Hiroko Kodama and Chie Fujisawa at the Teikyo University School of Medicine, Tokyo, Japan, weigh up why copper regulation is so crucial in the body

All living organisms need copper. It is an integral component of many enzymes, from the respiratory enzyme cytochrome c oxidase to the copper-carrying ceruloplasmin, which plays an important role in iron metabolism. But, in excess, copper can result in the generation of reactive free radicals, leading to cellular damage. The body's tight regulation of copper levels - by adjusting its uptake, transport, storage and excretion - is therefore essential. 

Disruption of this regulation is evident in three human genetic disorders: Menkes disease (MD), occipital horn syndrome (OHS) and Wilson's disease (WD). MD is a copper-deficiency disorder, which affects around 1 in every 140000 males. Typical features of the disease include neurological disturbances, connective tissue disorders, and hair abnormalities, and can be explained by the abnormally low activity of copper-dependent enzymes. The neurological disturbances, which become prominent from the age of 2, are severe and most patients die by the age of 3 years. The connective tissue disorders, including arterial abnormalities and osteoporosis, are also severe, and patients can suffer from internal bleeding and bone fractures. OHS is a rarer and milder form of MD characterised by connective tissue abnormalities.

WD affects around 1 in every 30000-35000 people. In contrast to MD and OHS, WD is characterised by a copper excess and symptoms are due to the toxic effects of chronic exposure to the metal. In typical cases, the liver and nervous systems are most severely affected. Symptoms include chronic or acute hepatitis, cirrhosis and liver failure; other symptoms, such as arthritis and anemia, can make an early diagnosis difficult. 

A mutation in gene ATP7B in Wilson's disease results in low levels of ceruloplasmin (centre) and excess copper being deposited in the liver © WELLCOME IMAGES

All three diseases result from the absence or dysfunction of copper-transporting proteins due to genetic mutation. The gene mutated in MD and OHS is ATP7A, while ATP7B is mutated in WD. Both proteins encoded by these genes facilitate copper transport from the cell fluid to the Golgi apparatus, where the cell processes macromolecules such as proteins and lipids. In cells with compromised ATP7A/B protein function, copper remains in the cell fluid and cannot be excreted. 

The difference in effect results from the specific cell types that make ATP7A or ATP7B proteins. ATP7A functions in almost all cells, so for patients with MD and OHS, when copper from the diet is absorbed by intestinal cells, it cannot be expelled and it accumulates, leading to a deficiency elsewhere in the body. ATP7B functions in hepatocytes - the cells that make up the majority of the liver - and in WD patients copper accumulates in these cells causing cell damage. 

MD is treated by injection with the copper salt of the amino acid histidine. Delayed treatment is less effective but when treatment is initiated in newborns, neurological degeneration can be prevented, meaning early screening is of great importance. Copper-histidine does not improve symptoms associated with the connective tissue disorders, however, and therapies directed towards these need to be developed simultaneously. OHS patients typically are treated in a similar manner to those with MD.

For WD, while chelating agents and zinc are effective treatments, they are ineffective in patients with liver failure, for whom a liver transplant is the most appropriate option. Some patients with neurological diseases can show poor response to chelating agents and zinc and others may show poor compliance with drug treatment. Moreover, WD patients may be at risk of liver cancer and a better understanding of the relationship between WD and cancer is an important problem that needs to be solved in the future.

Read more in Hiroko Kodama and Chie Fujisawa's critical review 'Copper metabolism and inherited copper transport disorders: molecular mechanisms, screening, and treatment' in Metallomics.

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