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We report an imported case of myositis caused by a rare parasite, Haycocknema perplexum, in Australia in a 37-year-old man who had progressive facial, axial, and limb weakness, dysphagia, dysphonia, increased levels of creatine kinase and hepatic aminotransferases, and peripheral eosinophilia for 8 years. He was given extended, high-dose albendazole.

Introduction/aims Intracellular congophilic inclusions within muscle fibers, although nonspecific, are one of the pathological hallmarks of sporadic inclusion body myositis (sIBM). Extracellular amyloid deposits in muscle, on the other hand, are the canonical findings of amyloid myopathies, which occur with or without systemic amyloidosis. Methods We reviewed the muscle biopsy database (1998-2020) to identify sIBM patients with extracellular amyloid deposits. Clinical and laboratory data were reviewed. Results We identified five sIBM patients (three clinicopathologically defined and two clinically defined) with extracellular amyloid deposits in muscle. Mean age at diagnosis was 74.8 y (range, 68-84 y). All patients had a typical sIBM pattern of weakness without associated sensory or autonomic symptoms. None had electrophysiological evidence of peripheral neuropathy. Only one patient had a monoclonal gammopathy (immunoglobulin M-lambda, IgM-λ) with normal bone marrow biopsy. This patient with monoclonal gammopathy and three other patients underwent abdominal fat pad aspirate and were negative for amyloid. Cardiac evaluation was unrevealing in the four patients tested. Three patients without monoclonal gammopathy had normal transthyretin gene sequencing and inconclusive mass spectrometry-based analysis. The patient with monoclonal gammopathy died of pneumosepsis 5 y after diagnosis and autopsy revealed multi-organ transthyretin amyloidosis. Discussion Detection of extracellular amyloid deposition in muscle should trigger an aggressive search for systemic amyloidosis independently from other associated myopathological abnormalities. Amyloid subtyping is crucial for early therapy and mortality prevention. An isolated monoclonal gammopathy should not halt a search for non-hematological causes of systemic amyloidosis.

Immune-mediated rippling muscle disease (iRMD) is a rare myopathy characterized by wavelike muscle contractions (rippling) and percussion- or stretch-induced muscle mounding. A serological biomarker of this disease is lacking.To describe a novel autoantibody biomarker of iRMD and report associated clinicopathological characteristics.This retrospective cohort study evaluated archived sera from 10 adult patients at tertiary care centers at the Mayo Clinic, Rochester, Minnesota, and BrighamWomen's Hospital, Boston, Massachusetts, who were diagnosed with iRMD by neuromuscular specialists in 2000 and 2021, based on the presence of electrically silent percussion- or stretch-induced muscle rippling and percussion-induced rapid muscle contraction with or without muscle mounding and an autoimmune basis. Sera were evaluated for a common biomarker using phage immunoprecipitation sequencing. Myopathology consistent with iRMD was documented in most patients. The median (range) follow-up was 18 (1-30) months.Diagnosis of iRMD.Detection of a common autoantibody in serum of patients sharing similar clinical and myopathological features.Seven male individuals and 3 female individuals with iRMD were identified (median [range] age at onset, 60 [18-76] years). An IgG autoantibody specific for caveolae-associated protein 4 (cavin-4) was identified in serum of patients with iRMD using human proteome phage immunoprecipitation sequencing. Immunoassays using recombinant cavin-4 confirmed cavin-4 IgG seropositivity in 8 of 10 patients with iRMD. Results for healthy and disease-control individuals (n = 241, including myasthenia gravis and immune-mediated myopathies) were cavin-4 IgG seronegative. Six of the 8 individuals with cavin-4 IgG were male, and the median (range) age was 60 (18-76) years. Initial symptoms included rippling of lower limb muscles in 5 of 8 individuals or all limb muscles in 2 of 8 sparing bulbar muscles, fatigue in 9 of 10, mild proximal weakness in 3 of 8, and isolated myalgia in 1 of 8, followed by development of diffuse rippling. All patients had percussion-induced muscle rippling and half had percussion- or stretch-induced muscle mounding. Four of the 10 patients had proximal weakness. Plasma creatine kinase was elevated in all but 1 patient. Six of the 10 patients underwent malignancy screening; cancer was detected prospectively in only 1. Muscle biopsy was performed in 7 of the 8 patients with cavin-4 IgG; 6 of 6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 patients whose results were seropositive and who received immunotherapy had complete resolution of symptoms, 1 had mild improvement, and 2 had no change.The findings indicate that cavin-4 IgG may be the first specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in muscle biopsies of patients with iRMD suggests the potential role of this autoantigen in disease pathogenesis.

ObjectivesTo determine the prevalence and natural history of sporadic inclusion body myositis (sIBM) and to test the hypothesis that patients with sIBM have higher cancer or mortality rates than the general population.MethodsWe sought patients with sIBM defined by the 2011 European Neuromuscular Centre (ENMC) diagnostic criteria among Olmsted County, Minnesota, residents in 40-year time period.ResultsWe identified 20 patients (10 clinicopathologically defined, 9 clinically defined, and 1 probable) according to the ENMC criteria and 1 patient with all features of clinicopathologically defined sIBM except for symptom onset at p = 0.24). Two-thirds of patients developed dysphagia, and half required a feeding tube. Nine patients required a wheelchair. The median time from symptom onset to wheelchair dependence was 10.5 (range 1–29) years. Overall life expectancy was shorter in the sIBM group compared to the general population (84.1 [95% CI 78–88.4] vs 87.5 [95% CI 85.2–89.5] years, p = 0.03). Thirteen patients died; 9 deaths were sIBM related (7 respiratory and 2 unspecified sIBM complications). Female sex (p = 0.03) and dysphagia (p = 0.05) were independent predictors of death.ConclusionOlmsted County has the highest prevalence of sIBM reported to date. Patients with sIBM have similar risk of cancer, but slightly shorter life expectancy compared to matched patients without sIBM.Classification of EvidenceThis study provides Class II evidence that patients with sIBM have similar risks of cancers and slightly shorter life expectancy compared to controls.

