Biomedical subjects
Publications and source records attributed to I H Scheinberg.
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The Atp7b protein is a copper-transporting ATPase expressed predominantly in the liver and to a lesser extent in most other tissues. Mutations in the ATP7B gene lead to Wilson disease, a copper toxicity disorder characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic and neuro-logical abnormalities. Using homologous recombination to disrupt the normal translation of ATP7B, we have generated a strain of mice that are homozygous mutants (null) for the Wilson disease gene. The ATP7B null mice display a gradual accumulation of hepatic copper that increases to a level 60-fold greater than normal by 5 months of age. An increase in copper concentration was also observed in the kidney, brain, placenta and lactating mammary glands of homo-zygous mutants, although milk from the mutant glands was copper deficient. Morphological abnormalities resembling cirrhosis developed in the majority of the livers from homozygous mutants older than 7 months of age. Progeny of the homozygous mutant females demonstrated neurological abnormalities and growth retardation characteristic of copper deficiency. Copper concentration in the livers of the newborn homozygous null mutants was decreased dramatically. In summary, inactivation of the murine ATP7B gene produces a form of cirrhotic liver disease that resembles Wilson disease in humans and the 'toxic milk' phenotype in the mouse.
Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase. A search for ATP7B mutations in WD patients from five population samples, including 109 North American patients, revealed 27 distinct mutations, 18 of which are novel. A composite of published findings shows missense mutations in all exons-except in exons 1-5, which encode the six copper-binding motifs, and in exon 21, which spans the carboxy-terminus and the poly(A) tail. Over one-half of all WD mutations occur only rarely in any population sample. A splice-site mutation in exon 12 accounts for 3% of the WD mutations in our sample and produces an in-frame, 39-bp insertion in mRNA of patients homozygous, but not heterozygous, for the mutation. The most common WD mutation (His1069Glu) was represented in approximately 38% of all the WD chromosomes from the North American, Russian, and Swedish samples. In several population cohorts, this mutation deviated from Hardy-Weinberg equilibrium, with an overrepresentation of homozygotes. We did not find a significant correlation between His1069Glu homozygosity and several clinical indices, including age of onset, clinical manifestation, ceruloplasmin activity, hepatic copper levels, and the presence of Kayser-Fleischer rings. Finally, lymphoblast cell lines from individuals homozygous for His1069Glu and 4 other mutations all demonstrated significantly decreased copper-stimulated ATPase activity.
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The pathogenic agent of both Wilson disease (WD) and non-Indian childhood cirrhosis (which we term idiopathic copper toxicosis, or ICT) is copper accumulating to excess in the liver. Inheritance of a pair of alleles of an autosomal recessive gene on chromosome 13 is necessary and sufficient to cause such copper accumulation in WD; reducing the dietary intake of copper cannot prevent the development of WD. In contrast, the lethal accumulations of copper in children with ICT have been attributed primarily to an increased dietary intake of copper. However, 64 124 child-year exposures of children under the age of 6 y to drinking water containing a copper concentration of approximately 125.9 micromol/L (8 mg/L) produced no deaths from any form of liver disease. Moreover, the ICT of seven infants was attributed primarily to drinking water containing < 110.2 micromol Cu/L (7 mg/L) despite evidence of the presence of a genetic defect in three of the patients, one of whom was exclusively breast-fed. These data suggest that ICT cannot be caused solely by increased dietary intake of copper and occurs only in children with an identified genetic defect.
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This study investigated the rate of information processing, independent of motor speed, in neurologically affected Wilson's disease (WD) patients. Two scanning tasks based on the Sternberg item-recognition paradigm were administered to 17 neurologically symptomatic WD patients and 17 normal control (NC) subjects. Although WD subjects do have longer response latencies than NC subjects, their rate of information processing is the same as the rate of the NC subjects. The longer response latencies are attributable to their motor deficits. The clear impact of motor impairment on test performance underlines the necessity for specialized assessment measures that can accurately reflect the cognitive abilities of motor-impaired patients. These findings suggest that Wilson's disease is not characterized by slowed information processing.
Indian childhood cirrhosis is generally believed to be caused by toxic excesses of hepatic copper derived from milk boiled in copper vessels. Sporadic cases of a disorder indistinguishable from Indian childhood cirrhosis have appeared in other countries where the toxic hepatic copper has been thought to be derived from drinking water. In published reports of seven 2-year-old or younger infants with non-Indian childhood cirrhosis (five of whom died), the copper content of their drinking water--which the authors considered the essential, if not the sole, aetiological factor--ranged from 0.05 to 6.8 mg Cu/L. We identified three Massachusetts towns in which between 1969 and 1991 there were 64,124 child-years of exposure of children under the age of 6 years to drinking water that contained between 8.5 and 8.8 mg Cu/L. Data from the Massachusetts Department of Public Health showed that there were 135 deaths among these children, but no deaths from cirrhosis or any form of liver disease. These data, and evidence of a genetic aetiology in three of the seven infants reported previously, suggest that non-Indian childhood cirrhosis is an inherited disorder.
