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A group of genetic disorders affecting the expression of the ceruloplasmin gene leading to an iron storage disorder with hepatic failure and progressive dementia.

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Hypoceruloplasminemia; Aceruloplasminemia.

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Unknown, but extremely rare.

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Autosomal recessive. A number of allelic variants exist. The responsible gene is located on chromosome 3q23-q24.

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The multicopper oxidase ceruloplasmin plays an essential role in the normal iron homeostasis. Ceruloplasmin is mainly synthesized in hepatocytes (to a lesser degree also in astrocytes, Sertoli cells, and macrophages) and after incorporation of six copper atoms (holoceruloplasmin) secreted into the plasma. Ceruloplasmin is also an acute phase protein. The rate of ceruloplasmin synthesis or its secretion is not affected by copper, however, its lack results in an unstable, rapidly degraded apoprotein without oxidase activity. The critical physiologic defect in this disorder is the absence of enzymatically active holoceruloplasmin. Within cells, iron is stored as the ferric form Fe3+, but is released as the ferrous form Fe2+, which can react spontaneously with oxygen-containing compounds, resulting in oxidization to Fe3+ and release of highly reactive free radicals. Ceruloplasmin, a copper-containing, 132-kDa plasma metalloprotein, is also known as ferroxidase, which catalyzes the oxidation of Fe2+ to Fe3+ with the complete reduction of oxygen to water without releasing free radicals. Fe3+ is strongly bound to transferrin, which is basically the only way iron is transported through the body, and the combination of Fe2+-oxidizing ceruloplasmin and Fe3+-binding transferrin guards against the presence of free Fe2+ in the circulation, with consequent antioxidant protection. The normal oxidation rate of Fe2+ may be too slow to support a regular supply of Fe3+, thus, ceruloplasmin may maintain a sufficient flow rate from storage Fe2+ to transferrin-Fe3+ by its ferroxidase action. Individuals with ceruloplasmin deficiency have hemosiderosis, shown by low serum iron, high serum ferritin (reflecting the degree of tissue iron overload), and iron accumulation in many tissues leading to neurologic abnormalities and diabetes, supporting ceruloplasmin's important role in the release of cellular iron. Although serum copper is low, urinary copper excretion is normal, and there is no abnormal accumulation of copper in hepatic or other tissues.

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The serum levels of ceruloplasmin, copper, and iron are decreased, whereas the serum level of ferritin is increased. Liver biopsy shows iron accumulation in hepatocytes and Kupffer cells. Computed tomography scanning and/or magnetic resonance imaging demonstrate the iron accumulation in the basal ganglia. Autopsy may confirm significant accumulation of iron and destruction in the basal ganglia, substantia nigra, and dentate nucleus. In addition, iron deposits can be found in neuronal and glial cells, whereas the cerebral cortex usually is not or only mildly affected.

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The clinical presentation is variable. Symptoms usually start between the fourth and sixth decade of life. Diabetes mellitus is a result of pancreatic fibrosis and often the first sign of the disorder, ...

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