Kohei Hamanaka

Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy

Objective To elucidate the common and distinct clinical features of immune-mediated necrotising myopathy (IMNM), also known as necrotising autoimmune myopathy associated with autoantibodies against signal recognition particle (SRP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Methods We examined a cohort of 460 patients with idiopathic inflammatory myopathies (IIMs) through a muscle biopsy-oriented registration study in Japan. Study entry was strictly determined by the comprehensive histological assessment to exclude other neuromuscular disorders. Anti-SRP and anti-HMGCR antibodies were detected by RNA immunoprecipitation and ELISA, respectively. Results Of 460 patients with IIM, we diagnosed 73 (16%) as having inclusion body myositis (IBM). Of 387 patients with IIMs other than IBM, the frequencies of anti-SRP and anti-HMGCR antibodies were 18% and 12%, respectively. One patient had both autoantibodies. Severe limb muscle weakness, neck weakness, dysphagia, respiratory insufficiency and muscle atrophy were more frequently observed in patients with anti-SRP antibodies than in those with anti-HMGCR antibodies. Serum creatine levels were markedly higher in the patients with autoantibodies than in those without. Histology was characterised by necrosis and regeneration of muscle fibres and was consistent with IMNM except in 1 HMGCR-positive IBM patient. Most patients were initially treated with corticosteroids; however, additional immunosuppressive drugs were required, especially in the patients with anti-SRP antibodies. Rates of unsatisfactory neurological outcome were similar in the 2 autoantibody groups. Conclusions Anti-SRP antibodies are associated with severe neurological symptoms, more so than are anti-HMGCR antibodies. Although these autoantibodies are independent serological markers associated with IMNM, patients bearing either share common characteristics.

Sarcoplasmic MxA expression: A valuable marker of dermatomyositis.

Objective: To evaluate the diagnostic value of myxovirus resistance A (MxA) expression in the cytoplasm of myofibers in the diagnosis of dermatomyositis (DM). Methods: We assessed the sensitivity and specificity of the sarcoplasmic expression of MxA in muscles with DM by immunohistochemistry in consecutive cases of DM (n = 34) and other idiopathic inflammatory myopathies (n = 120: 8 with polymyositis, 16 with anti–tRNA-synthetase antibody–associated myositis, 46 with immune-mediated necrotizing myopathy, and 50 with inclusion body myositis) and compared them with conventional pathologic hallmarks of DM, including perifascicular atrophy (PFA) and membrane attack complex (MAC) deposition on endomysial capillaries. Results: The sensitivity and specificity of sarcoplasmic MxA expression were 71% and 98%, respectively. While the specificity was almost comparable to that of PFA and capillary MAC deposition, the sensitivity was higher, with PFA showing 47% sensitivity and 98% specificity and capillary MAC deposition showing 35% sensitivity and 93% specificity. Of note, in patients with DM with typical skin rash but no PFA, 44% of the samples showed sarcoplasmic MxA expression, which was higher than the 17% sensitivity of capillary MAC deposition in the population. Conclusions: Sarcoplasmic MxA expression detected by immunohistochemistry is a more sensitive marker of DM than the conventional hallmarks, indicating its practical utility in the diagnosis of DM. It may well be included in the routine immunohistochemistry panel for myositis. Classification of evidence: This study provides Class II evidence that immunohistochemistry-detected sarcoplasmic MxA expression accurately identifies patients with dermatomyositis.

Pediatric necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies

Objective. Antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have recently been associated with immune-mediated necrotizing myopathy, especially in patients with statin exposure. As the data are very limited concerning phenotypes and treatment in paediatric patients, we aimed to identify the paediatric patients positive for anti-HMGCR antibodies and clarify their features and therapeutic strategies. Methods. We screened 62 paediatric patients who were clinically and/or pathologically suspected to have inflammatory myopathy for anti-HMGCR antibodies. We further re-assessed the clinical and histological findings and the treatment of the patients positive for anti-HMGCR antibodies. Results. We identified nine paediatric patients with anti-HMGCR antibodies (15%). This was more frequent than anti-signal recognition particle antibodies (four patients, 6%) in our cohort. The onset age ranged from infancy to 13 years. Five patients were initially diagnosed with muscular dystrophy, including congenital muscular dystrophy. Most patients responded to high-dose corticosteroid therapy first but often needed adjuvant immunosuppressants to become stably controlled. Conclusion.Paediatric necrotizing myopathy associated with anti-HMGCR antibodies may not be very rare. Phenotypes are similar to those of adult patients, but a chronic slowly progressive course may be more frequent. Some patients share the clinicopathological features of muscular dystrophy indicating that recognizing inflammatory aetiology would be challenging without autoantibody information. On the other hand, most patients responded to treatment, especially those who were diagnosed early. Our results suggest the importance of early autoantibody testing in paediatric patients who have manifestations apparently compatible with muscular dystrophy in addition to those who have typical features of inflammatory myopathy.

