Logan et al. (1994) reported 2 brothers with complete ceruloplasmin deficiency who presented in their late forties with dementia and diabetes mellitus. The proband had been admitted to hospital at the age of 49 ... - Aceruloplasminemia Logan et al. (1994) reported 2 brothers with complete ceruloplasmin deficiency who presented in their late forties with dementia and diabetes mellitus. The proband had been admitted to hospital at the age of 49 years with a 6-week history of thirst and polyuria and a 2-week history of progressive confusion. Neurologic examination was normal. He was started on a diabetic diet and oral sulfonylurea. At the age of 52, he suddenly left his work one day and was found at home the next day sitting in a chair with the appearance of not having been to bed. When asked why he was not at work he replied, 'What work?' Dementia progressed thereafter, confusion occurring episodically. The younger brother, who worked as a railway laborer, developed diabetes and mental slowing at the age of 47 years. The symptoms seemed to have developed over a period of days and were progressive thereafter. Twelve relatives had partial ceruloplasmin deficiency. Both brothers had low serum iron and increased liver iron, and there was no copper overload. Transmission of the abnormality was autosomal recessive. The abnormal ceruloplasmin in this case was referred to as ceruloplasmin Belfast. Morita et al. (1992) described a 55-year-old patient with complete ceruloplasmin deficiency who presented with dementia, diabetes, torticollis, chorea, and ataxia. A postmortem study of this proband demonstrated excessive iron deposition, mainly in the brain, liver, and pancreas. Morita et al. (1995) reported a clinical pathologic study of the family reported by Morita et al. (1992), which contained 3 affected sibs of consanguineous parents. Clinical symptoms were progressive dementia, extrapyramidal disorders, cerebellar ataxia, and diabetes mellitus, all of which appeared when they were between 30 and 50 years old. All had almost completely absent levels of serum ceruloplasmin and increased serum ferritin (see 134790) concentrations. The dentate nucleus, thalamus, putamen, caudate nucleus, and liver of each patient showed low signal intensities on T1- and T2-weighted MRIs. Autopsy revealed severe destruction of the basal ganglia and dentate nucleus with considerable iron deposition in neuronal and glial cells, whereas the cerebral cortex showed mild iron deposition in glial cells without neuronal involvement. Iron deposition in hepatocytes and in neural and glial cells of the brain was demonstrated by electron microscopy with energy-dispersive x-ray analysis. Harris et al. (1995) reported a 61-year-old Japanese woman who had had retinal degeneration and blepharospasm for the previous 10 years. She had also developed cogwheel rigidity and dysarthria. Her 51-year-old sister, who was asymptomatic at the time of the original presentation despite undetectable CP, had recent onset of retinal degeneration and basal ganglia symptoms. In each case, the absence of serum CP was associated with mild anemia, low serum iron, and elevated serum ferritin. Magnetic resonance imaging studies demonstrated changes in the basal ganglia suggestive of elevated iron content in the brain. The patient's daughter was entirely asymptomatic but had a serum CP concentration that was 50% of normal, consistent with an obligate heterozygote. There was no consanguinity in the family. Liver biopsy confirmed the presence of excess iron. Takahashi et al. (1996) reported a kindred with aceruloplasminemia. Their patient was a 45-year-old woman who came to attention after a several-month history of difficulty in walking and slurring of speech. She had previously been in excellent health with the exception of insulin-dependent diabetes mellitus beginning at age 31 years. Physical examination revealed ataxic gait, scanning speech, and retinal degeneration. MRI of the brain was consistent with increased basal ganglia iron content, and laboratory studies revealed a low serum iron concentration and no detectable serum ceruloplasmin. Okamoto et al. (1996) reviewed the findings in 4 pedigrees with aceruloplasminemia. Clinical manifestations, which occurred after middle age, included extrapyramidal signs, cerebellar ataxia, dementia, and memory loss. Neuroimaging studies revealed iron deposition in the basal ganglia and in the red and dentate nuclei. Diagnostic laboratory findings included deficiency of ceruloplasmin, low serum iron, and high serum ferritin. The hepatic iron content was high, but cirrhosis was not usually present. - Hypoceruloplasminemia Edwards et al. (1979) studied a kindred in which 14 members had low serum ceruloplasmin and low serum copper without the abnormalities of Wilson disease (277900). The phenotype segregated in a pattern suggesting heterozygosity for a mutant gene. One member of the family with low levels had been followed for over 25 years and had remained completely well. Miyajima et al. (1987) described a 52-year-old woman with blepharospasm, retinal degeneration, and high density areas in the basal ganglia and liver by CT scan. Studies showed accumulation of iron, not copper, in liver and brain. Serum ceruloplasmin was less than 0.6 mg/dl (normal, 17-37 mg/dl) and serum apoceruloplasmin was undetectable. A sister and a brother demonstrated retinal degeneration and iron deposition in the basal ganglia and liver, respectively. Serum ceruloplasmin was less than 0.8 mg/dl in both cases.
