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Abstract

Abstract 

  1. Wilson disease and Menkes disease are inherited disorders of copper transport. Each disease results from the absence or dysfunction of homologous copper-transporting adenosine triphosphatases (ATPases) present in the trans-Golgi network of cells. The Wilson disease ATPase transports copper into the hepatocyte secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Thus, individuals with this autosomal-recessive disease present with signs and symptoms arising from impaired biliary copper excretion. The Menkes disease ATPase transports copper across the placenta, gastrointestinal tract, and blood–brain barrier, and the clinical features of this X-linked disease arise from copper deficiency. Despite striking differences in the clinical presentation of these two diseases, the respective ATPases function in precisely the same fashion within the cell. The unique clinical features of each disease are the result of the tissue-specific expression of these ATPases.

  2. Copper is an essential transition element that plays a fundamental role in the biochemistry of all aerobic organisms. Proteins exploit the unique redox nature of this metal to undertake a series of facile electron transfer reactions using copper as a cofactor in a select number of critical enzymatic pathways. The function of these enzymes is essential for cellular respiration, iron homeostasis, pigment formation, neurotransmitter production, peptide biogenesis, connective tissue biosynthesis, and antioxidant defense. The signs and symptoms of copper deficiency are the result of impaired function of these cuproenzymes.

  3. Copper homeostasis is maintained entirely by gastrointestinal absorption and biliary excretion. Absorbed copper is efficiently removed from the portal circulation by the liver, which is the central organ of copper homeostasis, regulating both storage and excretion. Biliary copper is not absorbed from the gastrointestinal tract, so there is no enterohepatic circulation of this metal. Greater than 95 percent of plasma copper is contained in the multicopper oxidase ceruloplasmin, which is synthesized and secreted by the liver. Despite the abundance of this cuproprotein in the plasma, ceruloplasmin has no essential role in copper transport or metabolism.

  4. The reactivity of copper in biological systems also accounts for the potential toxicity of this metal when cellular copper homeostasis is disturbed. For this reason, specific pathways have evolved for the trafficking and compartmentalization of copper within cells. The delivery of copper along these pathways is mediated by unique proteins termed copper chaperones. Elucidation of the structure and function of these chaperones has revealed a remarkable evolutionary conservation of the mechanisms of cellular copper metabolism. The inherited disorders of copper transport dramatically underscore both the essential need for copper and the toxicity of this metal, and elucidation of the genetic basis of these diseases permits an understanding of the molecular mechanisms of copper homeostasis.

  5. In Wilson disease, impaired biliary copper excretion leads to accumulation of this metal in the liver. When the capacity for hepatic storage is exceeded, cell death ensues, with copper release into the plasma resulting in hemolysis and deposition of copper in extrahepatic tissues. Affected individuals usually present in the first or second decade of life with chronic hepatitis and cirrhosis or acute liver failure. Copper accumulation in the cornea results in Kayser-Fleischer rings. Neuropsychiatric symptoms are more common in adults and include dystonia, tremor, personality changes, and cognitive impairment as a result of copper accumulation in the basal ganglia and other brain regions.

  6. The diagnosis of Wilson disease is confirmed by decreased serum ceruloplasmin, increased urinary copper, and elevated hepatic copper concentration. A large number of different mutations occur in the Wilson disease gene, but allelic heterogeneity does not account for the marked clinical variability among patients. In specific families, haplotype analysis and examination for common mutations can prove diagnostically useful. Copper chelation with penicillamine is effective in most cases, and trientene and zinc are useful alternatives where toxicity is an issue. Hepatic transplantation ameliorates the disease but is reserved for patients with irreversible liver damage.

  7. In Menkes disease, failure to transport copper to the affected fetus results in copper deficiency in utero, and this is compounded after birth by impairment of copper absorption and ineffective copper transport into the central nervous system. The clinical features of Menkes disease result from the loss of function of specific cuproenzymes. These features include abnormal hair and pigmentation, laxity of the skin, metaphyseal dysplasia, cerebellar degeneration, and failure to thrive. Allelic heterogeneity results in milder forms of the disease, including the occipital horn syndrome in which neurologic symptoms are minimal or absent.

  8. The diagnosis of Menkes disease is confirmed by decreased serum copper and ceruloplasmin, but interpretation of these values is difficult in the first months of life. In such cases, analysis of copper accumulation in the placenta or cultured skin fibroblasts may be helpful in confirming the diagnosis. Most mutations detected in the Menkes disease gene are unique to an affected family, and about 20 percent of these are rearrangements or partial gene deletions that can be identified by Southern blot analysis. Severe Menkes disease is fatal, and no definitive therapeutic options are currently available. Early treatment with copper histidine may be of value in less severe cases where some residual expression of the Menkes gene occurs.

  9. Aceruloplasminemia is an autosomal-recessive disease characterized by absent serum ceruloplasmin and progressive neurodegeneration of the basal ganglia in association with specific inherited mutations in the ceruloplasmin gene. Affected individuals present with insulin-dependent diabetes and neurologic symptoms, including dysarthria, dystonia, and dementia as a direct result of iron accumulation in affected tissues. Although the basal ganglia symptoms and a lack of serum ceruloplasmin may lead to diagnostic confusion with Wilson disease, magnetic resonance imaging reveals the presence of iron in the basal ganglia. Recognition of this disease reveals an essential role for ceruloplasmin in iron homeostasis and neuronal survival in the central nervous system.

Abstract  When I see such things, I'm no longer sure that what's important is more important than what's not.Wisława Szymborska, 1993

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