Genetic diseases Menkes disease

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). 

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)... 

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. 

Recent reviews on copper homeostasis in E. col and yeast are available. Copper and iron metabolism are often intertwined. For instance, mammalian iron metabohsm depends on the copper protein, ceruloplasmin, a ferroxidase that facilitates iron efflux from cells see Copper Proteins Oxidases) Several important human diseases, including Menkes disease and Wilson s disease, result from mutations in copper transport see Metal-related Diseases of Genetic Origin) ... 

Intestinal absorption of copper is mediated by coppertransporting P-type ATPase 7A (ATP7A) or Menkes disease protein. Mutations in the ATP7A gene lead to Menkes disease in humans that is characterized by congenital impairment in intestinal transport of copper see Metal-related Diseases of Genetic Origin) ... 

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... 

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. 

Menkes disease is a genetic disease involving mental retardation and death before the age of 3 years. The disease is also called Menkes steely hair syndn me. I his term came from the abnormal, steely or kinky hair that results. The hair is tangled, grayish, and easily broken. 

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). 

Chelly, J., Turner, Z., Tormesen, T., Petterson, A., Ishikawa-Brush, Y, Tommerup, N., Horn, N., and Monaco, A. P. (1993). Isolation of a Ccmdidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nature Genet. 3,14-19. 

Turner, Z., Lund, C., Tolshave, J., Vural, B., Tonnesen, T., and Horn, N. (1997). Identification of point mutations in 41 unreleated patients affected with Menkes disease. Am. J. Hum. Genet. 60, 63-71. 

Vulpe, C., Levinson, B., Whitney, S., Packman, S., and Gitschier, J. (1993). Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nature Genet. 3, 7-13. 

Menkes disease is an X-linked inherited disorder in which dietary copper is absorbed from the gastrointestinal tract but cannot be transported to the vascular space because of the genetic absence of an intracellular ATPase. Hence, copper... 

Genetic disorders (not included above) tyrosine hydroxylase deficiency dopa-responsive dystonia dihydropteridine reductase deficiency aromatic L-amino acid decarboxylase deficiency Menkes disease monoamine oxidase deficiency. 

Christodoulou J, Danks DM, Sarkar B, Baerlocher KE, Casey R, Horn N et al. Early treatment of Menkes disease with parenteral copper-histidine long-term follow-up of four treated patients. Am J Med Genet 1998 76 154-64. 

Tanzi R, Petrukhin K, Chernov I, Pellequer J, Wasco W, Ross B, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993 5 344-50. 

Some of these symptoms are seen among people who suffer from the rare genetic disease known as Menkes kinky hair syndrome. The symptoms of this disease, which is caused by a defect in the ability to absorb copper from the intestine, include very low copper levels in the serum, kinky white hair, slowed growth, and degeneration of the brain. 

Kodama H and Murata Y (1999) Molecular genetics and pathophysiology of Menkes disease. Pediatr Int 41 430-435. 

Tonnesen K, Kleijer WJ and Horn N (1991) Incidence of Menkes disease. Hum Genet 86 408-410. 

Essentiality to Humans Copper deficiency in man is a rare exception, and would not occur if > 2 mg of copper is present in the daily diet. However, secondary copper deficiency can be caused by severe malabsorption, diarrhea accompanied by a copper-deficient diet in infants, or in the genetic disorder of copper transport and utilization that characterized Menkes disease. Except for Menkes disease (for which there is no effective treatment and which is invariably fatal), copper deficiency in man is simply treated by adding 5 mg copper (most conveniently as acetate) to the daily diet. In practical terms it is almost never necessary to supplement any but the most abnormal diets with copper to avoid its deficiency in man (Scheinberg... 

With the exception of genetically impaired individuals with Menkes disease and Wilson s disease, individuals who suffer from various grossly inadequate diets, diarrhea and severe malnutrition, and the patients who suffer from primary biliary cirrhosis, and cholestatic syndromes of Indian childhood cirrhosis, the development of copper deficiency and toxicity is not a significant risk for man. 

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