ObjectiveTo improve myasthenia gravis (MG) autoantibody testing.MethodsMG serologic tests with confirmatory or refuting clinical–electrodiagnostic (EDX) testing and cancer evaluations were reviewed over 4 years (2012–2015). All patients had acetylcholine receptor–binding (AChR-Bi), modulating (AChR-Mo), and striational (STR) autoantibody testing, and negatives reflexed to muscle-specific kinase (MuSK). Thymoma and cancer occurrences were correlated with STR and reflexed glutamic acid decarboxylase 65 (GAD65), ganglionic acetylcholine receptor (α3), collapsin response mediating protein-5, and voltage-gated potassium channel complex autoantibodies.ResultsOf 433 samples tested, 133 (31%) met clinical–EDX criteria for MG. Best sensitivity (90%) occurred at AChR-Bi >0.02 nmol/L, leaving 14 negative (6 ocular MG, 7 generalized MG, 1 MuSK MG) with specificity 90% (31 false-positives). Using AChR-Mo antibodies (>20% loss), specificity was better (92%, 24 false-positives), but sensitivity dropped (85%). Specificity improved (95%) by testing AChR-Mo when AChR-Bi are positive, resulting in 45% reduction of false-positives (31–17), maintaining AChR-Bi 90% sensitivity. Cutoff values recommended by area under the curve analysis did not outperform this approach. AChR-Bi and AChR-Mo values were significantly higher in true-positives. CT evaluations in 121 MG samples revealed 16 thymomas. Historical or subsequent cancers occurred in 22. STR and reflexed autoantibodies were not more common in MG with thymoma or other cancers. Full-body CT (n = 34) was performed in those with STR and reflex autoantibody positivity, but without additional cancers found.ConclusionAccuracy of MG serologic testing is improved by reflexing AChR-Bi–positive cases to AChR-Mo. STR and other reflexed cancer evaluation autoantibodies did not provide value beyond standard CT chest imaging at the time of MG diagnosis. Diagnostic certainty is informed by AChR-Bi and AChR-Mo with higher values increasing specificity.

Background Limited data exist regarding myopathies with early or prominent dysphagia. Methods A retrospective study was performed (January 2003 to August 2019) to identify myopathy patients in whom dysphagia was the initial symptom or was disproportionately severe compared with limb weakness. Results Thirty-two patients were identified. The median age at diagnosis was 65 y (range, 36-80 y). Inclusion body myositis (IBM) (n = 15), immune-mediated necrotizing myopathy (IMNM) (n = 5), and oculopharyngeal muscular dystrophy (n = 4), were the most common diagnoses. In 4 patients (3 IMNM and 1 nonspecific myositis) dysphagia evolved rapidly. At evaluation, 21 patients required diet alterations, 5 required feeding tubes, and 8 had aspiration pneumonia. Follow-up data were available for 20 patients (median, 24 mo). Eight patients received immunosuppressive therapies with improvement in 7, including 3 of 4 with rapidly progressive dysphagia. Conclusions IBM and IMNM accounted for approximately two-thirds of patients with early or prominent dysphagia at our institution. Rapidly progressive dysphagia may predict immunotherapy responsiveness.

Immune-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.We 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.Seven 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.IMNM 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.

The 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.

Objective To characterize the natural history and clinical features of myopathies caused by mono‐allelic, dominantly acting pathogenic variants in COL12A1. Methods Patients with dominant COL12A1‐related myopathies were characterized by history and clinical examination, muscle imaging, and genetic analysis. Pathogenicity of the variants was assessed by immunostaining patient‐derived dermal fibroblast cultures for collagen XII. Results Four independent families with childhood‐onset weakness due to novel, dominantly acting pathogenic variants in COL12A1 were identified. Adult patients exhibited distal‐predominant weakness. Three families carried dominantly acting glycine missense variants, and one family had a heterozygous, intragenic, in‐frame deletion of exon 52 of COL12A1. All pathogenic variants resulted in increased intracellular retention of collagen XII in patient‐derived fibroblasts as well as loss of extracellular, fibrillar collagen XII deposition. Since haploinsufficiency for COL12A1 is largely clinically asymptomatic, we designed and evaluated small interfering RNAs (siRNAs) that specifically target the mutant allele containing the exon 52 deletion. Immunostaining of the patient fibroblasts treated with the siRNA showed a near complete correction of collagen XII staining patterns. Interpretation This study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1‐related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele‐specific knockdown using siRNAs specifically designed to target a patient’s dominant COL12A1 disease allele.

Granulomatous myopathies are etiologically heterogeneous myopathies, pathologically characterized by the presence of intramuscular granulomas. Treatment outcomes are variable. We aimed to identify prognostic factors of treatment outcomes in myopathies featuring non-caseating granulomas. Sixteen patients were identified (9 sarcoid myopathy, 6 inclusion body myositis, and 1 granulomatous myopathy of indeterminate cause) over a 21-year period. The median age at diagnosis was 67 years in sarcoid myopathy group, and 64 years in inclusion body myositis group. Three inclusion body myositis patients were initially diagnosed with sarcoid myopathy based on the presence of systemic features of sarcoidosis and findings on muscle biopsies, but subsequent biopsies performed because of treatment refractoriness, showed all canonical pathologic features of inclusion body myositis. We identified sarcoplasmic congophilic inclusions in 6 sarcoid myopathy patients without associated rimmed vacuoles or typical weakness pattern of inclusion body myositis. Four inclusion body myositis and 4 of 5 sarcoid myopathy patients with congophilic inclusions were refractory to immunotherapy. Our study portrays the overlapping clinical and pathological features of sarcoid myopathy and inclusion body myositis. The presence of sarcoplasmic congophilic inclusions in sarcoid myopathy may predict an unfavorable outcome of immunosuppressive therapy, but a larger prospective study is required to further validate this observation.

