CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations

Masashi Ogasawara,Satoru Noguchi,Ichizo Nishino,Aritoshi Iida,Fumiaki Tanaka,Hisayoshi Nakamura,Hiroshi Takai,Ikuya Nonaka,Akinori Nakamura,Yasushi Oya,Shinichiro Hayashi,Theerawat Kumutpongpanich,Zhaoxia Wang,Ryuta Abe,Ritsuko Hanajima,Hiroshi Doi,Hirofumi Konishi,Ayami Ozaki

doi:10.1186/s40478-020-01084-4

Abstract

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. We aimed to identify and to clinicopathologically characterize patients with OPDM who have CGG repeat expansions in NOTCH2NLC (OPDM_NOTCH2NLC). Note that 211 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 identified patients with OPDM_NOTCH2NLC were re-reviewed. Intra-myonuclear inclusions were evaluated using immunohistochemistry and electron microscopy (EM). Seven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC. All seven patients clinically demonstrated ptosis, ophthalmoplegia, dysarthria and muscle weakness; they myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which were diagnostic of NIID (typically on skin biopsy), in addition to rimmed vacuoles. The sample for EM was available only from one patient, which demonstrated intranuclear inclusions of 12.6 ± 1.6 nm in diameter. We identified seven patients with OPDM_NOTCH2NLC. Our patients had various additional central and/or peripheral nervous system involvement, although all were clinicopathologically compatible; thus, they were diagnosed as having OPDM and expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC.

Highlights

Oculopharyngodistal myopathy (OPDM) is a rare adultonset hereditary muscle disease clinically characterized by progressive ocular, pharyngeal, and distal limb muscle involvement and pathologically by rimmed vacuoles in muscle fibers [11, 20]
Genetic analysis Note that 211 patients were screened for CGG expansions in NOTCH2NLC by repeat primed-PCR (RP-PCR), and the CGG repeat length in patients who had expanded CGG repeats was determined by fragment analysis and/ or Southern blotting, as previously described [6, 13]
Dysphagia and facial muscle weakness were detected in five (71%) patients

Summary

Introduction

Oculopharyngodistal myopathy (OPDM) is a rare adultonset hereditary muscle disease clinically characterized by progressive ocular, pharyngeal, and distal limb muscle involvement and pathologically by rimmed vacuoles in muscle fibers [11, 20]. Two causative genes, LRP12 and GIPC1, were identified for OPDM (thereby, Ogasawara et al acta neuropathol commun (2020) 8:204 we refer to them as OPDM_LRP12 and OPDM_GIPC1, respectively) In both diseases, CGG repeat expansions in the noncoding regions of the corresponding genes were believed to be the cause, the pathogenesis remained largely unclear [2, 6]. Patients with OPDM were rarely reported to have accompanying sensorineural hearing loss and demyelinating neuropathy [3] The presence of such patients with NIID and OPDM raised a possibility that OPDM in certain patients, those with additional neurological manifestations, could be caused by the same pathogenic mechanism as NIID. We evaluated CGG expansions in NOTCH2NLC in patients who were suspected to have OPDM

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