Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.16.3.1 (ceruloplasmin)
5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wilson's disease and Menkes disease are inherited genetic disorders of copper metabolism. Each disease results from the absence or dysfunction of homologous copper-transporting ATPases present in the trans-Golgi network of cells. The Wilson ATPase transports copper into the hepatocyte secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Thus, patients with Wilson's disease of the autosomal recessive trait present with signs and symptoms arising from impaired biliary copper excretion. The Menkes ATPase transports copper across the placenta, gastrointestinal tract, and blood-brain barrier, and the clinical features of this X-linked disease arise from copper deficiency. Despite striking differences in the clinical presentation of these two diseases, the respective ATPases function in precisely the same fashion within the cell. The different clinical features of each disease are the results of the tissue specific expression of these ATPases. In Wilson's disease, impaired biliary copper excretion leads to accumulation of this metal in the liver. When the capacity for hepatic storage is exceeded, cell death ensues, with copper release into the plasma resulting in hemolysis and deposition of copper in extrahepatic tissues. Affected patients usually present in the first or second decade of life with chronic hepatitis and cirrhosis or acute liver failure. Copper accumulation in the cornea results in Kayser-Fleischer rings. Neuropsychiatric symptoms are more common in adults and include dystonia, tremor, personality changes, and cognitive impairment as a results of copper accumulation in the basal ganglia and other brain regions. The diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper, and elevated hepatic copper concentration. A large number of different mutations occur in the genes of patients with Wilson disease. Copper chelation drugs and zinc are effective in most cases. New treatment guidelines now advise physicians to start patients on zinc.
...
PMID:[Genetic disorders of copper transport--diagnosis and new treatment for the patients of Wilson's disease]. 1577 21

Wilson disease (WND), an autosomal recessive disorder of copper transport, shows wide genotypic and phenotypic variability, with hepatic and/or neurological symptoms. The WND gene, ATP7B, encodes a copper transporting ATPase that is involved in the transport of copper into the plasma protein ceruloplasmin, and in the excretion of copper from the liver. ATP7B mutations result in copper storage in liver and brain. From 247 WND patients worldwide whose DNA has been sequenced in our laboratory, we have identified 24 new mutations. The origins of the patients were European white (one deletion, one nonsense, one splice site, and 18 missense), Chinese (one deletion, one missense) and Bangladeshi (one missense). Most of these had strong support as disease causing mutations, based on conservation between species, structural changes, and absence in controls. One missense mutation in a Chinese patient was considered uncertain because of its conservative nature and position in the protein. We also identified 15 nucleotide substitutions (11 of them new) causing silent or intronic changes, none of which produce an additional splice site that could lead to disease. Characterization of mutations, both disease-causing and normal variants, is essential for accurate molecular diagnosis of this condition.
...
PMID:Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. 1608 7

This study covers patients seen at a Wilson disease clinic between 1960 and 2002. The diagnosis of Wilson disease was confirmed in 316. Of 40 patients with a neurological presentation who were found not to have the disease, caeruloplasmin concentration was found to be reduced in 19. These 19 patients comprised 17 men and 2 women. The various diagnoses included Huntington's disease, multiple sclerosis, subacute sclerosing panencephalitis (SSPE), Hallervorden Spatz syndrome, and acaeruloplasminemia; in 9 no definite diagnosis was made. In view of the marked male preponderance, the lower limit of caeruloplasmin is calculated as for males. In an earlier study this was found to be 33.3 mg/dl (standard deviation, 6.1 mg/dl); therefore, 21.1 mg/dl is taken as the lower limit of normal. Particular attention is paid to 3 patients, 2 of whom had zero concentrations of caeruloplasmin and 1 had a very low level of the protein. Only 1 of these patients conformed to the classical picture of acaeruloplasminemia. The significance of a low caeruloplasmin concentration in patients with a variety of neurological syndromes is not clear but can lead to diagnostic confusion. When the concentration of this protein is very low or absent the diagnosis of acaeruloplasminemia must be considered.
...
PMID:Diagnostic significance of reduced serum caeruloplasmin concentration in neurological disease. 1609 17

Wilson disease is an autosomal recessive disorder of copper excess. This illness results from mutations of the ATP7B gene (chromosome 13, MIM# 277900). The discovery of the gene allowed a better understanding of cytosolic copper trafficking and its relationship with ceruloplasmin synthesis. Symptomatic patients may present with hepatic, neurologic or psychiatric forms. Clinical and phenotypic evidences provide only presumptive arguments for this disease which can be routinely assessed by molecular analysis. This genetic disease which can be efficiently treated was formerly biologically suspected after a careful but sometimes invasive study of copper metabolism. Genetic advances can now give a definite answer using linkage analysis and research for disease-causing mutations. However, this diagnosis strategy is limited since currently over 320 mutations and 80 polymorphisms have been currently identified.
...
PMID:[Wilson disease: clinical and biological aspects]. 1623 Feb 79