LRP4 is a post-synaptic membrane protein that promotes acetylcholine (AChR) clustering on the crest of post-synaptic neuromuscular folds. Autoantibodies against LRP4 are suggested to account for myasthenia gravis (MG) patients negative for antibodies to AChR.To report a clinical experience with service-line LRP4-IgG cell-based testing in electrodiagnostically confirmed MG patients and controls.We identified all Mayo patients undergoing MG evaluations with send out LRP4-IgG antibody testing by cell-based assay, having clinical-electrodiagnostic (EDX) testing. To be included, muscle acetylcholine receptor binding (AChR-Bi) and muscle-specific tyrosine kinase (MuSK) antibodies had to be absent prior to LRP4-IgG testing. Follow-up AChR-Bi antibody testing was reviewed. Also tested for LRP4-IgGs were 119 healthy subjects.Identified were 25 generalized MG, 24 ocular MG, and 55 patients initially considered to have MG prior to negative EDX testing. No seronegative patients with EDX confirmed MG had LRP4-IgG positivity but five non-MG patients did: Guillain-Barre syndrome with fatigue (N = 1); multiple cranial neuropathies (N = 1); functional neurologic disorders (N = 3). Of healthy subjects, 4% (5/119) were LRP4-IgG positive (N = 5) or had a borderline result (N = 1). Of MG patients with repeat AChR-Bi testing, 40% (10/25) seroconverted (5 with ocular MG and 5 with generalized MG) (median AChR IgG value: 0.34 nmol/L, range 0.2-20.9 nmol/L, median followup 26 months, range 2-72 months).Clinical review of LRP4-IgG commercial cell-based testing suggests lack of diagnostic utility in seronegative EDX-confirmed MG. The clinical utility of LRP4-IgG testing is not substantiated in service line testing. In contrast, repeat testing for AChR-Bi antibodies is shown clinically useful.

Despite recent advances in the understanding of inherited muscle and neuromuscular junction diseases, as well as the advent of a wide range of genetic tests, patients continue to face delays in diagnosis of sometimes treatable disorders. These guidelines outline an approach to genetic testing in such disorders. Initially, a patient's phenotype is evaluated to identify myopathies requiring directed testing, including myotonic dystrophies, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, mitochondrial myopathies, dystrophinopathies, and oculopharyngodistal myopathy. Initial investigation in the remaining patients is generally a comprehensive gene panel by next-generation sequencing. Broad panels have a higher diagnostic yield and can be cost-effective. Due to extensive phenotypic overlap and treatment implications, genes responsible for congenital myasthenic syndromes should be included when evaluating myopathy patients. For patients whose initial genetic testing is negative or inconclusive, phenotypic re-evaluation is warranted, along with consideration of genes and variants not included initially, as well as their acquired mimickers.

The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. MYH2-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Additional myopathological abnormalities have included rimmed vacuoles containing small p62 positive inclusions, 15–20 nm tubulofilaments, minicores and dystrophic changes. We report an adult patient with late-pediatric onset MYH2-myopathy caused by two heterozygous pathogenic variants: c.3331C>T, p.Gln1111* predicted to result in truncation of the proximal tail region of MyHC-IIA, and c.1546T>G, p.Phe516Val, affecting a highly conserved amino acid within the highly conserved catalytic motor head relay loop. This missense variant is predicted to result in a less compact loop domain and in turn could affect the protein affinity state. The patient’s genotype is accompanied by a novel myopathological phenotype characterized by centralized large myofilamentous tangles associated with clusters of nemaline rods, and ring fibers, in addition to the previously reported rimmed vacuoles, paucity and atrophy of type 2A fibers. Electron microscopy demonstrated wide areas of disorganized myofibrils which were oriented in various planes of direction and entrapped multiple nemaline rods, as corresponding to the large tangles with rods seen on light microscopy. Nemaline rods were rarely observed also in nuclei. We speculate that the mutated MyHC-IIA may influence myofibril disorganization. While nemaline rods have been described in myopathies caused by pathogenic variants in genes encoding several sarcomeric proteins, to our knowledge, nemaline rods have not been previously described in MYH2-myopathy.

Amyloidosis refers to an etiologically heterogeneous group of protein misfolding diseases, pathologically characterized by extracellular amyloid fibrils producing congophillic amorphous deposits in organs and tissues, which may lead to severe organ dysfunction and mortality. Clinical presentations vary and are often nonspecific, depending on what organs or tissues are affected. In systemic amyloidosis, the peripheral nervous system is commonly affected, whereas the skeletal muscles are only rarely involved. Immunoglobulin light chain (AL) amyloidosis and hereditary transthyretin (ATTRv) amyloidosis are the most frequent types of systemic amyloidosis involving the neuromuscular system. Localized amyloidosis can occur in skeletal muscle, so-called isolated amyloid myopathy. Amyloid neuropathy typically involves small myelinated and unmyelinated sensory and autonomic nerve fibers early in the course of the disease, followed by large myelinated fiber sensory and motor deficits. The relentlessly progressive nature with motor, painful sensory and severe autonomic dysfunction, profound weight loss, and systemic features are distinct characteristics of amyloid neuropathy. Amyloid myopathy presentation differs between systemic amyloidosis and isolated amyloid myopathy. Long-standing symptoms, distal predominant myopathy, markedly elevated creatine kinase level, and lack of peripheral neuropathy or systemic features are highly suggestive of isolated amyloid myopathy. In ATTR and AL amyloidosis, early treatment correlates with favorable outcomes. Therefore, awareness of these disorders and active screening for amyloidosis in patients with neuropathy or myopathy are crucial in detecting these patients in the everyday practice of neuromuscular medicine. Herein, we review the clinical manifestations of neuromuscular amyloidosis and provide a diagnostic approach to this disorder.

