Theerawat Kumutpongpanich1,2, Masashi Ogasawara1,2, Ayami Ozaki1,2, Hiroyuki Ishiura3, Shoji Tsuji3, Narihiro Minami1,2, Shinichiro Hayashi1,2, Satoru Noguchi1,2, Aritoshi Iida2, Ichizo Nishino1,2, Madoka Mori-Yoshimura4, Yasushi Oya4, Kenjiro Ono5, Toshio Shimizu6, Akihiro Kawata6, Shun Shimohama7, Keiko Toyooka8, Kaoru Endo9, Shuta Toru10, Oga Sasaki11, Kenji Isahaya11, Masanori P Takahashi12, Kazuo Iwasa13, Jun-Ichi Kira14, Tatsuya Yamamoto15, Michi Kawamoto16, Tadanori Hamano17, Kazuma Sugie18, Nobuyuki Eura18, Tomo Shiota18, Mizuho Koide19, Kanako Sekiya20, Hideaki Kishi21, Takuto Hideyama22, Shigeru Kawai23, Satoshi Yanagimoto23, Hiroyasu Sato24, Hajime Arahata25, Shigeo Murayama26, Kayoko Saito27, Hideo Hara28, Takashi Kanda29, Hiroshi Yaguchi30, Noboru Imai31, Yuichi Kawagashira32, Mitsuru Sanada33, Kazuki Obara34, Misako Kaido35, Minori Furuta36, Takashi Kurashige37, Wataru Hara38, Daisuke Kuzume39, Mamoru Yamamoto40, Jun Tsugawa41, Hitaru Kishida42, Naoki Ishizuka43, Kohei Morimoto44, Yukio Tsuji44, Atsuko Tsuneyama45, Atsuhiro Matsuno46, Ryo Sasaki47, Daigo Tamakoshi48, Erika Abe49, Shinichiro Yamada50, Akiyuki Uzawa15. 1. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. 2. Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. 3. Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan. 4. Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan. 5. Division of Neurology, Department of Internal Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan. 6. Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan. 7. Department of Neurology, Sapporo Medical University, Sapporo, Japan. 8. Department of Neurology, Osaka Toneyama Medical Center, Osaka, Japan. 9. Department of Neurology, Tohoku University School of Medicine, Miyagi, Japan. 10. Department of Neurology, Nitobe Memorial Nakano General Hospital, Tokyo, Japan. 11. Division of Neurology, Department of Internal Medicine, St Marianna University School of Medicine, Kanagawa, Japan. 12. Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan. 13. Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. 14. Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 15. Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan. 16. Department of Neurology, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan. 17. Second Department of Internal Medicine, Division of Neurology, Department of Aging and Dementia, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. 18. Department of Neurology, Nara Medical University, Nara, Japan. 19. Department of Neurology, Chiba-East National Hospital, Chiba, Japan. 20. Department of Neurology, Niigata City General Hospital, Niigata, Japan. 21. Department of Neurology, Asahikawa Medical Center, Asahikawa, Japan. 22. Department of Neurology, Tokyo Medical University, Tokyo, Japan. 23. Department of Neurology, Kindai University Faculty of Medicine, Osaka, Japan. 24. Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan. 25. Department of Neurology, National Hospital Organization Omuta National Hospital, Omuta, Japan. 26. Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital, Institute of Gerontology, Tokyo, Japan. 27. Institute of Medical Genetics, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan. 28. Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, Japan. 29. Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan. 30. Department of Neurology, The Jikei University Kashiwa Hospital, Kashiwa, Japan. 31. Department of Neurology, Japanese Red Cross Shizuoka Hospital, Shizuoka, Japan. 32. Department of Neurology, Tsushima City Hospital, Aichi, Japan. 33. Department of Neurology, Kanazawa Medical University Hospital, Ishikawa, Japan. 34. Department of Neurology, Anjo Kosei Hospital, Aichi, Japan. 35. Department of Neurology, Sakai City Medical Center, Osaka, Japan. 36. Department of Neurology, Gunma University, Maebashi, Japan. 37. Department of Neurology, National Hospital Organization Kure Medical Center, Chugoku Cancer Center, Kure, Japan. 38. Department of Neurology, Saitama Medical Center, Saitama, Japan. 39. Department of Neurology, Chikamori Hospital, Kochi, Japan. 40. Department of Neurology, Toyama University, Toyama, Japan. 41. Department of Neurology, Fukuoka University, Fukuoka, Japan. 42. Department of Neurology, Yokohama City University Medical Center, Yokohama, Japan. 43. Division of Neurology and Gerontology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Iwate, Japan. 44. Department of Neurology, Kobe University, Kobe, Japan. 45. Department of Neurology, Narita Red Cross Hospital, Chiba, Japan. 46. Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan. 47. Department of Neurology, Okayama University, Okayama, Japan. 48. Department of Neurology, Chukyo Hospital, Nagoya, Japan. 49. Department of Neurology, National Hospital Organization Akita Hospital, Akita, Japan. 50. Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Abstract
Importance: Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective: To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, Setting, and Participants: This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main Outcomes and Measures: Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results: Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and Relevance: This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.
Importance: Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective: To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, Setting, and Participants: This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main Outcomes and Measures: Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results: Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and Relevance: This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.