脑组织铁沉积性神经变性疾病的临床与基因学特点

脑组织铁沉积性神经变性（NBIA）疾病是一组以铁离子聚集于脑组织为特点的进行性锥体外系疾病,虽然其发病率尚无确切的统计学资料,但已知发病在种族人群、年龄、性别方面并无明显差异。     

脑组织铁沉积性神经变性疾病的临床与基因学特点

脑组织铁沉积性神经变性(NBIA)疾病是一组以铁离子聚集于脑组织为特点的进行性锥体外系疾病,虽然其发病率尚无确切的统计学资料,但已知发病在种族人群、年龄、性别方面并无明显差异。1922年,Hallervorden和Spatz首先详细描述该病并为其命名,目前认为Hallervorden-Spatz综合征(HSS)是NBIA最为常见的疾病类型之一。NBIA这一称谓已被广泛应用,不仅涵盖了之前被称之为HallervordenSpatz综合征的疾病,也包括由于脑组织内铁离子沉积引起     

朊蛋白与神经变性病传播

<正>近年来,朊蛋白(PrP)与神经变性病传播是此类疾病发病机制研究的一个关注点。目前认为,神经变性病是由于多种蛋白质构象改变所致,而特定的空间构象是蛋白质发挥其生物学功能的结构基础,对朊蛋白病(PrD)的研究业已发现,蛋白质的氨基酸序列虽未改变,但其空间结构或构象改变也能诱     

朊蛋白与神经变性病传播

近年来,朊蛋白（PrP）与神经变性病传播是此类疾病发病机制研究的一个关注点.目前认为,神经变性病是由于多种蛋白质构象改变所致,而特定的空间构象是蛋白质发挥其生物学功能的结构基础,对朊蛋白病（PrD）的研究业已发现,蛋白质的氨基酸序列虽未改变,但其空间结构或构象改变也能诱发疾病. 神经变性病如阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）和朊蛋白病有许多关键的相似点,尤其是特异性蛋白在脑组织聚集和神经元缺失.有关此类疾病的研究焦点已发展为研究由单个蛋白质构象异常所导致的特定疾病.     

快速眼动睡眠期行为障碍与神经变性病发病机制研究进展

快速眼动睡眠期行为障碍系指快速眼动睡眠期肌肉失弛缓,并出现梦境(通常是暴力梦境)相关肢体运动(梦境演绎行为)。其人群发病率为0.38%~2.01%,在神经变性病尤其是α-突触核蛋白病患者中的发病率明显增加。快速眼动睡眠期行为障碍可早于α-突触核蛋白病数十年出现,因此可以作为预测神经变性病的早期标记。本文拟就近年来关于快速眼动睡眠期行为障碍发病机制及其与神经变性病之间的关系进行简要综述。     

微循环与神经变性病

神经变性病是神经系统的退行性疾病,病因不明,病程持续进展,且无特效的药物治疗。因此对其病因和机制的研究业已成为国际神经科学领域的研究热点。现有研究认为,缺血缺氧、炎性反应、免疫、血管病理等多种因素可引起微循环障碍,而微循环障碍参与神经元变性过程,甚至先于神经元的变性发生,本文就微循环障碍与神经变性病,特别是阿尔茨海默病和肌萎缩侧索硬化的相关机制进行综述,以期为治疗性研究提供线索。     

脑内铁沉积神经变性病临床特点及PLA2G6基因突变研究

目的探讨中国脑内铁沉积神经变性病(neurodegeneration with brain iron accumulation,NBIA)患者的临床特点及PLA2G6基因的突变特点。方法对3个NBIA家系、6个散发性NBIA患者的临床特点进行回顾性分析,应用聚合酶链反应(PCR)结合DNA直接序列分析方法,对NBIA患者进行PLA2G6基因突变研究。结果所有患者主要表现为锥体外系症状;头部MRI T2加权像表现双侧苍白球、黑质等部位对称性低信号,其中1家系在苍白球低信号区的前内侧出现高信号,即"虎眼征";本组NBIA患者未发现PLA2G6基因的致病突变,共发现7个多态,分别为c.C511T、c.G87A、IVS2+16C→T、IVS4+71A→G、IVS5+43C→T、IVS6+19G→A、和IVS15+55G→A,其中2个(c.C511T、IVS6+19G→A)为新发现的多态。结论根据临床和头部MRI特征可临床诊断NBIA,中国人NBIA患者PLA2G6基因突变可能罕见。     

Hallervorden-Spatz综合征的临床与遗传学研究进展

HallervordenSpatz综合征(HSS)又称苍白球黑质红核色素变性,于1922年由Hallervorden和Spatz首先报道,故得此名。由于Hallervorden和Spatz在第二次世界大战中曾帮助纳粹从事非人道的研究,因此有些学者建议把HSS改称为脑内铁沉积性神经变性病(NBIA)[1～3]。HSS是因铁代谢障碍所引     

Klotho基因在神经变性病中的研究进展

Klotho(Kl)是一种衰老抑制基因,其对CNS有保护作用,与神经变性疾病如Alzheimer's病、帕金森病等具有明显的相关性.在Alzheimer's病中,Kl对抗β淀粉样物质对海马神经元造成的损害,细胞层面上能显著改善长时程记忆基础中的N-甲基-D-天冬氨酸受体结构功能和网络反应敏感性,分子层面上能调节硫氧还蛋...     