Background Anti-cytosolic 5'-nucleotidase 1A (cN1A) antibodies are commonly detected in patients with sporadic inclusion body myositis (sIBM). However, their pathogenic role has not been established. Moreover, efforts toward identifying sIBM distinct clinicopathologic characteristics associated with these antibodies have yielded conflicting results. Methods We first searched for patients, seen in our clinics, tested for anti-cN1A antibodies between December 2015 and December 2019. We identified 92 patients who were diagnosed with sIBM, according to the 2011 ENMC or Griggs et al criteria. Thereafter, we reviewed and compared the clinical and investigational findings of these patients in relation to their antibody status. Results Anti-cN1A antibodies were present in 47/92 (51%) patients with sIBM. Comparison of seropositive and seronegative cohorts yielded no significant difference in clinical features, including facial weakness, oropharyngeal and respiratory involvement, or disease severity. The antibody titer did not correlate with the clinical phenotype, CK value, or presence of myotonic discharges on EMG. Anti-cN1A antibody positive patients appeared to have more frequent auto-aggressive inflammation on muscle biopsy but not as an isolated myopathological feature. Conclusions Our study showed that anti-cN1A antibody positive and negative sIBM patients have similar clinical features and disease severity. Anti-cN1A antibodies in our sIBM cohort did not correlate with any studied clinical or laboratory parameter and, therefore, were of limited value in the patient's assessment.

ObjectiveTo describe neural autoantibody profiles and outcomes in patients with neurologic autoimmunity associated with immune checkpoint inhibitor (ICI) cancer immunotherapy.MethodsIn this retrospective descriptive study, 63 patients with ICI-related neurologic autoimmunity were included: 39 seen at the Mayo Clinic Neurology Department (clinical cohort) and 24 whose serum/CSF was referred to the Mayo Clinic Neuroimmunology Laboratory for autoantibody testing. Serum/CSF samples were tested for neural-specific autoantibodies. Predictors of unfavorable outcome (residual adverse event severity grade ≥3) were explored (logistic regression).ResultsMedian age at neurologic symptom onset was 65 years (range 31–86); 40% were female. Neurologic manifestations were CNS-restricted (n = 26), neuromuscular (n = 30), combined (n = 5), or isolated retinopathy (n = 2). Neural-specific autoantibodies were common in patients with CNS involvement (7/13 [54%] in the unbiased clinical cohort) and included known or unidentified neural-restricted specificities. Only 11/31 patients with CNS manifestations had neuroendocrine malignancies typically associated with paraneoplastic autoimmunity. Small-cell lung cancer (SCLC)–predictive antibodies were seen in 3 patients with non-neuroendocrine tumors (neuronal intermediate filament immunoglobulin G [IgG] and antineuronal nuclear antibody 1 with melanoma; amphiphysin IgG with non-SCLC). A median of 10 months from onset (range, 0.5–46), 14/39 in the clinical cohort (36%) had unfavorable outcomes; their characteristics were age ≥70 years, female, CNS involvement, lung cancer, higher initial severity grade, and lack of systemic autoimmunity. By multivariate analysis, only age remained independently associated with poor outcome (p = 0.01). Four of 5 patients with preexistent neurologic autoimmunity experienced irreversible worsening after ICI.ConclusionsNeural-specific autoantibodies are not uncommon in patients with ICI-related CNS neurologic autoimmunity. Outcomes mostly depend on the pre-ICI treatment characteristics and clinical phenotype.

Muscle disorders are characterized by differential involvement of various muscle groups. Among these, weakness predominantly affecting finger flexors is an uncommon pattern, most frequently found in sporadic inclusion-body myositis. This finding is particularly significant when the full range of histopathological findings of inclusion-body myositis is not found on muscle biopsy. Prominent finger flexor weakness, however, is also observed in other myopathies. It occurs commonly in myotonic dystrophy types 1 and 2. In addition, individual reports and small case series have documented finger flexor weakness in sarcoid and amyloid myopathy, and in inherited myopathies caused by ACTA1, CRYAB, DMD, DYSF, FLNC, GAA, GNE, HNRNPDL, LAMA2, MYH7, and VCP mutations. Therefore, the finding of finger flexor weakness requires consideration of clinical, myopathological, genetic, electrodiagnostic, and sometimes muscle imaging findings to establish a diagnosis.

Distal myopathies are a group of rare muscle diseases characterized by distal weakness at onset. Although acquired myopathies can occasionally present with distal weakness, the majority of distal myopathies have a genetic etiology. Their age of onset varies from early-childhood to late-adulthood while the predominant muscle weakness can affect calf, ankle dorsiflexor, or distal upper limb muscles. A spectrum of muscle pathological changes, varying from nonspecific myopathic changes to rimmed vacuoles to myofibrillar pathology to nuclei centralization, have been noted. Likewise, the underlying molecular defect is heterogeneous. In addition, there is emerging evidence that distal myopathies can result from defective proteins encoded by genes causative of neurogenic disorders, be manifestation of multisystem proteinopathies or the result of the altered interplay between different genes. In this review, we provide an overview on the clinical, electrophysiological, pathological, and molecular aspects of distal myopathies, focusing on the most recent developments in the field. Muscle Nerve 59:283-294, 2019.

ObjectiveTo investigate the diagnostic challenges of congenital myasthenic syndromes (CMS) in adult neuromuscular practice.MethodsWe searched the Mayo Clinic database for patients with CMS diagnosed in adulthood in the neuromuscular clinic between 2000 and 2016. Clinical, laboratory, and electrodiagnostic data were reviewed.ResultsWe identified 34 patients with CMS, 30 of whom had a molecular diagnosis (14 DOK7, 6 RAPSN, 2 LRP4, 2 COLQ, 2 slow-channel syndrome, 1 primary acetylcholine receptor deficiency, 1 AGRN, 1 GFPT1, and 1 SCN4A). Ophthalmoparesis was often mild and present in 13 patients. Predominant limb-girdle weakness occurred in 19 patients. Two patients had only ptosis. Age at onset ranged from birth to 39 years (median 5 years). The median time from onset to diagnosis was 26 years (range 4–56 years). Thirteen patients had affected family members. Fatigable weakness was present when examined. Creatine kinase was elevated in 4 of 23 patients (range 1.2–4.2 times the upper limit of normal). Repetitive nerve stimulation revealed a decrement in 30 patients. Thirty-two patients were previously misdiagnosed with seronegative myasthenia gravis (n = 16), muscle diseases (n = 15), weakness of undetermined cause (n = 8), and others (n = 4). Fifteen patients received immunotherapy or thymectomy without benefits. Fourteen of the 25 patients receiving pyridostigmine did not improve or worsen.ConclusionMisdiagnosis occurred in 94% of the adult patients with CMS and causes a median diagnostic delay of nearly 3 decades from symptom onset. Seronegative myasthenia gravis and muscle diseases were the 2 most common misdiagnoses, which led to treatment delay and unnecessary exposure to immunotherapy, thymectomy, or muscle biopsy.

