Aceruloplasminemia: a case report

Hereditary aceruloplasminemia is a rare autosomal recessive disease, firstly identified by Miyajima et al. in Japan in 1987 [1]. The disease is caused by the absence of an a2glycoprotein, the ceruloplasmin (Cp), a copper-containing ferroxidase, mainly synthesized in hepatocytes and widely expressed, including the central nervous system, which catalyses the oxidation of ferrous to ferric iron, a change required for release of iron to plasma transferrin [2]. It is hypothesized that in reticuloendothelial (RE) cells and hepatocytes Cp cooperates to export iron with the iron exporter protein ferroportin 1 (FPN1) [3]. As a consequence, Cp deficiency results in iron deposition in the liver, pancreas, basal ganglia, and other organs [2]. The Cp gene maps to chromosome 3q21–24 [4], consists of 19 exons [5] and encodes a protein of 1,046 amino acids [6]. Recently 20th exon has been recognized as the result of a brain-specific alternative splicing. This adds to the protein an aminoacid sequence that makes Cp a glycosylphosphatidylinositol (GPI)-anchored protein in the brain [7]. Under normal circumstances, infact, circulating Cp does not cross the blood–brain barrier. Through the oxidation mediated by GPI-linked Cp expressed in the astrocytes, iron could be taken from the circulation, incorporated into transferring derived from oligodendrocytes and then transferred to the neuronal cells [2]. Ceruloplasmin deficiency is a characteristic feature in copper metabolic disorders, including Wilson’s disease and Menkes’ disease. In Wilson’s disease, an inability to transfer copper into the Cp precursor protein, apoceruloplasmin, and a decrease in biliary copper excretion results in serum ceruloplasmin deficiency and excess copper accumulation. In Menkes’ disease, copper absorption from the intestine is decreased, leading to copper and Cp deficiencies in the body. In contrast, aceruloplasminemia, is an iron metabolic disorder in which ceruloplasmin deficiency is caused by a lack of apoceruloplasmin biosynthesis and copper metabolism is not disturbed. In Wilson’s disease and Menkes’ disease, several gene mutations in the coppertransporting ATPases (ATP-7B and ATP-7A) have been found within the last 10 years. Aceruloplasminemia is characterized by mutations in the ceruloplasmin gene itself [8]. Aceruloplasminemia, after the first description, has been reported mainly in Japanese patients [1, 2, 9–18] and rarely in whites [10, 19]. More than 30 aceruloplasminemiacausing mutations have been identified. Some of the mutations have been found in several families throughout the world, while other have been detected in a single patient. The majority of mutations in the CP gene are the truncated mutations leading to the formation of a premature stop codon. These mutations would be predicted to result in formation of a protein lacking the copper-binding sites resumed to be critical for enzymatic function. First clinical manifestation is usually diabetes mellitus secondary to pancreatic involvement [2]. A progressive neurological disease begins a few years later, typically with focal dystonia, followed by dysarthria, extrapyramidal D. Di Raimondo A. Pinto A. Tuttolomondo P. Fernandez G. Licata Dipartimento Biomedico di Medicina Interna e Specialistica, AOU Policlinico ‘‘P. Giaccone’’, Universita degli Studi di Palermo, Palermo, Italy