Iron is an essential
element necessary for energy production,
DNA and
neurotransmitter synthesis, myelination and
phospholipid metabolism.
Neurodegeneration with brain iron accumulation (NBIA) involves several
genetic disorders, two of which,
aceruloplasminemia and
neuroferritinopathy, are caused by mutations in genes directly involved in
iron metabolic pathway, and others, such as
pantothenate-kinase 2, phospholipase-A2 and
fatty acid 2-hydroxylase associated neurodegeneration, are caused by mutations in genes coding for
proteins involved in
phospholipid metabolism.
Phospholipids are major constituents of myelin and
iron accumulation has been linked to myelin derangements. Another group of NBIAs is caused by mutations in lysosomal
enzymes or transporters such as ATP13A2, mucolipin-1 and possibly also β-
galactosidase and α-
fucosidase. Increased cellular
iron uptake in these diseases may be caused by impaired recycling of
iron which normally involves lysosomes. Abnormal
iron utilization by mitochondria, as has been proposed in
Friedreich's ataxia, is another possible mechanism of
iron accumulation. Other, more common degenerative
movement disorders, such as
Parkinson's disease,
Huntington's disease,
multiple system atrophy and
progressive supranuclear palsy also exhibit increased brain
iron content. Finally, brain
iron deficiency has been implicated in
restless legs syndrome. This review provides an update on recent findings related to genetics, pathogenic mechanisms, diagnosis, and treatment of
movement disorders associated with dysregulation of brain
iron. We also propose a new classification of NBIAs.