GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. Aceruloplasminemia, a disorder of iron metabolism caused by the complete absence of ceruloplasmin ferroxidase activity, is caused by mutations in the CP gene, 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) to decrease serum ferritin concentration, decrease brain and liver iron stores, and prevent progression of neurologic 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 symptoms; antioxidants such as vitamin E may help prevent tissue damage to the liver and pancreas; oral administration of zinc may 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. Agents/circumstances to avoid: iron supplements. Testing 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. Prenatal testing for pregnancies at increased risk may be available through laboratories offering custom prenatal testing if the disease-causing mutations have been identified in an affected family member.
Aceruloplasminemia should be suspected in individuals with characteristic MRI findings and diabetes mellitus (DM), retinal degeneration, anemia, and neurologic disturbance.
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 a diagnosis of aceruloplasminemia.
).
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].
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 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 less than 10 µg/dL (normal range: 70-125 µg/dL).
Serum iron concentration is less than 45 µg/dL (normal range: male 60-180 µg/dL; female 10-140 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 by the method of Erel [Erel 1998]. Normal plasma ceruloplasmin ferroxidase activity is 500-680 U/L.
Note: Individuals with typical clinical symptoms who are compound heterozygotes for the 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 Gly969Ser mutation showed a decrease in serum ceruloplasmin concentration because of the secretion of only apoceruloplasmin without any ferroxidase activity [Kono et al 2006a]. 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].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. CP is the only gene known to be associated with aceruloplasminemia.
Research testing
Sequence analysis. More than 92% of individuals of Japanese heritage with clinical evidence of aceruloplasminemia have mutations in the CP gene detected by sequence analysis of the coding region and splice sites [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. The large size of the coding region (approximately 3.2 kb in a total of 20 exons) is a deterrent to clinical use of sequencing.
| Test Method | MutationsDetected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|
| Sequence analysis | CP sequence variants | >92% 1 | Research only 2 |
1. Individuals of Japanese heritage
2. No laboratories offering clinical molecular genetic testing for this disease are listed in the GeneTests Laboratory Directory. However, clinical confirmation of mutations identified in research laboratories may be available for families in which a disease-causing mutation(s) has been identified. For laboratories offering such testing, see
.
To confirm the diagnosis in a proband, the following tests are indicated:
MRI
Serum concentration of ceruloplasmin, copper, and ferritin
Plasma ceruloplasmin ferroxidase activity (very important in an atypical case)
Measurement of visceral iron content
Clinical manifestations of aceruloplasminemia are a triad of retinal degeneration, diabetes mellitus (DM), and neurologic symptoms [Miyajima 2003]. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or neurologic symptoms. Phenotypic expression varies even within families.
| Clinical Manifestation | Age of Onset |
|---|---|
| Retinal degeneration (93%) | Unknown because there are no subjective symptoms |
| Diabetes mellitus (89%) | 15-20 years: 28% 1 30-39 years: 38% 40-49 years: 22% 40-49 years: 22% >50 years: 12% |
| Anemia (80%) | <19 years: 41% 20-29 years: 38% 30-39 years: 18% >40 years: 5% |
Neurologic symptoms (73%)
| 30-39 years: 2% 40-49 years: 71% 50-59 years: 23% >60 years: 4% |
From Miyajima et al 2003
1. Two individuals had onset at age 17 and 18 years.
Neuropathology in the brain includes bizarrely formed astrocytes and grumose or foamy spheroid bodies [Kaneko et al 2002, Oide et al 2006].
No clear genotype-phenotype correlation exists for aceruloplasminemia.
Aceruloplasminemia was originally called familial apoceruloplasmin deficiency [Miyajima et al 1987].
| Parental Relatedness | Homozygotes | Heterozygotes |
|---|---|---|
| Non-consanguineous | 4.90 x 10-7 | 1.40 x 10-3 |
| Consanguineous | 3.29 x 10-6 | 1.39 x 10-3 |
From Miyajima et al 1999
Heterozygotes for the ceruloplasmin gene were estimated to be approximately 0.1% of individuals with diabetes in Japan [Daimon et al 1997].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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 the PANK2 gene [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 Parkinson Disease), dystonia (see Dystonia Overview), drug effects or toxicity, and hereditary spinocerebellar ataxias (see Ataxia Overview).
To establish the extent of disease 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
Desferrioxamine. Treatment with iron chelating agents (i.e., desferrioxamine) can be considered for symptomatic individuals whose blood hemoglobin concentration is greater 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 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, MRI studies 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.
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 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].
All affected individuals should have an annual glucose tolerance test starting at age 15 years to evaluate for the onset of diabetes mellitus.
Iron supplements. Individuals with aceruloplasminemia erroneously diagnosed as having iron deficiency anemia and treated with iron supplements had accelerated iron accumulation.
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.
Oral zinc sulfate has been used to treat one person [Kuhn et al 2007].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Aceruloplasminemia is inherited in an autosomal recessive manner.
This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis.—ED.
Parents of a proband
The parents of an individual with aceruloplasminemia are obligate heterozygotes and therefore each carry 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 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 testing of at-risk relatives may be available on a clinical basis from laboratories offering clinical confirmation of mutations identified in research labs if the mutations have been identified in the family. See
.
Family planning. The optimal time for determination of genetic risk 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 or at risk of being carriers.
DNA banking. 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. DNA banking is particularly relevant when molecular genetic testing is available on a research basis only. See
for a list of laboratories offering DNA banking.
No laboratories offering molecular genetic testing for prenatal diagnosis of aceruloplasminemia are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified. For laboratories offering custom prenatal testing, see
.
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). PGD may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | HGMD |
|---|---|---|---|
| CP | 3q23-q24 | Ceruloplasmin | CP |
Figure 2. Ceruloplasmin (Cp) biosynthesis. Several different mechanisms by which CP missense mutations result in the lack of enzymatic activity. As P177R, G176R, and I9F mutant protein is retained in the endoplasmic reticulum, aceruloplasminemia is one of diseases caused by defects in protein trafficking. Mutations G631R, A331D, and M966V cause CP deficiency through other mechanisms: indirect dysfunction of a copper-binding site or other structural abnormalities in the protein that prevent the incorporation of copper (Cu) into CP. H978Q mutant protein has no ferroxidase activity. Q146E and G876A mutant protein degrades rapidly when holoceruloplasmin is secreted into the extra-cellular space.
). Some mutant proteins are retained in the endoplasmic reticulum 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].
Normal allelic variants: The CP gene is approximately 4.4 kb in a total of 20 exons; it encodes the ceruloplasmin precursor.
Pathologic allelic variants: Thirty-seven mutations (4 frameshift, 4 nonsense, 7 splice site, and 18 missense mutations) in the CP gene have been identified in 45 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, Shang et al 2006, Kono et al 2006b]. No hot spots for mutations in the CP gene have been observed.
Normal gene product: The product of the CP gene, ceruloplasmin, is a blue copper oxidase that carries more than 95% of the plasma copper content in vertebrates.
Figure 3. 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).
) [Patel et al 2000]:
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 2006b]. In CP-null mice, different mechanisms could underlie the loss of astrocytes and neurons [Jeong & David 2006].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Research of aceruloplasminemia is funded in part by a Grant-in-Aid of Science from the Ministry of Education, Science, Culture, Sports and Technology, Japan.
15 May 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
