Citations

AbstractNon‐necrotizing granulomatous inflammation is a rare but easily recognized histopathological finding in skeletal muscle biopsy. A limited number of diseases are known to be associated with non‐necrotizing granulomatous myopathy. Once identified, a careful evaluation for evidence of extramuscular granulomatosis and other signs suggestive of sarcoidosis is warranted as about half of the patients have sarcoid myopathy. In addition, the presence of granulomatous myopathy should trigger a search for clinical and pathological clues of inclusion body myositis (IBM), which accounts for most of the remaining patients and can coexist with sarcoidosis. Recognizing the features of IBM in patients with granulomatous myopathy can potentially spare the patients from unnecessary exposure to immunosuppressive therapies. In patients whose granulomatous myopathy remain unexplained, further investigations should aim at identifying myasthenia gravis and other autoimmune disorders, especially those known to cause granulomatous inflammation in other organs. Laboratory investigations should include acetylcholine receptor, antimitochondrial, antineutrophil cytoplasmic, thyroglobulin, and thyroid peroxidase autoantibodies. In the appropriate clinical context, exposure to immune checkpoint inhibitors and chronic graft‐vs‐host disease can be causes of granulomatous myopathy. In cases of unexplained granulomatous myopathy, natural killer/T‐cell lymphoma should be considered and careful histopathological examination for atypical cells and appropriate immunostaining is crucial. Identifying the etiology of granulomatous myopathy in each patient can guide appropriate treatment.

See article on pages 679–685 in this issue.

Anoctaminopathy-5 refers to a group of hereditary skeletal muscle or bone disorders due to mutations in the anoctamin 5 (ANO5)-encoding gene, ANO5. ANO5 is a 913-amino acid protein of the anoctamin family that functions predominantly in phospholipid scrambling and plays a key role in the sarcolemmal repairing process. Monoallelic mutations in ANO5 give rise to an autosomal dominant skeletal dysplastic syndrome (gnathodiaphyseal dysplasia or GDD), while its biallelic mutations underlie a continuum of four autosomal recessive muscle phenotypes: (1). limb–girdle muscular dystrophy type R12 (LGMDR12); (2). Miyoshi distal myopathy type 3 (MMD3); (3). metabolic myopathy-like (pseudometabolic) phenotype; (4). asymptomatic hyperCKemia. ANO5 muscle disorders are rare, but their prevalence is relatively high in northern European populations because of the founder mutation c.191dupA. Weakness is generally asymmetric and begins in proximal muscles in LGMDR12 and in distal muscles in MMD3. Patients with the pseudometabolic or asymptomatic hyperCKemia phenotype have no weakness, but conversion to the LGMDR12 or MMD3 phenotype may occur as the disease progresses. There is no clear genotype–phenotype correlation. Muscle biopsy displays a broad spectrum of pathology, ranging from normal to severe dystrophic changes. Intramuscular interstitial amyloid deposits are observed in approximately half of the patients. Symptomatic and supportive strategies remain the mainstay of treatment. The recent development of animal models of ANO5 muscle diseases could help achieve a better understanding of their underlying pathomechanisms and provide an invaluable resource for therapeutic discovery.

AbstractObjectivesTo investigate immune-mediated necrotizing myopathy (IMNM) association with cancer and its clinical implications.MethodsIMNM cases were identified 1 January 2000 to 31 December 2020 matching sex and age controls (4:1).ResultsA total of 152 patients with IMNM were identified and among serologically tested, 60% (83/140) were HMGCR-IgG+, 14% (20/140) were SRP-IgG+ and 26% (37/140) were seronegative. Cancer rates were not significantly different between serological subgroups; 18.1% (15/83) HMGCR-IgG+, 25% (5/20) SRP-IgG+ and 30% (11/37) seronegative (P = 0.34). Cancer screening was performed within 12 months from IMNM diagnosis in 88% (134/152) (whole-body CT plus FDG-PET CT in 53, CT alone in 72 and FDG-PET alone in 9). FDG-PET/CT was positive in 73% (25/34) of cancers. Increasing age was the only risk associated with cancer (P = 0.02). The odds of developing cancer at ±3 or ±5 years from IMNM diagnosis was not higher than controls (OR = 0.49; CI: 0.325–0.76). Lifetime IMNM diagnosis of cancer was less compared with controls (OR = 0.5 CI: 0.33–0.78, P = 0.002). Most patients responded to treatment (137/147, P < 0.001). Death and treatment response did not significantly differ between cancer [23% (8/34); 88% (29/33)] and non-cancer patients [19% (23/118); 92% (108/118)]. In total, 13% (20/152) of patients died during follow-up compared with 14% (41/290) of medicine and 16% (46/290) of neurology controls (P = 0.8). Seropositives had greater life expectancy than seronegatives (P = 0.01).ConclusionsGreater cancer risk is not observed in IMNM vs controls. Cancer screening in IMNM should be individualized based on age-personal and family history, including consideration of FDG-PET/CT. Immune-treatment response did not differ with cancer.

