Wilson Disease: High Prevalence in a Mountaineous Area of Crete

Abstract

Wilson 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.

Diagnostic Accuracy of Serum Ceruloplasmin in Wilson Disease: Determination of Sensitivity and Specificity by ROC Curve Analysis among ATP7B-Genotyped Subjects

“…The disease frequency is highly variable, and WD is seen more frequently in Sardinia, China, Japan, and other Asian populations (2)(3)(4)(5)(6)(7)(8)(9). Underdiagnosis of WD is highly likely, especially during the asymptomatic phase and in patients with atypical presentations.…”

Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B

“…One of the tested variants, p.I1148T, is controversial, and has been classified as both nondisease causing and disease-causing in various populations [Abdelghaffar et al, 2008;Dedoussis et al, 2005;Gu et al, 2003;Haas et al, 1999;Loudianos et al, 1998Loudianos et al, , 2000Majumdar et al, 2004;Mak et al, 2006;Okada et al, 2000;Park et al, 2007;Tsai et al, 1998;Vrabelova et al, 2002;Wan et al, 2006]. Predictive analysis was similarly conflicting; SIFT and PolyPhen predicted that p.I1148T would be deleterious while Align-GVGD classified it as neutral.…”

“…Sequence was confirmed at the end of the experiment. The variant ATP7B cDNAs Butler et al, 2001;Gupta et al, 2007;Kumar et al, 2005Kumar et al, , 2006Loudianos et al, 2003;Thomas et al, 1995;Vrabelova et al, 2002 c.3443T>C 16 ATP loop Unknown Greek, Taiwanese, German, Chinese (Han), Korean, Egyptian, Japanese, Czech Abdelghaffar et al, 2008;Dedoussis et al, 2005;Gu et al, 2003;Haas et al, 1999;Loudianos et al, 1998Loudianos et al, , 2000Majumdar et al, 2004;Mak et al, 2006;Okada et al, 2000;Park et al, 2007;Tsai et al, 1998;Vrabelova et al, 2002;Wan et al, 2006 c Nucleotide numbering refers to the cDNA numbering with 11 being the A of the ATG translation initiation codon in the reference sequence, according to journal guidelines (www.hgvs.org/mutnomen). Codon 1 is the initiation codon.…”

Common local founder effects for Wilson's disease and hereditary hemochromatosis; mutation studies of a large family

“…Most cases of HH are homozygous for the HFE C282Y mutation, which is a common mutation having a north European origin, reaching high frequencies in isolated areas due to local founder effects [4,5]. A similar background may explain the high frequencies of WND in Mediterranean or Atlantic islands often with local, characteristic founder mutations [6][7][8][9][10]. Extensive pedigree studies have been made to find a local founder [11,12] and in Iceland all WND patients seemed to share a common origin and also one common mutation [9].…”