Pediatric Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening Permalink P Current Version Rule-Out Dashboard Release History Status (Pediatric): Incomplete (Consensus scoring is Incomplete) Curation Status (Pediatric): Entered 0.0.0 Status (Adult): Passed (Consensus scoring is Complete) A
GENE/GENE PANEL:
CP
Condition:
Aceruloplasminemia
Mode(s) of Inheritance:
Autosomal Recessive
Actionability Assertion
Gene Condition Pairs(s)
Final Assertion
CP⇔604290
Assertion Pending
Actionability Rationale
This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Condition
Clinical Features
(Signs / symptoms)
(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.
Natural History
(Important subgroups & survival / recovery)
(Important subgroups & survival / recovery)
Aceruloplasminemia presents in adulthood, from age 25 years to older than 70 years. The prognosis 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.
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
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.
Surveillance
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)
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?
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)
Penetrance
(Include any high risk racial or ethnic subgroups)
(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)
(Include any high risk racial or ethnic subgroups)
No information on relative risk was identified.
Expressivity
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.
5. Would the underlying risk or condition escape detection prior to harm in the setting 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.
Reference List
1.
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; 1993-2025.
Available from: http://www.ncbi.nlm.nih.gov/books/NBK1493
2.
Aceruloplasminemia.
Orphanet encyclopedia,
http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=48818
3.
Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD.
ACERULOPLASMINEMIA.
MIM: 604290:
2004 Dec 06.
World Wide Web URL: http://omim.org.
4.
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.
.
5.
Iron chelation therapy in aceruloplasminaemia: study of a patient with a novel missense mutation.
Gut.
(2004)
53(5):756-8.
.
6.
Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate.
Brain Dev.
(2007)
29(7):450-3.
.
7.
Investigated and available therapeutic options for treating aceruloplasminemia.
Expert Opinion on Orphan Drugs.
Publisher: Taylor & Francis.
(2015)
Accessed: 2019-02-13.
Website: https://www.tandfonline.com/doi/full/10.1517/21678707.2015.1067137
.