Diseases of copper metabolism

Table 50-6. Major laboratory tests used in the investigation of diseases of copper metabolism ...

In contrast, CopB extrudes excess copper (Figure 7.4). Both CopA and CopB belong to the PI subclass of I1-type ATPases, which includes the proteins involved in the human diseases of copper metabolism, Menkes and Wilson s disease (discussed in Chapter 14). 

Copper is an essential element to most life forms. In humans it is the third most abundant trace element only iron and zinc are present in higher quantity. Utilization of copper usually involves a protein active site which catalyzes a critical oxidation reaction, e.g., cytochrome oxidase, amine oxidases, superoxide dismutase, ferroxidases, dopamine-/ -hydrox-ylase, and tyrosinase. Accordingly, animals exhibit unique homeostatic mechanisms for the absorption, distribution, utilization, and excretion of copper (J). Moreover, at least two potentially lethal inherited diseases of copper metabolism are known Wilson s Disease and Menkes s Kinky Hair Syndrome (I). 

Biochemistry of Zinc and Copper Zinc in the -Cells of the Pancreas Absorption of Zinc and Copper Plasma Zinc and Copper Levels Metallothionein and Ceruloplasmin Zinc Excretion and Zinc Deficiency Copper Excretion and Copper Deficiency Genetic Diseases of Copper Metabolism Molybdenum, Sulfite, and Sulfate Molybdenum Molybdenum Biochemistry Sulfite Sulfate... 

Wilson s disease is an autosomal recessive disease of copper metabolism. It has a prevalence of 1 in 30,000 live births in most populations. The disease has a highly variable clinical presentation. It is characterized by impairment of biliary copper excretion, decreased incorporation of copper into ceruloplasmin, and accumulation of copper in the liver and, eventually, in the brain and other tissues. The biochemical findings include low serum ceruloplasmin, high urinary copper excretion, and high hepatic copper content. Some patients have normal serum cerulo-plasmia levels, and heterozygous individuals do not consistently show reduced levels of this protein. 

Menkes disease is a rare X-linked recessive disease of copper metabolism, the frequency of which has been estimated at between 0.8 and 2 per 100000 live male births (Tonnesen et al. 1991). Clinical manifestations begin in the first few months of life, or even in the neonatal period. Symptoms include hypothermia, hypotonia, poor weight gain, seizures, and neurodevelop-mental delay or regression. The outcome is poor, with death occurring usually by three years of age. Diagnostic characteristics include facial appearance with steely hair, and reduced levels of serum ceruloplasmin and copper (Menkes 1999, Jayawant etal. 

Further reading Sass-Kortsak, A. and Bearn, A. G. (1978 Hereditary diseases of copper metabolism. In Stanbury,... 

Menkes disease ( kinky or steely hair disease) is a disorder of copper metabolism. It is X-hnked, affects... 

Wilson s disease A disorder of copper metabolism characterized by cirrhosis of the liver and neurologic manifestations a potentially fatal genetic disorder that causes the body to retain copper. 

Creutzfeldt-Jakob and other prion diseases have been associated with disorders of copper metabolism. The first cases of Creuzfeldt-Jakob disease in humans were described by Creuzfeldt and Jakob over 80 years ago. Although scrapie was known as a fatal neurological... 

In many crucial biological processes, such as oxygen transport, electron transport, intermediary metabolism, metals play an important part. Therefore, disorders of metal homeostasis, metal bioavailability or toxicity caused by metal excess, are responsible for a large number of human diseases. We have already mentioned disorders of iron metabolism (see Chapter 7) and of copper metabolism (see Chapter 14). The important role, particularly of redox metals such as copper and iron, and also of zinc, in neurodegenerative diseases, such as Parkinson s disease, Alzheimer s disease, etc. has also been discussed (see Chapter 18). We will not further discuss them here. 

Zinc is used for a variety of indications. Zinc acetate (8.102) or, rarely, zinc sulfate (8.103) have been used orally to treat Wilson s disease, a recessively inherited disorder of copper metabolism, characterized by brain and liver dysfunction arising from excessive deposits of copper. Zinc pyrithione (8.104) is used in shampoos to treat seborrhea. Zinc propionate (8.105) and zinc caprylate (8.106) have been used as topical antifungal agents. 

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. 

Harrison, M. D., and Dameron, C. T. (1999). Molecular mechanisms of copper metabolism and the role of the Menkes disease protein./. Biochem. Mol. Toxicol. 13, 93-106. 

Caeruloplasmin Copper-incorporating a glycoprotein true function remains unclear but acts as a copper donor and oxidative enzyme Low caeruloplasmin levels may be seen in cirrhosis (especially primary biliary cirrhosis) as caeruloplasmin is excreted hepatically Levels increased in infection, injury or inflammation. Low levels are found in Wilson s disease, which is an autosomal recessive disorder of copper metabolism it results in copper deposition in the liver, basal ganglia and eyes, and culminates in cirrhosis and neurological impairment... 

Wilson s disease is an inherited disorder of copper metabolism. Copper accumulates initially in the liver and then in the nervous system, leading to severe liver and neurological disease. The retention of copper begins at birth, but it may take decades before the liver is sufficiently damaged... 

Menkes disease is another genetic disorder of copper metabolism characterized by an impairment in the absorption of dietary copper and severe disturbance in the intracellular... 

A boy with Menkes disease and low plasma concentrations of copper (3.6 pmol/l) and ceruloplasmin (50 mg/1) received copper histidine and died aged 10. Postmortem examination showed significant pathology of the mesenchymal tissues, including skeletal abnormalities, vascular degeneration, and bladder diverticula. The central nervous system, in contrast, showed minimal pathology of copper metabolism compared with classical Menkes disease. 

Wilson s disease is an autosomal recessive inherited disorder of copper metabolism resulting in accumulation of copper in various tissues. Rats raised to have a large accumulation of copper had 80 times greater concentration of MTs in their liver compared to controls (5016pgg vs. 65pgg ). 

Wilson s disease is an autosomal recessive disorder of copper metabolism (see Chapters 20 and 30). It has a gene frequency of 1 in 200 and a disease frequency of 1 in 30,000. It is due to one of more than 200 mutations in a gene on chromosome 13 coding for a copper transporting ATPase... 

Because of their importance in many enzymes, bacteria have had to develop uptake systems for both copper and zinc. Copper uptake (and homeostasis, which is discussed in Chapter 8) has been extensively studied in the Gram-positive bacteria Enterococcus hirae. At the membrane, a reductase, indicated as R in Fig. 7.10, reduces Cu to Cu" " which is taken up by CopA when copper is limiting. In contrast, when copper is in excess, CopB extrudes excess copper. Both CopA and CopB belong to the PI subclass of P-type ATPases, which includes the proteins involved in the disorders of copper metabolism in humans, Mentke s, and Wilson s disease (discussed in Chapter 14). 

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

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