Anemia and iron overload due to compound heterozygosity for novel ceruloplasmin mutations

Abstract

Aceruloplasminemia is a recessive disorder characterized by anemia, iron overload, and neurodegeneration, caused by the absence of ceruloplasmin (Cp), a multicopper oxidase important for iron export. Few patients homozygous for loss of function mutations of the Cp gene have been reported. We describe a 62-year-old white woman with heavy liver iron overload, diabetes, anemia, and neurologic symptoms. She was compound heterozygote for 2 novel mutations that result in the absence of hepatocyte Cp: an adenine insertion at nucleotide 2917 causing a truncated protein and a C-G transversion causing a glutamine3glutamic acid substitution at position 146. Although rare in whites, aceruloplasminemia should be considered in the differential diagnosis of unexplained anemia associated with iron overload, because these features anticipate progressive neurologic symptoms. We propose that anemia, secondary to the impaired macrophage iron release, plays a major role in hepatic iron overload through increased absorption mediated by the erythroid regulator. IntroductionHereditary aceruloplasminemia is a rare autosomal recessive disease characterized by iron overload and progressive neurodegeneration. The disease is caused by the absence of ceruloplasmin (Cp), a copper-containing ferroxidase, which catalyses the oxidation of ferrous to ferric iron, a change required for release of iron to plasma transferrin. 1 It is hypothesized that in reticuloendothelial (RE) cells and hepatocytes Cp cooperates with the iron export protein ferroportin 1 (FPN1). 2 Cp deficiency results in iron deposition in the liver, pancreas, basal ganglia, and other organs. Patients develop diabetes mellitus, retinal degeneration, ataxia, and dementia late in life. 3,4 A mild-to-moderate degree of anemia with low serum iron and elevated serum ferritin is a constant feature. [3][4][5][6] The Cp gene maps to chromosome 3q21-24. 7 It consists of 19 exons 8 and encodes a protein of 1046 amino acids. 9 Aceruloplasminemia has been described mainly in Japanese patients 3-6,10-17 and rarely in whites. 5,18 We report data on a 62-year-old Italian woman, compound heterozygote for 2 novel mutations that hamper Cp expression in hepatocytes. Our findings suggest that the disorder should be considered in the differential diagnosis of anemia associated with unexplained iron overload. Based on the severity of liver iron loading, the mechanisms leading to iron overload in aceruloplasminemia are revisited. Study design Case reportThe proband is a 62-year-old Italian woman. No family history of diabetes, iron overload, anemia, or neurologic disorders was recorded. At age 38 years the patient developed insulin-dependent diabetes mellitus. A mild degree of anemia (hemoglobin 9.1 g/L) with normal mean corpuscular volume (MCV; 86 fL) and low-normal values of mean corpuscular hemoglobin (MCH; 27.2 pg) and mean corpuscular hemoglobin concentration (MCHC; 31.7 g/dL) was documented at age 51 years. Serum iron concentration was 33 g/dL, transferrin saturation 12%, and serum ferritin 819 ...

Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis

“…A mild normocytic to microcytic anemia with low serum iron and elevated serum ferritin is a constant feature in ACP. 43 However, anemia was not the presenting symptom in any of the described patients. Disease onset typically occurs in the fourth to fifth decade of life with neurodegenerative symptoms.…”

Dominant Mutants of Ceruloplasmin Impair the Copper Loading Machinery in Aceruloplasminemia

“…It is worth noting that aceruloplasminemia is a late onset pathology, and these mutations were identified in heterozygous patients with mild neurologic symptoms (I9F and G876A) or also suffering from a multiple system atrophy (G606E) (33)(34)(35). Q146E is found in compound heterozygosity with a Cp truncated at residue 983 (36), and W264S is homozygous (37), with both patients exhibiting neurologic symptoms. The position of these mutations in the structure of Cp suggests that the protein can retain ferroxidase activity.…”

Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation

“…21 Hereditary aceruloplasminemia in humans as well as targeted deletion of the ceruloplasmin gene (Cp) in mice results in iron metabolism disorders characterized by anemia, hepatic iron overload, and neurodegeneration, demonstrating a tight connection between copper and iron metabolism. [22][23][24][25][26] Iron deficiency has been known for more than a decade to induce erythropoietin gene expression and HIF-1␣ protein stabilization. 27 Nowadays, these results are most likely explained by inactivation of the iron-dependent protein hydroxylases PHD1 to 3 and FIH.…”