Wilson and Menkes Diseases

Investigations of the normal distribution of trace elements among the organs of the body have been used and continue to be used for the detection and diagnosis of genetic defects such as Wilson and Menkes diseases [4]. Many attempts continue to be made to associate trace element distributions with such diseases as cancer, gastroenteropathic diseases, brain degeneration, and Blackfoot disease. 

The Malfunctioning of Copper Transport in Wilson and Menkes Diseases... 

Ceruloplasmin contains substantial amounts of copper, but albumin appears to be more important with regard to its transport. Both Wilson disease and Menkes disease, which reflect abnormahties of copper metabohsm, have been found to be due to mutations in genes encoding copper-binding P-type ATPases. 

Abnormalities in copper metabolism are normally associated with Wilson s disease [28] and Menkes disease [29,30,31], although total copper and hCP concentrations increase significantly in many inflammatory and infectious diseases including hepatitis and tuberculosis, and a number of different kinds of cancer. A direct connection between copper and coronary artery disease has also been proposed [32]. A useful general review of copper and disease has been given by Linder [33]. 

Two genetic disorders of copper metabolism, Wilson s disease (see Section 62.2.3.3) and Menkes disease, are known. The latter involves impaired intestinal absorption of copper56,57 as well as probably subcellular metabolic defects which result in copper deficiency with respect to metal-loenzyme activity. The characteristic steely hair in Menkes disease results from free SH bonds in hair protein because of failure of lysyl oxidase to produce the disulfide links. Depigmentation of hair and skin, hypothermia, cerebral degeneration, central nervous system retardation, skeletal demineralization and arterial degeneration are all seen. Copper supplements may benefit hypothermia and increase pigmentation but the disease is not generally cured. 

Severe alterations in copper metabolism occur in two genetic disorders, Wilson s disease and Menkes disease, both of these diseases arc rare and occur in about one in 100,000 birtKs. Both diseases involve naturally occurring mutations in copper transport proteins, i.e membrane-bound proteins that mediate the passage of copper ions through cell membranes. The copper transporters that are defective in these two diseases are not the same protein, but they are related. To express this relation in numbers, over half (57 a) of the sequence of amino adds, as they occur in the polypeptide chains, are identical. Both proteins are thought to utilize ATP to drive copper ions through membranes. 

Some copper compounds have been used therapeutically in the past. Small quantities of copper salts enhance the physiological utilization of iron and are thus often present in hemopoietic formulations. Copper chloride and copper sulfate are used in parenteral nutrition solutions. The artificial radioactive copper isotope Cu has been used in mineral metabolic studies. Excess accumulation of copper can occur due to an abnormality of ceruloplasmin and causes Wilson s disease and Menkes disease, which are both characterized by copper accumulation (SEDA-22, 244) (9). 

Copper poisoning can cause hepatic cirrhosis in Wilson s disease (SEDA-21, 234) (27), bnt no cases appear to be known in which this resulted from medicinal exposure. Apart from Wilson s disease and Menkes disease, much attention has been given to copper-associated liver disease in infancy and childhood, in which excessive dietary copper overload and a genetic predisposition can lead to high hver copper concentrations and progressive liver disease (28). 

Lutsenko, S., Petrukhin, K., Cooper, M. J., Gilliam, C., and Kaplan, J. H. (1997). N-terminus domains of human copper-transporting adenosine triphosphatases (the Wilson s and Menkes disease proteins) bind copper selectively in vivo and in vitro with stoichiometry of one copper per metal-binding repeat. /. Biol Chem. 272,18939-18944. 

The human hereditary disorders Wilson s disease and Menkes disease have provided further insight into copper metabolism. In Wilson s disease the ceruloplasmin content is low and copper gradually accumulates to high levels in the liver and brain. In Menkes syndrome, there is also a low ceruloplasmin level and an accumulation of copper in the form of... 

Disorders of Copper Metabolism — Wilson s and Menkes Diseases and Aceruloplasminaemia... 

Danks, D. M., 1983, Hereditary disorders of copper metabolism in Wilson s disease and Menkes disease, in The Metabolic Basis of Inherited Disease (J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. L. Goldstein, and M. S. Brown, eds.), pp. 1251-1268, McGraw-Hill, New York. 

Two caveats are required with respect to the hypotheses presented here First, the protein products of the candidate Wilson s and Menkes genes have not yet been seen, but only predicted from candidate cDNA sequences. Second, the biochemical and transport properties of these P-type ATPases have not been measured. However, fibroblasts from both Wilson s and Menkes disease patients appear to express the basic defects. These fibroblasts accumulate radioactive copper with apparently normal initial uptake kinetics but are defective in copper efflux or exchange. The fibroblasts from Menkes and Wilson s disease patients both overaccumulate Cu and bind Cu to metallothionein, but cannot pass on (or efflux) Cu appropriately (J. Camakaris, as reported by Danks 1989). 

Recently a new copper transport defect was described by Buchmann et al. [16] in a patient with symptoms of a demyelinating neuropathy, chronic intestinal pseudo-obstruction, osteoporosis, testicular failure, retinal degeneration and a cardiomyopathy with a tortuous aorta. In this patient, copper could not be incorporated into ceruloplasmin. The symptoms started at age 10 and the patient died at 21 years. These findings were clearly different from Wilson s and Menkes diseases. 

P-type copper transporters are important for neural function. Wilson s and Menke s diseases have major neurological components (Ch. 45). The Wilson s disease gene codes for a transporter, expressed chiefly in liver, that probably functions in Cu2+ excretion. The Menke s disease gene codes for a closely related transporter that regulates intestinal Cu2+ absorption [32],... 

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