2016 Volume 33 Issue 3 Pages 299-302
Iron is a bioactive metal essential for normal cellular functions. However, excessive iron leads to cell death because iron enhances oxidative stress due to the generation of highly cytotoxic hydroxyl radicals. Therefore, the tissue iron content is critically regulated by several iron metabolic molecules.
Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of inherited neurodegenerative disorders collectively characterized by extrapyramidal movement disorders and abnormal iron accumulation in the deep basal ganglia nuclei of the brain. Ten NBIA genes have been identified to date : eight are autosomal recessive, one is autosomal dominant, and one is X–linked dominant. Mutations in 10 genes have been associated with NBIA that include ceruloplasmin (Cp) and ferritin light chain (FTL), both directly involved in iron homeostasis, as well as pantothenate kinase–associated neurodegeneration (PKAN) [PANK2], phospholipase A2–associated neurodegeneration (PLAN) [PLA2G6], mitochondrial membrane protein–associated neurodegeneration (MPAN) [C19orf12], static encephalopathy of childhood with neurodegeneration in adulthood, beta–propeller protein–associated neurodegeneration (SENDA, BPAN) [WDR45], fatty acid hydroxylase–associated neurodegeneration (FAHN) [FA2H], Coenzyme A synthase protein–associated neurodegeneration (CoPAN) [COASY], Kufor–Rakeb syndrome [ATP13A2], Woodhouse–Sakati syndrome [DCAF17]. These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy.
A greater understanding of the NBIA genes and any shared cellular function will ultimately help to link common clinical presentation. In this review, I will discuss clinical findings for each NBIA–related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis, and speculate the new targets for drug discovery (new iron chelators, zinc treatment, etc).
