脑组织铁沉积性神经变性病遗传学研究进展

黄啸君 曹立

脑组织铁沉积性神经变性病遗传学研究进展

黄啸君 曹立

脑组织铁沉积性神经变性病是以脑组织铁代谢异常、中枢神经系统过量铁沉积为特征的神经变性病.常见临床症状为不同类型运动障碍,同时合并不同程度锥体束、小脑、周围神经系统、自主神经系统、精神认知和视觉障碍,具有高度临床异质性.目前共明确10种亚型的10种致病基因,分别为PANK2、COASY、PLA2G6、C19orf12、FA2H、WDR45、ATP13A2、FTL、CP、DCAF17.发病机制涉及线粒体功能障碍、氧化应激损伤、脂质代谢障碍、铁沉积和自噬障碍等.脑组织铁沉积性神经变性病可能与多种神经变性病如帕金森病、额颞叶痴呆、肌萎缩侧索硬化症等存在共同的发病机制.

神经变性疾病; 铁代谢障碍; 遗传学; 综述

脑组织铁沉积性神经变性病(NBIA)是一组以脑组织铁代谢异常和过量铁沉积为特征的神经变性病,过量铁沉积于苍白球、黑质及其相邻部位而致病[1].临床表现具有高度异质性,最常见症状为不同类型运动障碍,包括进行性加重的运动减退和(或)运动过度,亦可合并不同程度锥体束、小脑、周围神经系统、自主神经系统、精神认知、视觉功能障碍.脑组织铁沉积性神经变性病系神经系统遗传性疾病,随着分子遗传学技术的发展,迄今已明确10种亚型的致病基因,致病机制涉及线粒体代谢、脂质代谢和细胞自噬等;仍有约20%患者未明确致病基因.本文拟就目前已明确的脑组织铁沉积性神经变性病各亚型遗传学特点(表1)及相关研究进展进行阐述.

表1 脑组织铁沉积性神经变性病各亚型遗传学和临床特点Table 1. Genetic and clinical features of NBIA

一、泛酸激酶相关性神经变性病

PANK2基因突变导致的泛酸激酶相关性神经变性病[PKAN,在线人类孟德尔遗传数据库(OMIM)编号:234200]是最常见亚型,占所有脑组织铁沉积性神经变性病的35%～50%[2].PANK2基因定位于20p13,包含7个外显子,相对分子质量1.85X103,编码PANK2蛋白.泛酸激酶的主要作用是催化ATP依赖的泛酸磷酸化,维生素B5在其作用下磷酸化为4⁃磷酸泛酰胺,这一过程是辅酶A(CoA)生物合成的第一步,辅酶A在体内脂肪酸、糖和氨基酸代谢中发挥关键作用.PANK2基因突变可以导致泛酸激酶活性缺失,使辅酶A生物合成受阻以及合成底物N⁃泛酰半胱氨酸和游离半胱氨酸蓄积,半胱氨酸可以螯合铁离子,故可以造成异常铁沉积.此外,游离半胱氨酸在铁离子存在的情况下可以发生氧化反应并产生活性氧(ROS),并通过脂质过氧化导致广泛性氧化损伤和细胞死亡[2].PANK2基因参与辅酶A的生物合成,其与辅酶A和酰基辅酶A(acyl⁃CoA)之间存在负性调控,PANK2基因还可以感受辅酶A表达变化,进而调节线粒体和胞质代谢[3],由此可以解释部分基因突变虽未直接引起酶活性改变却同样导致临床表型出现.此外,研究显示,PANK2蛋白存在于线粒体[4].动物实验显示,PANK2基因突变的纤维母细胞[4]以及PANK2基因敲除小鼠和果蝇模型存在线粒体功能缺陷,包括线粒体膜电位降低、线粒体肿胀和线粒体嵴改变等[5],其中,线粒体膜电位降低可以影响线粒体运动速度、融合和运输.PANK2基因突变还可以引起线粒体特异性脂肪酸合成途径破坏,此合成途径对线粒体膜的组装和功能维持至关重要[6].研究显示,PANK2基因突变可以使脂质代谢失调[6].PANK2基因突变除可以引起泛酸激酶相关性神经变性病外,还可以导致低β脂蛋白血症⁃棘红细胞增多症⁃视网膜色素变性⁃苍白球变性综合征(HARP),二者在临床表型上存在一定重叠,提示PANK2基因突变与脂肪合成缺陷相关[6].

泛酸激酶相关性神经变性病是常染色体隐性遗传性疾病,错义突变为最主要突变类型,常见点突变有c.1231G>A和c.1253C>T,此外还包括碱基缺失、重复突变、插入、剪切位点突变等[7].某些突变引起的临床表型轻微[8⁃9].泛酸激酶相关性神经变性病的临床表型包括典型和非典型,其中,典型也称早发型,多于6岁前发病[8,10],表现为锥体束征和锥体外系症状,如步态异常、肌张力障碍、帕金森样症状、共济失调等,同时合并精神异常[8,11⁃12]和视觉障碍等,病情进展迅速,通常于发病15年内丧失行走能力,20岁前生活不能自理;而非典型发病年龄较晚,病情进展缓慢,运动功能受累相对较轻[13],认知功能障碍和精神异常是常见症状,表现为抑郁、情绪不稳、冲动性提高等.研究显示,部分非典型泛酸激酶相关性神经变性病患者表现出年龄依赖性,青少年或成年早期发病的患者多有肌张力障碍表现,帕金森样症状通常出现于发病年龄较晚的患者[14].

二、辅酶A合成酶相关性神经变性病

COASY基因突变导致的辅酶A合成酶相关性神经变性病(CoPAN,OMIM编号:609855)是继泛酸激酶相关性神经变性病之后的第2个影响辅酶A的脑组织铁沉积性神经变性病亚型,呈常染色体隐性遗传[15].COASY基因位于与PANK2基因相同的代谢途径中,是催化辅酶A合成的最后2个步骤的双功能酶[16⁃17].COASY蛋白包含2个催化激酶结构域,均具有线粒体定位信号、调节区和结构域.COASY蛋白定位于线粒体基质[15⁃16],包括2种异构体,较长的β⁃异构体具有脑组织特异性,且具有额外富含脯氨酸的蛋白质相互作用结构域,但在酶活性上与替他组织普遍存在的α⁃异构体无明显差异[18].

突变的COASY蛋白在体外无活性,而在辅酶A合成酶相关性神经变性病患者和正常对照纤维母细胞中辅酶A水平正常[15],表明残留的COASY蛋白在体内仍具有维持辅酶A水平的功能,或可能存在其他未知途径替代辅酶A合成.

COASY基因和PANK2基因在相同代谢途径中发挥作用表明,泛酸激酶相关性神经变性病和辅酶A合成酶相关性神经变性病可能具有共同发病机制,如酰基辅酶A和脂质合成减少导致线粒体功能障碍等.

