2299delC, and IVS3+1G>T, respectively).…”

“…25 The highest incidence reported was six out of 90 births in the island of Crete, Greece, where a founder effect was significant. 20 The discrepancies between the old figures and the more recent studies were likely due to analytical insensitivity and the under-or mis-diagnosis of WD in the past that may have occurred in patients with a typical phenotypes, or death due to unexplained liver failure. In our experience, WD is one of the most common inherited liver disorders in East Asian populations.…”

Letter to the editor

“…Wilson's disease occurs worldwide, is caused by mutations of the ATP7B gene, on chromosome 13 and is very rare (2), particularly in Sweden (4). In Europe, it reaches its highest frequency in Mediterranean islands (5,6), probably caused by founder effects similar to the accumulation of haemochromatosis in northern Europe (1). Whether a remote consanguinity may explain the homozygosity for ATP7B H1069Q in the present case is unknown.…”