Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy
Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy
复制标题
CSF1R相关白质脑病的临床病理特征和异常自噬
DOI：
10.1186/s40035-019-0171-y
复制
发表时间：
2019-12-02
影响因子：
12.6
通讯作者：
Cao, Li
中科院分区：
文献类型：
--
作者：
Tian, Wo-Tu;Zhan, Fei-Xia;Cao, Li
背景
CSF1R相关白质脑病，又称遗传性球形弥漫性白质脑病(HDLS)，是一种罕见的以集落刺激因子1受体(CSF1R)基因突变引起的运动和神经精神症状为特征的白质脑病。很少有CSF1R基因突变被功能证实，其发病机制尚不清楚。
方法
为了解CSF1R相关性白质脑病患者的临床和病理特点，探讨CSF1R基因突变的潜在影响，我们分析了来自10个无关家系的15例患者的临床表现，其中2例行脑活检。对10个先证者进行下一代测序以确认诊断。利用Sanger测序、分离分析和表型再评估来证实研究结果。对已鉴定的突变进行了进一步的功能检查。
结果
总结其临床和神经影像特点。发病年龄24~46岁，平均(35.9±6.4)岁。女性的发病年龄比男性年轻(34.2岁比39.2岁)。最常见的最初症状是言语障碍、认知能力下降和帕金森症状。一名患者也有明显的周围神经病变。2例脑活检显示典型的病理改变，包括髓鞘丢失、轴突球形、磷酸化的神经丝和活化的巨噬细胞。电子显微镜显示气球状轴突内线粒体空泡化增加，神经丝排列紊乱。共鉴定出7个致病变异体(4个新变异体，3个已报道变异体)，其中c.2342C T仍具有部分自磷酸化功能。Western blotting显示C.2026C-T(p.R676*)水平显著低于野生型。Western blotting和免疫荧光染色显示，自噬的经典标志物微管相关蛋白1轻链3-II(LC3-II)在突变型表达细胞中的表达水平明显低于野生型表达细胞。
结论
我们的发现支持发病机制中的功能丧失和单倍体功能不全假说。自噬异常可能在该病中起一定作用。修复或促进突变型CSF1R的磷酸化水平可能为未来的治疗靶点提供线索。然而，外周多发性神经病是否可能属于CSF1R相关谱值得进一步研究，需要更长的随访时间和更多的患者入选。
试行登记
ChiCTR，ChiCTR1800015295。注册于2018年3月21日。
Background
CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown.
Methods
In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored.
Results
Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9 ± 6.4 years (range 24–46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonian symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C T (p.R676*) than wild type. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining.
Conclusions
Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled.
Trial registration
ChiCTR, ChiCTR1800015295. Registered 21 March 2018.