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:

1. Low serum copper concentration

2. Low serum iron concentration

3. High serum ferritin concentration

4. 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.