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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, ...