Abstract
Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. 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 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C 19orf12, WDR 45 and DCAF 17 (C 2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA‐related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis, and speculate the potential overlap between NBIA subtypes.
Highlights
Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative diseases characterized by iron accumulation in the basal ganglia
Other NBIA genes seem more obscure with regard to iron homeostasis, but similar neuropathology and gross clinical symptoms could argue that mechanisms are conserved between all NBIA subtypes
FAH2 is involved in ceramide production, and both Pantothenate Kinase 2 (PANK2) and Coenzyme A synthase (COASY) are required for sphingomyelin production, demonstrated as PANK2 mutation carriers have decreased sphingosine and cholesterol [50], two critical components of myelin
Summary
Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative diseases characterized by iron accumulation in the basal ganglia. Genetic screening over the last decade has identified 10 disease-associated genes which lead to NBIA; around 20% of NBIA cases remain genetically undefined [8]. A greater understanding of the NBIA genes and any shared cellular function will help to link common clinical presentation, MRI findings and disease processes. Mutations in the Pantothenate Kinase 2 gene (PANK2) lead to Pantothenate Kinase-associated neurodegeneration (PKAN, NBIA type 1). A prominent hypothesis for neurodegeneration caused by PANK2 deficiency is that the lack of active enzyme leads to build-up of substrates in the CoA biosynthetic pathway. This leads to an accumulation of N-pantothenyl cysteine and free cysteine.
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