遗传性弥漫性白质脑病合并轴索球样变研究进展
遗传性弥漫性白质脑病合并轴索球样变 (HDLS) 是临床罕见的遗传性中枢神经系统白质变性病, 临床表现多样, 主要包括性格改变、精神行为异常、认知功能障碍、帕金森样症状和癫发作等。1984年, 由Axelsson等[1]首次报告并命名。Rademakers等[2]于2011年通过全基因组相关性研究 (GWAS) 和全外显子组测序 (WES) , 确定位于染色体5q32的集落刺激因子1受体 (CSF1R) 基因是遗传性弥漫性白质脑病合并轴索球样变的致病基因。已报道70余种致病性CSF1R基因突变[3,4]。
2013年, Nicholson等[5]在色素性脑白质营养不良 (POLD) 家系中也发现CSF1R基因突变。基于两种疾病具有相似的临床表现和病理学特点, 即临床和影像学均表现为以额叶功能障碍为主的精神症状和认知损害[6]；病理学表现为遗传性弥漫性白质脑病合并轴索球样变的患者存在与色素性脑白质营养不良相似的色素性巨噬细胞, 色素性脑白质营养不良患者轴突扩张与遗传性弥漫性白质脑病合并轴索球样变相一致[5,6], 故目前将这两种疾病视为同一疾病谱, 即成年发病的白质脑病合并轴索球样变和色素性胶质细胞 (ALSP) [3,5,6]。
目前, 对其确切的发病机制尚不清楚。本文拟就遗传性弥漫性白质脑病合并轴索球样变的临床研究、分子遗传学研究和发病机制研究进展进行综述, 以期提高临床对疾病的认识并促进疾病的深入研究。
一、临床研究进展
1. 临床表现
遗传性弥漫性白质脑病合并轴索球样变临床表现多样且存在异质性, 个体间亦存在显著差异, 即使同一家系中携带同一突变的个体之间临床表现也明显不同, 且存在疾病外显不全等特点, 即部分患者出现早期影像学改变或携带CSF1R突变基因而无任何临床表现。
发病年龄15～78岁, 平均35～40岁；病程1～30年[7,8]。临床首发症状主要是显著的神经精神症状[3,5,9,10,11], 包括性格和行为改变 (如易激惹、攻击行为、缺乏主动性、孤僻、淡漠) 、精神症状 (如焦虑、抑郁) 、进行性认知功能障碍 (如计算力、定向力、记忆力减退和执行功能障碍) ；随后或同时出现运动障碍和步态障碍, 包括非对称性帕金森综合征 (如运动迟缓、姿势性震颤、肌强直) [12,13]、锥体束征、步态拖曳等；随着病情进展, 逐渐出现皮质功能障碍, 包括失用症 (如失语、偏盲) [7,14]、癫发作[5,9]、共济失调[15]、构音障碍、吞咽困难等；最终丧失运动功能、缄默、长期卧床, 死于各种并发症。
其他少见症状与体征为痉挛性下肢瘫、四肢瘫或偏瘫[16,17]、肌阵挛[18,19]、严重头痛[20]、舌肌纤颤和萎缩[21]、急性脑卒中[22]、视神经萎缩[23]、眼睑痉挛和非对称性镜像运动表现[24]等。
2. 影像学特点
遗传性弥漫性白质脑病合并轴索球样变典型MRI表现为早期双侧、非对称性、局限性T2WI或FLAIR成像高信号 (图1a) 和T1WI低信号, 以额叶或额顶叶显著, 累及深部脑白质和皮质下脑室周围白质纤维束[7,25,26]；亦可见皮质脊髓束受累, 弥漫性脑萎缩和脑室扩大 (图1b) , 伴胼胝体发育不良 (图1c) 和异常信号 (通常认为是疾病早期影像学特征) [7,27,28,29,30]。
随着病情进展, 病灶逐渐融合呈片状, 并呈对称性分布。一般不累及皮质下U型纤维、脑干和小脑皮质。研究显示, 在CSF1R基因缺失性突变类型中, 遗传性弥漫性白质脑病合并轴索球样变患者头部MRI脑白质病变严重性评分更高, 且与病程呈负相关[26]。
此外, 亦有研究显示, 部分遗传性弥漫性白质脑病合并轴索球样变患者头部CT可见多发点状钙化灶[7,28,31,32], 具有一定诊断价值, 但与疾病进展无关[33]。扩散加权成像 (DWI) 呈小点状高信号, 同时伴水分子扩散受限被认为是该病的特征性影像学表现[25]。磁敏感加权成像 (SWI) 无微出血灶, 与遗传性脑小血管病可资鉴别。磁共振波谱 (MRS) 显示, N-乙酰天冬氨酸 (NAA) 峰值降低, 胆碱 (Cho) 、乳酸 (Lac) 和肌醇 (mI) 峰值升高, 且部分无症状性CSF1R基因携带者早期即可出现上述代谢改变[19,25,34]。
3. 病理学特点
遗传性弥漫性白质脑病合并轴索球样变的尸体解剖学研究结果显示, 大体标本可见脑组织广泛萎缩, 弥漫性脑白质变性, 呈黄褐色、海绵状或胶冻状, 胼胝体变薄, 皮质下U型纤维和小脑皮质多保留[3,19,27,35]；光学显微镜观察显示, 轴索球样变伴色素性胶质细胞, 以及弥漫性轴索变性、髓鞘缺失, 是特征性病理改变[2,3,5]。