After the cloning of the Wilson disease gene, Harris et al. (1995) investigated a number of patients referred for molecular diagnosis with neurologic degeneration and low or absent serum ceruloplasmin. In the course of this analysis, they recognized ... After the cloning of the Wilson disease gene, Harris et al. (1995) investigated a number of patients referred for molecular diagnosis with neurologic degeneration and low or absent serum ceruloplasmin. In the course of this analysis, they recognized several patients who did not have Wilson disease. One such patient identified in Japan and reported as a case of familial apoceruloplasmin deficiency (Miyajima et al., 1987) was found to have a mutation in the ceruloplasmin gene (117700.0002). The patient's daughter was heterozygous for the 5-bp insertion. In the Japanese family reported by Morita et al. (1992), Yoshida et al. (1995) demonstrated a homozygous mutation in the ceruloplasmin gene (117700.0001) in 4 sibs with aceruloplasminemia, 3 of whom showed extrapyramidal disorders, cerebellar ataxia, progressive dementia, and diabetes mellitus. Roy and Andrews (2001) reviewed disorders of iron metabolism, with emphasis on aberrations in hemochromatosis (235200), Friedreich ataxia (229300), aceruloplasminemia, and other inherited disorders.
Aceruloplasminemia should be suspected in individuals with characteristic MRI findings and more than one of the following findings: diabetes mellitus (DM), retinal degeneration, anemia, and neurologic disturbance (ataxia, involuntary movement)....
DiagnosisClinical DiagnosisAceruloplasminemia should be suspected in individuals with characteristic MRI findings and more than one of the following findings: diabetes mellitus (DM), retinal degeneration, anemia, and neurologic disturbance (ataxia, involuntary movement).MRI. Abnormal low intensities in the liver as well as the striatum, thalamus, and dentate nucleus of the brain on T1 and T2 weighted images are consistent with iron deposition and support a diagnosis of aceruloplasminemia (see Figure 1).FigureFigure 1. The upper row (A) indicates brain T2-weighted MRI; the bottom row (B) indicates abdominal T2-weighted MRI. Abnormal low intensities in the liver as well as striatum, thalamus, and dentate nucleus are consistent with iron deposition and support (more...)Retinal degeneration. Ninety-three percent of Japanese individuals with aceruloplasminemia demonstrate retinal degeneration [Miyajima et al 2003]. Visual acuity is not disturbed. Several small yellowish opacities are scattered over grayish atrophy of the retinal pigment epithelium. Fluorescein angiography demonstrates window defects corresponding to the yellowish opacities. These findings differ from diabetic retinopathy [Yamaguchi et al 1998].TestingSerum ceruloplasmin is not detectable by Western blot analysis (normal serum concentration: 21-36 mg/dL).Note: Individuals with normal serum ceruloplasmin concentration and all other signs/symptoms of aceruloplasminemia may have a splice variant that results in the glycosylphosphatidylinositol (GPI)-anchored form in the central nervous system.Serum copper concentration is lower than 10 µg/dL (normal range: 70-125 µg/dL).Serum iron concentration is lower than 45 µg/dL (normal range: male 60-180 µg/dL; female 60-140 µg/dL).Serum ferritin concentration is 850-4000 ng/mL (normal range: male 45-200 ng/mL; female 30-100 ng/mL).Plasma ceruloplasmin ferroxidase activity is not detectable using the method described by Erel [1998]. Normal plasma ceruloplasmin ferroxidase activity is 500-680 U/L.Note: Individuals with typical clinical signs/symptoms who are compound