临床表现方面,辅酶A合成酶相关性神经变性病与典型泛酸激酶相关性神经变性病存在相似之处[15]:患者多于儿童早期出现步态异常和认知功能障碍,此后逐渐进展为痉挛性肌无力、口下颌肌张力障碍、帕金森样肌强直、精神症状和轴索性周围神经病;二者不同之处是,辅酶A合成酶相关性神经变性病患者眼底镜和视觉诱发电位(VEP)检查正常,且无视网膜病变.

三、磷脂酶A2相关性神经变性病

PLA2G6基因突变致磷脂酶A2相关性神经变性病(PLAN,OMIM编号:256600/610217)是第2位临床常见亚型[19⁃20],约占所有脑组织铁沉积性神经变性病的20%,呈常染色体隐性遗传[20⁃21].该基因编码钙非依赖型磷脂酶A2⁃β蛋白,包含806个氨基酸,相对分子质量88X103.PLA2G6基因突变可以导致3种临床表型,即典型婴儿神经轴索营养不良(INAD)、非典型婴儿神经轴索营养不良和PLA2G6相关性肌张力障碍⁃帕金森综合征(PLAN⁃DP),其中,典型婴儿神经轴索营养不良是最常见类型,通常于婴儿期和儿童早期发病,表现为进展迅速的精神运动发育迟滞或倒退,继而出现肌无力,严重躯干肌张力降低,小脑共济失调,腱反射减弱或消失,视神经萎缩致视力障碍、斜视、眼震[21];非典型婴儿神经轴索营养不良通常于儿童期发病,发病年龄1.50～6.50岁,临床表现较典型婴儿神经轴索营养不良多样、进展相对缓慢,首发症状和主要表现为小脑共济失调致步态异常,伴视神经萎缩、斜视、眼震、癫发作、构音障碍、神经精神症状(如情绪不稳、多动、注意力下降、冲动等)、痉挛性截瘫,部分患者以肌张力障碍为主要表现;PLA2G6相关性肌张力障碍⁃帕金森综合征通常于青少年期或成年早期发病,主要表现为帕金森样症状、肌张力障碍、认知功能障碍和精神行为异常,部分患者伴锥体束征、眼球活动障碍、自主神经功能障碍、肌阵挛、癫发作等.

磷脂酶A2(PLA2)家族包括20余种蛋白质,分为4种类型,即分泌型磷脂酶A2(sPLA2)、钙依赖型磷脂酶A2、血小板活化因子乙酰水解酶和钙非依赖型磷脂酶A2[22].脑组织中约70%活性磷脂酶A2由PLA2G6基因编码[23].尽管PLA2G6基因突变致病主要累及中枢神经系统,但钙非依赖型磷脂酶A2在全身各组织中均有表达[24].PLA2G6基因主要表达于线粒体[25],对维持线粒体功能具有一定作用[26],亦表达于细胞核核膜和灵长类动物脑组织轴突末端[27].PLA2G6蛋白可以水解甘油磷脂以产生溶血磷脂和游离脂肪酸,其中,游离脂肪酸(如白三烯和前列腺素等)下游代谢产物具有特定的细胞功能并参与多种信号转导,包括细胞膜重塑、脂肪酸氧化、细胞生长和凋亡[22];溶血磷脂也在信号转导中起一定作用,如参与血小板活化因子生成.细胞膜完整性依靠磷脂再循环和内环境稳态,故磷脂酶活性对保持细胞膜完整性至关重要,而PLA2G6蛋白介导的神经退行性变系细胞膜重塑、脂肪酸氧化障碍和磷脂结构破坏所致.线粒体多不饱和脂肪酸如心磷脂对活性氧极为敏感.PLA2G6蛋白在过氧化氢处理的细胞中对细胞膜亲和力增加,导致其自身活性增加和游离脂肪酸释放增加[28].细胞异常产生的活性氧可以螯合PLA2G6基因至线粒体,是阻止细胞凋亡的机制之一[26],但超微结构已出现线粒体功能缺陷.线粒体呼吸链和相关去极化解耦联作用可以导致线粒体内PLA2G6蛋白活化,使游离脂肪酸蓄积[29],继而通过细胞色素C释放而引起细胞凋亡[30];而PLA2G6蛋白活性降低可以使此过程失调,导致功能异常的线粒体清除障碍.此外,PLA2G6蛋白在维持细胞膜稳态中发挥重要作用.PLA2G6蛋白功能缺陷可以导致线粒体内膜和轴突末端退行性变[31].轴索和(或)细胞器包膜完整性破坏可以导致轴突传导障碍和细胞成分在轴突远端蓄积,从而发生弥漫性轴索阻滞和变性[32].

迄今发现的PLA2G6基因突变分布于基因全长,无突变热点可以导致酶活性降低[33],且降低程度与病情严重程度相关.PLA2G6基因全部缺失可以导致最严重的临床表型[20].导致PLA2G6相关性肌张力障碍⁃帕金森综合征的PLA2G6基因突变不影响酶活性,但改变蛋白质之间相互作用[34].既往认为,PLA2G6基因是帕金森病致病基因PARK14,且阿尔茨海默病患者脑组织PLA2G6蛋白水平降低[35].因此,磷脂酶A2相关性神经变性病发病机制可能与线粒体功能障碍、脂质代谢障碍和tau蛋白病理改变均有关.

四、线粒体膜蛋白相关性神经变性病

线粒体膜蛋白相关性神经变性病(MPAN,OMIM编号:614297)系C19orf12基因突变所致,是第3位临床常见亚型[36],呈常染色体隐性遗传,占所有脑组织铁沉积性神经变性的6%～10%[37].C19orf12蛋白是位于线粒体外膜的功能未知的蛋白质,C19orf12基因突变除可以导致线粒体膜蛋白相关性神经变性病外,还与苍白球⁃锥体综合征[38]、遗传性痉挛性截瘫43型(SPG43型)[39]和肌萎缩侧索硬化症(ALS)[36]有关.常见突变类型有移码突变p.Gly69ArgfsX10和错义突变p.Thr11Met.通常于儿童期发病,也可于成年早期发病,儿童期发病首发症状为锥体束受累导致的痉挛步态,而认知功能障碍、构音障碍、视神经萎缩、锥体外系症状、精神行为异常、上下运动神经元受累为常见临床表现;成年早期发病主要表现为帕金森样症状、混合步态障碍、认知功能障碍、精神行为异常.几乎所有线粒体膜蛋白相关性神经变性病患者均存在认知功能障碍,最终进展为痴呆,伴神经精神异常.病变主要累及苍白球和黑质,亦可见大脑皮质和小脑萎缩.神经病理学研究显示,基底节区、新旧大脑皮质和脊髓束均可见铁沉积、病理性球状轴突、tau蛋白和路易小体(LB)[37].C19orf12蛋白是包含2个替代起始密码子的跨膜蛋白,表达于内质网和线粒体[39],导致SPG43型或线粒体膜蛋白相关性神经变性病的基因突变可以改变蛋白质分布、错误蛋白质折叠或酶活性降低.C19orf12蛋白在神经元、白细胞和脂肪细胞中呈高表达[40].细胞模型研究显示,白细胞体外分化期间,C19orf12蛋白水平与脂肪酸代谢密切相关[41],推测该蛋白功能与辅酶A代谢相关,表明线粒体膜蛋白相关性神经变性病与辅酶A合成酶相关性神经变性病和磷脂酶A2相关性神经变性病的发病机制有相似之处.