组织学形态亦可见反应性胶质细胞增生以及少量富脂质的巨噬细胞和钙化灶[35,36]。
免疫组织化学染色显示, 轴索肿胀、球样变, 髓鞘变薄或消失[36]。超微结构观察可见肿胀、球样变的轴索内含杂乱的神经纤维丝、线粒体和非特异性电子致密物, 髓鞘不连续, 呈碎片状或缺失[3,35]。
4. 诊断
遗传性弥漫性白质脑病合并轴索球样变临床表现多样, 且部分呈非典型, 故临床极易误诊[18]。加之临床医师对该病的认识不足, 其发病率远被低估。
如果出现进行性认知功能下降、记忆力减退和人格障碍, 结合可疑阳性家族史和典型脑白质改变, 可以考虑遗传性弥漫性白质脑病合并轴索球样变, 应注意与多种其他遗传性脑白质病变[37]或伴脑白质病变的遗传性脑小血管病[18]等相鉴别。
2018年, Konno等[38]提出特异度较高 (>96%) 的诊断标准。其核心特征包括: (1) 发病年龄≤60岁。(2) 至少具备以下2种症状与体征, (1) 认知功能障碍或精神症状。(2) 锥体束征。(3) 帕金森病。(4) 癫发作。(3) 常染色体显性遗传或散发。(4) 头部CT和 (或) MRI显示, (1) 双侧脑白质病变。(2) 胼胝体变薄。(5) 排除导致脑白质病变的其他原因, (1) 血管性痴呆 (VaD) , 多发性硬化 (MS) 。(2) 脑白质营养不良, 如肾上腺脑白质营养不良 (ALD) 、Krabbe病、异染性脑白质营养不良 (MLD) 等。其排除依据包括: (1) 发病年龄≤10岁。(2) 除癫发作外, 脑卒中样发作≥2次。(3) 突出的周围神经病变。其支持依据 包括: (1) 临床表现或认知功能评价提示额叶功能障碍。(2) 病情进展迅速 (发病5年内卧床) 。(3) 头部CT显示脑白质斑点状微小钙化灶。(4) 与遗传性弥漫性白质脑病合并轴索球样变相符的病理改变。根据上述特征, 分为确定的 (definite) 诊断, 即满足核心特征 (2) 、 (3) 和 (4) 中 (1) , 且存在CSF1R基因突变；很可能的 (probable) 诊断, 即满足核心特征 (1) ～ (5) , 但未行基因检测；可能的 (possible) 诊断, 即满足核心特征 (2) 中 (1) 、 (3) 和 (4) 中 (1) , 但未行基因检测。
二、分子遗传学机制
CSF1R基因包含22个外显子, 全长4006 bp, 编码细胞表面膜蛋白CSF1R, 该蛋白是包含972个氨基酸的多肽, 是Ⅲ型受体酪氨酸激酶 (RTK) , 属于血小板源性生长因子受体 (PDGFR) 家族。此类受体具有相似的分子结构, 包括高度糖基化的胞外配体结合结构域、螺旋跨膜结构域、近膜结构域以及胞内酪氨酸激酶结构域, 其被一个插入结构域分为两部分[2,10,39]。酪氨酸激酶结构域高度保守, 作为大多数细胞信号转导通路的关键调节因子, 与多种疾病如肿瘤、糖尿病、炎症反应、严重骨骼疾病、动脉粥样硬化等相关[40,41]。通过与配体主要是集落刺激因子1 (CSF1) 相结合, 形成受体同源二聚体, 磷酸化胞质内酪氨酸残基, 进而磷酸化下游分子靶点, 激活一系列信号转导通路, 主要调节巨噬细胞存活、增殖、分化和功能发挥[42,43], 尤其在中枢神经系统, CSF1R主要表达于小胶质细胞, 对神经发生、神经连接和突触重塑等有重要调节作用, 还参与其他多种生理功能, 如胚胎发育调控、促进血管和淋巴细胞生成, 调节心、肺、肾、胰、骨骼等器官发育[44,45]。
亦有研究显示, CSF1R还可以与表达于皮肤和前脑的白细胞介素-34 (IL-34) 结合, 发挥相似作用[43]。
遗传性弥漫性白质脑病合并轴索球样变呈常染色体显性遗传, 亦可见散发病例报道[9,46,47]。迄今已报道70余种致病性CSF1R基因突变[4], 但尚无明确的表型-基因型关联性[48]。CSF1R基因突变主要为错义突变、无义突变、插入/缺失、移码突变, 亦有剪切位点突变的报道[2,3,27]。绝大多数突变位于酪氨酸激酶结构域 (外显子12～22) , 其中外显子17～20为突变高发区域[2,3]。