家族性肌萎缩性侧索硬化的分子遗传学研究

肌萎缩性侧索硬化(amyotrophic lateral sclerosis，AIS)是一种选择性侵犯大脑皮质、脑干、脊髓运动神经元及锥体束的神经变性疾病，是运动神经元病的典型代表；多于40～50岁起病，临床主要表现为肌尤力、肌萎缩、肌束颤动和锥体束征等，一般于发病后3～5年因呼吸肌受累而死亡。国外统计的ALS患病率为3／10万～5／10万，一般为散发性，约     

Rethinking the role of ceruloplasmin in brain iron metabolism

For more than three decades, it has been widely accepted that ceruloplasmin plays an important role in iron efflux from mammalian cells, including brain cells, via the activity of ferroxidase. However, in light of recent findings, this view might not be completely accurate and the role of ceruloplasmin in brain iron metabolism may need to be re-evaluated. Based on recent studies, we propose in this article that the role of ceruloplasmin in iron uptake by brain neuronal cells might be more important than its role in iron release from the cells. A possible explanation of why the absence of ceruloplasmin induces excessive iron accumulation in neurons in aceruloplasminemia (ceruloplasmin gene mutations) was also discussed.     

Update on neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) defines a heterogeneous group of progressive neurodegenerative disorders characterized by excessive iron accumulation in the brain, particularly affecting the basal ganglia. In the recent years considerable development in the field of neurodegenerative disorders has been observed. Novel genetic methods such as autozygosity mapping have recently identified several genetic causes of NBIA. Our knowledge about clinical spectrum has broadened and we are now more aware of an overlap between the different NBIA disorders as well as with other diseases. Neuropathologic point of view has also been changed. It has been postulated that pantothenate kinase-associated neurodegeneration (PKAN) is not synucleinopathy. However, exact pathologic mechanism of NBIA remains unknown. The situation implicates a development of new therapies, which still are symptomatic and often unsatisfactory. In the present review, some of the main clinical presentations, investigational findings and therapeutic results of the different NBIA disorders will be presented.     

Syndromes of neurodegeneration with brain iron accumulation

In parallel to recent developments of genetic techniques, understanding of the syndromes of neurodegeneration with brain iron accumulation has grown considerably. The acknowledged clinical spectrum continues to broaden, with age-dependent presentations being recognized. Postmortem brain examination of genetically confirmed cases has demonstrated Lewy bodies and/or tangles in some forms, bridging the gap to more common neurodegenerative disorders, including Parkinson disease. In this review, the major forms of neurodegeneration with brain iron accumulation (NBIA) are summarized, concentrating on clinical findings and molecular insights. In addition to pantothenate kinase-associated neurodegeneration (PKAN) and phospholipase A2-associated neurodegeneration (PLAN), fatty acid hydroxylase-associated neurodegeneration (FAHN) NBIA, mitochondrial protein-associated neurodegeneration, Kufor-Rakeb disease, aceruloplasminemia, neuroferritinopathy, and SENDA syndrome (static encephalopathy of childhood with neurodegeneration in adulthood) are discussed.     

Therapeutic advances in neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) includes a heterogeneous group of genetically defined disorders characterized by progressive extrapyramidal deterioration and iron accumulation in the basal ganglia. Current medical options for these disorders remain largely unsatisfactory and do not prevent the disease from progressing to a severe and disabling state. In select cases, surgical techniques, such as deep brain stimulation, may be effective in ameliorating some of the symptoms of the disease. The availability of chelating agents with specific properties that have been demonstrated to be effective in other disorders with regional iron accumulation as well as magnetic resonance imaging techniques that allow for quantitative assessment of iron have stimulated interest in the use of chelating agents in NBIA. This review aims to describe the role of surgical therapies in NBIA, discuss the use of chelating agents in NBIA, and presents new therapeutic approaches under consideration.     