五、脂肪酸羟化酶相关性神经变性病

FA2H基因突变与脑白质营养不良、遗传性痉挛性截瘫35型(SPG35型)和脑组织铁沉积性神经变性病均有关[42⁃44],统称为脂肪酸羟化酶相关性神经变性病(FAHN,OMIM编号:611026)[42],呈常染色体隐性遗传.通常于儿童期发病,首发症状为步态异常、易跌倒,逐渐进展为痉挛性步态、肌张力障碍、小脑共济失调、构音障碍、吞咽障碍、视神经萎缩致视力障碍.大多数患者存在不同程度认知功能障碍,可伴癫发作,部分患者头部MRI检查显示铁沉积.

FA2H蛋白是存在于内质网、相对分子质量为43X103的膜结合蛋白[45].其羧基末端(C末端)含甾醇去饱和酶结构域,其内含铁结合组氨酸序列并具有催化活性;氨基末端(N末端)含细胞色素B与血红蛋白结合结构域,涉及氧化还原活性和向C末端传递电子[46⁃47].FA2H蛋白主要作用是催化脂肪酸N⁃酰基链羟化.2⁃羟基脂肪酸是神经酰胺前体,是髓鞘形成的关键成分[45].FA2H基因突变使酶活性缺失,导致羟化作用丧失而影响正常髓鞘形成.异常髓鞘形成可能诱发神经元功能障碍和凋亡.FA2H基因突变还可以导致神经酰胺信号转导通路异常.此外,神经酰胺还在神经元凋亡和神经变性过程中发挥重要作用[48].通过FA2H蛋白介导的髓鞘形成依靠溶酶体酸性神经酰胺酶和过氧化物酶中的脂肪酸氧化,上述过程均与脑组织铁沉积性神经变性病相关,故各种亚型之间存在潜在的相互联系.业已证实,具有铁存储功能的铁蛋白与髓鞘形成相关,并推测异常铁沉积可能与髓鞘影响铁蛋白的动力学有关[42].轴突髓鞘形成可能是脑组织铁沉积性神经变性病各亚型共同的致病因素.如前所述,PANK2和COASY蛋白均参与辅酶A合成,后者具有多种生物学功能,尤其对神经鞘脂的生成至关重要,而神经鞘脂是髓鞘的另一个主要成分[49],因此,泛酸激酶相关性神经变性病、辅酶A合成酶相关性神经变性病与脂肪酸羟化酶相关性神经变性病具有类似的发病机制,均影响髓鞘形成.值得注意的是,脂肪酸羟化酶相关性神经变性病虽与髓鞘形成有关,但通常不累及周围神经系统.

六、β⁃螺旋蛋白相关性神经变性病

WDR45基因突变可以导致β⁃螺旋蛋白相关性神经变性病(BPAN,OMIM编号:300526)[50],亦称为儿童期静态性脑病成年期神经变性(SENDA),具有特征性双相病程,即儿童期出现全面性发育迟滞,包括运动功能、言语功能和认知功能;成年早期出现进行性加重的肌张力障碍、帕金森样症状和痴呆,亦可见锥体束受累.有1/4患者表现为儿童期智力下降和成年早期(<40岁)帕金森样症状[51].头部MRI显示,疾病早期铁沉积主要位于黑质,至晚期逐渐累及苍白球[52],与其他脑组织铁沉积性神经变性病亚型有所不同.

WDR45蛋白(亦称WIPI4蛋白)是一种在自噬过程中发挥作用的β⁃螺旋支架蛋白,是WD40蛋白家族成员,主要为蛋白质之间的相互作用提供基础,并发挥如自噬、控制细胞周期和转录等功能.WDR45基因可以与磷脂和自噬相关蛋白结合[53],是自噬相关基因之一,对自噬体形成至关重要[54].有研究显示,WDR45基因可以调节自噬体大小和成熟度[54].由于自噬相关基因存在于线粒体外膜,提示WDR45蛋白自噬体与线粒体功能之间可能存在一定联系[55].

尽管WDR45基因定位于X染色体,但β⁃螺旋蛋白相关性神经变性病并不遵循常见的X⁃连锁显性遗传方式.在已报道的病例中,男性和女性患者均为散发,且临床特征相似,推测WDR45基因突变导致无功能性蛋白质,且该蛋白质对男性胚胎具有致死性作用,男性患者基因突变多为新生突变且存在体细胞或生殖细胞嵌合现象,而女性患者基因突变可能与野生型X染色体失活有关[56].

由于WDR45基因与自噬有关,而帕金森病、Crohn病、痉挛性截瘫和肿瘤的发病机制同样存在自噬障碍,考虑β⁃螺旋蛋白相关性神经变性病的主要病变部位和病理学特征,推测其与帕金森病可能具有类似的发病机制.

七、Kufor⁃Rakeb 病

Kufor⁃Rakeb病(KRD,OMIM 编号:606693)[57],亦称PARK9相关性帕金森综合征[58],系ATP13A2基因突变所致,呈常染色体隐性遗传.通常于青少年期发病,主要表现为多巴反应性帕金森综合征、锥体束征,伴眼球运动障碍(核上性凝视麻痹、动眼危象)、认知功能障碍、神经精神症状,部分表现为面部⁃咽喉⁃手指轻度肌阵挛和幻视.

