Aceruloplasminemia

Clinical 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 30 years to older than 70 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. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition.

Diagnosis/testing.

Aceruloplasminemia, a disorder of iron metabolism caused by the complete absence of ceruloplasmin ferroxidase activity, is associated with very low to absent serum ceruloplasmin and some combination of the following:

• Low serum copper concentration
• Low serum iron concentration
• High serum ferritin concentration
• Increased hepatic iron concentration

The diagnosis of aceruloplasminemia is established in a proband with typical clinical findings and the identification of biallelic pathogenic variants in CP by molecular genetic testing.

Management.

Treatment of manifestations: Iron chelating agents (i.e., desferrioxamine, deferiprone, or deferasirox) 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; ECG evaluation early in the course of the disease; evaluation of thyroid and liver function and complete blood count annually starting at the time of diagnosis.

Agents/circumstances to avoid: Iron supplements.

Evaluation of relatives at risk: If the pathogenic variants in the family are known, molecular genetic testing of asymptomatic sibs of a proband allows for early diagnosis and initiation of surveillance and treatment. If pathogenic variants are unknown, monitoring of serum concentrations of hemoglobin and hemoglobin A1c in asymptomatic sibs is recommended.

Genetic counseling.

Aceruloplasminemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the CP pathogenic variants in the family have been identified.

Suggestive Findings

Aceruloplasminemia should be suspected in individuals with characteristic MRI findings, more than one of the following clinical findings, and typical results on laboratory testing.

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.

CT and T₁- and T₂-weighted MRI of an individual with aceruloplasminemia. CT (A, D), T₂- (B, E), and T₁- (C) weighted axial images of the brain (upper row) and abdomen (bottom row). Brain and abdomen CT show abnormal high-density areas in the basal ganglia (more...)

Clinical findings

• Characteristic retinal degeneration findings (which differ from diabetic retinopathy [Yamaguchi et al 1998]):
  • Evidence of early-onset macular degeneration
  • Undisturbed visual acuity
  • Several small yellowish opacities scattered over grayish atrophy of the retinal pigment epithelium
  • On fluorescein angiography: window defects corresponding to the yellowish opacities
• Diabetes mellitus (DM)
• Anemia
• Neurologic disturbance (ataxia, involuntary movement)

Laboratory test results

• Serum ceruloplasmin <2 mg/dL (normal serum concentration: 21-36 mg/dL)
• Serum copper concentration <20 µg/dL (normal range: 70-125 µg/dL)
• Serum iron concentration <45 µg/dL (normal range: male 60-180 µg/dL; female 60-140 µg/dL)
• Serum ferritin concentration >400 ng/mL (normal range: male 45-200 ng/mL; female 30-100 ng/mL)
• Plasma ceruloplasmin ferroxidase activity that is not detectable using the method described by Erel [1998] (normal activity: 500-680 U/L)

Establishing the Diagnosis

The diagnosis of aceruloplasminemia is established in a proband with typical clinical findings and identification of biallelic pathogenic variants in CP by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of aceruloplasminemia is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical clinical findings or in whom the diagnosis of aceruloplasminemia has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

When the diagnosis of aceruloplasminemia is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Aceruloplasminemia

Clinical Description

The clinical manifestations of aceruloplasminemia are retinal degeneration, diabetes mellitus (DM), and neurologic signs/symptoms [Miyajima 2003]. Individuals with aceruloplasminemia often present with iron-restricted microcytic anemia prior to onset of DM or neurologic signs/symptoms. Phenotypic expression varies even within families.

A summary of clinical manifestations and age of onset in 71 Japanese individuals is shown in Table 2. The manifestations (in order of frequency) are anemia, retinal degeneration, diabetes mellitus, and neurologic signs/symptoms. The neurologic signs/symptoms correspond to regions of brain iron accumulation and include ataxia, involuntary movement, parkinsonism, and cognitive dysfunction [Miyajima et al 2003, Kono 2012, Kono & Miyajima 2015].

