Chapter 49 - Aceruloplasminemia

Abstract

Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis that is classified as an inherited neurodegenerative disorder, known as “neurodegeneration with brain iron accumulation.” This disorder is caused by loss-of-function mutations in the ceruloplasmin gene. The clinical presentation involves hepatic iron overload, microcytic anemia, retinal degeneration, diabetes mellitus, and neurological symptoms, including cerebellar ataxia, involuntary movements, and cognitive dysfunction. The diagnosis of aceruloplasminemia is made based on the complete absence of serum ceruloplasmin, marked elevation of the ferritin concentration, and abnormally low levels of intensity in the liver and brain, including the basal ganglia, thalamus, and dentate nucleus, on both T1- and T2-weighted magnetic resonance imaging. Hypometabolism in the basal ganglia has been revealed by studies using fluorodeoxyglucose-positron emission tomography in patients with aceruloplasminemia. Genetic analyses have identified more than 50 distinct mutations in the ceruloplasmin gene. Most of the mutations are unique to specific families, and there is no genotype–phenotype association. Astrocytes play important roles in the development of the pathological conditions in aceruloplasminemia. Iron-chelating agents reduce the brain and liver iron stores and thereby improve the diabetic mellitus condition and prevent the progression of neurologic symptoms in symptomatic individuals. While the zinc concentrations in these patients were also decreased in the brain and visceral organs, zinc showed different distributions from iron. Because zinc exerts antioxidant activity, treatment with an iron chelator accompanied by zinc may be effective in patients with aceruloplasminemia.