SYNE1-ataxia: clinicopathologic features of an autopsied patient with novel compound heterozygous mutations
SYNE1-ataxia: clinicopathologic features of an autopsied patient with novel compound heterozygous mutations
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SYNE1-共济失调：具有新型复合杂合突变的尸检患者的临床病理特征
DOI：
10.1093/jnen/nlac120
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Kakita Akiyoshi
中科院分区：
文献类型：
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作者：
Saito Rie;Hara Norikazu;Tada Mari;Wakabayashi Masatoshi;Miyashita Akinori;Nishizawa Masatoyo;Onodera Osamu;Ikeuchi Takeshi;Kakita Akiyoshi
含血影蛋白重复序列的核膜蛋白1（SYNE 1）基因突变已被证明可导致常染色体隐性小脑性共济失调（ARCA），称为ARCA 1或常染色体隐性脊髓小脑性共济失调-8（SCAR 8）;这些突变已在世界范围内被发现。SYNE 1-共济失调的典型特征是纯迟发性小脑共济失调。然而，越来越多的报告描述了频繁的复杂表型，具有各种小脑外神经和非神经表现（1-6）。SYNE 1编码核被膜血影蛋白1（nesprin-1），属于连接质膜和肌动蛋白细胞骨架的血影蛋白结构蛋白家族。它定位于各种组织的核膜。在骨骼肌中，nesprin-1与内核膜蛋白、核纤层蛋白A/C和emerin结合;编码这些蛋白质的基因突变，即EMD、LMNA和SYNE 1，导致Emery-Dreifuss肌营养不良症（EDMD）（1，7，10）。有趣的是，在SYNE 1-共济失调患者的肌肉组织中，nesprin-1的表达减少，而核纤层蛋白A/C和emerin的表达保留（2），而在携带SYNE 1杂合突变的EDMD患者的肌肉中，所有这些蛋白质的表达改变（7）。这可能反映了这些疾病的发病机制的差异。然而，神经病理学特征和Nesprin-1在中枢神经系统中的表达与SYNE 1-共济失调患者的变化仍然未知。在这里，我们调查了一个日本晚发性小脑性共济失调患者的临床病理特征，该患者在SYNE 1中携带复合杂合突变。一名34岁的日本男性，来自一个非血缘家庭，表现为复视。他的祖父也有类似的症状。在39岁时，他出现行走困难并被送进医院。神经系统检查显示凝视诱发的眼球震颤、张力减退、肢体和躯干共济失调、上下肢深腱反射和足底伸肌反射增加。脑MRI显示小脑和脑干弥漫性萎缩（图1A）。患者被诊断为橄榄桥脑小脑萎缩，此后，其病情缓慢恶化。虽然没有明显的感觉障碍，但在50岁时，下肢的振动感觉丧失和感觉过敏，以及伴有爪趾畸形的高脚变得明显（图1B）;这些情况逐渐恶化，直到他在72岁时死于败血症。进行了一般尸检，当时大脑重量为1180 g。神经系统的组织病理学特征为橄榄-桥脑小脑系统的显著变性和背柱通路的轻度受累。小脑弥漫性萎缩明显，但前叶和小脑蚓部相对保留（图1C）。显微镜下，浦肯野细胞（PJC）和颗粒细胞的丢失伴Bergmann胶质增生（箭头）在半球后叶更为明显。与病程相似的疾病对照组（6型SCAR）相比，患者颗粒细胞的损失更为明显，甚至在PJC类似耗竭的区域也是如此（图1D）。PJC的局灶性树突状细胞（即小行星体），已知在颗粒细胞明显缺失时发生（8），分散在前叶（图1 E）。在小脑传入系统中，脑桥核和下橄榄核的变性是显著的（图1F，G）。前庭神经核的变性程度较轻，
Mutations in the spectrin repeat-containing nuclear envelope protein 1 (SYNE1) gene have been shown to cause an autosomal recessive cerebellar ataxia (ARCA) known as ARCA1 or autosomal recessive spinocerebellar ataxia-8 (SCAR8); these mutations have been identified worldwide. SYNE1-ataxia has been classically characterized by pure late-onset cerebellar ataxia. However, an increasing number of reports have described frequent complex phenotypes with various extracerebellar neurological and nonneurological manifestations (1–6). SYNE1, encoding nuclear envelope spectrin 1 (nesprin-1) belongs to the spectrin family of structural proteins linking the plasma membrane to the actin cytoskeleton. It localizes to the nuclear membrane in various tissues. In skeletal muscle, nesprin-1 binds to the inner nuclear membrane proteins, lamin A/C and emerin; mutations in the genes encoding these proteins, namely EMD, LMNA, and SYNE1, cause Emery–Dreifuss muscular dystrophy (EDMD)(1, 7, 10). Interestingly, the expression of nesprin-1 is reduced, while that of lamin A/C and emerin is retained in muscle tissue of patients with SYNE1-ataxia (2), whereas expression of all these proteins is altered in the muscle of patients with EDMD harboring a heterozygous mutation of SYNE1 (7). This may reflect differences in the pathogenetic mechanisms of these disorders. However, the neuropathologic features and alterations of nesprin-1 expression in the CNS of patients with SYNE1-ataxia remain unknown. Here, we investigated the clinicopathologic features of a Japanese patient with late-onset cerebellar ataxia harboring compound heterozygous mutations in SYNE1. A 34-year-old Japanese man from a nonconsanguineous family presented with diplopia. His paternal grandfather had similar symptoms. At the age of 39 years, he developed walking difficulty and was admitted to a hospital. Neurological examination revealed gaze-evoked nystagmus, hypotonus, limb and trunk ataxia, increased deep tendon reflexes in the upper and lower limbs, and extensor plantar reflexes. Brain MRI revealed diffuse atrophy of the cerebellum and brainstem (Fig. 1A). The patient was diagnosed as having olivo-ponto-cerebellar atrophy, and thereafter, his condition slowly deteriorated. Although no sensory disturbance was evident, at the age of 50, loss of vibration sense and hyperesthesia in the lower limbs, and pes cavus with claw toe deformities became obvious (Fig. 1B); these worsened gradually until his death from sepsis at the age of 72. A general autopsy was performed, at which time the brain weighted 1180 g. The histopathologic features of the nervous system were characterized by marked degeneration of the olivo-pontocerebellar system, and mild involvement of the dorsal column pathway. Diffuse atrophy of the cerebellum was evident, but the anterior lobe and vermis were relatively preserved (Fig. 1C). Microscopically, loss of Purkinje cells (PJCs) and granule cells with Bergmann gliosis (arrows) was more prominent in the posterior lobe of the hemisphere. In comparison with a disease control having a similar disease duration (SCAR type 6), loss of granule cells was more conspicuous in the patient, even in regions where PJCs were similarly depleted (Fig. 1D). Focal dendritic swellings of the PJCs (ie asteroid bodies), known to occur when granule cells loss is prominent (8), were scattered in the anterior lobe (Fig. 1E). In the cerebellar afferent system, degeneration of the pontine nucleus and inferior olivary nucleus was remarkable (Fig. 1F, G). The degeneration of the vestibular nuclei was milder than that of