Iron is essential for oxidation-reduction catalysis and bioenergetics; however, unless appropriately shielded, this
metal plays a crucial role in the formation of toxic
oxygen radicals that can attack all
biological molecules. Organisms are equipped with specific
proteins designed for
iron acquisition, export and transport, and storage, as well as with sophisticated mechanisms that maintain the intracellular labile
iron pool at an appropriate level. Despite these homeostatic mechanisms, organisms often face the threat of either
iron deficiency or
iron overload. This review describes several hereditary
iron-overloading conditions that are confined to the brain. Recently, a mutation in the L-subunit of
ferritin has been described that causes the formation of aberrant
L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of
L-ferritin have abnormal aggregates of
ferritin and
iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited
late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for
iron regulatory protein 2 (IRP2), a translational repressor of
ferritin, misregulate
iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of
ferritin and
iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a
movement disorder consisting of
ataxia,
bradykinesia, and
tremor. Mutations in the
frataxin gene are responsible for
Friedreich's ataxia, the most common of the inherited
ataxias.
Frataxin appears to regulate mitochondrial
iron-
sulfur cluster formation, and the neurologic and cardiac manifestations of
Friedreich's ataxia are due to
iron-mediated mitochondrial toxicity. Patients with
Hallervorden-Spatz syndrome, an autosomal recessive, progressive
neurodegenerative disorder, have mutations in a novel
pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic
iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of
cysteine, which binds
iron and causes oxidative stress in the
iron-rich globus pallidus. Finally,
aceruloplasminemia is an autosomal recessive disorder of
iron metabolism caused by loss-of-function mutations in
ceruloplasmin gene that leads to misregulation of both systemic and central nervous system
iron trafficking. Affected individuals suffer from extrapyramidal signs,
cerebellar ataxia, progressive neurodegeneration of retina, and
diabetes mellitus. Excessive
iron depositions are found in the brain, liver, pancreas, and other parenchymal cells, but plasma
iron concentrations are decreased. These conditions are not common, but awareness about them is important for differential diagnosis of various
neurodegenerative disorders.