Background Oculopharyngodistal myopathy (OPDM) is a rare hereditary muscle disease characterized by progressive distal limb weakness, ptosis, ophthalmoplegia, bulbar muscle weakness and rimmed vacuoles on muscle biopsy. Recently, CGG repeat expansions in the noncoding regions of two genes, LRP12 and GIPC1, have been reported to be causative for OPDM. Furthermore, neuronal intranuclear inclusion disease (NIID) has been recently reported to be caused by CGG repeat expansions in NOTCH2NLC. Objectives To identify and to clinicopathologically characterize OPDM patients who have CGG repeat expansions in NOTCH2NLC (OPDM_NOTCH2NLC). Methods Two hundred eleven patients from 201 families, who were clinically or clinicopathologically diagnosed with OPDM or oculopharyngeal muscular dystrophy, were screened for CGG expansions in NOTCH2NLC by repeat primed-PCR. Clinical information and muscle pathology slides of the identified OPDM_NOTCH2NLC patients were re-reviewed. Intra-myonuclear inclusions were further evaluated by immunohistochemistry and electron microscopy. Results Seven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC. All seven patients clinically had ptosis, ophthalmoplegia, dysarthria, and muscle weakness, and myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which are diagnostic of NIID typically on skin biopsy, in addition to rimmed vacuoles. Sample for electron microscopy was available only from one patient, which showed intranuclear inclusions of 12.6 ± 1.6 nm in diameter. Conclusions We identified seven OPDM_NOTCH2NLC patients. Our patients had various additional central and/or peripheral nervous system involvement, albeit all being clinicopathologically compatible; thus, diagnosed as having OPDM, expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC.

中文翻译：

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NOTCH2NLC中的CGG扩展与具有神经系统表现的眼咽二部肌病有关

背景咽咽部肌病（OPDM）是一种罕见的遗传性肌肉疾病，其特征是进行渐进性四肢远端无力，上睑下垂，眼肌麻痹，延髓肌无力和肌肉活检上的边缘性液泡。最近，据报道CGG在两个基因LRP12和GIPC1的非编码区中的重复扩增是OPDM的病因。此外，近来已报道神经元核内包涵体疾病（NIID）是由NOTCH2NLC中的CGG重复扩增引起的。目的鉴定并在NOTCH2NLC（OPDM_NOTCH2NLC）中具有CGG重复扩增的OPDM患者并进行临床病理学表征。方法通过重复引物PCR筛选201例家庭或临床诊断为OPDM或眼咽肌营养不良症的211例患者的CGG扩增。重新审查已确定的OPDM_NOTCH2NLC患者的临床信息和肌肉病理切片。通过免疫组织化学和电子显微镜进一步评估了肌内核包裹体。结果7名日本OPDM患者在NOTCH2NLC中出现CGG重复扩增。所有7例患者在临床上均患有上睑下垂，眼肌麻痹，构音困难和肌肉无力，并且在肌病理学上具有被抗多泛素化蛋白，抗SUMO1和抗p62抗体染色的肌核内包裹物，这些抗体通常可在皮肤活检中诊断为NIID，除了有边缘的液泡。仅一名患者可获得用于电子显微镜检查的样品，该样品显示出核内夹杂物的直径为12.6±1.6 nm。结论我们确定了7名OPDM_NOTCH2NLC患者。尽管所有患者在临床病理上都是相容的，但他们的中枢神经系统和/或周围神经系统也有多种受累。因此，被诊断为患有OPDM，会扩大NOTCH2NLC中CGG重复扩增引起的神经退行性疾病的表型。