Menkes’ disease copper

The causes of human copper deficiency include (1) low intake - malnutrition, total parenteral nutrition (TPN) (2) high loss - cystic fibrosis, nephrotic syndromes and (3) genetic factors — Menkes disease. Copper deficiency may also be associated with chronic malabsorption, a situation which is made much worse in cases of gastric and bowel resection. Several special diets, including powdered milk, liquid protein and standard hospital diets are a means of inducing copper deficiency. The amount of copper in US food has decreased steadily since 1942, and may be related to the rising incidence of coronary artery disease. A copper deficiency may also occur as the result of the use of chelators for other purposes for example, diethyl dithiocarbamate is an in vivo metabolite of ANTABUSE (disulfiram). 

In Menkes disease, copper is not absorbed in the intestine and is not available for distribution throughout the body. Consequently, cuproenzymes such as cytochrome c oxidase, lysyl oxidase, and dopamine beta hydroxylase cannot function normally. Sufferers exhibit severe developmental delay subnormal body temperature kinky, steel-colored hair seizures and ultimately the degeneration of muscle, bone, and organs. Baby boys bom with the most severe form of Menkes disease typically do not live beyond then-third year of life. 

Menkes Disease Is Due to Mutations in the Gene Encoding a Copper-Binding P-Type ATPase... 

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

The cause of Wilson disease was also revealed in 1993, when it was reported that a variety of mutations in a gene encoding a copper-binding P-type ATPase were responsible. The gene is estimated to encode a protein of 1411 amino acids, which is highly homologous to the product of the gene affected in Menkes disease. In a manner not yet fully explained, a nonfunctional ATPase causes defective excretion of copper into the bile, a reduction of incorporation of copper into... 

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]. 

Strain genetically deficient in copper (Menkes disease) given subcutaneous injections of 50 pg copper chloride (CuCI2) on postnatal days 7 and 10. Before therapy, liver copper concentration was 3.1 mg/kg FW (vs. 30.1 mg/kg FW in normal mice)... 

Figure 7.31 Schematic structures for Menkes and Wilson disease copper-transporting P type ATPases. (Adapted with permission from Figure 2 of Sarkar, B. Chem. Rev., 1999, 99(9), 2535-2544. Copyright 1999, American Chemical Society.)...

The amino acid histidine is used for the treatment of copper overload in Wilson s disease and forms a strong 1 2 complex (Fig. 27) (553). Copper-histidine therapy is also an efficient treatment for copper deficiency in Menkes disease (554). 

Menkes disease Deficient cross-linking secondary to functional copper deficiency Depigmented (steely) hair Arterial tortuosity, rupture Cerebral degeneration Osteoporosis, anemia... 

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. 

At the moment only Menkes disease, a condition which arises from an impairment of copper transport across the gut wall27, is in this category. Again, it is possible that other diseases of this nature will be identified. Suitable copper supplementation will suppress development of the disease in the foetus. The disease is characterized by progressive degeneration of the brain and the spinal cord of infants. 

Keen et al.86 have demonstrated the prophylactic value of copper(II) chelated by NTA for Menkes disease by using as a laboratory model the crinkled mutant mouse. As this syndrome does not respond to dietary supplementation with either copper sulphate or copper acetate then therapy with chelated copper would appear to have advantages. 

Copper absorption appears to occur through both a rapid, low-capacity system, and a slower, high-capacity system, which may be similar to the two processes seen with calcium absorption. Inactivating mutations in the gene encoding an intracellular copper ATPase have been shown to be responsible for the failure of intestinal copper absorption in Menkes disease. 

Today, copper homeostasis is a research area of intense interest and work in this field has recently uncovered several surprising new concepts of trace metal homeostasis, and more are likely to emerge. The molecular defects in the inherited disorders of copper metabohsm, Menkes disease... 

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