title: Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure.
abstract: BACKGROUND
  In hereditary myopathy with early respiratory failure (HMERF), cytoplasmic bodies (CBs) are often localised in subsarcolemmal regions, with necklace-like alignment (necklace CBs), in muscle fibres although their sensitivity and specificity are unknown.
  
  
  OBJECTIVE
  To elucidate the diagnostic value of the necklace CBs in the pathological diagnosis of HMERF among myofibrillar myopathies (MFMs).
  
  
  METHODS
  We sequenced the exon 343 of TTN gene (based on ENST00000589042), which encodes the fibronectin-3 (FN3) 119 domain of the A-band and is a mutational hot spot for HMERF, in genomic DNA from 187 patients from 175 unrelated families who were pathologically diagnosed as MFM. We assessed the sensitivity and specificity of the necklace CBs for HMERF by re-evaluating the muscle pathology of our patients with MFM.
  
  
  RESULTS
  TTN mutations were identified in 17 patients from 14 families, whose phenotypes were consistent with HMERF. Among them, 14 patients had necklace CBs. In contrast, none of other patients with MFM had necklace CBs except for one patient with reducing body myopathy. The sensitivity and specificity were 82% and 99%, respectively. Positive predictive value was 93% in the MFM cohort.
  
  
  CONCLUSIONS
  The necklace CB is a useful diagnostic marker for HMERF. When muscle pathology shows necklace CBs, sequencing the FN3 119 domain of A-band in TTN should be considered.
authors.affiliation: Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, Tokyo, Japan Department of Education, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Uruha
authors.affiliation: Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, Tokyo, Japan Department of Neurophysiology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.affiliation: Department of Neurology, National Center Hospital, NCNP, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Oya
authors.affiliation: Department of Neurology, National Center Hospital, NCNP, Tokyo, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Mori-Yoshimura
authors.affiliation: Department of Neurology, National Center Hospital, NCNP, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kanai
authors.affiliation: Department of Neurology, National Center Hospital, NCNP, Tokyo, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Murata
authors.affiliation: Department of Neurology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kawamura
authors.affiliation: Institute of Clinical Research/Department of Neurology, National Hospital Organization Higashisaitama Hospital, Saitama, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Department of Neurology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Matsumura
authors.affiliation: Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Neurology, Osaka Red Cross Hospital, Osaka, Japan Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Aomori, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawarabayashi
authors.affiliation: Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Norito
authors.initials: N
authors.lastname: Kokubun
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yokoi
authors.affiliation: Department of Neurology, National Hospital Organization Maizuru Medical Center, Kyoto, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Yasuda
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kira
authors.affiliation: Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, Tokyo, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Mitsuhashi
authors.affiliation: Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, Tokyo, Japan Institute of Clinical Research/Department of Neurology, National Hospital Organization Higashisaitama Hospital, Saitama, Japan.
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.affiliation: Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, Tokyo, Japan.
authors.forename: Ichizo
authors.identifier: http://orcid.org/0000-0001-9452-112X
authors.initials: I
authors.lastname: Nishino
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D064211:Connectin / Q000235:genetics; D003593:Cytoplasm / Q000473:pathology* / Q000648:ultrastructure; D005260:Female; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D012131:Respiratory Insufficiency / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human
keywords: MYOPATHY; PATHOLOGY