Metabolic changes in 37 newly diagnosed Wilson's disease patients assessed by magnetic resonance spectroscopy.

Wilson's Disease (WD) is a rare autosomal recessive disorder. The literature about proton MR spectroscopy (MRS) in WD is based mostly on data derived from patients undergoing treatment. The aim of this study was to identify brain metabolic changes in newly diagnosed WD patients using MRS to elucidate the pathomechanism of the cerebral pathology of WD. The globus pallidus and thalamus of 37 patients with WD were examined bilaterally with MRS. The calculations were performed for: myoinositol (mI), choline (Cho), creatine (Cr), N-acetyl-aspartate (NAA), lipid (Lip), glutamine, and glutamate (Glx). In all WD patients a significantly decreased mI/Cr and NAA/Cr ratio levels and an increased Lip/Cr ratio in the pallidum were observed. Analysis revealed a significantly increased Glx/Cr and Lip/Cr ratio in the thalamus. In the pallidum of neurologically impaired patients, Cho/Cr, Glx/Cr and Lip/Cr ratios were higher than in control subjects, and the NAA/Cr was significantly lower. In hepatic patients, the mI/Cr, Cho/Cr and NAA/Cr ratio levels were lower than in controls. The Cho/Cr and Lip/Cr ratios were higher in the thalami of neurologically impaired patients, and Lip/Cr ratios were higher than controls' in hepatic patients. Both findings were statistically significant. Compared to the thalamus, the basal ganglia are more sensitive to ongoing degenerative changes and portal-systemic encephalopathy in WD. The NAA/Cr reduction in hepatic and neurologically impaired patients could indicate that neurodegeneration is associated with all presentations of WD. In hepatic patients a mI and Cho decrease and in neurological Glx increase can be caused by porto-systemic shunting.

Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease.

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. The clinical phenotype of the disease is varied. It is proposed that this variation may be a result of differential functional disruption of ATPase7B (ATP7B) resulting from mutations in the gene ATP7B. We aimed to assess the relationship between specific mutational defects in ATP7B and divergence in the phenotypic expression of WD. One hundred and forty-two patients with clinically, biochemically and genetically diagnosed WD were included in the study. The phenotypic expression of WD was compared between patients with different types of mutations in ATP7B, detected by direct sequencing of exons 1-21 of the gene. Twenty-six mutations were identified in ATP7B; eleven of them were mutations predicted to result in the absence of a full-length normal protein [frameshift/nonsense mutations; classified as 'severe' mutations (SMs)], 14 were missense mutations (MMs) and one was a splice site mutation. Patients with one or two SMs on their alleles had lower serum copper and ceruloplasmin and were younger when the first symptoms of the disease appeared, compared with individuals with two MMs. The effect of SMs on the WD phenotype was dose-dependent. It is concluded that mutations within ATP7B are very heterogeneous. Frameshift and nonsense mutations are associated with a severe phenotype of WD.

Sonographic detection of basal ganglia lesions in asymptomatic and symptomatic Wilson disease.

OBJECTIVE: To investigate whether transcranial brain parenchyma sonography (TCS) detects basal ganglia abnormalities in asymptomatic and symptomatic patients with Wilson disease (WD) and whether findings correlate with disease severity. METHODS: Twenty-one patients with WD with (n = 18) or without (n = 3) neurologic symptoms were investigated. Disease severity was assessed by three independent neurologists using a WD rating scale (WDRS) with the items dysarthria, akinesia, ataxia, tremor, and dystonia; the raters' median score was used for further analysis. Basal ganglia TCS was performed according to a standardized protocol. RESULTS: TCS revealed lenticular nucleus (LN) hyperechogenicity in all assessable neurologically symptomatic and in two of the three asymptomatic patients. Size of LN hyperechogenic area correlated with the WDRS score (Spearman correlation, rho = 0.604, p = 0.006), as did the size of thalamus hyperechogenic area (n = 7, rho = 0.891, p = 0.007), the width of third ventricle (n = 21, rho = 0.613, p = 0.003), and the width of lateral ventricles (n = 20, rho = 0.642, p < 0.001). Substantia nigra hyperechogenicity, detected in 10 patients, did not correlate with disease severity. There was no correlation between age at disease onset or disease duration and any TCS finding. Of the 19 patients with LN hyperechogenicity, only 12 showed abnormal LN on MRI. CONCLUSIONS: Transcranial brain parenchyma sonography (TCS) detects lenticular nucleus hyperechogenicity, likely to be caused by copper accumulation, in neurologically symptomatic and asymptomatic Wilson disease (WD). TCS findings correlate with disease severity. TCS appears a promising tool for disease monitoring in WD.