Programmed death-1 (PD-1) inhibitors are increasingly used in cancer immunotherapy. Various immune-related adverse events are reported, including infrequent individual case reports of myositis or rhabdomyolysis. The frequency and diagnostic spectrum of immune-related adverse events affecting skeletal muscle in PD-1 inhibitor-treated patients are unknown. We searched the Mayo Clinic Pharmacy database (2014-2016) to identify patients who developed myopathies during or after PD-1 inhibitor therapy. Among 654 cancer patients received PD-1 inhibitors (pembrolizumab=389; nivolumab=264; both=1), we identified 5 patients (pembrolizumab=5) with biopsy-proven myopathies (2 necrotizing myopathy, 1 early dermatomyositis, and 2 nonspecific myopathy). Four patients developed concomitant autoimmune disorders. Weakness occurred after a median of 2 treatments (range, 1-4). All patients had proximal or axial weakness. Four patients had either bulbar or extraocular weakness, but only 1 patient had acetylcholine receptor antibodies. Creatine kinase levels were elevated in 3 patients (necrotizing myopathy=2; nonspecific myopathy=1). Brain magnetic resonance imaging revealed abnormal T2 signal and enhancement of extraocular muscles in 1 patient with ophthalmoparesis. Pembrolizumab was discontinued in all patients. All patients received immunosuppressive therapy, with fatal outcome in 2 necrotizing myopathy patients and favorable outcome in others. We conclude that myopathy is a rare, but unique complication of PD-1 inhibitors with frequent involvement of extraocular or bulbar muscles, mimicking myasthenia gravis. Muscle biopsy is an important test for PD-1 inhibitor-treated patients who develop oculobulbar weakness and hyperCKemia, to distinguish patients with necrotizing myopathy from myasthenia gravis. Necrotizing myopathy patients may require more aggressive immunotherapy due to their grave prognosis.

The limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous, autosomal inherited muscular dystrophies with a childhood to adult onset, manifesting with hip- and shoulder-girdle muscle weakness. When the term LGMD was first conceptualized in 1954, it was thought to be a single entity. Currently, there are 8 autosomal dominant (LGMD1A-1H) and 26 autosomal recessive (LGMD2A-2Z) variants according to the Online Mendelian Inheritance in Man database. In addition, there are other genetically identified muscular dystrophies with an LGMD phenotype not yet classified as LGMD. This highlights the entanglement of LGMDs, which represents an area in continuous expansion. Herein we aim to simplify the complexity of LGMDs by subgrouping them on the basis of the underlying defective protein and impaired function. Muscle Nerve 58: 167-177, 2018.

Background and purpose Amyloid myopathy frequently occurs in the setting of systemic amyloidosis and less commonly in isolation (isolated amyloid myopathy). Anoctaminopathy-5 and dysferlinopathy were recently recognized as causes of isolated amyloid myopathy. The present study aimed to characterize the isolated amyloid myopathy and to compare it with amyloid myopathy associated with systemic amyloidosis. Methods We searched the Muscle Laboratory database to identify patients with pathologically confirmed amyloid myopathy seen in neurology clinics between January 1998 and September 2016. Patients with monoclonal gammopathy, peripheral neuropathy, organomegaly or symptoms or pathologic evidence of amyloid deposition outside skeletal muscle were classified as having systemic amyloidosis-associated myopathy. Results Fifty-two patients were identified, including 14 with isolated amyloid myopathy (eight anoctaminopathy-5, two dysferlinopathy and four genetically unknown) and 38 with systemic amyloidosis (32 immunoglobulin light-chain amyloidosis, four familial amyloid polyneuropathy and two senile systemic amyloidosis). Compared with patients with systemic amyloidosis, patients with isolated amyloid myopathy had a younger age of onset (median, 41.5 vs. 65 years), no dysphagia (0% vs. 26%) or weight loss (0% vs. 26%), but more frequent calf atrophy (57% vs. 0%), small collections of inflammatory cells on muscle biopsy (43% vs. 0%) and asymptomatic hyperCKemia at onset (21% vs. 0%). All patients with isolated amyloid myopathy had creatine kinase (CK) values >2.5 times the upper limit of normal. Conclusions Isolated amyloid myopathy accounts for 27% of patients with amyloid myopathy, mostly due to anoctaminopathy-5. There are various clinical and laboratory parameters that can help to differentiate isolated amyloid myopathy from systemic amyloidosis.

A 31-year-old man presented with a 6-year history of slowly progressive calf atrophy and weakness. EMG showed distal myopathy with fibrillation potentials. Creatine kinase (CK) was 2,848 U/L (normal T and novel c.145-1G>A variants in the dysferlin gene ( DYSF ). Intramuscular interstitial amyloid deposits can occur in systemic amyloidosis (AL or ATTR)1 or less commonly in muscular dystrophies ( DYSF and ANO5 ).2 Longstanding symptoms, young age at onset, calf atrophy, markedly elevated CK, and lack of systemic involvement are suggestive of muscular dystrophies.2

We describe a 70 year-old independently ambulatory man with a 10-year history of progressive axial and limb-girdle weakness, hyperCKemia, and a 5-year history of dyspnea requiring nocturnal ventilatory support due to a known c.1309C>T (p.Arg437Cys) variant and a novel in-frame deletion of exons 17–19 in the calpain-3 encoding gene (CAPN3). Pulmonary function tests revealed neuromuscular respiratory weakness. Biceps femoris biopsy showed chronic myopathic changes, numerous lobulated fibers, and reduced calpain-3 immunoreactivity. Muscle immunoblot showed markedly reduced calpain-3 expression. Respiratory insufficiency is uncommon in autosomal recessive calpainopathy, and generally develops in the advanced stages of the disease when individuals become wheelchair-dependent. Our patient broadens the phenotypic spectrum of recessive calpainopathy to include early respiratory insufficiency and also further expands its molecular spectrum.

