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Copper metabolism and inherited copper transport disorders: molecular mechanisms, screening, and treatment

Content Provider	Royal Society of Chemistry (RSC)
Author	Fujisawa, Chie Kodama, Hiroko
Copyright Year	2009
Abstract	In this review, we discuss genetic disorders involving altered copper metabolism, particularly in relation to Menkes disease (MD), occipital horn syndrome (OHS), and Wilson’s disease (WD). The responsible genes for MD and WD are ATP7A and ATP7B, respectively. Both proteins encoded by these genes are responsible for transporting copper from the cytosol to the Golgi apparatus. However, the pathology of MD is completely different from that of WD, that is, MD is characterized by a copper deficiency while WD is caused by a toxic excess of copper. The reason for this difference is related to the particular cell types in which the ATP7A and ATP7B proteins are expressed. ATP7A is expressed in almost all cell types except hepatocytes, whereas ATP7B is mainly expressed in hepatocytes. MD and OHS are X-linked recessive disorders characterized by copper deficiency. Typical features of MD, such as neurological disturbances, connective tissue disorders, and hair abnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The current standard-of-care treatment for MD is parenteral administrations of copper–histidine. When the treatment is initiated in newborn babies prior to two months of age, the neurological degeneration may be prevented, but delayed treatment is considerably less effective. Moreover, copper–histidine treatment does not improve symptoms of the connective tissue disorders. As such, systems for mass screening of neonates for MD should be implemented. At the same time, novel treatments targeting connective tissue disorders need to be developed. OHS is a milder form of MD and is characterized by connective tissue abnormalities. Although formal trials have not been conducted for OHS, OHS patients are typically treated in a similar manner to those with MD. WD is an autosomal recessive disorder characterized by the toxic effects of chronic exposure to high levels of copper. The hepatic and nervous systems are typically most severely affected. Numerous other symptoms can also be observed, however, making an early diagnosis difficult. Chelating agents and zinc are effective for the treatment of WD, but they are ineffective for the patients with fulminant hepatic failure. Some patients with neurological diseases show poor response to chelating agents; here again, early diagnosis and treatment are critical. Screening of newborn babies or infants for WD can help lead to timely diagnosis and treatment. Patients with WD may have a risk of hepatocellular carcinoma despite receiving treatment. An understanding of the relation between WD and hepatocellular carcinoma will provide clues to help prevent hepatocellular carcinoma in patients with WD.
Starting Page	42
Ending Page	52
Page Count	11
File Format	HTM / HTML PDF
ISSN	17565901
Volume Number	1
Issue Number	1
Journal	Metallomics
DOI	10.1039/b816011m
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Connective tissue disease Carcinoma X-linked recessive inheritance Wilson Parenteral nutrition Menkes Zinc deficiency Metabolism Cytosol Syndrome Menkes disease Golgi apparatus Myelopathy Hepatocyte Copper ATP7A Dominance (genetics)
Content Type	Text
Resource Type	Article
Subject	Chemistry Medicine Metals and Alloys Biochemistry Biomaterials Biophysics

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