Table 2.

Clinical Manifestations / Age at Onset in 71 Individuals with Aceruloplasminemia

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 nonconsanguineous marriages in Japan [Miyajima et al 1999].

There is no data on the prevalence of this disorder outside of Japan are available.

Table 3.

Frequencies of Aceruloplasminemia

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

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with aceruloplasminemia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Iron deposition. Serum ferritin concentration; brain and abdomen MRI findings
• Neurologic findings. Brain MRI
• Diabetes mellitus. Glucose tolerance test; blood concentrations of insulin and HbA1c
• Retinal degeneration. Examination of the optic fundi and fluorescein angiography
• Anemia. Complete blood count
• Other. Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Note: Individual case reports indicate the effectiveness of treatment in individuals with aceruloplasminemia; however, no large series of symptomatic persons treated with iron chelators and zinc is available and there is no universally accepted treatment regimen. A systematic review/analysis of studies designed to evaluate the clinical effectiveness of desferrioxamine, deferiprone, deferasirox, and zinc as monotherapy for the initial treatment of various clinical presentations of aceruloplasminemia is needed.

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 was also 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 deferoxamine or fresh-frozen plasma therapy [Skidmore et al 2008]. Oral administration of deferasirox may prevent tissue damage, particularly to the liver and pancreas [Finkenstedt et al 2010].

Deferiprone has a lower molecular weight and more lipophilic properties. Deferiprone therapy had no beneficial effects in an individual in a previous report [Mariani et al 2004]; however, it has been shown to protect against retinal degeneration and neurodegeneration and to increase the life span if initiated early in mice exhibiting knockout for ceruloplasmin and hephaestin [Hadziahmetovic et al 2011].

Fresh-frozen human plasma (FFP). After the intravenous administration of 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].

Complications of aceruloplasminemia. Diabetes is treated in the standard manner. Transfusion is not needed for anemia, and there is no specific treatment for retinal disease.

Prevention of Primary Manifestations

Zinc concentrations in affected individuals were decreased in the brain and visceral organs, and zinc showed opposing distributions to those for iron. Because zinc has antioxidant activity, treatment with an iron chelator accompanied by zinc may be useful in individuals with aceruloplasminemia to diminish iron accumulation in the brain and body and to prevent or ameliorate systemic and neurologic symptoms [Miyajima 2015].

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.
• Cardiac evaluation should be performed early in the course of the disease and repeated every year.
• Evaluation of thyroid and liver function and complete blood count are indicated annually starting at the time of diagnosis.

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

It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband (starting at age 15 years) in order to identify as early as possible those who would benefit from surveillance and initiation of treatment. However, the proper preventive approach for asymptomatic sibs is unknown. Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Monitoring of serum concentrations of hemoglobin and hemoglobin A1c as anemia and diabetes may precede neurologic symptoms (see also Surveillance).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

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 (i.e., carriers of one CP pathogenic variant).
• Clinical disease is not known to occur in heterozygotes, 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.
• 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. The offspring of an individual with aceruloplasminemia are obligate heterozygotes (carriers) for a pathogenic variant in CP.

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

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the CP pathogenic variants in the family.

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 individuals. Consideration of molecular genetic testing of young, at-risk sibs is appropriate for guiding medical management (see Management, Evaluation of Relatives at Risk). Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members if both CP pathogenic variants have been identified in an affected family member.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the CP pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for aceruloplasminemia are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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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

• 27 September 2018 (ha) Comprehensive update posted live
• 5 November 2015 (me) Comprehensive update posted live
• 18 April 2013 (me) Comprehensive update posted live
• 17 February 2011 (me) Comprehensive update posted live
• 29 April 2008 (me) Comprehensive update posted live
• 15 August 2005 (me) Comprehensive update posted live
• 12 August 2003 (me) Review posted live
• 23 June 2003 (hm) Original submission