Menkes’ syndrome

Two inherited human diseases that represent abnormal copper metabolism are Menkes syndrome and Wilson s disease. Menkes syndrome, with symptoms similar to those of copper deficiency, is characterized by a progressive brain disease, abnormally low copper concentrations in liver and other tissues, and diminished ability to transfer copper across the absorptive cells of the intestinal mucosa (USEPA 1980 Aaseth and Norseth 1986). Wilson s disease (hepatolenticular degeneration) is the only significant example of copper toxicity in humans. Wilson s disease is an autosomal recessive disorder that affects normal copper homeostasis and is characterized by excessive... 

Incontinentia pigmenti Wiskott-Aldrich syndrome Menkes syndrome Androgen insensitivity Kennedy disease ... 

Copper deficiency may present as hematological changes (anemia, leukopenia, and neutropenia) and skeletal demineralization. In severe cases, such as in Menkes syndrome, copper deficiency is further manifested as hypothermia, depigmentation of hair and skin, progressive mental deterioration, and growth retardation. Factors predisposing to copper deficiency include malabsorption states, protein-losing enteropathy, nephrotic syndrome, copper-free parenteral nutrition, and copper-deficient enteral nutrition. 

The high sensitivity of ETA—AAS for Cu has stimulated the development of methods to measure concentrations of the Cu carrier species in biological fluids. Delves [7] analysed the Cu content of the protein fractions separated from 2 pi volumes of serum by cellulose acetate membrane (CAM) electrophoresis. The separated protein bands were cut from the CAM and placed directly into the ETA via a 6 mm x 1 mm hole cut in the wall of the graphite tube. Calibration was achieved by adding 2 pi volumes of aqueous standards to 8 mm x 6 mm strips of CAM. Background correction was essential. Approximately 94% of the Cu was located in the a2 band, where carulo-plasmin would run, whereas other fractions contained less than 5% of the total serum Cu. The recovery of Cu after electrophoresis was quantitative, 99%, and the RSD was 0.086 at 1.74 ng Cu. This method was applied to studies of Cu changes in patients with Menkes Syndrome receiving intramuscular injections of copper as the EDTA complex, and in children with acute lymphoblastic leukaemia. 

Important disorders associated with transition metals include insufficient intake or absorption (e.g. iron deficiency anaemia), defective transport (e.g. Menkes syndrome), and excessive storage (e.g. Wilson s disease, haemochromatosis). 

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... 

Except in genetic disorders such as Menkes Syndrome, caused by abnormalities in protein metabolism in children (62), hypocupremia has not been demonstrated to occur in man (49), Two other disorders, nephrosis and iron deficiency, are known to have low serum copper concentrations. 

The genetic syndrome referred to as Menkes kinky hair has been studied by Williams et al. (73). No changes were observed following oral copper supplementation in plasma copper concentration or ceruloplasmin concentration in these patients. However, when copper was given intravenously, a rise in ceruloplasmin was seen. The results indicate that in Menkes syndrome, there is a defect in copper-binding protein which leads to excessive losses of copper from the gastrointestinal tract. 

Although genetic defects in the metahoUsm of trace elements are rare, they are nonetheless important because of the information they have provided as to homeostatic control mechanisms. This in turn has led to development of effective therapeutic strategies. The most commonly investigated disorders are those affecting iron (hemochromatosis), copper (Wilson s disease and Menkes syndrome), zinc (acrodermatitis enteropathica), and molybdenum (molybdenum cofactor disease). 

Copper is necessary, together with iron, for hematopoiesis, probably partly because it is needed for the synthesis of fer-roxidase (ceruloplasmin). Many enzymes require copper for activity. Examples of some of the copper-enzymes and their functions are given in Table 37-5. Mitochondrial iron uptake may be blocked by deficiency of a cuproprotein, perhaps cytochrome oxidase. Several inherited diseases involving abnormalities in copper metabolism (Wilson s disease, Menkes syndrome) or copper enzymes (X-linked cutis laxa, albinism) occur in human and in several animal species. 

Menkes syndrome (Menkes steely-hair syndrome) is a rare, X-linked recessive disorder in which infants have low levels of copper in serum and in most tissues except kidney and intestine, where the concentration is very high. They also have greatly reduced plasma ceruloplasmin levels. Hair of the affected infants has a characteristic color and texture (pili torti, twisted hair ). It appears tangled and dull, has an ivory or grayish color, and is friable. Weakness and depigmentation of hair and defects in arterial walls (leading to aneurysms) are explained by loss of activity of copper-dependent enzymes (Table 37-5). Cerebral dysfunction may be due to a disturbance in energy metabolism or neurotransmitter synthesis secondary to decreased activity of cytochrome oxidase and dopamine... 

The molecular defect in Menkens syndrome, like that in Wilson s disease, resides in a P-type ATPase. The gene for the enzyme is located on the X chromosome. Wilson s disease is characterized by defective biliary excretion in Menkes syndrome, the defect is a failure to transport copper to the fetus during development as well as failure to absorb copper from the gastrointestinal tract after birth. 

J. F. B. Mercer Menkes syndrome and animal models. Clinical Nutrition 67, 1022S (1998). 

In Menkes syndrome intestinal absorption of copper is defective. How can affected infants be treated to avoid the symptoms of the disorder, which include seizures, retarded growth, and brittle hair ... 

There are two inbttrn errors of ettpper metabolism Menkes syndrome and Wilson s disease. 

Menkes syndrome is a very rare but fatal condition which presents in infants as growth failure and mental retardation, with lesions of the major blt)od vessels and bone disease. A characteristic sign is steely hair (pilo torti). 

Menkes syndrome is a genetic disorder of kinked hair in which the sul-phydryl groups of human hair are only partly converted to disulfide bonds (about 50% oxidized). Mercer [135] suggested that this disease is linked to a copper deficiency caused by a mutation in a protein involved in copper transport. 

Menkes syndrome is linked to a copper deficiency resulting in abnormal keratinization [167]. In this genetic disorder, the kinky hair symptomatic of this disease results from an unusually high mercaptan level of cysteine, wherein only about 50% of the cysteine is oxidized to disulfide bonds during keratinization. 

Monilethrix is a genetic anomaly in which hair fibers contain periodic constrictions along the fiber axis. Monilethrix hairs tend to fracture at these constrictions [63] and therefore must exhibit abnormal stretching behavior. Trichorrhexis nodosa is another abnormal condition, where hair fibers contain nodes at irregular intervals along the fiber axis. These nodes actually contain tiny fractures and tend to form broom like breaks [63] under stress. Therefore, nodosa hair fibers should also exhibit abnormal stretching behavior. Other hair shaft anomalies such as trichothiodystrophy and Menkes syndrome should also display abnormal stretching behavior consistent with the abnormal hair shaft condition associated with these diseases. 

Copper Component of important enzymes Anemia, Menkes syndrome Green vegetables, fish, oysters, liver 1.2... 

Ceruloplasmin (EC 1.12.3.1) Plasma 132 6 Blue Polyamine oxidase ferroxidase Unkno m Deficient or absent in Wilson s disease. and in Menkes syndrome Glycoprotein... 

Cytochrome c oxidase EC 1.9.3.1 Liver 200-250 2 Colorless Cytochrome c oxygen oxido-reductase Electron transport - Activity depressed in Menkes syndrome Hemoprotein 1 heme/1 copper... 

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