Yoshihiko Saito1,2,3,4,5,6,7,8,9, Atsuko Nishikawa1,2,3,4,5,6,7,8,9, Aritoshi Iida1,2,3,4,5,6,7,8,9, Madoka Mori-Yoshimura1,2,3,4,5,6,7,8,9, Yasushi Oya1,2,3,4,5,6,7,8,9, Akihiko Ishiyama1,2,3,4,5,6,7,8,9, Hirofumi Komaki1,2,3,4,5,6,7,8,9, Seigo Nakamura1,2,3,4,5,6,7,8,9, Susumu Fujikawa1,2,3,4,5,6,7,8,9, Takashi Kanda1,2,3,4,5,6,7,8,9, Misaki Yamadera1,2,3,4,5,6,7,8,9, Hiroshi Sakiyama1,2,3,4,5,6,7,8,9, Shinichiro Hayashi1,2,3,4,5,6,7,8,9, Ikuya Nonaka1,2,3,4,5,6,7,8,9, Satoru Noguchi10,11,12,13,14,15,16,17,18, Ichizo Nishino1,2,3,4,5,6,7,8,9. 1. Yoshihiko Saito, Atsuko Nishikawa, Shinichiro Hayashi, Ikuya Nonaka, Satoru Noguchi and Ichizo Nishino, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Department of Neuromuscular Research, Tokyo, Japan. 2. Yoshihiko Saito, Aritoshi Iida, Shinichiro Hayashi, Satoru Noguchi and Ichizo Nishino, Medical Genome Center, NCNP, Tokyo, Japan. 3. Yoshihiko Saito, University of Yamanashi, Integrated Graduate School of Medicine, Engineering, and Agricultural Science, Yamanashi, Japan. 4. Madoka Mori-Yoshimura and Yasushi Oya, National Center Hospital, NCNP, Department of Neurology, Tokyo, Japan. 5. Akihiko Ishiyama and Hirofumi Komaki, National Center Hospital, NCNP, Department of Child Neurology, Tokyo, Japan. 6. Seigo Nakamura, National Hospital Organization, Shizuoka Medical Center, Department of Neurology, Shizuoka, Japan. 7. Susumu Fujikawa and Takashi Kanda, Yamaguchi University Graduate School of Medical Science, Department of Neurology and Clinical Neuroscience, Yamaguchi, Japan. 8. Misaki Yamadera and Hiroshi Sakiyama, Osaka Toneyama Medical Center, Department of Neurology, Osaka, Japan. 9. Hiroshi Sakiyama, Osaka University Graduate School of Medicine, Department of Neurology, Osaka, Japan. 10. Yoshihiko Saito, Atsuko Nishikawa, Shinichiro Hayashi, Ikuya Nonaka, Satoru Noguchi and Ichizo Nishino, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Department of Neuromuscular Research, Tokyo, Japan noguchi@ncnp.go.jp. 11. Yoshihiko Saito, Aritoshi Iida, Shinichiro Hayashi, Satoru Noguchi and Ichizo Nishino, Medical Genome Center, NCNP, Tokyo, Japan noguchi@ncnp.go.jp. 12. Yoshihiko Saito, University of Yamanashi, Integrated Graduate School of Medicine, Engineering, and Agricultural Science, Yamanashi, Japan noguchi@ncnp.go.jp. 13. Madoka Mori-Yoshimura and Yasushi Oya, National Center Hospital, NCNP, Department of Neurology, Tokyo, Japan noguchi@ncnp.go.jp. 14. Akihiko Ishiyama and Hirofumi Komaki, National Center Hospital, NCNP, Department of Child Neurology, Tokyo, Japan noguchi@ncnp.go.jp. 15. Seigo Nakamura, National Hospital Organization, Shizuoka Medical Center, Department of Neurology, Shizuoka, Japan noguchi@ncnp.go.jp. 16. Susumu Fujikawa and Takashi Kanda, Yamaguchi University Graduate School of Medical Science, Department of Neurology and Clinical Neuroscience, Yamaguchi, Japan noguchi@ncnp.go.jp. 17. Misaki Yamadera and Hiroshi Sakiyama, Osaka Toneyama Medical Center, Department of Neurology, Osaka, Japan noguchi@ncnp.go.jp. 18. Hiroshi Sakiyama, Osaka University Graduate School of Medicine, Department of Neurology, Osaka, Japan noguchi@ncnp.go.jp.
Abstract
OBJECTIVE: To elucidate the prevalence of Japanese ADSSL1 myopathy and determine the clinicopathological features of the disease. METHODS: We searched for ADSSL1 variants in myopathic patients from January 1978 to March 2019 in our repository and assessed the clinicopathological features of patients with variants. RESULTS: We identified 63 patients from 59 families with bi-allelic variants of ADSSL1. Among the seven distinct variants identified, c.781G>A and c.919delA accounted for 53.2% and 40.5% of alleles, respectively, suggesting the presence of common founders, while the other five were novel. Most of the identified patients displayed more variable muscle symptoms, including symptoms in the proximal and/or distal leg muscles, tongue, masseter, diaphragm, and paraspinal muscles, in adolescence than previously reported patients. Dysphagia with masticatory dysfunction developed in 26 out of 63 patients; hypertrophic cardiomyopathy developed in 12 out of 48 patients; and restrictive ventilatory insufficiency developed in 26 out of 34 patients in later stages. Radiologically, fat infiltration into the periphery of vastus lateralis, gastrocnemius, and soleus muscles was observed in all patients. Pathologically, nemaline bodies in addition to increased lipid droplets and myofibrillar disorganization were commonly observed in all patients, suggesting that the disease may be classified as nemaline myopathy. This finding revealed that ADSSL1 myopathy is the most frequent among all genetically-diagnosable nemaline myopathies in our center. CONCLUSIONS: ADSSL1 myopathy is characterized by more variable manifestations than previously reported. It is the most common among all genetically-diagnosable nemaline myopathies in our center, although mildly increased lipid droplets are also constantly observed features.
OBJECTIVE: To elucidate the prevalence of Japanese ADSSL1myopathy and determine the clinicopathological features of the disease. METHODS: We searched for ADSSL1 variants in myopathicpatients from January 1978 to March 2019 in our repository and assessed the clinicopathological features of patients with variants. RESULTS: We identified 63 patients from 59 families with bi-allelic variants of ADSSL1. Among the seven distinct variants identified, c.781G>A and c.919delA accounted for 53.2% and 40.5% of alleles, respectively, suggesting the presence of common founders, while the other five were novel. Most of the identified patients displayed more variable muscle symptoms, including symptoms in the proximal and/or distal leg muscles, tongue, masseter, diaphragm, and paraspinal muscles, in adolescence than previously reported patients. Dysphagia with masticatory dysfunction developed in 26 out of 63 patients; hypertrophic cardiomyopathy developed in 12 out of 48 patients; and restrictive ventilatory insufficiency developed in 26 out of 34 patients in later stages. Radiologically, fat infiltration into the periphery of vastus lateralis, gastrocnemius, and soleus muscles was observed in all patients. Pathologically, nemaline bodies in addition to increased lipid droplets and myofibrillar disorganization were commonly observed in all patients, suggesting that the disease may be classified as nemaline myopathy. This finding revealed that ADSSL1myopathy is the most frequent among all genetically-diagnosable nemaline myopathies in our center. CONCLUSIONS:ADSSL1myopathy is characterized by more variable manifestations than previously reported. It is the most common among all genetically-diagnosable nemaline myopathies in our center, although mildly increased lipid droplets are also constantly observed features.