RFC1扩增导致的CANVAS运动神经元病理学
Motor neuron pathology in CANVAS due to RFC1 expansions
摘要：
由RFC 1双等位基因扩增引起的CANVAS是遗传性感觉神经元病的主要原因。RFC 1扩增的检测具有挑战性，CANVAS可能与非典型特征相关。我们的临床和遗传特征的50例患者，选择的基础上存在的感觉神经元病证实的肌电图。我们通过PCR、重复引物PCR和长距离PCR产物的Southern印迹（一种新开发的方法）筛选RFC 1扩增。对1例患者的脑和脊髓进行了神经病理学表征。大多数患者（88%）在RFC 1中携带双等位基因（AAGGG）n扩增。除了核心CANVAS表型（感觉神经元病、小脑综合征和前庭损伤）外，我们还观察到慢性咳嗽（97%）、眼部体征（85%）、运动神经元受累（55%）、自主神经功能障碍（50%）和帕金森综合征（10%）。运动神经元受累24例（63.1%）。29%的患者出现第一运动神经元体征，如快速反射、足底伸肌反应和/或痉挛状态，18%的患者出现第二运动神经元体征，如肌束震颤、消瘦、虚弱或EMG上的神经源性模式，16%的患者同时出现这两种体征。在19%的患者中观察到混合运动和感觉神经元病。在6名非RFC 1患者中，1名患者携带杂合AAGGG扩增和GRM 1致病性变体。1例RFC 1患者的神经病理学检查显示，患者具有丰富的表型，包括帕金森综合征、自主神经功能障碍和认知能力下降，表现为后柱和腰椎后根萎缩。前庭脊髓束和脊髓小脑束轻度变性。我们观察到明显的星形胶质细胞增生和轴突肿胀的突触之间的第一和第二运动神经元的前角在腰椎水平。小脑显示浦肯野细胞轻度耗竭，空篮，鱼雷和星形胶质细胞增生，其特征在于伯格曼放射状胶质细胞的解体。我们在迷走神经核发现了神经元缺失。黑质的延髓部被耗尽，蓝斑、黑质、海马、内嗅皮质和杏仁核中广泛存在路易体。我们提出了新的指导方针筛选RFC 1扩展，考虑不同的扩展图案。在这里，我们开发了一种新的方法来更容易地检测致病性RFC 1扩增。我们报告频繁的运动神经元受累和不同的神经元病亚型。帕金森综合征在该队列中比在一般人群中更普遍，10%比预期的1%（p <0.001）。我们首次描述了CANVAS的脊髓病理，显示了后柱和根的改变，星形胶质细胞增生和轴突肿胀，表明运动神经元突触功能障碍。
英文摘要：
CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome, and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (p < .001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.
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