2. Academic Validation
  3. CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations

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

  • Acta Neuropathol Commun. 2020 Nov 25;8(1):204. doi: 10.1186/s40478-020-01084-4.
Masashi Ogasawara 1 2 3,  Aritoshi Iida 2,  Theerawat Kumutpongpanich 1,  Ayami Ozaki 1,  Yasushi Oya 4,  Hirofumi Konishi 5,  Akinori Nakamura 6,  Ryuta Abe 7,  Hiroshi Takai 8,  Ritsuko Hanajima 9,  Hiroshi Doi 10,  Fumiaki Tanaka 10,  Hisayoshi Nakamura 2,  Ikuya Nonaka 1,  Zhaoxia Wang 11,  Shinichiro Hayashi 1 2,  Satoru Noguchi 1 2,  Ichizo Nishino 12 13
Affiliations

Affiliations

  • 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.
  • 2 Medical Genome Center, NCNP, Kodaira, Tokyo, Japan.
  • 3 Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
  • 4 Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • 5 Department of Neurology, Toyama University Hospital, Toyama, Japan.
  • 6 Department of Clinical Research, National Hospital Organization Matsumoto Medical Center, Matsumoto, Japan.
  • 7 Department of Neurology and Rheumatology, Shinshu University School of Medicine, Matsumoto, Japan.
  • 8 Department of Neurology, Matsue City Hospital, Matsue, Japan.
  • 9 Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
  • 10 Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Fukuura, Kanazawa-ku, Yokohama, Japan.
  • 11 Department of Neurology, Peking University First Hospital, Beijing, China.
  • 12 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan. [email protected].
  • 13 Medical Genome Center, NCNP, Kodaira, Tokyo, Japan. [email protected].
PMID: 33239111 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.

Keywords

CGG repeat expansion; NOTCH2NLC; Neuronal intranuclear inclusion disease; Oculopharyngeal muscular dystrophy; Oculopharyngodistal myopathy.

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