No abstract

No abstract

Wilson's disease is a disorder of biliary copper excretion that may result in severe neurological symptoms and advanced liver disease. The wide variation of phenotypic disease expression cannot be fully explained by the different mutations of the Wilson disease gene. In neurological disorders, such as Alzheimer's disease, temporal lobe epilepsy and cerebral trauma, the presence of the apolipoprotein E (ApoE) allele epsilon4 is associated with an increased vulnerability of the brain to the effects of the disease, whereas the presence of the ApoE genotype epsilon3/3 appears to provide moderate neuroprotection. We examined whether this hypothesis holds true for the development of neurological symptoms in patients with Wilson's disease. The ApoE genotype and the H1069Q mutation (the most common in Wilson's disease) status were determined by polymerase chain reaction-based mutation assays in 121 well-characterized, symptomatic index patients with Wilson's disease. An investigation profile was established in which the patients were grouped according to the clinical symptoms at presentation, the ApoE genotypes and the status of the H1069Q mutation. Fifty-nine per cent of the 121 patients had the allele combination ApoE epsilon3/3 (21% ApoE epsilon3/4, 19% ApoE epsilon3/2, 1% ApoE epsilon4/2). The distribution of ApoE genotypes did not deviate from known distributions in healthy European subjects. Within the group of 40 H1069Q-homozygous patients, the onset of symptoms was significantly delayed in patients with the ApoE epsilon3/3 genotype (25 +/- 6 years at presentation) compared with patients with the ApoE epsilon3/4 genotype (20 +/- 3 years at presentation). In this study, the ApoE genotype was established as an important factor delaying the onset of neurological and hepatic symptoms, but not modifying phenotypic disease expression in a homogeneous group of patients with Wilson's disease (all H1069Q-homozygotes, similar genetic background). The presence of ApoE epsilon3/3 attenuates clinical manifestations in Wilson's disease by mechanisms which might involve the antioxidant and membrane-stabilizing properties of the ApoE 3 protein.

The His1069Gln mutation was detected in 61% of Austrian patients with Wilson disease. Polymerase chain reaction may be useful for diagnosis and screening of family members of homozygous index patients, even if first-degree relatives are not available for examination.

No abstract

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. The H1069Q mutation in exon 14 of ATP7B is far the most frequent in Wilson patients of European origin. Mutations in exon 8 and 15 are also common among the over 150 described mutations in the WD gene. The aim was to investigate the frequency of these common WD gene mutations in Hungarian patients. A total of 42 patients with WD from 39 Hungarian families were examined. The H1069Q mutation was assessed by a seminested polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay, while mutations in exons 8, 13, 15, and 18 of WD gene were identified by sequencing. In addition, haplotype analysis was performed using three common microsatellite markers (D13S314, D13S301, D13S316). The H1069Q mutation was found in 27 patients (64.3%). Nine patients were H1069Q homozygous. Eighteen patients were H1069Q compound heterozygous, two of them had H1069Q/P969Q and one patient H1069Q/3400delC genotype. In two of the 15 H1069Q-negative patients a novel mutation in exon 13 (T977M) was detected. One H1069Q-negative patient had a mutation in exon 8 (G710S). None of the studied mutations was detected in 12 WD patients. H1069Q-positive patients from various European countries had the same haplotype pattern. The H1069Q point mutation is frequent in Hungarian patients with WD and appears to have originated from a single founder in Eastern Europe. In contrast, mutations in exons 8, 13, 15, and 18 are uncommon in Hungarian WD patients.

Galectin-3 (Gal 3) is a glycan-binding protein that can be secreted by activated macrophages and mast cells at inflammation sites and plays an important role in inflammatory diseases caused by Bacteria and their products, such as lipopolysaccharides (LPS). Although it is well established that Gal 3 can interact with LPS, the pathophysiological importance of LPS/Gal 3 interactions is not fully understood. Data presented herein demonstrate for the first time that the interaction of Gal 3, either via its carbohydrate binding C-terminal domain or via its N-terminal part, with LPS from different bacterial strains, enhances the LPS-mediated neutrophil activation in vitro. Gal 3 allowed low LPS concentrations (1 µg/mL without serum, 1 ng/mL with serum) to upregulate CD11b expression and reactive oxygen species (ROS) generation on human neutrophils in vitro and drastically enhanced the binding efficiency of LPS to the neutrophil surface. These effects required LPS preincubation with Gal 3, before neutrophil stimulation and involved specific Gal 3/LPS interaction. A C-terminal Gal-3 fragment, which retains the lectin domain but lacks the N-terminal part, was still able to bind both to Escherichia coli LPS and to neutrophils, but had lost the ability to enhance neutrophil response to LPS. This result emphasizes the importance of an N-terminus-mediated Gal 3 oligomerization induced by its interaction with LPS. Finally we demonstrated that Balb/C mice were more susceptible to LPS-mediated shock when LPS was pretreated with Gal 3. Altogether, these results suggest that multimeric interactions between Gal 3 oligomers and LPS potentiate its pro-inflammatory effects on neutrophils.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a late consequence of severe liver disease. Patients with genetic hemochromatosis may be at risk for HCC, but limited information is available on the relationship of HCC and heterozygosity for the HFE gene mutations. METHODS:HFE mutations (C282Y and H63D) were assessed in 162 consecutive patients (131 men/31 women) with HCC. A total of 159 patients had cirrhosis. The most common etiologies of cirrhosis were chronic viral hepatitis (hepatitis C 39%, hepatitis B 9%) and alcoholic liver disease (36%). RESULTS:Five patients were C282Y homozygotes, four C282Y/H63D compound heterozygotes, and three H63D homozygotes. The C282Y and H63D allele frequencies in HCC were 8.3 (95% confidence limit ϭ 5.3-11.3) and 11.1 (7.8 -14.6), respectively, and not different from previously published data in healthy subjects or patients with chronic hepatitis C in Austria. Furthermore, there was no difference in the age at diagnosis in patients with or without HFE gene mutations. C282Y homozygotes had a 19-fold increased risk to develop HCC. In contrast, all other HFE allele constellations were not associated with such a risk. CONCLUSIONS:Except for C282Y homozygotes, HFE gene mutations do not increase the risk to develop HCC in patients with cirrhosis. (Am J Gastroenterol 2003;98:442-447.