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Aceruloplasminemia

, MD
First Department of Medicine
Hamamatsu University School of Medicine
Hamamatsu, Japan

Initial Posting: ; Last Update: April 18, 2013.

Summary

Disease characteristics. Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus (DM), and neurologic disease is seen in individuals ranging from age 25 years to older than 60 years. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron deposition in the brain. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or obvious neurologic problems. Psychiatric disturbance includes depression and cognitive dysfunction in individuals older than age 50 years.

Diagnosis/testing. Aceruloplasminemia, a disorder of iron metabolism caused by the complete absence of ceruloplasmin ferroxidase activity, is caused by mutations in CP, which encodes ceruloplasmin. The diagnosis of aceruloplasminemia in a symptomatic individual relies on demonstration of the absence of serum ceruloplasmin and some combination of the following: low serum copper concentration, low serum iron concentration, high serum ferritin concentration, and increased hepatic iron concentration. The diagnosis is strongly supported by characteristic MRI findings of abnormal low intensities reflecting iron accumulation in the brain (striatum, thalamus, dentate nucleus) and liver on both T1- and T2-weighted images.

Management. Treatment of manifestations: Iron chelating agents (i.e., desferrioxamine or deferasiox) to decrease serum ferritin concentration, decrease brain and liver iron stores, and prevent progression of neurologic signs/symptoms in symptomatic individuals with blood hemoglobin concentration higher than 9 g/dL; combined IV desferrioxamine and fresh-frozen human plasma (FFP) is effective in decreasing iron content in the liver; repetitive FFP treatment can improve neurologic signs/symptoms; 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.

Surveillance: Annual glucose tolerance test starting at age 15 years to evaluate for the onset of diabetes mellitus; ECC evaluation should be performed early in the course of the disease.

Agents/circumstances to avoid: Iron supplements.

Evaluation of relatives at risk: Monitoring of serum concentrations of hemoglobin and hemoglobin A1c in asymptomatic sibs.

Genetic counseling. Aceruloplasminemia is inherited in an autosomal recessive manner. Each sib of an affected individual is at a 25% risk for aceruloplasminemia. Offspring of an affected individual are obligate carriers. If the disease-causing mutations have been identified in a family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Diagnosis

Clinical Diagnosis

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).

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).

Figure 1

Figure

Figure 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].

Testing

Serum 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 Testing

Gene. CP is the only gene in which mutations are known to cause aceruloplasminemia.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Aceruloplasminemia

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
CPSequence analysisSequence variants 4>92% 5

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

1. 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. For issues to consider in interpretation of sequence analysis results, click here.

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.

Testing Strategy

To confirm/establish the diagnosis in a proband, the following tests are indicated:

  • Brain and abdomen MRI
  • Serum concentration of ceruloplasmin, copper, and ferritin
  • Plasma ceruloplasmin ferroxidase activity (very important in an atypical case)
  • Measurement of visceral iron content

Single 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.

Clinical Description

Natural History

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.

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 Aceruloplasminemia

Clinical ManifestationsAge at Onset of
Manifestation
Anemia (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, akinesia
Cognitive dysfunction, dementia (36%)

Additional findings

Laboratory findings

  • Undetectable serum ceruloplasmin
  • Elevated serum ferritin
  • Decreased serum iron, iron refractory microcytic anemia
  • Low serum copper and normal urinary copper levels

MRI (magnetic resonance imaging) findings

  • Low intensity on both T1- and T2-weighted MRI in the liver and the basal ganglia, including the caudate nucleus, putamen and pallidum, and the thalamus

Liver biopsy results

  • Excess iron accumulation ( >1200 µg/gram dry weight) within hepatocytes and reticuloendothelial cells
  • Normal hepatic architecture and histology without cirrhosis or fibrosis
  • Normal copper accumulation

Neuropathology in the brain includes bizarrely formed astrocytes and grumose or foamy spheroid bodies [Kaneko et al 2002, Oide et al 2006].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlation exists for aceruloplasminemia.

Nomenclature

Aceruloplasminemia was originally called familial apoceruloplasmin deficiency [Miyajima et al 1987].