The polymorphism in the human prion protein gene at codon 129 (PRNP 129) determines susceptibility to prion disease, and has been associated with early onset and a more severe course of other neurodegenerative disorders. Here, we tested the hypothesis that PRNP is a disease-modifying gene in clinical Wilson disease with a neurological phenotype. Allele frequencies in patients with clinical Wilson disease were not different from those of a healthy German control population, and PRNP 129 genotypes did not result in different serum copper, serum ceruloplasmin, or copper in 24-h urine concentrations. PRNP 129 methionine homozygosity, however, led to significantly more severe neurological symptoms in elderly patients, particularly tremor, supporting the notion that PRNP 129 homozygosity contributes to neuronal vulnerability.
...
PMID:Prion protein gene codon 129 modulates clinical course of neurological Wilson disease. 1654 24

Wilson disease (WD) is an autosomal recessive disorder due to the defect in ATP7B gene characterized by excessive accumulation of copper in the liver with progressive hepatic damage and subsequent redistribution to various extrahepatic tissues including the brain, kidneys, and cornea. Strikingly, the total serum copper concentration is always low in WD, even though the non-ceruloplasmin copper level is still expected to be high. To assess the role of free radical reactions catalyzed by non-ceruloplasmin copper, we investigated erythrocyte metabolism and oxidative stress as a mechanism for hemolysis in eight WD patients during episodes of acute hemolysis and compared them with eight follow-up cases of WD on d-penicillamine therapy and eight healthy, age-matched children. Elevated levels of non-ceruloplasmin copper were found in all the WD patients during an episode of hemolytic anemia. There was marked inhibition in erythrocyte enzymes, namely, hexokinase, total adenosine triphosphatase (ATPase), and glucose-6-phosphate dehydrogenase (G-6-PD) from WD patients compared with patients on penicillamine and healthy children, indicating altered erythrocyte metabolism during a hemolytic crisis. Antioxidant status was also found to be compromised as is evident from decreased glutathione (GSH) levels, decreased antioxidant enzymes (namely, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase), increased lipid peroxidation, and deranged plasma antioxidants. Uric acid showed maximum decrease followed by ascorbic acid. These findings suggest that the free radical production by elevated non-ceruloplasmin copper through transition metal catalyzed reactions leads to oxidative injury resulting in altered erythrocyte metabolism and severely compromised antioxidant status of WD patients during hemolytic anemia.
...
PMID:Erythrocyte metabolism and antioxidant status of patients with Wilson disease with hemolytic anemia. 1654 36

Wilson disease is an autosomal recessive disorder of copper transport, caused by the reduced or absent function of the Wilson disease gene ATP7B on chromosome 13. The disease is characterized by reduced incorporation of copper into the ceruloplasmin protein and reduced excretion of copper into the bile. Wilson disease is effectively treated if detected early. Our study goals were to determine the feasibility of a population screening for Wilson disease using dried blood spots and to characterize the base-line ceruloplasmin concentration in newborn blood spots of patients with Wilson disease. Ceruloplasmin was analyzed in dried blood spots obtained from 353 Mayo Clinic pediatric volunteers aged from 3 months to 18 years and from 1045 anonymous newborn screening specimens using a sandwich enzyme-linked immunosorbent assay. The original newborn screening blood spots were retrieved from two patients with Wilson disease along with age-matched controls for ceruloplasmin determination. The mean (+/-SD) concentration of ceruloplasmin in the pediatric blood spots was 40.0+/-14.4 mg/dL (range 13.1 to >60 mg/dL) and newborn blood spots was 47.2+/-15.5mg/dL (range 6.5 to >60 mg/dL). Ceruloplasmin in the newborn blood spots from two Wilson disease patients were 2.6 and 2.8 mg/dL, respectively. The newborns affected with Wilson disease had significantly lower ceruloplasmin levels in blood spots than unaffected newborns. These findings support that presymptomatic screening for Wilson disease using dried blood spots could be possible, even in the newborn period.
...
PMID:Retrospective determination of ceruloplasmin in newborn screening blood spots of patients with Wilson disease. 1664 58