研究显示, CSF1R基因突变可使酪氨酸激酶失活, 但不影响受体同源二聚体形成, 可能导致无信号转导功能的突变同源二聚体或野生型-突变型异源二聚体形成, 从而影响下游靶点磷酸化, 即显性负性机制 (dominant-negative disease mechanism) [2]。亦有研究显示, 与野生型相比, 致病性CSF1R基因突变在全身各组织的表达水平和自身磷酸化程度均降低[28,41,49]。但位于不同结构域的CSF1R基因突变对自身和下游靶点磷酸化的影响不同:位于酪氨酸激酶结构域的致病性突变, 其磷酸化信号完全丧失；而位于近膜区或激酶插入区的致病性突变, 残留部分磷酸化信号[22,41]。
突变的CSF1R基因仍表达于细胞膜表面, 且不影响野生型CSF1R基因结合配体形成二聚体, 以及后续功能发挥。Eichler等[50]报告1例CSF1R基因突变嵌合体遗传性弥漫性白质脑病合并轴索球样变患者, 经异基因造血干细胞移植引入野生型CSF1R基因, 病情得到有效控制。上述研究表明, CSF1R基因突变可能导致酪氨酸激酶活性部分或完全丧失, 从而影响下游靶点信号转导, 即功能丧失性机制 (loss of function mechanism) 。而位于关键结构域的截短突变可能与无义突变介导的mRNA降解有关[28]。
CSF1R基因在中枢神经系统主要表达于小胶质细胞[51], 通过与配体结合, 对小胶质细胞存活、增殖、分化和功能发挥以及对神经细胞稳态维持均具有调节作用[45,52]。脑组织正常发育过程中, 小胶质细胞对突触功能的监测以及与中枢神经系统各种成分直接或间接相互作用, 对神经功能的发挥和组织完整性的维持有显著影响[53,54]。
近年来, 小胶质细胞成为研究热点, 其功能异常与多种疾病相关, 包括神经变性病[如阿尔茨海默病 (AD) 、帕金森病 (AD) 、亨廷顿病 (HD) 、多发性硬化等]、创伤性病变[如颅脑创伤 (TBI) 、脊髓病变]、精神障碍 (如精神分裂症) 等[54,55]。CSF1R基因突变患者脑组织中可见小胶质细胞数目和形态改变, 分布不均匀, 且蛋白合成功能障碍, 因此遗传性弥漫性白质脑病合并轴索球样变被认为是一种小胶质细胞病[51,56], 然而小胶质细胞异常如何引起疾病的作用机制尚待进一步阐明。
部分具有典型临床表现、影像学和病理学特征的遗传性弥漫性白质脑病合并轴索球样变患者未发现CSF1R基因或其他已知的遗传性脑白质病变相关基因突变[57], 表明该类脑白质病变具有高度遗传异质性, 可能由于不同致病基因突变所致, 但与趋向于相似的信号转导和代谢通路等机制有关, 即可能由于基因突变或各种应激反应引起的小胶质细胞或巨噬细胞免疫应答或炎症反应的异常激活所致。
有文献报道, 具有典型遗传性弥漫性白质脑病合并轴索球样变临床表现但CSF1R基因突变阴性的患者, 在条件受限的情况下, 应结合临床考虑丙氨酰转移t RNA合成酶2 (AARS2) 相关脑白质病变的可能[58]。AARS2基因编码tRNA合成酶主要负责在线粒体翻译时转运丙氨酸, 呈常染色体隐性遗传, 与致死性婴幼儿心肌病[59]、进行性白质脑病伴卵巢功能衰竭[60]有关。尚待进一步研究AARS2基因相关疾病的表型谱, 以提高与遗传性弥漫性白质脑病合并轴索球样变临床表现相似的疾病的鉴别诊断水平。
其他疾病如多囊性脂膜性骨发育不良伴硬化性白质脑病 (PLOSL) 的致病基因DAP12和TREM2突变, 也可以引起类似遗传性弥漫性白质脑病合并轴索球样变的临床和病理表现[57]。
三、治疗与展望
目前尚无针对遗传性弥漫性白质脑病合并轴索球样变的有效治疗方法, 通常采取对症支持治疗。拟多巴胺类药或抗抑郁药对帕金森样症状、抑郁等精神症状的有效性尚未证实。随着疾病进展, 患者性格、心理和运动功能显著改变, 并影响生活质量, 应监测患者行为改变并定期进行临床评估, 同时辅以适当康复治疗, 提高生活质量。
有文献报道1例经异基因造血干细胞移植治疗的遗传性弥漫性白质脑病合并轴索球样变患者的病情得到有效控制和延缓[50], 但其长期疗效尚待进一步研究。
CSF1R基因突变如何影响酪氨酸激酶相关信号转导通路、如何调控小胶质细胞或神经元功能, 以及异常小胶质细胞在脑白质病变、轴索和髓鞘病变中扮演的角色, 尚待进一步探究, 这对于脑白质变性病或小胶质细胞病发病机制的研究具有重要意义, 将为探索新的治疗方法提供更多依据。
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参考文献
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文献出处：詹飞霞,曹立.遗传性弥漫性白质脑病合并轴索球样变研究进展[J].中国现代神经疾病杂志,2019,19(02):125-131.