Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released Status (Pediatric): Passed (Consensus scoring is Complete) P

Condition: Aceruloplasminemia
Mode(s) of Inheritance: Autosomal Recessive
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
CP0011426 (aceruloplasminemia)
Moderate Actionability
Actionability Rationale
The preliminary assertion based on the rubric was strong. However, due to a lack of large studies to clearly inform effectiveness, the experts changed the assertion to moderate.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: CP 0011426 (OMIM:604290)
Morbidity due to iron accumulation / Iron chelation and avoidance of iron supplementation

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
To date, 56 cases of aceruloplasminemia have been reported and the prevalence has been estimated at about 1/1,000,000-1/1,200,000. In Japan, the prevalence of aceruloplasminemia in non-consanguineous marriages was estimated at 1/2,000,000.
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Clinical Features
(Signs / symptoms)
Aceruloplasminemia is a disorder of iron metabolism caused by the complete absence of ceruloplasmin ferroxidase activity. It is characterized by iron accumulation in the brain and viscera leading to a triad of clinical manifestations: retinal degeneration, diabetes mellitus, and various neurologic symptoms. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, and chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron accumulation in the brain. Affected individuals often present with anemia prior to onset of diabetes mellitus or neurologic symptoms. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition.
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Natural History
(Important subgroups & survival / recovery)
The clinical triad of retinal degeneration, diabetes mellitus and neurologic disease in aceruloplasminemia generally presents in adulthood, from age 25 years to older than 70 years. At least 2 patients diagnosed at age 16 years have been reported, one presenting with refractory anemia and the other with neurologic signs. The prognosis of aceruloplasminemia may include heart failure due to cardiac iron overload. At least five patients are known to have died from heart failure, probably due to cardiac iron overload, in their sixties. In the absence of heart failure and with good treatment of diabetes mellitus, the prognosis is good.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
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
• 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 (Tier 4)
Individual case reports indicate the effectiveness of treatment in patients with aceruloplasminemia; however, no large series of symptomatic patients treated with iron chelators and zinc is available and there is no universally accepted treatment regimen.
Treatment with iron chelating agents 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 symptoms.
• Desferrioxamine: Three case reports indicated improvement following treatment: one patient had increased signal intensity of the basal ganglia on T2-weighted MRI, serum ferritin concentration and hepatic iron concentration was decreased, serum iron concentration was elevated, and anemia and diabetes mellitus were ameliorated; a second patient did not show a change on brain MRI, but excess iron in the liver was removed; and a third patient demonstrated improvement in low-intensity areas in the basal ganglia on brain MRI.
• Deferasirox: Therapy led to 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 (FFP).
• Deferiprone: Therapy had no beneficial effects in a patient in a previous report; 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. (Tier 3)
After the intravenous administration of FFP containing ceruloplasmin in a single case, serum iron content increased for several hours because of ferroxidase activity of ceruloplasmin. Iron content in the liver decreases more with combined intravenous administration of FFP and desferrioxamine than with FFP administration alone. Neurologic signs/symptoms can improve following repetitive FFP treatment. (Tier 3)
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. (Tier 3)
All affected individuals should have an annual glucose tolerance test starting at age 15 years to evaluate for the onset of diabetes mellitus. (Tier 4)
No evidence for the effectiveness of screening for diabetes mellitus in patients with aceruloplasminemia was found. A systematic review of screening for type 2 diabetes mellitus in the general population reported that screening and treatment of asymptomatic diabetes, identified by impaired fasting glucose or impaired glucose tolerance, is associated with delayed progression to diabetes and lifestyle modifications are associated with decreased risk of both outcomes. However, no 10-year mortality benefits were detected for screening vs. no screening. (Tier 1)
Electrocardiography evaluation should be performed early in the course of the disease. (Tier 4)
Evaluation of thyroid, liver function and complete blood count are indicated annually starting at the time of diagnosis. (Tier 4)
Circumstances to Avoid
Iron supplements should be avoided, as individuals with aceruloplasminemia erroneously diagnosed as having iron deficiency anemia and treated with iron supplements had accelerated iron accumulation. (Tier 4)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
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Prevalence of Genetic Variants
A study screened the serum ceruloplasmin concentrations in nearly 5,000 Japanese adults (with subsequent sequence determination in 31 individuals), found an estimated pathogenic variant frequency of 1/14000. The frequency of homozygotes and heterozygotes was estimated as 1/2,000,000 and 1/700, respectively, in non-consanguineous marriages with a higher homozygote frequency estimated in consanguineous marriages (1/300,000). The heterozygote frequency in consanguineous parents was similar to non-consanguineous parents at 1/700 (Tier 3)
(Include any high risk racial or ethnic subgroups)
A summary of clinical manifestations (age of onset) in 71 Japanese individuals with aceruloplasminemia found the following distribution of symptoms:
• Anemia - 80%
• Diabetes mellitus - 70% (<30 yrs: 18%; 30-39 yrs: 35%; 40-49 yrs: 31%; >50 yrs: 16%)
• Retinal degeneration - 76% (At least >20 yrs)
• Neurologic symptoms - 68% (<40 yrs: 7%; 40-49 yrs: 38 %; 50-59 yrs: 42%; >60 yrs: 13%)
• Ataxia - 71%, including: dysarthria, gait ataxia, limb ataxia, nystagmus
• Involuntary movement - 64%, including: dystonia (blepharospasm, grimacing, neck dystonia), tremors, chorea
• Parkinsonism - 20%, including: rigidity, akinesia
• Cognitive dysfunction - 60%, including: apathy, forgetfulness (Tier 3)
Relative Risk
(Include any high risk racial or ethnic subgroups)
No information on relative risk was identified.
