Relative exchangeable copper: a promising tool for family screening in Wilson disease.

BACKGROUND: Family screening is a main step for the diagnosis in Wilson disease. This study was undertaken to evaluate the value of relative exchangeable copper for family screening. METHODS: Data from family screening were collected from the French National Center of Reference for Wilson disease. Subjects who were first- or second-degree relatives of the index case underwent clinical examination and biological parameters. RESULTS: Of 127 subjects examined, copper abnormalities or low ceruloplasminemia were detected in 21 subjects, corresponding to 5 patients with Wilson disease, 14 heterozygous ATP7B carriers and 2 subjects with no ATP7B mutations. Relative exchangeable copper determination significantly discriminates heterozygous ATP7B carriers and subjects with no ATP7B mutations from WD patients with a cutoff of 15%. CONCLUSIONS: Exchangeable copper appears to be a promising tool for family screening in Wilson disease.

Wilson disease in offspring of affected patients: report of four French families.

BACKGROUND: Wilson disease (WD) is an autosomal recessive genetic disorder caused by mutations in the ATP7B gene resulting in toxic accumulation of copper mainly in the liver and brain. Early treatment may prevent irreversible tissue damage. AIM: We report on four families with an occurrence of WD in two consecutive generations in order to highlight the need for screening offspring of affected parents. RESULTS: In all families, one parent was known to be affected with WD. Screening for the disease was not performed in children from two families until occurrence of liver disease in one and of neurological symptoms in the other. In two other families, screening of children as soon as diagnosis was performed in the affected parent allowed a timely rescue of advanced liver disease in one while two affected children were asymptomatic. In three children, diagnosis required direct sequencing of the ATP7B gene. Two novel disease-causing mutations are reported. CONCLUSION: Patients with WD should be offered genetic counselling when considering pregnancy and offspring should always be screened for the disease. Diagnostic difficulties based on copper disturbances in asymptomatic children that are obligate carriers of the Wilson gene and the usefulness of molecular diagnosis are discussed.

Elucidation of the ATP7B N-domain Mg2+-ATP coordination site and its allosteric regulation.

The diagnostic of orphan genetic disease is often a puzzling task as less attention is paid to the elucidation of the pathophysiology of these rare disorders at the molecular level. We present here a multidisciplinary approach using molecular modeling tools and surface plasmonic resonance to study the function of the ATP7B protein, which is impaired in the Wilson disease. Experimentally validated in silico models allow the elucidation in the Nucleotide binding domain (N-domain) of the Mg(2+)-ATP coordination site and answer to the controversial role of the Mg(2+) ion in the nucleotide binding process. The analysis of protein motions revealed a substantial effect on a long flexible loop branched to the N-domain protein core. We demonstrated the capacity of the loop to disrupt the interaction between Mg(2+)-ATP complex and the N-domain and propose a role for this loop in the allosteric regulation of the nucleotide binding process.

Relative exchangeable copper: a new highly sensitive and highly specific biomarker for Wilson's disease diagnosis.

Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism. Failure to diagnose WD can be dramatic leading to irreversible damages. The molecular genetic analysis of ATP7B gene is the reference test for diagnosis but the number of reported mutations of the ATP7B gene is on the rise. The analysis is cumbersome and requires tedious work. Other clinical and biological tests are proposed but it is often difficult to interpret some patients' results. A rapid and reliable biological test for WD diagnosis is still needed. Analytical reliability of Exchangeable copper (CuEXC) determination procedure is examined by studying the repeatability, the short term stability and stability in frozen serum. Relative exchangeable copper (REC=CuEXC/total copper%) is proposed and evaluated as a new diagnostic test and compared to classic tests used for WD diagnosis. Sixteen new Wilson disease patients were diagnosed in our institution between January 2009 and May 2011. The different biological tests used for WD diagnosis yielded lower sensitivity and specificity compared to our new biomarker, the REC. We show that REC is an excellent discriminatory tool for the diagnosis of WD offering 100% sensitivity and 100% specificity.