Objective To characterize the cardiorespiratory abnormalities in patients with necrotizing autoimmune myopathy (NAM). Patients and Methods Cardiopulmonary features of patients with NAM evaluated in our neuromuscular clinic (January 1, 2004, to September 20, 2018) were reviewed retrospectively with respect to autoantibody status and history of cardiac disease. Clinical characteristics and laboratory findings were compared among patient subgroups. Results We identified 109 patients with NAM: 36 anti–3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibody (anti-HMGCR Ab)–positive, 18 anti–signal recognition particle antibody (anti-SRP Ab)–positive (3 dual anti-HMGCR/anti–SRP Ab–positive), and 58 seronegative. Median age at diagnosis was 60 years (range, 18-86 years). Forty-three patients had dyspnea at presentation and 32 patients had preexisting risk for cardiac disease (10 coronary artery disease and 28 hypertension). The electrocardiogram was abnormal in 55 of 86 patients (33 without cardiac risk factors), including prolonged corrected QT interval (QTc) (n=31), conduction blocks (n=19), and atrial or ventricular ectopic beats (n=10). Echocardiography was abnormal in 34 of 72 patients, including 19 of 45 without preexisting cardiac disease risks. Echocardiographic abnormalities included left ventricular diastolic dysfunction (n=31) and systolic dysfunction (n=8). The left ventricular diastolic dysfunction improved in 4 of 11 patients after treatment. Pulmonary function testing showed changes suggestive of neuromuscular respiratory muscle weakness in 51 of 66 patients and reduced carbon monoxide diffusing capacity in 11 of 35 patients. However, only 6 patients had radiographic evidence of interstitial lung disease (2 anti-HMGCR Ab–positive and 4 seronegative). Overnight oximetry revealed desaturations in 24 of 38 patients. Six patients required mechanical ventilation and 7 required noninvasive ventilatory support. Conclusion Most patients with NAM exhibited cardiac and respiratory muscle dysfunction. Immunotherapy can improve echocardiographic abnormalities. Interstitial lung disease was rarely identified. Formal evaluation of cardiac and respiratory status should be integral in assessment of patients with NAM.

Introduction Although peripheral neuropathy and cardiomyopathy are well-recognized manifestations of transthyretin (ATTR) amyloidosis, myopathy has been rarely reported. Methods In this study we reviewed our muscle biopsy database (January 1998 to June 2018) to identify patients with ATTR amyloid myopathy confirmed by molecular or proteomic analysis. Clinical and laboratory findings were reviewed. Results We identified eight ATTR amyloid myopathy patients (5 hereditary ATTR [ATTRv] and 3 wild-type ATTR [ATTRwt]). Myopathy was the initial manifestation in all ATTRwt patients and followed peripheral neuropathy (4 patients) or cardiomyopathy (1 patient) in ATTRv patients. One ATTRv patient developed myopathy after liver transplant. Peripheral neuropathy and cardiac amyloidosis occurred in seven and six patients, respectively. Muscle biopsy showed interstitial amyloid deposition in all patients, rare necrotic/regenerating fibers in six, and vacuoles in four. Discussion Myopathy can be the initial manifestation of ATTRwt amyloidosis and can precede the peripheral neuropathy or occur after liver transplant in ATTRv amyloidosis.

Although myopathies and neuromuscular junction disorders are typically distinct, their coexistence has been reported in several inherited and acquired conditions. Affected individuals have variable clinical phenotypes but typically display both a decrement on repetitive nerve stimulation and myopathic findings on muscle biopsy. Inherited causes include myopathies related to mutations in BIN1, DES, DNM2, GMPPB, MTM1, or PLEC and congenital myasthenic syndromes due to mutations in ALG2, ALG14, COL13A1, DOK7, DPAGT1, or GFPT1. Additionally, a decrement due to muscle fiber inexcitability is observed in certain myotonic disorders. The identification of a defect of neuromuscular transmission in an inherited myopathy may assist in establishing a molecular diagnosis and in selecting patients who would benefit from pharmacological correction of this defect. Acquired cases meanwhile stem from the co-occurrence of myasthenia gravis or Lambert-Eaton myasthenic syndrome with an immune-mediated myopathy, which may be due to paraneoplastic disorders or exposure to immune checkpoint inhibitors.

Mutations in GMPPB cause a wide spectrum of neuromuscular syndromes, including muscular dystrophies and congenital myasthenic syndrome. The mechanisms by which GMPPB mutations impair neuromuscular transmission however remain incompletely understood. We expand here upon a previous report of one such patient presenting with a myopathy-congenital myasthenic syndrome overlap phenotype. Fatigable proximal muscle weakness developed gradually between 13 and 25 years of age, with subsequent stabilization. Low-frequency repetitive nerve stimulation showed a decrement, while a muscle biopsy demonstrated the presence of a centronuclear myopathy. Genetic testing identified a homozygous c.458C > T (p.Thr153Ile) variant in GMPPB. In-vitro microelectrode recordings and ultrastructural studies showed impairment of both pre- and postsynaptic neuromuscular transmission, thus demonstrating the presence of not only postsynaptic, but also presynaptic pathology in GMPPB-related disorders.