AbstractIntroduction/AimsImmune‐mediated necrotizing myopathy (IMNM) is considered a rare subtype of the immune‐mediated myopathies, but its incidence and prevalence are unknown. In this study we aimed to determine the incidence and prevalence of IMNM among adults in Olmsted County, Minnesota.MethodsWe identified adult patients with IMNM, as defined by the 2016 European Neuromuscular Centre diagnostic criteria, among residents of Olmsted County, Minnesota over a 20‐year period.ResultsSeven patients fulfilled the inclusion criteria. Six patients were tested for IMNM antibodies: four were anti–3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) positive, one was anti–signal recognition particle positive, and one was seronegative. The incidence of IMNM during 2010‐2019 was 8.3 per million person‐years. The prevalence of IMNM in 2010 was 1.85 per 100 000 people at least 50 years of age. Median age at symptom onset was 64 (range, 52‐86) years and median time from symptom onset to diagnosis was 3 (range, <1 to 156) months. Statin use among anti‐HMGCR IMNM patients, but not the entire IMNM cohort, was higher than in controls (P = .024). Two IMNM patients developed cancers. The incidence of malignancy in IMNM was not higher than that of the general population. Treatment outcome was favorable in all patients except for one patient with delayed treatment and another with insufficient therapy. Among three deceased patients, one died of cancer and another died of IMNM‐related cardiorespiratory complications.DiscussionIMNM is a rare disease. Its prevalence is one tenth that of inclusion‐body myositis in Olmsted County, Minnesota. IMNM patients in our cohort were not at higher risk for developing cancer.

AbstractThe diagnostic evaluation of a patient with suspected hereditary muscle disease can be challenging. Clinicians rely largely on clinical history and examination features, with additional serological, electrodiagnostic, radiologic, histopathologic, and genetic investigations assisting in definitive diagnosis. Hematological testing is inexpensive and widely available, but frequently overlooked in the hereditary myopathy evaluation. Hematological abnormalities are infrequently encountered in this setting; however, their presence provides a valuable clue, helps refine the differential diagnosis, tailors further investigation, and assists interpretation of variants of uncertain significance. A diverse spectrum of hematological abnormalities is associated with hereditary myopathies, including anemias, leukocyte abnormalities, and thrombocytopenia. Recurrent rhabdomyolysis in certain glycolytic enzymopathies co‐occurs with hemolytic anemia, often chronic and mild in phosphofructokinase and phosphoglycerate kinase deficiencies, or acute and fever‐associated in aldolase‐A and triosephosphate isomerase deficiency. Sideroblastic anemia, commonly severe, accompanies congenital‐to‐childhood onset mitochondrial myopathies including Pearson marrow‐pancreas syndrome and mitochondrial myopathy, lactic acidosis, and sideroblastic anemia phenotypes. Congenital megaloblastic macrocytic anemia and mitochondrial dysfunction characterize SFXN4‐related myopathy. Neutropenia, chronic or cyclical, with recurrent infections, infantile‐to‐childhood onset skeletal myopathy and cardiomyopathy are typical of Barth syndrome, while chronic neutropenia without infection occurs rarely in DNM2‐centronuclear myopathy. Peripheral eosinophilia may accompany eosinophilic inflammation in recessive calpainopathy. Lipid accumulation in leukocytes on peripheral blood smear (Jordans' anomaly) is pathognomonic for neutral lipid storage diseases. Mild thrombocytopenia occurs in autosomal dominant, childhood‐onset STIM1 tubular aggregate myopathy, STIM1 and ORAI1 deficiency syndromes, and GNE myopathy. Herein, we review these hereditary myopathies in which hematological features play a prominent role.

See article on pages 284–290 in this issue.