[Wilson disease]. / Maladie de Wilson.

UNLABELLED: Wilson Disease must be considered in very varied circumstances, including in patients older than 50 years. Its diagnosis is not based on a single test but on a group of findings. The copper levels may be difficult to interpret. Molecular biology can confirm the diagnosis in only 80% of cases. The advice of the reference center is necessary before beginning treatment: chelators or zinc salts. Lifetime treatment is required. Follow-up of these patients must be regular and multidisciplinary and should be conducted in association with the reference center. Inclusion in the national registry for Wilson Disease must be suggested to all patients. CONTACT: cmr.wilson@lrb.aphp.fr.

Effect of low dose antioxidant vitamin and trace element supplementation on the urinary concentrations of thromboxane and prostacyclin metabolites.

OBJECTIVE: This trial evaluated the effect of antioxidant supplementation on the urinary excretion of 11-dehydro TXB(2)/2,3 dinor 6 keto PGF(1alpha) ratio, a marker of the pathogenesis of thrombosis and arteriosclerosis. METHODS: This study was a randomised, double-blind, placebo-controlled trial involving 186 presumably healthy volunteers. One hundred received a multi-antioxidant supplementation and 86 a placebo for two years. Blood zinc, selenium, beta-carotene, vitamin C and E and urinary excretion of 11-dehydro TXB(2) and 2,3 dinor 6 keto PGF(1alpha) were measured. RESULTS: Baseline subject characteristics did not differ between the two groups. Blood zinc, selenium, and beta-carotene concentrations significantly increased between baseline and two years in the multi-antioxidant supplementation group supporting subject compliance (p < 0.05). At two years, the median urinary 11-dehydro TXB(2)/2,3 dinor 6 keto PGF(1alpha) ratio was significantly lower in the multi-antioxidant supplementation group (3.4 versus 2.78, p = 0.015). Serum selenium concentration was the only antioxidant studied that was significantly related to the urinary 11-dehydro TXB(2)/2,3 dinor 6 keto PGF(1alpha) ratio. CONCLUSIONS: These results support the hypothesis that a low-dose multi-antioxidant supplementation may contributes to a reduction in platelet activation which is beneficial for cardiovascular function.

Adrenal response in patients with septic shock of abdominal origin: relationship to survival.

OBJECTIVE: To evaluate the prognostic value of adrenocortical response to corticotropin in septic shock patients operated on exclusively for an intra-abdominal source of infection. DESIGN AND SETTING: Prospective, observational, single-center study in a surgical intensive care unit of a university hospital PATIENTS: 118 consecutive septic shock patients undergoing laparotomy or drainage for intra-abdominal infection. MEASUREMENTS AND RESULTS: Baseline cortisol (t (0)) and cortisol response to corticotropin test (Delta) were measured during the first 24 h following onset of shock. The relationship between adrenal function test results and survival was analyzed as well as the effect of etomidate anesthesia. Cortisol plasma level at t (0) was higher in nonsurvivors than in survivors (33 +/- 23 vs. 25 +/- 14 microg/dl), but the response to corticotropin test did not differ between these two subgroups. ROC analysis showed threshold values for t (0) (32 microg/dl) and Delta (8 microg/dl) that best discriminated survivors from nonsurvivors in our population. We observed no difference in survival at the end of hospital stay using log rank test when patients were separated according to t (0), Delta, or both. In addition, adrenal function tests and survival did not differ in patients who received etomidate anesthesia (n = 69) during the surgical treatment of their abdominal sepsis. CONCLUSIONS: In this cohort of patients with abdominal septic shock baseline cortisol level and the response to corticotropin test did not discriminate survivors from nonsurvivors. No deleterious impact of etomidate anesthesia on adrenal function tests and survival was observed in these patients.

Late neurological presentations of Wilson disease patients in French population and identification of 8 novel mutations in the ATP7B gene.