ATP13A2蛋白是二价阳离子转运蛋白的溶酶体P型ATP.P型ATP是转运蛋白超家族成员,包括钙泵、质子泵和磷脂翻转酶,由高度保守的10次跨膜蛋白组成,通过ATP跨膜转运离子[59].ATP13A2蛋白与溶酶体膜、线粒体和突触膜相关,其表达下调可以影响自噬体大小和数目[60].研究显示,ATP13A2基因过表达可以抵御潜在的细胞毒性环境,如α⁃突触核蛋白(α⁃Syn)过表达[61]和重金属离子(镉、锰、镍、硒等)[62].ATP13A2基因突变患者纤维母细胞表现出溶酶体缺陷,在α⁃Syn和锌离子[63⁃64]存在的情况下出现细胞毒性作用.与野生型细胞相比,ATP13A2基因突变细胞锰离子水平较高,提示基因突变使细胞外分泌能力下降[61],可能直接导致细胞色素C从线粒体释放或细胞凋亡.在基因突变的细胞中可见细胞内重金属离子沉积与片段化线粒体有关[60,65].Kufor⁃Rakeb病患者纤维母细胞和嗅神经元存在片段化线粒体,ATP生成减少,出现氧化应激反应和线粒体DNA损伤[66].有趣的是,ATP13A2基因缺陷细胞中并无铁代谢失调,因此,Kufor⁃Rakeb病患者如何发生壳核铁沉积是进一步研究的方向.肝豆状核变性[HLD,亦称Wilson病(WD)]的致病基因ATP7B也属P型ATP.生理条件下细胞质内铜离子水平升高,ATP7B蛋白从高尔基体转移至溶酶体,由此将铜离子转运至溶酶体,富含铜离子的溶酶体经胞吐作用分泌至细胞外[67].肝豆状核变性是由功能异常的ATP7B蛋白引起,导致铜离子水平升高和氧化还原状态改变.因此推测,ATP13A2蛋白功能缺陷可能导致重金属离子非典型性细胞排泄减少.ATP13A2基因突变可能与溶酶体沉积之间存在联系.此外,Kufor⁃Rakeb病患者还表现出痴呆和大脑皮质萎缩,以及尾状核和壳核铁沉积,提示可能与额颞叶痴呆(FTD)、亨廷顿病(HD)有关.与其他脑组织铁沉积性神经变性病亚型相似,ATP13A2蛋白同样对线粒体存在影响.

八、神经铁蛋白变性病

神经铁蛋白变性病(NFT,OMIM编码:606159),亦称遗传性铁蛋白病,系铁蛋白轻链(FTL)基因突变所致,呈常染色体显性遗传[68].铁蛋白是主要贮存铁离子的蛋白质,由重链和轻链亚基组成,重链具有铁氧化酶活性,轻链有助于铁蛋白结构内矿化.FTL基因突变可以引起蛋白稳定性下降、亲水性通道变宽[69],从而导致铁离子贮存量下降.此外,多个细胞系和动物实验证实,神经铁蛋白变性病存在线粒体功能异常,且铁沉积导致氧化应激损伤[70],参与疾病发生.

最常见的突变类型是插入突变,主要发生于第4外显子[71⁃72].头部MRI显示,基因携带者从儿童期即存在脑组织铁沉积,直到40岁出现症状[73].神经铁蛋白变性病通常于40岁左右发病,临床表现与亨廷顿病相似[71],主要表现为成年期出现的精神症状、舞蹈样动作和认知功能障碍,亦可见肌张力障碍、共济失调、帕金森样症状和锥体束征等.亨廷顿病无锥体束受累可资鉴别.

九、血浆铜蓝蛋白缺乏症

CP基因突变可以导致血浆铜蓝蛋白缺乏症(ACP,OMIM编码:604290)[74].通常于成年期发病,主要表现为糖尿病合并视网膜病变和成年期(25～60岁)出现的神经系统症状[75],如认知功能障碍、面部和颈部肌张力障碍、构音障碍、震颤、舞蹈样动作和共济失调等[76].约70%患者以糖尿病为首发症状,常合并贫血.患者血清铁和血清铜水平较低,血清铁蛋白水平明显升高,达正常参考值3～40倍[77].

CP基因编码铜蓝蛋白,在中枢神经系统中,铜蓝蛋白主要以与糖基磷脂酰肌醇相结合的方式存在于星形胶质细胞内[78],病理状态下可在星形胶质细胞中大量聚集.目前已发现超过40种致病性突变[79].与其他脑组织铁沉积性神经变性病亚型不同,血浆铜蓝蛋白缺乏症除脑组织异常铁沉积外,还有全身脏器的异常铁沉积.

十、Woodhouse⁃Sakati综合征

Woodhouse⁃Sakati综合征(WSS,OMIM 编号:241080)系DCAF17基因(曾称C2orf37基因)突变所致,呈常染色体隐性遗传.通常于青春期发病,主要表现为性功能障碍、脱发、糖尿病、智力发育迟滞、听力障碍[80],以及锥体外系症状、肌张力障碍、构音障碍和认知功能障碍等神经系统症状[81].部分女性患者首发症状为闭经和性发育障碍,亦可见黄体生成素(LH)和卵泡刺激素(FSH)水平升高;男性患者均出现非梗阻性无精子症[80].眉毛脱落和脱发程度不一,部分患者表现为发质粗糙.老年患者脱发最为严重.所有患者均出现糖尿病,血清胰岛素水平降低.智力障碍程度不尽一致.部分患者可出现听力丧失,心电图显示T波低平.

DCAF17蛋白是一种多通道跨膜蛋白.动物模型显示,Woodhouse⁃Sakati综合征小鼠脑、肝、皮肤和雄鼠生精小管中均可见DCAF17蛋白高表达[74],但其具体功能尚不明确.相关临床研究显示,DCAF17蛋白与参与DNA损伤和细胞周期控制的蛋白泛素化有关[82].临床表型和蛋白表达均提示Woodhouse⁃Sakati综合征与RBM28基因突变引起的核糖体合成缺陷相似[83],后者表现为垂体功能障碍,从而影响下丘脑⁃垂体⁃肾上腺(HPA)轴[75].

综上所述,尽管脑组织铁沉积性神经变性病的10种亚型由10种致病基因所致,但在发病机制上相互重叠,线粒体功能障碍、氧化应激损伤、脂质代谢障碍、铁沉积和自噬障碍存在于多种亚型中.脑组织异常铁沉积究竟是脑组织铁沉积性神经变性病的原因还是结果,目前尚不明确.脑组织铁沉积不仅见于脑组织铁沉积性神经变性,亦见于其他多种神经变性病如阿尔茨海默病、帕金森病、亨廷顿病.脑组织铁沉积可以引起氧化应激反应,从而产生神经毒性作用.在所有脑组织铁沉积性神经变性病亚型中,仅CP和FTL基因直接参与铁代谢,而其他几种致病基因与铁稳态的维持可能无直接关系.研究显示,铁螯合剂可以减少泛酸激酶相关性神经变性病患者脑组织铁沉积,但对临床症状的改善并不明显[84],因此推测脑组织铁沉积并非导致临床症状的主要原因.目前认为,脑组织铁沉积并不直接与疾病相关联,铁代谢异常可能引起其他金属离子(如铜或锌)稳态异常,进而导致神经变性病.脑组织铁沉积性神经变性病与其他神经变性病如帕金森病、额颞叶痴呆、肌萎缩侧索硬化症之间的相互联系,既有病理学依据,如tau蛋白和α⁃Syn,也有共同的临床表现和铁稳态异常.因此,这些潜在的相互关联的发病机制也可能是今后研究的方向.

[1]Schneider SA. Neurodegenerations with brain iron accumulation.Curr Neurol Neurosci Rep,2016,16:9.