heterozygotes for the p.His978Gln mutation showed normal serum ceruloplasmin concentrations but absent ferroxidase activity [Takeuchi et al 2002]. Another individual with retinal degeneration and diabetes mellitus who was homozygous for the p.Gly969Ser mutation showed a decrease in serum ceruloplasmin concentration because of the secretion of only apoceruloplasmin without any ferroxidase activity [Kono et al 2006b]. This is a caveat in making the diagnosis on normal ceruloplasmin concentrations alone. Pathologic diagnosis. Visceral organs, especially the liver, pancreas, and heart, have iron deposition:The liver shows no cirrhotic changes. The iron content in the liver is greater than the iron content in the brain. The hepatic iron concentration (HIC) is determined in µmol/g of dry weight. The hepatic iron index (HII) is then calculated by dividing the hepatic iron concentration by the age (in years) of the individual. Normal individuals have an HII of 1.1 or less; more than 80% of individuals with aceruloplasminemia have an HII greater than 1.3. (HIC [µg/g dry weight] 56 = HIC [µmol/g dry weight], HIC [µmol/g dry weight]/age [years] = HII).Islet beta cells demonstrate iron deposition, which results in diabetes mellitus.The distribution in order of iron level in the brain is globus pallidus > putamen > cerebral cortex > cerebellar cortex. Severe iron overload and extensive neuronal loss are observed in the basal ganglia, while iron deposition and neuronal cell loss are trivial in the frontal cortices. The cerebellar cortex shows marked loss of Purkinje cells. Iron deposition is more prominent in the astrocytes than in the neurons. Astrocytic deformity and globular structures are characteristic features in brains of individuals with aceruloplasminemia. The globular structures in the astrocytes are seen in proportion to the degree of iron deposition [Kaneko et al 2002, Miyajima 2003, Oide et al 2006].Molecular Genetic TestingGene. CP is the only gene in which mutations are known to be associated with aceruloplasminemia.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in AceruloplasminemiaView in own windowGeneTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCPSequence analysisSequence variants 2>92% 3Research only1. The ability of the test method used to detect a mutation that is present in the indicated gene 2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. Individuals of Japanese heritage [Miyajima et al 1999]. Sequence analysis identifies at least one mutation in all individuals with abnormal low-intensity areas in both the basal ganglia and the liver on MRI. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband, the following tests are indicated:Brain and abdomen MRISerum concentration of ceruloplasmin, copper, and ferritinPlasma ceruloplasmin ferroxidase activity (very important in an atypical case)Measurement of visceral iron contentSingle gene testing. Sequence analysis of CP may also be used to confirm a diagnosis in a proband who has clinical features suggestive of aceruloplasminemia. Multi-gene panels. Another strategy for molecular diagnosis of a proband suspected of having aceruloplasminemia is use of a multi-gene panel.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo phenotype other than those discussed in this GeneReview is currently known to be associated with mutations in CP.
Clinical manifestations of aceruloplasminemia are a triad of retinal degeneration, diabetes mellitus (DM), and neurologic signs/symptoms [Miyajima 2003]. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or neurologic signs/symptoms. Phenotypic expression varies even within families....