The objective of this study was to determine the indications for and results of liver transplantation in patients with Wilson's disease on the basis of results of a survey with retrospective review of data obtained on 55 transplants performed at centers in the United States and Europe. The study group comprised 32 females and 23 males, aged 8.5 to 51 yr, with features diagnostic of Wilson's disease. Indication for orthotopic liver transplantation included hepatic insufficiency (n = 32), wilsonian fulminant hepatitis (n = 21), intractable neurological Wilson's disease (n = 1) and gastrointestinal hemorrhage (n = 1). Forty-three patients have survived, at this writing, from 3 mo to 20 yr. Mean and median survival after orthotopic liver transplantation were 2.7 and 2.5 yr, respectively. Survival at 1 yr was 79%. Nonfatal complications occurred in five patients. Of the seven patients given transplants for hepatic insufficiency who manifested neurological and/or psychiatric manifestations at the time of orthotopic liver transplantation, four showed improvement of these symptoms. One patient given a transplant for intractable neurological disease improved but died of a vascular complication. Our data demonstrate that liver transplantation is life-saving but not without risk for patients with wilsonian fulminant hepatitis or chronic severe hepatic insufficiency unresponsive to medical therapy. Furthermore, neurological or psychiatric symptoms due to Wilson's disease may improve after liver transplantation; however, the role of this procedure in the management of patients with neurological Wilson's disease in the absence of hepatic insufficiency is still uncertain.
Wilson disease (WD), an autosomal recessive disorder of copper metabolism, has been previously mapped to chromosome 13q. Highly informative PCR-based polymorphic microsatellites closely linked to the WD locus (WND) at 13q14.3, as well as sequence-tagged sites for closely linked loci, are described. Two polymorphic microsatellite markers at D13S118 and D13S119 lie within 3 cM of WND. Two others (D13S227 and D13S228) were derived from a yeast artificial chromosome containing D13S31. These were placed on a genetic linkage map of chromosome 13 and were typed in 74 multiplex WD families from a variety of geographic origins (166 affected members). Multipoint analysis provides very high odds that the location of WND is between D13S31/D13S227/D13S228 and D13S59. Previous odds with RFLP-based markers were only 7:1 more likely than any other location. Current odds are 5,000:1. Preclinical testing of three cases of WD by using the highly informative polymorphic microsatellite markers is described. The markers described here ensure that 95% of predictive tests using DNA from both parents and from at least one affected sib will have an accuracy > 99%.
Measures of the degree of motor, psychiatric, and declarative memory disability were made in neurologically impaired and neurologically asymptomatic patients with Wilson's disease. All three types of disability were significantly greater in the neurologically impaired than in the asymptomatic patients. There was no significant interaction between these disabilities in the impaired patients suggesting that motor, psychiatric, and memory symptoms are three relatively independent sequelae of the copper-induced central nervous system (CNS) damage that underlies Wilson's disease.
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Twenty of 320 patients with Wilson's disease initially presented with chemical and laboratory features of chronic active hepatitis, confirmed histologically in 17. When first seen, cirrhosis was present in all 20 and was complicated by ascites and/or jaundice in 11. Within 1 week to 8 years of the onset of over liver disease the diagnosis of Wilson's disease was established, and treatment with D-penicillamine was promptly initiated in 19 patients. One man refused treatment and died 4 months later. Treated patients received D-penicillamine or trientine for a total of 264 patient-years (median, 14 patient-years). Abnormal water retention, for which salt restriction and diuretics were added to penicillamine or trientine, disappeared in all but 1 of the patients so affected. Symptomatic improvement and virtually normal levels of serum albumin, bilirubin, aspartate aminotransferase, and alanine aminotransferase followed within 1 year in the majority of subjects. One woman died after 9 months of treatment. Two patients, who became noncompliant with the therapeutic regimen after 9 and 17 years of successful pharmacological treatment, required liver transplants. These results indicate that the prognosis of specifically treated Wilsonian chronic active hepatitis is very good in spite of the presence of cirrhosis.
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Spinocerebellar degeneration in a 17-yr-old boy with abetalipoproteinemia was associated with vitamin E deficiency and hepatic steatosis. In liver biopsy samples before and after 15 mo of vitamin E treatment, hepatocellular peroxisomes were morphologically abnormal; pleomorphic, with a broadened range of sizes; often larger than normal; and with marginal bars in some. In the first sample, peroxisomes exhibited matrical heterogeneity and dense nucleoids. Peroxisomes in the second biopsy sample lacked nucleoids and contained more homogeneous matrices. The mean peroxisomal diameter increased from 0.77 +/- 0.33 to 0.86 +/- 0.32 microM (normal, 0.62 +/- 0.14). These observations raise the possibility that peroxisomes may be involved in the metabolism of apolipoprotein B or may be affected by the disturbances of hepatocellular lipid metabolism caused by this disease.
Tests of memory and verbal fluency were administered to 19 neurologically impaired Wilson's patients, 12 non-neurologically impaired Wilson's patients and 15 normal control subjects. Wilson's patients with neurologic disease recalled significantly fewer words on the delayed recall version of the Rey Auditory Verbal Learning Test than control subjects (p less than .05) but they showed no impairment on the recognition version of this test. On a verbal fluency test (FAS) requiring the subject to retrieve items from different categories, Wilson's patients with neurologic disease generated significantly fewer words than control subjects (p less than .01). Results suggest that retrieval memory is mildly impaired in the neurologic WD group but rate of learning and rate of forgetting is normal.
We studied the mechanisms by which excess copper exerts, and zinc mitigates, toxic effects on HepG2 cells. Survival and cell growth were reduced in media containing greater than 500 microM copper chloride for 48 h; LD50 was 750 microM. At 1,000 microM copper for 1 h, there was a general reduction of protein synthesis, and no recognizable changes in cellular ultrastructure. Incubation of cells with 200 microM zinc acetate before exposure to copper, raised the LD50 for confluent cells to 1,250 microM copper chloride, improved protein synthesis, and increased synthesis of a 10-kD protein, apparently metallothionein. The mitigation, by zinc, of copper's toxicity may in part be mediated through induction of this protein in the hepatocyte.