[2]Zhou B,Westaway SK,Levinson B,Johnson MA,Gitschier J,Hayflick SJ.A novel pantothenate kinase gene(PANK2)is defective in Hallervorden⁃Spatz syndrome.Nat Genet,2001,28:345⁃349.

[3]Leonardi R,Rock CO,Jackowski S,Zhang YM.Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine.Proc Natl Acad Sci USA,2007,104:1494⁃1499.

[4]Campanella A,Privitera D,Guaraldo M,Rovelli E,Barzaghi C,Garavaglia B,Santambrogio P,Cozzi A,Levi S.Skin fibroblasts from pantothenate kinase⁃associated neurodegeneration patients show altered cellular oxidative status and have defective iron⁃handling properties.Hum Mol Genet,2012,21:4049⁃4059.

[5]Chen H,Chan DC.Mitochondrial dynamics:fusion,fission,movement,and mitophagy in neurodegenerative diseases.Hum Mol Genet,2009,18:169⁃176.

[6]Leoni V,Strittmatter L,Zorzi G,Zibordi F,Dusi S,Garavaglia B,Venco P,Caccia C,Souza AL,Deik A,Clish CB,Rimoldi M,Ciusani E,Bertini E,Nardocci N,Mootha VK,Tiranti V.Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations.MolGenet Metab,2012,105:463⁃471.

[7]Hartig MB,Hörtnagel K,Garavaglia B,Zorzi G,Kmiec T,Klopstock T,Rostasy K,Svetel M,Kostic VS,Schuelke M,Botz E,Weindl A,Novakovic I,Nardocci N,Prokisch H,Meitinger T.Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation.Ann Neurol,2006,59:248⁃256.

[8]Hayflick SJ,Westaway SK,Levinson B,Zhou B,Johnson MA,Ching KH,GitschierJ.Genetic,clinical,and radiographic delineation of Hallervorden⁃Spatz syndrome.N Engl J Med,2003,348:33⁃40.

[9]Aggarwal A,Schneider SA,Houlden H,Silverdale M,Paudel R,Paisan⁃Ruiz C,Desai S,Munshi M,Sanghvi D,Hardy J,Bhatia KP,BhattM.Indian⁃subcontinentNBIA:unusual phenotypes,novel PANK2 mutations,and undetermined genetic forms.Mov Disord,2010,25:1424⁃1431.

[10]Hayflick SJ.Neurodegeneration with brain iron accumulation:from genes to pathogenesis.Semin Pediatr Neurol,2006,13:182⁃185.

[11]Marelli C,Piacentini S,Garavaglia B,Girotti F,Albanese A.Clinical and neuropsychological correlates in two brothers with pantothenate kinase⁃associated neurodegeneration.Mov Disord,2005,20:208⁃212.

[12]Thomas M,Hayflick SJ,Jankovic J.Clinical heterogeneity of neurodegeneration with brain iron accumulation(Hallervorden⁃Spatz syndrome) and pantothenate kinase⁃associated neurodegeneration.Mov Disord,2004,19:36⁃42.

[13]Gregory A,PolsterBJ,Hayflick SJ.Clinicaland genetic delineation of neurodegeneration with brain iron accumulation.J Med Genet,2009,46:73⁃80.

[14]Lee JH,Park J,Ryu HS,Park H,Kim YE,Hong JY,Nam SO,Sung YH,Lee SH,Lee JY,Lee MJ,Kim TH,Lyoo CH,Chung SJ,Koh SB,Lee PH,Cho JW,Park MY,Kim YJ,Sohn YH,Jeon BS, Lee MS. Clinical heterogeneity of atypical pantothenate kinase⁃associated neurodegeneration in Koreans.J Mov Disord,2016,9:20⁃27.

[15]Dusi S,Valletta L,Haack TB,Tsuchiya Y,Venco P,Pasqualato S,Goffrini P,Tigano M,Demchenko N,Wieland T,Chwarzmayr T,Strom TM,Invernizzi F,Garavaglia B,Gregory A,Sanford L,Hamada J,Bettencourt C,Houlden H,Chiapparini L,Zorzi G,Kurian MA,Nardocci N,Prokisch H,Hayflick S,Gout I,Tiranti V.Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation.Am J Hum Genet,2014,94:11⁃22.

[16]Daugherty M,Polanuyer B,Farrell M,Scholle M,Lykidis A,de Crecy⁃Lagard V,Osterman A.Complete reconstitution of the human coenzyme a biosynthetic pathway via comparative genomics.J Biol Chem,2002,277:21431⁃21439.

[17]Aghajanian S,Worrall DM.Identification and characterization of the gene encoding the human phosphopantetheine adenylyltransferase and dephospho⁃CoA kinasebifunctional enzyme(CoA synthase).Biochem J,2002,365:13⁃18.

[18]Nemazanyy I,Panasyuk G,Breus O,Zhyvoloup A,Filonenko V,Gout IT.Identification of a novel CoA synthase isoform,which is primarily expressed in thebrain.Biochem BiophysRes Commun,2006,341:995⁃1000.

[19]Kurian MA,Morgan NV,MacPherson L,Foster K,Peake D,Gupta R,Philip SG,Hendriksz C,Morton JE,Kingston HM,Rosser EM,Wassmer E,Gissen P,Maher ER.Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene(PLAN).Neurology,2008,70:1623⁃1629.

[20]Gregory A,Westaway SK,Holm IE,Kotzbauer PT,Hogarth P,Sonek S,CoryellJC,Nguyen TM,NardocciN,ZorziG,Rodriguez D,Desguerre I,Bertini E,Simonati A,Levinson B,Dias C,Barbot C,Carrilho I,Santos M,Malik I,Gitschier J,Hayflick SJ.Neurodegeneration associated with genetic defects in phospholipase A(2).Neurology,2008,71:1402⁃1409.

[21]Schneider SA,Dusek P,Hardy J,Westenberger A,Jankovic J,Bhatia KP.Genetics and pathophysiology of neurodegeneration with brain iron accumulation (NBIA).Curr Neuropharmacol,2013,11:59⁃79.

[22]Balsinde J,Balboa MA.Cellularregulation and proposed biologicalfunctions of group VIA calcium⁃independent phospholipase A2 in activated cells.Cell Signal,2005,17:1052⁃1062.

[23]Yang HC,Mosior M,Johnson CA,Chen Y,Dennis EA.Group⁃specific assays that distinguish between the four major types of mammalian phospholipase A2.Anal Biochem,1999,269:278⁃288.

[24]Song H,Bao S,Lei X,Jin C,Zhang S,Turk J,Ramanadham S.Evidence for proteolytic processing and stimulated organelle redistribution ofiPLA(2)beta.Biochim BiophysActa,2010,1801:547⁃558.