Natural HistoryClinical manifestations of aceruloplasminemia are a triad of retinal degeneration, diabetes mellitus (DM), and neurologic signs/symptoms [Miyajima 2003]. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or neurologic signs/symptoms. Phenotypic expression varies even within families.A summary of clinical manifestations in 45 Japanese individuals is shown in Table 2 [Miyajima et al 2003]. The manifestations (in order of frequency) are retinal degeneration, diabetes mellitus, anemia, and neurologic signs/symptoms. The neurologic signs/symptoms correspond to regions of brain iron accumulation and include ataxia, involuntary movement, parkinsonism, and cognitive dysfunction. Molecular genetic testing of CP on a research basis allowed for confirmation of the diagnosis in individuals with atypical clinical findings, further expanding the phenotypic spectrum.Table 2. Clinical Manifestations/Age at Onset in 64 Individuals with AceruloplasminemiaView in own windowClinical ManifestationsAge at OnsetAnemia (85%)Diabetes mellitus (81%)20-29 yrs: 20% 30-39 yrs: 40% 40-49 yrs: 30% >50 yrs: 10%Retinal degeneration (77%)Neurologic symptoms (65%)Ataxia (81%) incl dysarthria, gait ataxia, limb ataxia, nystagmus30-39 yrs: 5% 40-49 yrs: 40% 50-59 yrs: 35% >60 yrs: 20%Involuntary movement (60%) incl dystonia (blepharospasm, grimacing, neck dystonia), tremors, chorea Parkinsonism (23%) incl rigidity, akinesiaCognitive dysfunction, dementia (36%)From Kono [2012]Additional findingsLaboratory findingsUndetectable serum ceruloplasmin Elevated serum ferritinDecreased serum iron, iron refractory microcytic anemiaLow serum copper and normal urinary copper levelsMRI (magnetic resonance imaging) findingsLow intensity on both T1- and T2-weighted MRI in the liver and the basal ganglia, including the caudate nucleus, putamen and pallidum, and the thalamusLiver biopsy resultsExcess iron accumulation ( >1200 µg/ gram dry weight) within hepatocytes and reticuloendothelial cellsNormal hepatic architecture and histology without cirrhosis or fibrosisNormal copper accumulationNeuropathology in the brain includes bizarrely formed astrocytes and grumose or foamy spheroid bodies [Kaneko et al 2002, Oide et al 2006].
Neurodegeneration with brain iron accumulation (NBIA) is a group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually the basal ganglia. Later-onset, slowly progressive NBIA includes atypical pantothenate kinase-associated neurodegeneration (PKAN) [Hayflick et al 2003], which results from mutations in PANK2 [Zhou et al 2001]; neuroferritinopathy, a disorder associated with mutations in the gene encoding the ferritin light chain [Curtis et al 2001]; and aceruloplasminemia. ...
Differential DiagnosisNeurodegeneration with brain iron accumulation (NBIA) is a group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually the basal ganglia. Later-onset, slowly progressive NBIA includes atypical pantothenate kinase-associated neurodegeneration (PKAN) [Hayflick et al 2003], which results from mutations in PANK2 [Zhou et al 2001]; neuroferritinopathy, a disorder associated with mutations in the gene encoding the ferritin light chain [Curtis et al 2001]; and aceruloplasminemia. Low serum concentration of ceruloplasmin is not specific for aceruloplasminemia. Ceruloplasmin deficiency is a characteristic feature in copper metabolic disorders, including Wilson disease and Menkes disease:In Wilson disease, an inability to transfer copper into the ceruloplasmin 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 ceruloplasmin 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 (see ATP7A -Related Copper Transport Disorders).Aceruloplasminemia is characterized by marked iron accumulation in the brain as well as in the visceral tissues despite low serum iron concentrations. In these findings, aceruloplasminemia differs significantly from HFE-associated hereditary hemochromatosis, the most common iron metabolic disorder.Because aceruloplasminemia has features of Wilson disease and HFE-associated hereditary hemochromatosis, it could be incorrectly diagnosed as "mild hemochromatosis with hypoceruloplasminemia" or "mild Wilson disease with hemosiderosis."Ceruloplasmin synthesis can be reduced with acute liver failure or decompensated cirrhosis of any etiology. Decreased serum concentrations of ceruloplasmin are observed in protein-losing enteropathy, nephrotic syndrome, and malnutrition.Differential diagnoses for the neurologic manifestations of aceruloplasminemia include Huntington disease, dentatorubral-pallidoluysian atrophy (DRPLA), juvenile Parkinson disease including Parkin type of juvenile parkinsonism (see also Parkinson Disease Overview), dystonia (see Dystonia Overview), drug effects or toxicity, and hereditary spinocerebellar ataxias (see Ataxia Overview).Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with aceruloplasminemia, evaluations for the following are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with aceruloplasminemia, evaluations for the following are recommended:Iron deposition. Serum ferritin concentration, brain and abdomen MRI findings, and hepatic iron and copper content by the liver biopsyNeurologic findings. Brain MRI and protein concentration in CSFDiabetes mellitus. Blood concentrations of insulin and HbA1cRetinal degeneration. Examination of the optic fundi and fluorescein angiographyMedical genetics consultationTreatment of ManifestationsDesferrioxamine. Treatment with iron chelating agents (i.e., desferrioxamine) can be considered for symptomatic individuals whose blood hemoglobin concentration is higher than 9 g/dL. Treatment can decrease serum ferritin concentration as well as brain and liver iron stores, and can prevent progression of the neurologic signs/symptoms [Miyajima et al 1997].Intravenous infusions of 500 mg of desferrioxamine (desferoxamine mesylate) dissolved in 100 mL of isotonic saline solution are given over one hour. Desferrioxamine is infused twice a week for six to ten months.In the Miyajima et al [1997] study, head MRI evaluations were performed before and after treatment to evaluate the effect of treatment on iron storage in the brain. Serum concentrations of iron, ferritin, copper, hemoglobin, and hemoglobin A1c, as well as C-peptide immunoreactivity, were measured before and after treatment. Lipid peroxidation in plasma samples also was measured by the thiobarbituric acid method. T2-weighted MRI showed an increase in the signal intensity of the basal ganglia. Serum ferritin concentration was markedly reduced and hepatic iron concentration was decreased, whereas serum iron concentration was elevated and anemia and DM were ameliorated.In the Mariani et al [2004] report, the brain MRI did not change after more than one year of desferoxamine treatment, whereas excess iron in the liver was removed.Pan et al [2011] reported an affected individual age 52 years who was treated with desferrioxamine (500 mg) by intravenous infusion in a 5% glucose solution once a week for four years. After four years of treatment, brain MRI evaluation demonstrated improvement in low-intensity areas in the basal ganglia, suggesting that iron chelation can reduce abnormal iron deposition in the central nervous system. Deferasirox. Iron chelation therapy with deferasirox, an oral iron chelating agent, led to a mild improvement in clinical symptoms, including cognitive performance, gait and balance, in an individual with aceruloplasminemia who had no response to both deferoxamine and fresh-frozen plasma therapy [Skidmore et al 2008].Fresh-frozen human plasma. After the intravenous administration of fresh-frozen human plasma (FFP) containing ceruloplasmin, serum iron content increases for several hours because of ferroxidase activity of ceruloplasmin. Iron content in the liver decreases more with the combined intravenous administration of FFP and desferrioxamine than with FFP administration alone. Neurologic signs/symptoms can improve following repetitive FFP treatment [Yonekawa et al 1999]. Antioxidants such as vitamin E may be used along with a chelator or oral administration of zinc to prevent tissue damage, particularly to the liver and pancreas [Kuhn et al 2007].SurveillanceMarked accumulation of iron in parenchymal tissues including the liver, pancreas, heart, and thyroid can result in diabetes mellitus, cardiac failure, and hypothyroidism. All affected individuals should have an annual glucose tolerance test starting at age 15 years to evaluate for the onset of diabetes mellitus.ECG evaluation should be performed early in the course of the disease.Agents/Circumstances to AvoidIron supplements. Individuals with aceruloplasminemia erroneously diagnosed as having iron deficiency anemia and treated with iron supplements had accelerated iron accumulation.Evaluation of Relatives at RiskThe proper preventive approach for asymptomatic sibs is unknown:Monitoring of serum concentrations of hemoglobin and hemoglobin A1c is warranted.When hemoglobin A1c is elevated to 7.5% and hemoglobin is higher than 9 g/dL, desferrioxamine treatment may be started. Infusion of 500 mg of desferrioxamine is performed once a week for one to two months.