Actinopathy is a group of clinically and pathologically heterogeneous myopathies due to mutations in the skeletal muscle sarcomeric α-actin 1-encoding gene (ACTA1). Disease-onset spans from prenatal life to adulthood and weakness can preferentially affect proximal or distal muscles. Myopathological findings include a spectrum of structural abnormalities with nemaline rods being the most common. We report a daughter and father with prominent finger flexors and/or quadriceps involvement. Muscle biopsies revealed rimmed vacuoles in both patients, associated with type 1 fiber atrophy in the daughter, and nemaline rods in the father. Next generation sequencing identified a novel dominant ACTA1 variant, c.149G > A (p.Gly50Asp) in both individuals and no abnormal variants in vacuolar myopathy-associated genes. Our findings expand the clinico-pathological spectrum of actinopathy.

In recent years, immune checkpoint inhibitors have been increasingly used in patients with metastatic cancers with favorable oncological outcomes; however, there have also been increasing number of cancer survivors who have developed immune-related adverse events. Little is known about PD-1 inhibitor-associated neuromuscular complications. Neuromuscular disorders are the most common neurological complication reported in PD-1 inhibitor-treated patients. Myasthenia gravis, immune-mediated myopathies, and Guillain-Barre syndrome are among commonly reported immune-related neuromuscular complications. HyperCKemia occurs frequently in patients with PD-1 inhibitor-associated myasthenia gravis, indicating coexisting myopathies or myocarditis. Oculobulbar weakness is a unique and common presentation of PD-1 inhibitor-associated immune-mediated myopathies with or without concomitant myasthenia gravis. High-dose steroid monotherapy may be associated with clinical deterioration in some patients with PD-1 inhibitor-associated myasthenia gravis, immune-mediated myopathies, or Guillain-Barre syndrome. PD-1 inhibitor-associated neuromuscular complications have some characteristic features compared to their idiopathic counterparts. Although steroid monotherapy is commonly used in non-neuromuscular autoimmune disorders triggered by anti-PD-1 therapy, this may lead to unfavorable outcomes in some patients with PD-1 inhibitor-associated neuromuscular complications.

Recessive mutations in the anoctamin-5-encoding gene (ANO5) cause muscular dystrophy of various phenotypes. Intramuscular interstitial amyloid deposits were detected in a few patients with anoctaminopathy-5, some with cardiac involvement. The frequency of amyloid deposition in anoctaminopathy-5 and its impact on phenotype are unknown.We retrospectively identified patients with genetically proven anoctaminopathy-5 who had undergone muscle biopsy and reviewed their clinical and laboratory data.Eight of 15 patients with anoctaminopathy-5 had intramuscular interstitial amyloid deposits. The median age at onset of weakness was 40 and 45 years in the amyloidosis and nonamyloidosis groups, respectively. Mutations occurred throughout the entire gene in the amyloidosis group. Atrial arrhythmia was noted in 4 patients with amyloidosis and in 4 patients without amyloidosis. The latter group also had premature ventricular contractions. One nonamyloidosis patient had septal hypokinesia.Intramuscular amyloidosis occurred in 53% of patients with anoctaminopathy-5 who underwent muscle biopsy and had no impact on the phenotype. Muscle Nerve 59:133-137, 2019.

I thank Dr. Budhram for his interest in this topic.1 The antibody isotype was not included due to the limited word count. The test was done at the commercial laboratory and it detected only immunoglobulin G subtype.

The formation of tubular aggregates (TA) within muscle fibers has been associated with toxic, metabolic, and hereditary myopathies, congenital myasthenic syndromes (CMS),1 and recently with pembrolizumab-associated myopathy.2 On electron microscopy, TA have the appearance of parallel tubules in crystalline arrangements, and are continuous extensions of the sarcotubular membrane system.1 TA have not been reported in necrotizing autoimmune myopathy associated with 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) antibodies. A 60-year-old man experienced muscle pain and cramping within 18 months of initiating statin treatment, followed by bilateral proximal lower limb and hand grip weakness that progressed over 8 months. Creatine kinase (CK) was 18,674 U/L (normal 200 units (normal < 20). The quadriceps muscle biopsy is shown in the figure. Repetitive nerve stimulation showed no decrement. Next-generation sequencing of 166 myopathy/CMS genes, including those associated with TA, demonstrated no pathogenic variants. IV immunoglobulin therapy led to clinical improvement and normalization of CK.

Progressive muscular atrophy (PMA) is a rare, sporadic, adult-onset motor neuron disease, clinically characterized by isolated lower motor neuron features; however, clinically evident upper motor neuron signs may emerge in some patients. Subclinical upper motor neuron involvement is identified pathologically, radiologically, and neurophysiologically in a substantial number of patients with PMA. Patients with subclinical upper motor neuron involvement do not fulfill the revised El Escorial criteria to participate in amyotrophic lateral sclerosis clinical trials. Intravenous immunoglobulin therapy is only marginally beneficial in a small subgroup of patients with lower motor neuron syndrome without conduction block.

A 52-year-old woman presented with a 12-year history of progressive limb weakness. She first had trouble climbing stairs and later difficulty getting up from a chair. She also experienced hip and shoulder pain. Over the previous 2 years, combing her hair became difficult. She denied any eyelid drooping, double vision, chewing or swallowing difficulty, slurred speech, shortness of breath, numbness, tingling, autonomic symptoms, or cognitive problems. She did not have any rashes or joint pain. She had no other medical problems and was not taking any medications. She was born full-term and had normal developmental milestones. She was able to keep up with her peers and was a good runner during her childhood. The patient was of German descent and her father and paternal uncle developed leg weakness in their early 40s and were diagnosed with limb-girdle muscular dystrophy (LGMD). They died in a plane crash in their late 40s. The patient's older brother and her uncle's son developed leg weakness in their early 40s and were also diagnosed with LGMD. Both died in their mid-to-late 50s due to respiratory failure. Her brother also had peripheral neuropathy. The diagnosis of LGMD in all family members is based on clinical presentations and muscle biopsies. Genetic studies were not performed. There was no family history of dementia, bone disorder, or motor neuron disease. Her neurologic examination revealed symmetrical weakness of shoulder and hip girdle muscles (Medical Research Council [MRC] grade 4), as well as anterior leg compartment muscles (MRC grade 4+). She also had scapular winging bilaterally. There was no myotonia, muscle rippling, fasciculation, muscle atrophy, or hypertrophy. Deep tendon reflexes were normal except for absent ankle reflexes on both sides. Cognition, cranial nerves, sensory examination, and coordination were normal. She had high-arched feet and hammertoes. There was neither joint contracture nor spinal rigidity.

