Aceruloplasminemia
Synonyms
5
Overview
Aceruloplasminemia is an autosomal recessive disorder characterized by progressive neurodegeneration of the retina and basal ganglia and diabetes mellitus. Iron accumulates in the pancreas, liver and brain. Iron accumulation in the brain results in neurological problems that generally appear in adulthood and worsen over time. Accumulation in the eye may lead to retinal degeneration. Signs and symptoms begin in adulthood. People with this disorder tend to develop anemia and diabetes in their 20's. As the condition progresses, movement problems are common, such as tremors, chorea, ataxia, eyelid twitching, and grimacing. Some experience psychiatric problems and dementia in their 40's and 50's. Eye examination may reveal changes in the retina, but these changes typically do not affect vision.
Symptoms
- Dementia
- Diabetes mellitus
- Excessive thirst
- Increased urination
- Confusion
- Torticollis
- Chorea
- Ataxia
- Abnormal iron deposits in organs
- Extrapyramidal disorders
- Abnormal iron deposits in the brain, pancreas and liver
- Increased serum ferritin
- Retinal degeneration
- Slurred speech
- Low serum iron level
- Memory impairment
- Blepharospasm
- Grimacing
- Facial dystonia
- Neck dystonia
- Tremors
- Dysarthria
- Depression
- Cognitive dysfunction
- Psychiatric disturbances
- Low serum copper concentration
- Increased liver iron concentration
- Abnormal renal physiology
- Abnormality of iron homeostasis
- Anemia
- Diabetes mellitus
- Retinopathy
Causes
The disease is caused by mutations in the ceruloplasmin gene. Aceruloplasminemia belongs to the group of genetic disorders called neurodegeneration with brain iron accumulation (NBIA). It is caused by mutations in the gene (CP gene) encoding ceruloplasmin on chromosome 3q. The gene is located in bands 3q23-q25 and are inherited in an autosomal recessive fashion.
Prevention
Children of affected individuals are obligate carriers for aceruloplasminemia. If the CP mutations has been identified in a related individual, prenatal testing is recommended. Siblings of those affected by the disease are at a 25% of aceruloplasminemia. In asymptomatic siblings, serum concentrations of hemoglobin and hemoglobin A1c should be monitored.
To prevent the progression of symptoms of the disease, annual glucose tolerance tests beginning in early teen years to evaluate the onset of diabetes mellitus. Those at risk should avoid taking iron supplements.
Diagnosis
When a person has more than one of the following symptoms, aceruloplasminemia should be suspected:
- Diabetes mellitus
- Retinal degeneration
- Anemia
- Movement disorder
Also, 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
- increased hepatic iron concentration
- absent serum ceruloplasmin concentration
Patients also tend to demonstrate altered serum ceruloplasmin ferroxidase activity. Genetic testing is available on a research basis. 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.
Treatment
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 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 help prevent tissue damage to the liver and pancreas; oral administration of zinc and deferasirox (iron chelator) 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.
Evaluation of relatives at risk: Monitoring of serum concentrations of hemoglobin and hemoglobin A1c in asymptomatic sibs.
Resources
- NIH
- Genetics home reference