Phenotypic expression varies even within families. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
The interventions identified in the report include treatment with intravenous iron chelating agents and FFP, oral iron chelating agents and oral antioxidants. The intravenous iron chelator desferrioxamine is infused during one hour sessions twice a week for six to ten months. Deferasirox is administered orally and daily. Some case reports have shown that high doses of iron chelators can cause severe side effects, particularly aggravated anemia, that may lead to discontinuation of therapy. One report of three patients treated with oral deferasirox indicated that all three discontinued therapy within five months due to side effects, including diarrhea, anemia, and skin rash. Additional case reports have proposed a combination of iron chelating agents along with oral zinc as an antioxidant, as zinc therapy has been shown to ameliorate neurological symptoms with minimal side effects. Additional interventions include surveillance for diabetes mellitus and organ damage due to iron deposition as well as the avoidance of iron supplementation which may accelerate iron accumulation.
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Individuals affected with aceruloplasminemia often present with anemia prior to onset of other symptoms, and there is evidence that patients erroneously diagnosed as having iron deficiency anemia and treated with iron supplements had accelerated iron accumulation. (Tier 4)
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Disease Associations
Disease Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. H Miyajima, Y Hosoi. Aceruloplasminemia. 2003 Aug 12 [Updated 2018 Sep 27]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from:
2. Aceruloplasminemia. Orphanet encyclopedia,
3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ACERULOPLASMINEMIA. MIM: 604290: 2004 Dec 06. World Wide Web URL:
4. McNeill A, Pandolfo M, Kuhn J, Shang H, Miyajima H. The neurological presentation of ceruloplasmin gene mutations. Eur Neurol. (2008) 60(4):200-5.
5. Meral Gunes A, Sezgin Evim M, Baytan B, Iwata A, Hida A, Avci R. Aceruloplasminemia in a Turkish adolescent with a novel mutation of ceruloplasmin gene: the first diagnosed case from Turkey. J Pediatr Hematol Oncol. (2014) 36(7):e423-5.
6. Selph S, Dana T, Blazina I, Bougatsos C, Patel H, Chou R. Screening for type 2 diabetes mellitus: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. (2015) 162(11):765-76.
7. Finkenstedt A, Wolf E, Hofner E, Gasser BI, Bosch S, Bakry R, Creus M, Kremser C, Schocke M, Theurl M, Moser P, Schranz M, Bonn G, Poewe W, Vogel W, Janecke AR, Zoller H. Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation. J Hepatol. (2010) 53(6):1101-7.
8. Mariani R, Arosio C, Pelucchi S, Grisoli M, Piga A, Trombini P, Piperno A. Iron chelation therapy in aceruloplasminaemia: study of a patient with a novel missense mutation. Gut. (2004) 53(5):756-8.
9. Kuhn J, Bewermeyer H, Miyajima H, Takahashi Y, Kuhn KF, Hoogenraad TU. Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate. Brain Dev. (2007) 29(7):450-3.
10. Hiroaki Miyajima. Investigated and available therapeutic options for treating aceruloplasminemia. Expert Opinion on Orphan Drugs. Publisher: Taylor & Francis. (2015) Accessed: 2019-02-13. Website:
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