Arber C E, Li A, Houlden H, Wray S
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
Reta Lila Weston Institute, Institute of Neurology, University College London, London, UK.
Neuropathol Appl Neurobiol. 2016 Apr;42(3):220-41. doi: 10.1111/nan.12242. Epub 2015 Jun 2.
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), C19orf12, WDR45 and DCAF17 (C2orf37). 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.
脑铁沉积神经退行性疾病（NBIA）是一组以肌张力障碍、帕金森综合征和痉挛为特征的疾病。铁在基底神经节中蓄积，根据NBIA亚型的不同，可能伴有路易小体、轴突肿胀和tau蛋白过度磷酸化。已有10个基因的突变与NBIA相关，包括铜蓝蛋白（Cp）和铁蛋白轻链（FTL），二者均直接参与铁稳态，还有泛酸激酶2（PANK2）、磷脂酶A2第6组（PLA2G6）、脂肪酸羟化酶2（FA2H）、辅酶A合酶（COASY）、C19orf12、WDR45和DCAF17（C2orf37）。这些基因参与了看似不相关的细胞途径，如脂质代谢、辅酶A合成和自噬。需要更深入地了解连接这些基因的细胞途径以及导致铁稳态失调的疾病机制。此外，NBIA与更常见的神经退行性疾病之间的主要重叠可能凸显了保守的疾病过程。在这篇综述中，我们将讨论每个与NBIA相关基因的临床和病理发现，讨论提出的疾病机制，如线粒体健康、氧化损伤、自噬/线粒体自噬和铁稳态，并推测NBIA亚型之间的潜在重叠。
