Akinori Uruha1, Yukiko K Hayashi2, Yasushi Oya3, Madoka Mori-Yoshimura3, Masahiro Kanai3, Miho Murata3, Mayumi Kawamura4, Katsuhisa Ogata5, Tsuyoshi Matsumura6, Shigeaki Suzuki7, Yukako Takahashi8, Takayuki Kondo9, Takeshi Kawarabayashi10, Yuko Ishii11, Norito Kokubun11, Satoshi Yokoi12, Rei Yasuda13, Jun-ichi Kira14, Satomi Mitsuhashi15, Satoru Noguchi15, Ikuya Nonaka16, Ichizo Nishino15. 1. 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. 2. 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. 3. Department of Neurology, National Center Hospital, NCNP, Tokyo, Japan. 4. Department of Neurology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan. 5. Institute of Clinical Research/Department of Neurology, National Hospital Organization Higashisaitama Hospital, Saitama, Japan. 6. Department of Neurology, National Hospital Organization Toneyama National Hospital, Osaka, Japan. 7. Department of Neurology, Keio University School of Medicine, Tokyo, Japan. 8. Department of Neurology, Osaka Red Cross Hospital, Osaka, Japan Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 9. Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 10. Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Aomori, Japan. 11. Department of Neurology, Dokkyo Medical University, Tochigi, Japan. 12. Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 13. Department of Neurology, National Hospital Organization Maizuru Medical Center, Kyoto, Japan. 14. Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 15. 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. 16. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.