Aceruloplasminemia is an ultra-rare hereditary disorder caused by defective production of
ceruloplasmin. Its phenotype is characterized by
iron-restricted erythropoiesis and tissue
iron overload, diabetes, and progressive
retinal and neurological degeneration.
Ceruloplasmin is a
ferroxidase that plays a critical role in
iron homeostasis through the oxidation and mobilization of
iron from stores and subsequent incorporation of ferric
iron into
transferrin (Tf), which becomes available for cellular uptake via the Tf receptor. In addition,
ceruloplasmin has
antioxidant properties preventing the production of deleterious
reactive oxygen species via the Fenton reaction. Some recent findings suggest that
aceruloplasminemia phenotypes can be more heterogeneous than previously believed, varying within a wide range. Within this large heterogeneity, microcytosis with or without
anemia, low serum
iron and high serum
ferritin, and diabetes are the early hallmarks of the disease, while
neurological manifestations appear 10-20 years later. The usual therapeutic approach is based on
iron chelators that are efficacious in reducing systemic
iron overload. However, they have demonstrated poor efficacy in counteracting the progression of
neurologic manifestations, and also often aggravate
anemia, thereby requiring
drug discontinuation. Open questions remain regarding the mechanisms leading to
neurological manifestation and development of diabetes, and
iron chelation therapy (ICT) efficacy. Recent studies in animal models of
aceruloplasminemia support the possibility of new therapeutic approaches by parenteral
ceruloplasmin administration. In this review we describe the state of the art of
aceruloplasminemia with particular attention on the pathogenic mechanisms of the disease and therapeutic approaches, both current and perspective.