泛酸激酶相关性神经变性疾病遗传学与临床研究进展

泛酸激酶相关性神经变性疾病是脑组织铁沉积性神经变性(NBIA,曾称为Hallervorden-Spatz综合征)疾病的主要发病类型之一,系由泛酸激酶2(PANK2)基因突变所导致的常染色体隐性遗传性疾病。PANK2基因突变可干扰PANK2蛋白表达水平和催化活性,以及线粒体靶蛋白的成熟与稳定性,引起神经元线粒体脂类代谢异常改变,导致脑组织铁沉积性神经变性疾病。本文对该病分子遗传学机制及其与临床表型和影像学特征相关的研究成果和进展进行概述。     

Current concepts and controversies in neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) encompasses at least 7 genetically distinct disorders, and additional causative genes likely await identification. Recent advances have included the characterization of new genes associated with new subtypes of NBIA and also highlighted the phenotypic heterogeneity of this class of disorders. Herein, we summarize current concepts of NBIA pathogenesis and discuss important gaps in current knowledge, outlining key questions in the field.     

Excessive iron accumulation in the brain: A possible potential risk of neurodegeneration in Parkinson's disease

Summary In this study a chronic cerebral iron-loaded model was established by feeding mice with high iron diet. Data indicated that brain iron concentrations were significantly increased in iron-fed mice compared with those of controls. A significant increase in oxidized glutathione (GSSG), decrease in total glutathione (oxidized and reduced glutathione, GSSG + GSH), and therefore increase in the GSSG/(GSSG + GSH) ratios were observed in iron-loaded mice. Hydroxyl radical (^.OH) levels in striatum and brainstem were also significantly increased. Excessive iron alone did not change either dopamine (DA) or lipid peroxidation (LPO) concentrations in striatum. However, a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30mg/kg, i.p.) into the iron-loaded mice caused a great enhancement in all these biochemical abnormalities. These findings suggest that iron does induce oxidative stress, but not severely injury neurons per se. Excessive iron accumulation in the brain, however, is a potential risk for neuronal damage, which may promote by triggering factor(s). This supports the hypothesis that excessive cerebral iron may contribute to the aetiology of Parkinson's disease (PD).     

Early-onset neurodegeneration with brain iron accumulation due to PANK2 mutation

Background: Pantothenate kinase-associated neurodegeneration (PKAN) is a neurodegenerative disorder caused by pantothenate kinase (PANK2) gene mutations. Brain magnetic resonance imaging (MRI) typically shows the “eye-of-the-tiger” sign, i.e. bilateral pallidal T2 hypointensity with a small central region of T2-hyperintensity. Aims: To describe clinical and MRI findings of a boy with early-onset neurodegeneration with brain iron accumulation due to PANK2 mutation. Methods: Clinical, neuroradiological and molecular investigations have been performed. Results: At first observation (2 years and 10 months) the boy presented only with developmental delay and toe-walking and isolated T2 hyperintensity within globi pallidi on brain MRI. One year later, small rounded areas of markedly low signal within the globi pallidi on T2∗- weighted images appeared in association with mild dystonia. PANK2 gene homozygous mutation confirmed the diagnosis of PKAN. Conclusions: In young children, PKAN should be suspected also before clinical and neuroradiological picture is fully indicative, to avoid delayed diagnosis of a genetic disease for which therapeutical options could be potentially useful if administered in paucisymptomatic subjects.     

Childhood disorders of neurodegeneration with brain iron accumulation (NBIA)

Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of progressive complex motor disorders characterized by the presence of high brain iron, particularly within the basal ganglia. A number of autosomal recessive NBIA syndromes can present in childhood, most commonly pantothenate kinase-associated neurodegeneration (PKAN; due to mutations in the PANK2 gene) and phospholipase A2 group 6-associated neurodegeneration (PLAN; associated with genetic defects in PLA2G6). Mutations in the genes that cause these two neuroaxonal dystrophies are thought to disrupt the normal cellular functions of phospholipid remodelling and fatty acid metabolism. A significant proportion of children with an NBIA phenotype have no genetic diagnosis and there are, no doubt, additional as yet undiscovered genes that account for a number of these cases. NBIA disorders can be diagnostically challenging as there is often phenotypic overlap between the different disease entities. This review aims to define the clinical, radiological, and genetic features of such disorders, providing the clinician with a stepwise approach to appropriate neurological and genetic investigation, as well as a clinical management strategy for these neurodegenerative syndromes.     

Excess iron harms the brain: the syndromes of neurodegeneration with brain iron accumulation (NBIA)

Regulation of iron metabolism is crucial: both iron deficiency and iron overload can cause disease. In recent years, our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. These are characterized by excessive iron deposition in the brain, mainly the basal ganglia. Pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2) are the core syndromes, but several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). These conditions show a wide clinical and pathological spectrum, with clinical overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies, and neuronal ceroid lipofuscinosis. Lewy body pathology was confirmed in some clinical subtypes (C19orf12-associated neurodegeneration and PLAN). Research aims at disentangling the various NBIA genes and their related pathways to move towards pathogenesis-targeted therapies. Until then treatment remains symptomatic. Here we will introduce the group of NBIA syndromes and review the main clinical features and investigational findings.