Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Department of Physiology and Medicine, McGill University, Montreal, Quebec, Canada
Address for correspondence: Dr. Prem Ponka, Lady Davis Institute for Medical Research, LDI, Room 202, 3755 Cote St. Catherine Road, Montreal, Quebec H3T 1E2, Canada. Voice: 514-340-8260; fax: 514-340-7502. prem.ponka{at}mcgill.ca
Ann. N.Y. Acad. Sci. 1012: 267-281 (2004).
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.