[25]Liou JY,Aleksic N,Chen SF,Han TJ,Shyue SK,Wu KK.Mitochondrial localization of cyclooxygenase⁃2 and calcium ⁃independent phospholipase A2 in human cancer cells:implication in apoptosis resistance.Exp Cell Res,2005,306:75⁃84.

[26]Seleznev K,Zhao C,Zhang XH,Song K,Ma ZA.Calcium⁃independent phospholipase A2 localizes in and protects mitochondria during apoptotic induction by staurosporine.J Biol Chem,2006,281:22275⁃22288.

[27]Ong WY,Yeo JF,Ling SF,Farooqui AA.Distribution of calcium⁃independent phospholipase A2 (iPLA2)in monkey brain.J Neurocytol,2005,34:447⁃458.

[28]Balboa MA,Balsinde J.Involvement of calcium⁃independent phospholipase A2 in hydrogen peroxide⁃induced accumulation of free fatty acids in human U937 cells.J Biol Chem,2002,277:40384⁃40389.

[29]Broekemeier KM,Iben JR,LeVan EG,Crouser ED,Pfeiffer DR.Pore formation and uncoupling initiate a Ca2+⁃independent degradation of mitochondrial phospholipids.Biochemistry,2002,41:7771⁃7780.

[30]Gadd ME,Broekemeier KM,Crouser ED,Kumar J,Graff G,Pfeiffer DR.Mitochondrial iPLA2 activity modulates the release of cytochrome c from mitochondria and influences the permeability transition.J Biol Chem,2006,281:6931⁃6939.

[31]Beck G,Sugiura Y,Shinzawa K,Kato S,Setou M,Tsujimoto Y,Sakoda S,Sumi⁃Akamaru H.Neuroaxonal dystrophy in calcium⁃independentphospholipase A2 beta deficiency resultsfrom insufficient remodeling and degeneration of mitochondrial and presynaptic membranes.J Neurosci,2011,31:11411⁃11420.

[32]Roy S,Zhang B,Lee VM,Trojanowski JQ.Axonal transport defects:a common theme in neurodegenerative diseases.Acta Neuropathol,2005,109:5⁃13.

[33]Morgan NV,Westaway SK,Morton JE,Gregory A,Gissen P,Sonek S,Cangul H,Coryell J,Canham N,Nardocci N,Zorzi G,Pasha S,Rodriguez D,Desguerre I,Mubaidin A,Bertini E,Trembath RC,Simonati A,Schanen C,Johnson CA,Levinson B,Woods CG,Wilmot B,Kramer P,Gitschier J,Maher ER,Hayflick SJ.PLA2G6,encoding a phospholipase A2,is mutated in neurodegenerative disorders with high brain iron.Nat Genet,2006,38:752⁃754.

[34]Engel LA,Jing Z,O'Brien DE,Sun M,Kotzbauer PT.Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia⁃parkinsonism.PLoS One,2010,5:E12897.

[35]Ross BM,Moszczynska A,Erlich J,Kish SJ.Phospholipid⁃metabolizing enzymes in Alzheimer's disease: increased lysophospholipid acyltransferase activity and decreased phospholipase A2 activity.J Neurochem,2002,70:786⁃793.

[36]Deschauer M,Gaul C,Behrmann C,Prokisch H,Zierz S,Haack TB.C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.J Neurol,2012,259:2434⁃2439.

[37]Arber CE,Li A,Houlden H,Wray S.Review:insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation.unifying theories.Neuropathol Appl Neurobiol,2016,42:220⁃241.

[38]Kruer MC,Salih MA,Mooney C,Alzahrani J,Elmalik SA,Kabiraj MM,Khan AO,Paudel R,Houlden H,Azzedine H,Alkuraya F.C19orf12 mutation leads to a pallido⁃pyramidal syndrome.Gene,2014,537:352⁃356.

[39]Landouré G,Zhu PP,Lourenço CM,Johnson JO,Toro C,Bricceno KV,Rinaldi C,Meilleur KG,Sangaré M,Diallo O,Pierson TM,Ishiura H,Tsuji S,Hein N,Fink JK,Stoll M,Nicholson G,Gonzalez MA,Speziani F,Dürr A,Stevanin G,Biesecker LG;NIH Intramural Sequencing Center;Accardi J,Landis DM,Gahl WA,Traynor BJ,Marques W Jr,Züchner S,Blackstone C,Fischbeck KH,Burnett BG.Hereditary spastic paraplegia type 43(SPG43)is caused by mutation in C19orf12.Hum Mutat,2013,34:1357⁃1360.

[40]Iuso A,Sibon OC,Gorza M,Heim K,Organisti C,Meitinger T,Prokisch H.Impairment of drosophila orthologs of the human orphan protein C19orf12 induces bang sensitivity and neurodegeneration.PLoS One,2014,9:E89439.

[41]Hartig MB,Iuso A,Haack T,Kmiec T,Jurkiewicz E,Heim K,Roeber S,Tarabin V,Dusi S,Krajewska⁃Walasek M,Jozwiak S,Hempel M,Winkelmann J,Elstner M,Oexle K,Klopstock T,Mueller⁃FelberW,GasserT,TrenkwalderC,TirantiV,Kretzschmar H,Schmitz G,Strom TM,Meitinger T,Prokisch H.Absence of an orphan mitochondrial protein,c19orf12,causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.Am J Hum Genet,2011,89:543⁃550.

[42]Kruer MC,Paisán ⁃Ruiz C,Boddaert N,Yoon MY,Hama H,Gregory A,Malandrini A,Woltjer RL,Munnich A,Gobin S,Polster BJ,Palmeri S,Edvardson S,Hardy J,Houlden H,Hayflick SJ.Defective FA2H leads to a novelform of neurodegeneration with brain iron accumulation(NBIA).Ann Neurol,2010,68:611⁃618.

[43]Edvardson S,Hama H,Shaag A,Gomori JM,Berger I,Soffer D,Korman SH,Taustein I,Saada A,Elpeleg O.Mutations in the fatty acid 2⁃hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia.Am J Hum Genet,2008,83:643⁃648.

[44]Dick KJ,Eckhardt M,Paisán⁃Ruiz C,Alshehhi AA,Proukakis C,Sibtain NA,Maier H,Sharifi R,Patton MA,Bashir W,Koul R,Raeburn S,Gieselmann V,Houlden H,Crosby AH.Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia(SPG35).Hum Mutat,2010,31:E1251⁃1260.

[45]Eckhardt M,Yaghootfam A,Fewou SN,Zoller I,Gieselmann V.A mammalian fatty acid hydroxylase responsible for the formation of alpha⁃hydroxylated galactosylceramide in myelin.Biochem J,2005,388:245⁃254.

[46]Alderson NL,Rembiesa BM,Walla MD,Bielawska A,Bielawski J,Hama H.The human FA2H gene encodes a fatty acid 2⁃hydroxylase.J Biol Chem,2004,279:48562⁃48568.