Wilson disease (WD) is an autosomal recessive disorder of copper biliary excretion caused by an impaired function of ATP7B, a metal-transporting P-type ATPase encoded by WD gene. It results in copper accumulation, mostly in liver and brain tissues. Mutation analysis was carried out on 11 WD French unrelated patients presenting a predominant neurological form of this illness. SSCP and dHPLC analysis followed by sequencing of the 21 exons and their flanking introns were performed. Thirteen different mutations in a total of 17, and, among them, 10 novel variants were evidenced. Two deletions (c.654_655delCC and c.1745_1746delTA), 4 missense mutations (p.F763Y, p.G843R, p.D918A and p.L979Q), 1 nonsense mutation (p.Q1200X), 1 splice site mutation (c.1947-1G>C) and 2 intronic silent substitutions (c.2448-25G>T and c.3412+13T>A) were detected. These data extend the mutational spectrum of the disease, already known to be a very heterogeneous genetic disorder. As compared to hepatic manifestations, the phenotypes associated to these mutations confirm that neurological presentations associated with other mutations than p.H1069Q are also often late in their onset. Most of these neurological forms probably correspond to an attenuated impairment of copper metabolism, as compared to hepatic forms of the disease, mostly diagnosed earlier.

Extensive cortico-subcortical lesions in Wilson's disease: clinico-pathological study of two cases.

Wilson's disease (WD) with extensive cortico-subcortical lesions represents a rare neuropathological subgroup, the pathogenesis of which is not clearly determined. We report two new cases with identical lesions. In the families of each of the patient, there were mutations in the ATPase7B gene, especially in the family of proband 1, and in the first cousin of proband 2. These cases included massive destruction of the white matter in superior gyri, mostly frontal, extending to the deep cortex with neuronal loss and capillary proliferation. Astrocytes were of Alzheimer type 1 and 2; and type 1 were labeled by anti-metallothionein. Opalski cells were abundant and their macrophagic lineage was confirmed by immunostaining. Among the possible mechanisms proposed, the role of vascular factors and penicillamine treatment could be excluded. Cerebral copper content in white matter and putamen of case 1 was at the same level as in common WD but accumulation of unbound copper in the white matter was a distinctive feature, which suggested a pathological neurotoxic effect.

Nutritional status of preschool Senegalese children: long-term effects of early severe malnutrition.

The prevalence of malnutrition remains high in many developing countries. However, data relating to the long-term effects of severe malnutrition, specifically, serum levels of biochemical indicators of nutritional status, are still scarce in the literature. Hence the present study aimed to investigate the nutritional, biological and growth status of Senegalese preschool children previously hospitalised for severe malnutrition. The study involved twenty-four 7-year-old children who had suffered from marasmus 5 years earlier, twenty-four siblings living in the same household, and nineteen age-matched children living in the centre of Dakar. The siblings were of similar age to the post-marasmic children. Anthropometry, serum biochemical indicators of nutritional status, growth factors, and haematological and mineral parameters were measured. The prevalence of stunting and wasting was the same in the post-marasmic children as in the siblings. Body-fat and fat-free-mass (FFM) deficits in both groups were corroborated by abnormally low concentrations of transthyretin, osteocalcin, insulin-like growth factor (IGF)-1, and insulin-like growth factor-binding protein (IGFBP)-3. FFM was positively and significantly correlated with concentrations of IGF-1 and IGFBP-3. In the post-marasmic children, height for age was also correlated with IGF-1. Of the post-marasmic children, 53 % had Fe-deficiency anaemia, as did 35 % of the siblings and 29 % of the controls. No significant associations were found between the serum concentrations of Ca, Cu, K, Mg, Na, P, Se, Zn and growth retardation. At 5 years after nutritional rehabilitation, the post-marasmic children remained stunted with nutritional indices significantly lower than the control children. However, these children were doing as well as their siblings except for minor infections.