Wilson's disease-cause of mortality in 164 patients during 1992-2003 observation period.

We studied the cause of death in a consecutive series of 164 patients with Wilson's disease (WD) diagnosed over an 11 year period. A total of 20 [12% (95% CI 10.3-16.0)] died during the observation period. The relative survival rate of all patients in our group was statistically smaller than in Polish population. The main cause of death was the diagnosis in advanced stage of disease, but in six patients presenting with mild signs, we observed the progression of the disease despite treatment. There was no difference in mortality rate in patients treated with d-penicillamine or zinc sulphate as initial therapy. The prognosis for survival in the majority of WD patients is favourable, provided that therapy is introduced early.

Frequency of His1069Gln and Gly1267Lys mutations in Polish Wilson's disease population.

Wilson's disease is an autosomal recessive disorder. More than 60 mutations of the Wilson's disease gene have been described so far. We have analysed 148 Polish Wilson's disease patients from 95 families for His1069Gln and Gly1267Lys mutations and correlated this finding with age and clinical form of the disease at presentation. To identify these mutations, single strand conformation polymorphism analysis was performed. In our group there were 94 patients with neurological presentation, 28 with hepatic presentation, whilst 26 were in a pre-clinical stage of the disease. His1069Gln mutation was present on 171 (57%) of the 296 studied chromosomes, and Gly1267Lys mutation was present on 27 chromosomes (9.1%). Most of our patients were homozygous or heterozygous for His1069Gln mutation (39.9% and 30.4%, respectively); 4% of the patients were homozygous for Gly1267Lys mutation and 5.4% had both of these described mutations on their chromosomes. His1069Gln and Gly1267Lys mutations occurred often in our Wilson's disease patient population but we did not find any relationship between investigated mutations and the clinical form of Wilson's disease or age of first symptoms.

The level of serum lipids, vitamin E and low density lipoprotein oxidation in Wilson's disease patients.

UNLABELLED: The aim of this study was to estimate the level of lipids and of the main serum antioxidant, alpha-tocopherol (vitamin E), and to evaluate the susceptibility of low density lipoprotein (LDL) to oxidation in Wilson's disease patients. It was assumed that enhanced LDL peroxidation caused by high copper levels could contribute to the injury of liver and other tissues. The group investigated comprised 45 individuals with Wilson's disease treated with penicillamine or zinc salts and a control group of 36 healthy individuals. Lipids were determined by enzymatic methods, alpha-tocopherol by high performance liquid chromatography, the susceptibility of LDL to oxidation in vitro by absorption changes at 234 nm during 5 h and end-products of LDL lipid oxidation as thiobarbituric acid reacting substances. In Wilson's disease patients total cholesterol, LDL cholesterol and alpha-tocopherol levels were significantly lower compared with the control group. No difference in LDL oxidation in vitro between the patients and the controls was stated. CONCLUSION: enhanced susceptibility of isolated LDL for lipid peroxidation in vitro was not observed in Wilson's disease patients. One cannot exclude, however, that because of low alpha-tocopherol level lipid peroxidation in the tissues can play a role in the pathogenesis of tissue injury in this disease.

Procreation ability in Wilson's disease.

OBJECTIVES: The clinical manifestations of Wilson's disease (WD) take the form of hepatic, neurological, renal as well as hormonal disturbances. Infertility and amenorrhea are reported in women and hypogonadism in men with WD. Our study was designed to analyse the procreation abilities of patients with WD. MATERIAL AND METHODS: We investigated by a questionnaire the course of pregnancy and delivery in 31 untreated women (mean age 22.5 years, 82 pregnancies) and 15 women (mean age 26.2, 25 pregnancies,) treated with D-penicillamine (D-p) or zinc sulphate (ZnS). We studied also procreation ability of 27 men (mean age 27.2 years). We analysed the congenital abnormalities and frequency of WD in children of our patients. RESULTS: One of 10 untreated women had difficulties with conception. The number and type of pathology (imminent abortions, gestosis, stillbirth, preterm births) were similar in treated and untreated patients. In both mentioned groups the most frequent pathology were spontaneous abortions, which were found in 26% of untreated and in 26.6% of treated women. This percentage is higher than in general population. Most of deliveries in patients with WD were spontaneous. Neither developmental malformations nor serious disorders were noticed in the offspring of our treated patients, 3 children of untreated patients were born with congenital heart disease. In 78 of the 110 children of our patients we examined the copper metabolism and we diagnosed WD in 5 cases (from 3 families). Among 27 investigated men only 1 was impotent. CONCLUSION: The risk of complications during pregnancy in asymptomatic and treated patients is higher than in general population, but it does not make the procreation impossible.