Wilson's disease (WD), caused by a mutation in the P-type copper transporting ATPase (Atp7b) gene, results in excessive accumulation of copper in the liver. Long Evans Cinnamon rats (LEC) bear a mutation in the atp7b gene and share clinical characteristics of human WD. To explore hepatocyte transplantation (HT) as therapy for metabolic liver diseases, 8-week-old LEC rats (n = 12) were transplanted by intrasplenic injection of hepatocytes from donor Long Evans (LE) rats. Immunosuppression was maintained with intraperitoneal tacrolimus. The success of HT was monitored at 24 weeks of life. Serum aminotransferases and bilirubin peaked at 14-21 weeks in both HT rats and nontransplanted controls, but at 24 weeks, survival was 97% in LEC-HT versus 63% in controls. All transplanted rats showed restored biliary copper excretion and reduced liver iron concentration associated with increased ceruloplasmin oxidase activity. Liver tissue expressed atp7b mRNA (11.9 +/- 13.6%) indicative of engraftment of normal cells in 7 of 12 HT rats, associated with a reduced liver copper concentration compared to untreated LEC rats. Periportal islets of normal appearing hepatocytes, recognized by atp7b antibody, were observed in transplanted livers while lobular host cells showed persistent pleomorphic changes and inflammatory infiltrates. In conclusion, transplantation of normal hepatocytes prevented fulminant hepatitis, reduces chronic inflammation, and improved 6-month survival in LEC rats. Engraftment of transplanted cells, which express atp7b mRNA, repopulated the recipient liver with normal functional capacity.
...
PMID:Hepatocyte transplantation in the Long Evans Cinnamon rat model of Wilson's disease. 1670 Mar 26

Wilson disease (WD) is an autosomal recessive disorder of copper transport that results in accumulation of copper primarily in the liver, the brain and the cornea. WD is the most common inherited liver disease with the prevalence of 1: 37,000 in the pediatric population in Korea. Mutations in the ATP7B gene cause failure of copper excretion into the bile and a defective incorporation of copper into ceruloplasmin. More than 300 mutations in the ATP7B gene have been described so far. Mutations differ between ethnic groups. The p.R778L (an allele frequency of 37%), p.A874V (13%), p.L1083F (8%) and p.N1270S (6%) are the common major mutations in Korea. Conflicting results on genotype/phenotype correlations of the most common mutations have been reported in various countries. There seems to be no correlation between the R778L mutation and age of onset or clinical manifestations in Korean patients. None of the laboratory parameters alone allows a definite diagnosis of WD. In a nation-wide survey of WD, low serum ceruloplasmin (<20 mg/dL), high 24 hour urine copper (>100 microgram), high hepatic copper content (>250 microgram/g of dry liver) and Kayser-Fleischer rings were found in 96%, 86%, 88%, and 73% of the 550 Korean patients respectively. A combination of any two of the above 4 laboratory findings is strong support for a diagnosis of WD. For the last couple of years, genetic testing has been playing an increasingly important role in diagnosing WD. Direct DNA sequencing did confirm WD in 98% of the Korean patients. Two mutations were detected in 70% and one mutation in 28% of the patients who showed characteristic biochemical and clinical findings of WD. Genetic testing, either by haplotype analysis or by mutation analysis, is the only reliable tool for differentiating heterozygote carriers from affected asymptomatic patients. The agents of the first choice among chelators and zinc in specific clinical situations of WD is still a matter of debate. Because of frequent side effects and initial neurologic deterioration of penicillamine therapy, less toxic trientine or zinc has gradually replaced penicillamine over the past few years. Trientine or tetrathiomolybdate has been increasingly recommended as the first-line treatment for neurologic WD. Currently, liver transplantation is not recommended as primary treatment for neurologic WD. Recently published data show that initial zinc therapy for asymptomatic/presymptomatic patients and maintenance zinc therapy in patients after long term chelation are safe and effective. Further researches and the new guidelines on the proper management of patients with WD are needed.
...
PMID:[Wilson disease: an update]. 1699 87

The present study was intended to estimate the frequencies of the most common mutations (R778L, R778W, R778G, I1102T and H1069Q) of ATP7B in Indian Wilson disease (WD) population and to explore the correlation between genotype/phenotype and copper ATPase activity. A total of 33 WD patients and their family members from North West states of India were examined. The H1069Q, R778W and R778L mutations were absent in these WD patients. R778W and I1102T mutations were present in 36% of WD patients. Family analysis for these mutations using PCR-RFLP documented 5 carriers and 2 asymptomatic WD patients. The copper ATPase activity in WD patients was significantly reduced (50%) than that of control individuals. No significant difference was observed in copper stimulated ATPase activity between homozygous (R778W/R778W, I1102T/I1102T) and compound heterozygous (R778W/unknown mutation, I1102T/unknown mutation) WD patients. Serum ceruloplasmin, serum copper levels were significantly lower in homozygous WD patients than that of compound heterozygous. However, no significant difference was observed in liver copper contents between heterozygous and homozygous patients. In conclusion, the data suggest that R778W and I1102T are most common mutations and provide the basis of genetic (PCR-RFLP) diagnostic tool for Indian WD patients as well as in siblings/parents where biochemical parameters are ambiguous.
...
PMID:Analysis of most common mutations R778G, R778L, R778W, I1102T and H1069Q in Indian Wilson disease patients: correlation between genotype/phenotype/copper ATPase activity. 1716 Mar 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---