Table_1_Case report: Adult-onset neuronal intranuclear inclusion disease with an amyotrophic lateral sclerosis phenotype.XLSX

Amyotrophic lateral sclerosis (ALS) is one of the differential diagnoses of diseases that occur in adulthood and lead to progressive generalized muscle weakness. Neuronal intranuclear inclusion disease (NIID) is a disease in which histopathologically eosinophilic nuclear inclusion bodies are found in various systems. Both familial and sporadic forms of the disease have been reported. Most cases of sporadic NIID are of the dementia type, in which the main symptom is dementia at the first onset. Familial NIID is more diverse, with the main dominant symptoms being muscle weakness (NIID-M), dementia (NIID-D), and parkinsonism (NIID-P). Furthermore, recently, a GGC-repeat expansion in the Notch 2 N-terminal like C (NOTCH2NLC) gene, which produces a toxic polyglycine-containing protein (uN2CpolyG) in patients with NIID, has been associated with the pathogenesis of ALS. These results suggest that sporadic NIIDs may have more diverse forms. To date, no autopsy cases of NIID patients with an ALS phenotype have been reported. Here, we describe the first autopsy case report of a patient with sporadic NIID who had been clinically diagnosed with ALS. A 65-year-old Japanese man with no family history of neuromuscular disease developed progressive muscle atrophy and weakness in all limbs. The patient was diagnosed with ALS (El Escoriral diagnostic criteria: probable ALS, laboratory-supported ALS). He had no cognitive dysfunction or neuropathies suggestive of NIID. He required respiratory assistance 48 months after onset. He died of pneumonia at the age of 79 years. Postmortem examinations revealed neuronal loss in the spinal anterior horns and motor cortex. In these affected regions, eosinophilic, round neuronal intranuclear inclusions were evident, which were immunopositive for ubiquitin, p62, and uN2CpolyG. No Bunina bodies or TDP-43-positive inclusions were observed in the brain or spinal cord. Our findings suggest that a small proportion of patients with NIID can manifest a clinical phenotype of ALS. Although skin biopsy is commonly used for the clinical diagnosis of NIID, it may also be useful to identify cases of NIID masquerading as ALS.

肌萎缩侧索硬化（Amyotrophic lateral sclerosis, ALS）是一类成年起病、以进行性全身性肌无力为表现的疾病的鉴别诊断之一。神经元核内包涵体病（Neuronal intranuclear inclusion disease, NIID）是一类在多系统中可检出组织病理学嗜酸性核包涵体的疾病，目前已报道其家族性与散发性两种发病形式。绝大多数散发性NIID为痴呆型，以痴呆为首发主要症状；家族性NIID临床表现更为多样，主要显性表型包括肌无力型NIID（NIID-M）、痴呆型NIID（NIID-D）以及帕金森综合征型NIID（NIID-P）。

近期研究发现，NOTCH2NLC基因（Notch 2 N-terminal like C, NOTCH2NLC）的GGC重复扩增可在NIID患者体内产生毒性含聚甘氨酸蛋白（uN2CpolyG），该异常与ALS的发病机制相关。上述结果提示散发性NIID可能存在更为丰富的表型类型。迄今为止，尚无伴ALS表型的NIID患者尸检病例报道。本文报道首例临床诊断为ALS的散发性NIID患者尸检病例。

该患者为65岁日本男性，无神经肌肉疾病家族史，出现进行性四肢肌萎缩与无力，经El Escorial诊断标准确诊为很可能ALS、实验室支持型ALS。患者无认知功能障碍，亦无提示NIID的神经病变表现；发病48个月后需接受呼吸辅助支持，最终于79岁时因肺炎去世。

尸检可见脊髓前角与运动皮层神经元丢失，上述受累区域内可见嗜酸性圆形神经元核内包涵体，该包涵体呈泛素（ubiquitin）、p62及uN2CpolyG免疫阳性。脑与脊髓组织中未检出布尼纳小体（Bunina bodies）或TDP-43阳性包涵体。

本研究结果提示，小部分NIID患者可表现出ALS的临床表型。尽管皮肤活检常用于NIID的临床诊断，但识别伪装为ALS的NIID病例同样具有临床价值。