[47]Hama H.Fatty acid 2⁃hydroxylation in mammalian sphingolipid biology.Biochim Biophys Acta,2010,1801:405⁃414.

[48]Jana A,Hogan EL,Pahan K.Ceramide and neurodegeneration:susceptibility of neurons and oligodendrocytes to cell damage and death.J Neurol Sci,2009,278:5⁃15.

[49]Liman J,Wellmer A,Rostasy K,BahrM,Kermer P.Transcranial ultrasound in neurodegeneration with brain iron accumulation(NBIA).Eur J Paediatr Neurol,2012,16:175⁃178.

[50]Doorn JM, Kruer MC. Newly characterized forms of neurodegeneration with brain iron accumulation.Curr Neurol Neurosci Rep,2013,13:413.

[51]NishiokaK,OyamaG,YoshinoH,LiY,MatsushimaT,Takeuchi C,Mochizuki Y,Mori⁃Yoshimura M,Murata M,Yamasita C,Nakamura N,Konishi Y,Ohi K,Ichikawa K,Terada T,Obi T,FunayamaM,Saiki S,Hattori N.High frequency of beta⁃propeller protein⁃associated neurodegeneration (BPAN)among patients with intellectual disability and young⁃onsetparkinsonism.NeurobiolAging,2015,36:2004.

[52]Hayflick SJ,Kruer MC,Gregory A,Haack TB,Kurian MA,Houlden HH,Anderson J,Boddaert N,Sanford L,Harik SI,Dandu VH,Nardocci N,Zorzi G,Dunaway T,Tarnopolsky M,SkinnerS,Holden KR,FruchtS,HanspalE,Schrander⁃Stumpel C,Mignot C,Héron D,Saunders DE,Kaminska M,Lin JP,Lascelles K,Cuno SM,Meyer E,Garavaglia B,Bhatia K,de Silva R,Crisp S,Lunt P,Carey M,Hardy J,Meitinger T,Prokisch H,Hogarth P.β ⁃Propellerprotein⁃associated neurodegeneration:a new X⁃linked dominant disorder with brain iron accumulation.Brain,2013,136:1708⁃1717.

[53]Lu Q,Yang P,Huang X,Hu W,Guo B,Wu F,Lin L,Kovacs AL,Yu L,Zhang H.The WD40 repeat PtdIns(3)P⁃binding protein EPG⁃6 regulates progression ofomegasomes to autophagosomes.Dev Cell,2011,21:343⁃357.

[54]Dall'Armi C,Devereaux KA,Di Paolo G.The role of lipids in the control of autophagy.Curr Biol,2013,23:33⁃45.

[55]Hailey DW,Rambold AS,Satpute⁃Krishnan P,Mitra K,Sougrat R,Kim PK,Lippincott⁃Schwartz J.Mitochondria supply membranes forautophagosome biogenesis during starvation.Cell,2010,141:656⁃667.

[56]Haack TB,Hogarth P,Kruer MC,Gregory A,Wieland T,Schwarzmayr T,Graf E,Sanford L,Meyer E,Kara E,Cuno SM,Harik SI,Dandu VH,NardocciN,ZorziG,DunawayT,Tarnopolsky M,Skinner S,Frucht S,Hanspal E,Schrander⁃Stumpel C,Héron D,Mignot C,Garavaglia B,Bhatia K,Hardy J,Strom TM,Boddaert N,Houlden HH,Kurian MA,Meitinger T,Prokisch H,Hayflick SJ.Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct,X⁃linked dominant form of NBIA.Am J Hum Genet,2012,91:1144⁃1149.

[57]Najim al⁃Din AS,al⁃Kurdi A,Dasouki M,Wriekat AL,al⁃Khateeb M,Mubaidin A,al⁃Hiari M.Autosomal recessive ataxia,slow eyemovements and psychomotor retardation.J Neurol Sci,1994,124:61⁃66.

[58]Di Fonzo A,Chien HF,Socal M,Giraudo S,Tassorelli C,Iliceto G,Fabbrini G,Marconi R,Fincati E,Abbruzzese G,Marini P,Squitieri F,Horstink MW,Montagna P,Libera AD,Stocchi F,Goldwurm S,Ferreira JJ,Meco G,Martignoni E,Lopiano L,Jardim LB,Oostra BA,Barbosa ER;Italian Parkinson Genetics Network;Bonifati V.ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.Neurology,2007,68:1557⁃1562.

[59]Kühlbrandt W.Biology,structure and mechanism of P ⁃type ATPases.Nat Rev Mol Cell Biol,2004,5:282⁃295.

[60]Ramonet D,Podhajska A,Stafa K,Sonnay S,Trancikova A,Tsika E,Pletnikova O,Troncoso JC,Glauser L,Moore DJ.PARK9⁃associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity.Hum Mol Genet,2012,21:1725⁃1743.

[61]Tan J,Zhang T,Jiang L,Chi J,Hu D,Pan Q,Wang D,Zhang Z.Regulation of intracellular manganese homeostasis by Kufor⁃Rakeb syndrome⁃associated ATP13A2 protein.J Biol Chem,2011,286:29654⁃29662.

[62]Schmidt K,Wolfe DM,Stiller B,Pearce DA.Cd2+,Mn2+,Ni2+and Se2+toxicity to saccharomyces cerevisiae lacking YPK9p the orthologue of human ATP13A2.Biochem Biophys Res Commun,2009,383:198⁃202.

[63]UsenovicM,Tresse E,Mazzulli JR,Taylor JP,Krainc D.Deficiency of ATP13A2 leads to lysosomal dysfunction,alpha⁃synuclein accumulation,and neurotoxicity.J Neurosci,2012,32:4240⁃4246.

[64]Tsunemi T,Krainc D.Zn2+dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha⁃synuclein accumulation.Hum Mol Genet,2014,23:2791⁃2801.

[65]Park JS,Koentjoro B,Veivers D,Mackay⁃Sim A,Sue CM.Parkinson'sdisease⁃associated human ATP13A2 (PARK9)deficiency causes zinc dyshomeostasis and mitochondrial dysfunction.Hum Mol Genet,2014,23:2802⁃2815.

[66]Grunewald A,Arns B,Seibler P,Rakovic A,Munchau A,Ramirez A,Sue CM,KleinC.ATP13A2mutations impair mitochondrial function in fibroblasts from patients with Kufor⁃Rakeb syndrome.Neurobiol Aging,2012,33:1843.

[67]Polishchuk EV,Concilli M,Iacobacci S,Chesi G,Pastore N,Piccolo P,Paladino S,Baldantoni D,van IJzendoorn SC,Chan J,Chang CJ,Amoresano A,Pane F,Pucci P,Tarallo A,Parenti G,Brunetti⁃Pierri N,Settembre C,Ballabio A,Polishchuk RS.Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis.Developmental Cell,2014,29:686⁃700.