Skeletal Muscle Involvement in Antisynthetase Syndrome

Importance Antisynthetase syndrome, characterized by myositis, interstitial lung disease, skin rash, arthropathy, and Raynaud phenomenon, is a clinical entity based on the presence of aminoacyl transfer RNA synthetase (ARS) antibodies in patients’ serum. However, antisynthetase syndrome is not included in the histological subsets of idiopathic inflammatory myopathies. Objective To elucidate the clinical features of myositis in patients with antisynthetase syndrome. Design, Setting, and Participants In this cohort study, muscle biopsy and blood samples were collected from 460 patients with idiopathic inflammatory myositis from various regional referral centers throughout Japan between October 2010 and December 2014. Data were analyzed in March 2016. Exposures Six different anti-ARS antibodies were detected in serum by RNA immunoprecipitation. Line blot assay and protein immunoprecipitation were also performed. HLA-DRB1 alleles were genotyped. Main Outcomes and Measures The main outcomes were muscle manifestations and histological findings. Predisposing factors, extramuscular symptoms, and follow-up information were also studied. Results Of 460 patients with idiopathic inflammatory myopathies, 51 (11.1%) had anti-ARS antibodies. Of this subset, 31 (61%) were women, with a mean (SD) age at disease onset of 60.2 (16.1) years. Among 6 different anti-ARS antibodies, only 1—the anti-OJ antibody—was not detected by line blot assay but by RNA immunoprecipitation. There were no significant HLA-DRB1 alleles associated with anti-ARS antibodies. All 51 patients presented with muscle limb weakness; 14 (27%) had severe limb weakness, 17 (33%) had neck muscle weakness, 15 (29%) had dysphagia, and 15 (29%) had muscle atrophy. Although patients with anti-OJ antibodies showed severe muscle weakness, the clinical presentations of antisynthetase syndrome were relatively homogeneous. In histology, perifascicular necrosis, the characteristic finding of antisynthetase syndrome, was found in 24 patients (47%). Myositis with anti-ARS antibodies responded to the combination of immunosuppressive therapy with favorable outcomes. Interstitial lung disease, found in 41 patients (80%), was more closely associated with mortality than myositis. Conclusions and Relevance Although clinical presentations of antisynthetase syndrome were relatively homogeneous, anti-OJ antibodies were associated with severe muscle involvement. Antisynthetase syndrome is a clinical and histological subset among idiopathic inflammatory myopathies.

HLA-DRB1 alleles in immune-mediated necrotizing myopathy

Immune-mediated necrotizing myopathy (IMNM), also known as necrotizing autoimmune myopathy, is a histologic entity characterized by marked necrosis in the absence of prominent lymphocytes.1 Risk factors or triggers for IMNM include statin treatment, cancer, and connective tissue disease (CTD).1,2 Although autoantibodies against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are regarded as markers for IMNM, they are not always detected in sera of pathologically defined patients with IMNM. The autoimmune mechanisms of IMNM are not elucidated.

Muscle from a 20-week-old myotubular myopathy fetus is not myotubular

Muscle from a 20-week-old myotubular myopathy fetus is not myotubular Kohei Hamanaka , Ikuhiro Inami , Takahito Wada , Satomi Mitsuhashi , Satoru Noguchi , Yukiko K. Hayashi , Ichizo Nishino * a Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan b Department of Neurology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan c Inami Pediatrics & Family Medical Clinic, 1-45 Hodononaka, Akita, Akita 010-0905, Japan d Department of Medical Ethics and Medical Genetics, School of Public Health, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan e Department of Clinical Development, Medical Genome Center, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8551, Japan f Department of Pathophysiology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan

Corrigendum to “Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations”: [Neuromuscular Disorders 26/4–5 (2016) 300–308]

Corrigendum to “Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations” [Neuromuscular Disorders 26/4–5 (2016) 300–308] Kohei Hamanaka, Kanako Goto, Mami Arai, Koji Nagao, Chikashi Obuse, Satoru Noguchi, Yukiko K. Hayashi, Satomi Mitsuhashi*, Ichizo Nishino Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan Department of Neurology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan Graduate School of Life Science, Hokkaido University, Kita 10 Nishi 8, Kita, Sapporo, Hokkaido 060-0810, Japan Department of Clinical Development, Medical Genome Center, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan Department of Pathophysiology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan

A 62-Year-Old Woman with A History of Muscle Pain and Skin Rash for 1 Month: Correspondence

The patient was a 62-year-old woman who presented at the hospital with a one-month history of muscle pain and skin rash. Before this visit, she had experienced fever for 2 months. She had no other underlying medical condition except for rheumatoid arthritis which had been treated for over 20 years. Physical examination revealed mild symmetrical proximal muscle weakness of both upper and lower extremities (Medical Research Council grade 4). Erythema was observed in lower legs. Serum creatine kinase (CK) was 2048 U/L (normal range 32–180 U/L). Muscle biopsy was performed in the left tibialis anterior muscle.

Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations

Facioscapulohumeral muscular dystrophy 2 (FSHD2) is a genetic muscular disorder characterized by DNA hypomethylation on the 4q-subtelomeric macrosatellite repeat array, D4Z4. FSHD2 is caused by heterozygous mutations in the gene encoding structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1). Because there has been no study on FSHD2 in Asian populations, it is not known whether this disease mechanism is widely seen. To identify FSHD2 patients with SMCHD1 mutations in the Japanese population, bisulfite pyrosequencing was used to measure DNA methylation on the D4Z4 repeat array, and in patients with DNA hypomethylation, the SMCHD1 gene was sequenced by the Sanger method. Twenty patients with D4Z4 hypomethylation were identified. Of these, 13 patients from 11 unrelated families had ten novel and one reported SMCHD1 mutations: four splice-site, two nonsense, two in-frame deletion, two out-of-frame deletion, and one missense mutations. One of the splice-site mutations was homozygous in the single patient identified with this. In summary, we identified novel SMCHD1 mutations in a Japanese cohort of FSHD2 patients, confirming the presence of this disease in a wider population than previously known.