CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations
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(2020) 8:204
Open Access
RESEARCH
CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations Masashi Ogasawara1,2,3, Aritoshi Iida2, Theerawat Kumutpongpanich1, Ayami Ozaki1, Yasushi Oya4, Hirofumi Konishi5, Akinori Nakamura6, Ryuta Abe7, Hiroshi Takai8, Ritsuko Hanajima9, Hiroshi Doi10, Fumiaki Tanaka10, Hisayoshi Nakamura2, Ikuya Nonaka1, Zhaoxia Wang11, Shinichiro Hayashi1,2, Satoru Noguchi1,2 and Ichizo Nishino1,2*
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. Keywords: Oculopharyngodistal myopathy, NOTCH2NLC, CGG repeat expansion, Neuronal intranuclear inclusion disease, Oculopharyngeal muscular dystrophy
*Correspondence: [email protected] 1 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4‑1‑1 Ogawahigashi, Kodaira, Tokyo 187‑8502, Japan Full list of author information is available at the end of the article
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
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