[68]Curtis AR,Fey C,Morris CM,Bindoff LA,Ince PG,Chinnery PF,Coulthard A,Jackson MJ,Jackson AP,McHale DP,Hay D,Barker WA,Markham AF,Bates D,Curtis A,Burn J.Mutation in the gene encoding ferritin light polypeptide causes dominant adult⁃onset basal ganglia disease.Nat Genet,2001,28:350⁃354.

[69]Colombelli C,Aoun M,Tiranti V.Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA)syndromes:not only a matter of iron.J Inherit Metab Dis,2015,38:123⁃136.

[70]Mancuso M,Davidzon G,Kurlan RM,Tawil R,Bonilla E,Di Mauro S, Powers JM. Hereditary ferritinopathy: a novel mutation,its cellular pathology,and pathogenetic insights.J Neuropathol Exp Neurol,2005,64:280⁃294.

[71]Chinnery PF,Crompton DE,Birchall D,Jackson MJ,Coulthard A,Lombès A,Quinn N,Wills A,Fletcher N,Mottershead JP,Cooper P,Kellett M,Bates D,Burn J.Clinical features and naturalhistory ofneuroferritinopathy caused by the FTL1 460InsA mutation.Brain,2007,130:110⁃119.

[72]Chinnery PF,Curtis AR,Fey C,Coulthard A,Crompton D,Curtis A,Lombes A,Burn J.Neuroferritinopathy in a French family with late onset dominant dystonia.J Med Genet,2003,40:E69.

[73]Keogh MJ,JonasP,Coulthard A,ChinneryPF,Burn J.Neuroferritinopathy:a new inborn error of iron metabolism.Neurogenetics,2012,13:93⁃96.

[74]Yoshida K,Furihata K,Takeda S,Nakamura A,Yamamoto K,Morita H,Hiyamuta S,Ikeda S,Shimizu N,Yanagisawa N.A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans.Nat Genet,1995,9:267⁃272.

[75]Miyajima H.Aceruloplasminemia.Rinsho Shinkeigaku,2000,40:1290⁃1292.

[76]McNeill A,Pandolfo M,Kuhn J,Shang H,Miyajima H.The neurological presentation of ceruloplasmin gene mutations.Eur Neurol,2008,60:200⁃205.

[77]Ogimoto M,Anzai K,Takenoshita H,Kogawa K,Akehi Y,Yoshida R,Nakano M,Yoshida K,Ono J.Criteria for early identification of aceruloplasminemia.Intern Med,2011,50:1415⁃1418.

[78]Wild EJ,Mudanohwo EE,Sweeney MG,Schneider SA,Beck J,Bhatia KP,Rossor MN,Davis MB,Tabrizi SJ.Huntington's disease phenocopies are clinically and genetically heterogeneous.Mov Disord,2008,23:716⁃720.

[79]Crompton DE,Chinnery PF,Bates D,Walls TJ,Jackson MJ,Curtis AJ,Burn J.Spectrum ofmovement disorders in neuroferritinopathy.Mov Disord,2005,20:95⁃99.

[80]WoodhouseNJ,SakatiNA.A syndromeofhypogonadism,alopecia,diabetes mellitus,mental retardation,deafness,and ECG abnormalities.J Med Genet,1983,20:216⁃219.

[81]Al⁃Semari A,Bohlega S.Autosomal⁃recessive syndrome with alopecia,hypogonadism,progressive extra⁃pyramidal disorder,white matter disease,sensory neural deafness,diabetes mellitus,and low IGF1.Am J Med Genet A,2007,143A:149⁃160.

[82]Jin J,Arias EE,Chen J,Harper JW,Walter JC.A family of diverse Cul4⁃Ddb1⁃interacting proteins includes Cdt2,which is required for S phase destruction of the replication factor Cdt1.Mol Cell,2006,23:709⁃721.

[83]Nousbeck J,Spiegel R,Ishida⁃Yamamoto A,Indelman M,Shani⁃Adir A,Adir N,Lipkin E,Bercovici S,Geiger D,van Steensel MA,Steijlen PM,Bergman R,Bindereif A,Choder M,Shalev S,Sprecher E.Alopecia,neurological defects,and endocrinopathy syndrome caused by decreased expression ofRBM28,a nucleolar protein associated with ribosome biogenesis.Am J Hum Genet,2008,82:1114⁃1121.

[84]Zorzi G,Zibordi F,Chiapparini L,Bertini E,Russo L,Piga A,Longo F,Garavaglia B,Aquino D,Savoiardo M,Solari A,NardocciN.Iron⁃related MRIimages in patients with pantothenate kinase⁃associated neurodegeneration (PKAN)treated with deferiprone:results of a phaseⅡpilot trial.Mov Disord,2011,26:1756⁃1759.

Genetic research advance on neurodegeneration with brain iron accumulation

HUANG Xiao⁃jun1,CAO Li21Department of Neurology,North Department of Ruijin Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai 201801,China
2Department of Neurology and Institute of Neurology,Ruijin Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai 200025,China

CAO Li(Email:caoli2000@yeah.net)

Neurodegeneration with brain iron accumulation(NBIA)is a neurodegenerative disorder characterized by abnormal accumulation of iron in central nervous system.Common clinical symptoms in NBIA include different types of dyskinesia,pyramidal tract involvement,cerebellar ataxia,peripheral neuropathy,autonomic neuropathy,cognitive impairment and visual dysfunction.So far,10 genes have been identified as the causative gene for NBIA subtypes,which are PANK2,COASY,PLA2G6,C19orf12,FA2H,WDR45,ATP13A2,FTL,CP and DCAF17.The pathogenesis of NBIA involves mitochondrial involvement,oxidative stress damage,lipid metabolism and autophagy.Furthermore,NBIA may share the same pathogenetic mechanism with some other neurodegenerative disorders,such as Parkinson's disease(PD),frontotemporal dementia(FTD)and amyotrophic lateral sclerosis(ALS).

Neurodegenerative diseases; Iron metabolism disorders; Genetics; Review

This study was supported by the National Natural Science Foundation of China(No.81571086),the National Natural Science Foundation of China for Young Scientists(No.81600978),Shanghai Jiaotong University School of Medicine Peak and Plateau Program(No.20161401),and Crossing Program between Medicine and Industry supported by Shanghai Jiaotong University(No.YG2016MS64).

10.3969/j.issn.1672⁃6731.2017.07.004

国家自然科学基金资助项目(项目编号:81571086);国家自然科学基金青年科学基金资助项目(项目编号:81600978);上海交通大学医学院高峰高原计划(项目编号:20161401);上海交通大学"医工交叉研究基金"资助项目(项目编号:YG2016MS64)

201801上海交通大学医学院附属瑞金医院北院神经内科(黄啸君);200025上海交通大学医学院附属瑞金医院神经科 上海交通大学医学院神经病学研究所(曹立)

曹立(Email:caoli2000@yeah.net)

2017⁃05⁃31)