A genetic disorder affecting the biosynthesis of ceruloplasmin leading to an iron storage disorder with diabetes mellitus, hepatic failure, progressive dementia, and retinal degeneration.
A Japanese study reported an estimated prevalence of approximately one per 2,000,000 in non-consanguineous marriages, and subsequent studies have now identified more than 35 affected families worldwide. Consanguinity is a risk factor.
Autosomal recessive. A number of allelic variants exist. The clinical phenotype in most patients is independent of the specific mutation. The responsible gene is located on chromosome 3q24-q25.
The multi-copper oxidase ceruloplasmin (also known as ferroxidase or iron (II):oxygen-oxidoreductase) is a 132-kDa plasma metalloprotein that contains 95% of the plasma copper and plays an essential role in normal iron homeostasis. Only approximately 5% of the normal ceruloplasmin concentration is required to maintain iron homeostasis. Ceruloplasmin is mainly synthesized in hepatocytes (and 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 are 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 oxidation to Fe3+ and release of highly reactive-free radicals. Ceruloplasmin catalyzes the oxidation of Fe2+ to Fe3+ with 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 subsequent antioxidant protection. Only a small amount of total iron originates from absorption by enterocytes, while the major source of the iron stems from heme recycling of aging red blood cell turn over in the reticuloendothelial system. Recycled iron released liver and the spleen binds to plasma transferrin to return to the bone marrow for erythropoiesis. 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 transferring 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 several neurologic abnormalities and diabetes mellitus, emphasizing the importance of ceruloplasmin in the release of cellular iron. ...