Abstract：
BACKGROUND: Oculopharyngodistal myopathy (OPDM) is a rare adult-onset neuromuscular disease, associated with CGG repeat expansions in the 5\' untranslated region of LRP12, GIPC1, NOTCH2NLC and RILPL1. However, the genetic cause of a proportion of pathoclinically confirmed cases remains unknown.
METHODS: A total of 26 OPDM patients with unknown genetic cause(s) from 4 tertiary referral hospitals were included in this study. Clinical data and laboratory findings were collected. Muscle samples were observed by histological and immunofluorescent staining. Long-read sequencing was initially conducted in six patients with OPDM. Repeat-primed PCR was used to screen the CGG repeat expansions in LOC642361/NUTM2B-AS1 in all 26 patients.
RESULTS: We identified CGG repeat expansion in the non-coding transcripts of LOC642361/NUTM2B-AS1 in another two unrelated Chinese cases with typical pathoclinical features of OPDM. The repeat expansion was more than 70 times in the patients but less than 40 times in the normal controls. Both patients showed no leucoencephalopathy but one showed mild cognitive impairment detected by Montreal Cognitive Assessment. Rimmed vacuoles and p62-positive intranuclear inclusions (INIs) were identified in muscle pathology, and colocalisation of CGG RNA foci with p62 was also found in the INIs of patient-derived fibroblasts.
CONCLUSIONS: We identified another two unrelated cases with CGG repeat expansion in the long non-coding RNA of the LOC642361/NUTM2B-AS1 gene, presenting with a phenotype of OPDM. Our cases broadened the recognised phenotypic spectrum and pathogenesis in the disease associated with CGG repeat expansion in LOC642361/NUTM2B-AS1.
METHODS: A total of 26 OPDM patients with unknown genetic cause(s) from 4 tertiary referral hospitals were included in this study. Clinical data and laboratory findings were collected. Muscle samples were observed by histological and immunofluorescent staining. Long-read sequencing was initially conducted in six patients with OPDM. Repeat-primed PCR was used to screen the CGG repeat expansions in LOC642361/NUTM2B-AS1 in all 26 patients.
RESULTS: We identified CGG repeat expansion in the non-coding transcripts of LOC642361/NUTM2B-AS1 in another two unrelated Chinese cases with typical pathoclinical features of OPDM. The repeat expansion was more than 70 times in the patients but less than 40 times in the normal controls. Both patients showed no leucoencephalopathy but one showed mild cognitive impairment detected by Montreal Cognitive Assessment. Rimmed vacuoles and p62-positive intranuclear inclusions (INIs) were identified in muscle pathology, and colocalisation of CGG RNA foci with p62 was also found in the INIs of patient-derived fibroblasts.
CONCLUSIONS: We identified another two unrelated cases with CGG repeat expansion in the long non-coding RNA of the LOC642361/NUTM2B-AS1 gene, presenting with a phenotype of OPDM. Our cases broadened the recognised phenotypic spectrum and pathogenesis in the disease associated with CGG repeat expansion in LOC642361/NUTM2B-AS1.
摘要：
背景：眼咽远端肌病（OPDM）是一种罕见的成人发作的神经肌肉疾病，与LRP12、GIPC1、NOTCH2NLC和RILPL1的5'非翻译区中的CGG重复扩增相关。然而,部分病理临床确诊病例的遗传原因尚不清楚.
方法：本研究纳入了来自4所三级转诊医院的26例遗传原因不明的OPDM患者。收集临床数据和实验室检查结果。通过组织学和免疫荧光染色观察肌肉样品。长读测序最初在6名OPDM患者中进行。使用重复引发的PCR在所有26名患者中筛选LOC642361/NUTM2B-AS1中的CGG重复扩增。
结果：我们在另外两个具有典型OPDM病理临床特征的无关中国病例中，在LOC642361/NUTM2B-AS1的非编码转录物中发现CGG重复扩增。患者的重复扩张超过70倍，但正常对照组的重复扩张少于40倍。两名患者均未表现出白质脑病，但其中一名患者表现出通过蒙特利尔认知评估发现的轻度认知障碍。在肌肉病理学中鉴定出菱形空泡和p62阳性核内包涵体（INIs），在患者来源的成纤维细胞的INI中也发现了CGGRNA病灶与p62的共定位。
结论：我们在LOC642361/NUTM2B-AS1基因的长非编码RNA中发现了另外两个不相关的CGG重复扩增病例，呈现OPDM表型。我们的病例扩大了LOC642361/NUTM2B-AS1中CGG重复扩增相关疾病的公认表型谱和发病机理。
方法：本研究纳入了来自4所三级转诊医院的26例遗传原因不明的OPDM患者。收集临床数据和实验室检查结果。通过组织学和免疫荧光染色观察肌肉样品。长读测序最初在6名OPDM患者中进行。使用重复引发的PCR在所有26名患者中筛选LOC642361/NUTM2B-AS1中的CGG重复扩增。
结果：我们在另外两个具有典型OPDM病理临床特征的无关中国病例中，在LOC642361/NUTM2B-AS1的非编码转录物中发现CGG重复扩增。患者的重复扩张超过70倍，但正常对照组的重复扩张少于40倍。两名患者均未表现出白质脑病，但其中一名患者表现出通过蒙特利尔认知评估发现的轻度认知障碍。在肌肉病理学中鉴定出菱形空泡和p62阳性核内包涵体（INIs），在患者来源的成纤维细胞的INI中也发现了CGGRNA病灶与p62的共定位。
结论：我们在LOC642361/NUTM2B-AS1基因的长非编码RNA中发现了另外两个不相关的CGG重复扩增病例，呈现OPDM表型。我们的病例扩大了LOC642361/NUTM2B-AS1中CGG重复扩增相关疾病的公认表型谱和发病机理。