Mutations in skeletal muscle α-actin 1-encoding gene (ACTA1) cause autosomal dominant or recessive myopathies with marked clinical and pathological heterogeneity. Patients typically develop generalized or limb-girdle pattern of weakness, but recently a family with scapuloperoneal myopathy was reported. We describe a father and 2 children with childhood-to-juvenile onset distal myopathy, carrying a novel dominant ACTA1 variant, c.757G>C (p.Gly253Arg). Father had delayed motor development and developed significant proximal weakness later in life; he was initially misdiagnosed as having spinal muscular atrophy based on electromyographic findings. His children had predominant anterior distal leg and finger extensor involvement. Nemaline rods were abundant on the daughter's biopsy, absent on the father's initial biopsy, and extremely rare on the father's subsequent biopsy a decade later. The father's second biopsy also showed myofibrillar pathology and rare fibers with actin filament aggregates. The present family expands the spectrum of actinopathy to include a distal myopathy.

We report a 58-year-old woman with slowly progressive facio-scapulo-peroneal muscle weakness due to congenital nemaline myopathy (NM) caused by a novel ACTA1 mutation (c.118A>G, p.Met271Val). In adult patients, congenital NM should be distinguished from sporadic late-onset nemaline myopathy (SLONM), which is a treatable acquired muscle disease often associated with monoclonal gammopathy or HIV infection. Both congenital NM and SLONM are characterized by the presence of nemaline rods in muscle. The patient's clinical history of difficulty running since childhood and weakness in other family members favored a congenital NM. The type 1 fiber atrophy and clusters of rods in normal size muscle fibers supported the diagnosis of congenital NM and prompted genetic molecular testing, which led to discovery of the novel ACTA1 variant causative of the myopathy.

Objective To characterize the natural history of immunoglobulin light chain amyloidosis–associated myopathy and to provide guidelines for recognition. Patients and Methods Fifty-one patients with systemic immunoglobulin light chain amyloidosis and biopsy-confirmed muscle amyloid deposition diagnosed between January 1, 1995, and December 31, 2015, were included in this study. Results Common presenting symptoms were muscle weakness in 49 patients (96%), dysphagia in 23 (45%), myalgia in 17 (33%), macroglossia in 17 (33%), jaw claudication in 13 (25%), and hoarseness in 9 (18%). The median time from the onset of symptoms to diagnosis was almost 2 years. Less than two-thirds of the patients with an outside muscle biopsy (16 of 27) had an established pathologic confirmation of amyloidosis due to failure to routinely incorporate Congo red staining. Moreover, 12 patients were incorrectly treated before diagnosis of amyloid myopathy. More than half of the patients had normal creatine kinase levels at diagnosis. Cardiac troponin T levels were elevated above the reference range in 5 of 12 patients who lacked evidence of cardiac involvement. Median overall survival was 32 months. Factors associated with inferior survival were involvement of more than 2 organs (median survival, 13 months), cardiac involvement (median survival, 15 months), and absence of stem cell transplant (median survival, 18 months). With the exclusion of patients treated with stem cell transplant, no improvement in survival was seen over the 1995-2004 and 2005-2015 decades. Conclusion Immunoglobulin light chain amyloidosis–associated myopathy is rare. Delay in diagnosis is common, and there is a high rate of pathologic and clinical misdiagnosis. Awareness of elevation of cardiac troponin T levels in the absence of cardiac disease may be a clue to diagnosis.

Multiminicore disease is a congenital myopathy characterized pathologically by the presence of multiple minicore structures in the sarcoplasm. Mutations in the selenoprotein N1-encoding gene (SEPN1) and ryanodine receptor 1-encoding gene (RYR1) are responsible for half of the reported cases. Mutations in multiple epidermal growth factor-like domains 10-encoding gene (MEGF10) have been identified only recently in a few patients with antenatal to infantile-onset myopathy, with and without minicore pathology.We report 2 sisters with adult-onset respiratory insufficiency followed by development of limb weakness. Both had scoliosis, distal joint hyperlaxity, and high-arched feet.A biopsy of the right triceps muscle in 1 sister showed multiple minicore structures. She had electromyographic changes of myopathy with fibrillation potentials and myotonic discharges. Next generation sequencing identified novel compound heterozygous missense variants in MEGF10 c.230GA (p.Arg77Gln) and c.1833TG (p.Cys611Trp) in both sisters.MEGF10 mutations can cause myopathy with adult-onset respiratory insufficiency. Muscle Nerve, 2016 Muscle Nerve 53: 984-988, 2016.

Camptocormia is a debilitating gait disorder characterized by the hyperflexion of the thoracolumbar spine during the upright position. Its etiologies are heterogenous, including parkinsonism and various neuromuscular disorders. Here, we report a camptocormia patient due to a late-onset axial myopathy with numerous lobulated fibers. The patient's father reportedly had similar symptoms. Myriad lobulated fibers are common among patients with an autosomal recessive muscular dystrophy due to calpain-3 gene (CAPN3) mutations or calpainopathy. CAPN3 sequencing revealed a single c.759-761delGAA mutation. Calpainopathy carriers are generally asymptomatic. The presence of lobulated fibers in this patient suggests that camptocormia could be a manifestation of calpainopathy carrier, although the possibility of a coexisting undiagnosed myopathy cannot be excluded. The current patient should spur the evaluation of camptocormia among calpainopathy carriers.