Prevalence

The serum ceruloplasmin concentrations of about 5,000 adults undergoing medical examination were screened (Table 3). The prevalence of aceruloplasminemia was estimated at one in 2,000,000 in non-consanguineous marriages in Japan [Miyajima et al 1999].

Table 3. Frequencies of Aceruloplasminemia

Parental RelatednessHomozygotesHeterozygotes
Non-consanguineous4.90 x 10-71.40 x 10-3
Consanguineous3.29 x 10-61.39 x 10-3

Heterozygotes for the ceruloplasmin gene were estimated to account for 0.1% of individuals with diabetes in Japan [Daimon et al 1997].

Differential Diagnosis

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.

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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 biopsy
  • Neurologic findings. Brain MRI and protein concentration in CSF
  • Diabetes mellitus. Blood concentrations of insulin and HbA1c
  • Retinal degeneration. Examination of the optic fundi and fluorescein angiography
  • Medical genetics consultation

Treatment of Manifestations

Desferrioxamine. 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].

Surveillance

Marked 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 Avoid

Iron supplements. Individuals with aceruloplasminemia erroneously diagnosed as having iron deficiency anemia and treated with iron supplements had accelerated iron accumulation.

Evaluation of Relatives at Risk

The 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 Investigation

Oral 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Aceruloplasminemia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an individual with aceruloplasminemia are obligate heterozygotes; therefore, each carries one mutant allele.
  • Clinical disease is not known to occur in carriers, although data are not adequate to exclude the possibility in older individuals.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) with clinical signs/symptoms have not been reported, although data are not adequate to exclude the possibility in older individuals.

Offspring of a proband. Offspring of an affected individual are obligate carriers.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

If the disease-causing mutations have been identified in the family, carrier testing for at-risk family members is possible through laboratories offering either testing for the gene of interest or custom testing.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic adults. Neurologic evaluation (including MRI) and molecular genetic testing may be considered for the seemingly healthy sibs of probands, especially when they are younger than the proband. Molecular genetic testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for aceruloplasminemia, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in a family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Requests for prenatal testing for typically adult-onset conditions such as aceruloplasminemia are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • NBIA Disorders Association
    2082 Monaco Court
    El Cajon CA 92019-4235
    Phone: 619-588-2315
    Fax: 619-588-4093
    Email: info@NBIAdisorders.org
  • Association for Neuro-Metabolic Disorders (ANMD)
    5223 Brookfield Lane
    Sylvania OH 43560-1809
    Phone: 419-885-1809; 419-885-1497
    Email: volk4olks@aol.com
  • NBIA Disorders Association Research Registry and Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) Registry
    CA 92019-4235
    Phone: 619-588-2315
    Fax: 619-588-4093
    Email: pwood@nbiadisorders.org
  • Registry for NBIA and Related Disorders
    Oregon Health & Science University
    Phone: 503-494-4344
    Fax: 503-494-6886
    Email: gregorya@ohsu.edu

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
CP3q24-q25CeruloplasminCP databaseCP

Data 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)

117700CERULOPLASMIN; CP
604290ACERULOPLASMINEMIA

Molecular Genetic Pathogenesis

About 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].

Figure 2

Figure

Figure 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.

Pathogenic 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.

Figure 3

Figure

Figure 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]:

Figure 4

Figure

Figure 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].

References

Literature Cited

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Suggested Reading

  1. McNeill A, Pandolfo M, Kuhn J, Shang H, Miyajima H. The neurological presentation of ceruloplasmin gene mutations. Eur Neurol. 2008;60:200–5. [PubMed: 18667828]

Chapter Notes

Acknowledgments

Aceruloplasminemia research is funded in part by a Grant-in-Aid of Science from the Ministry of Education, Science, Culture, Sports, and Technology, Japan.

Revision History

  • 18 April 2013 (me) Comprehensive update posted live
  • 17 February 2011 (me) Comprehensive update posted live
  • 29 April 2008 (me) Comprehensive update posted to live Web site
  • 15 August 2005 (me) Comprehensive update posted to live Web site
  • 12 August 2003 (me) Review posted to live Web site
  • 23 June 2003 (hm) Original submission
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