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationOral zinc sulfate (200 mg/day) has been used to treat one affected person with extrapyramidal and cerebellar symptoms [Kuhn et al 2007]. A marked neurologic improvement was found after 15 months of treatment.Oral administration of deferasirox, an iron chelator, may prevent tissue damage, particularly to the liver and pancreas [Finkenstedt et al 2010].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Aceruloplasminemia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCP3q24-q25CeruloplasminCP homepage - Mendelian genesCPData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Aceruloplasminemia (View All in OMIM) View in own window 117700CERULOPLASMIN; CP 604290ACERULOPLASMINEMIAMolecular Genetic PathogenesisAbout 50 aceruloplasminemia-causing mutations have been identified [Kono 2012]. More than half of the mutations in CP 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 presumed to be critical for enzymatic function. Molecular analysis of the missense mutations has shown several different mechanisms by which mutations in the ceruloplasmin gene can result in the lack of enzymatic activity (see Figure 2). Some mutant proteins are retained in the endoplasmic reticulum (ER) caused by defects in protein trafficking. Ceruloplasmin deficiency can arise through other mechanisms, either by indirect dysfunction of a copper-binding site or by other structural abnormalities in the protein that prevent the incorporation of copper into ceruloplasmin [Kono & Miyajima 2006].FigureFigure 2. Ceruloplasmin (Cp) biosynthesis. Several different mechanisms by which CP missense mutations result in the lack of enzymatic activity. As p.Pro177Arg, p.Gly176Arg, and p.Ile9Phe mutant protein is retained in the endoplasmic reticulum (ER), aceruloplasminemia (more...)Normal allelic variants. CP is approximately 4.4 kb in a total of 20 exons; it encodes the ceruloplasmin precursor.Pathologic allelic variants. Fifty-one mutations (15 frameshift, 6 nonsense, 9 splice site, and 21 missense mutations) in CP have been identified in 60 affected families belonging to different racial groups [Yoshida et al 1995, Yazaki et al 1998, Miyajima et al 1999, Daimon et al 2000, Hellman et al 2000, Kohno et al 2000, Bosio et al 2002, Hellman et al 2002, Loreal et al 2002, Hatanaka et al 2003, Mariani et al 2004, Kuhn et al 2005, Perez-Aguilar et al 2005, Kono et al 2006a, Shang et al 2006, Kono 2012]. See Figure 3. No hot spots for mutations in CP have been observed.FigureFigure 3. Genetic mutations characterized in patients with aceruloplasminemia and their family members Note: Mutations and their nomenclature in Figure 3 were provided by the author (H Miyajima) and not reviewed by GeneReviews staff. (more...)Normal gene product. The product of CP, ceruloplasmin, is a blue copper oxidase that carries more than 95% of the plasma copper content in vertebrates.Ceruloplasmin has two forms: (1) a secreted form (1040 amino acids) mainly produced and secreted by hepatocytes; and, (2) a glycosylphosphatidylinositol (GPI)-anchored form (1065 amino acids) mainly expressed in astrocytes as well as visceral organs (see Figure 4) [Patel et al 2000]:FigureFigure 4. The secreted and GPI-anchored forms of ceruloplasmin generated by alternative splicing. Northern blot analyses of two forms of ceruloplasmin in the organs (lane 1: brain; lane 2: lung; lane 3: liver; lane 4: heart; lane 5: kidney; lane 6: pancreas). (more...)The secreted form, alpha2-glycoprotein, is synthesized mainly in the liver; it plays an important role in iron mobilization from the tissues as a ferroxidase.The GPI-anchored form is generated by alternative RNA splicing. The splicing occurs downstream of exon 18 and replaces the five C-terminal amino acids of the secreted form with an alternative 30-amino acid sequence that signals GPI anchor addition. The GPI-anchored form of ceruloplasmin is expressed in astrocytes and plays an important role in iron metabolism in the central nervous system through its ferroxidase activity [Jeong & David 2003].Abnormal gene product. Abnormal gene products are usually degraded immediately after release from the hepatocytes. With some nonsense CP mutations, abnormal ceruloplasmin is retained within the endoplasmic reticulum (early secretory pathway); and, with other mutations, abnormal ceruloplasmin results in decreased copper incorporation into ceruloplasmin in the Golgi apparatus (late secretory pathway) [Hellman et al 2002, Kono & Miyajima 2006, Kono et al 2006a]. In CP-null mice, different mechanisms could underlie the loss of astrocytes and neurons [Jeong & David 2006].