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• Ophthalmoparesis has not been previously described in anti-HMGCR antibody-associated myopathies and two cases are presented. • Other causes of ophthalmoparesis and proximal weakness were extensively ruled out. • Consider anti-HMGCR antibody-associated myopathies in patients with proximal weakness, elevated creatine kinase, and ophthalmoparesis. We describe two anti-3‑hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) antibody-positive patients with treatment-responsive ophthalmoparesis. Patient 1 was a 53-year-old male with progressive proximal limb weakness, dysphagia, ptosis, and diplopia over 6 weeks and creatine kinase (CK) of 3,512 units/L. Patient 2 was a 55-year-old female with progressive proximal weakness, dysarthria, ptosis, diplopia, and dyspnea over 2 weeks with CK of 31,998 units/L. Both patients had normal thyroid studies and repetitive nerve stimulation, myopathic electromyography with fibrillation potentials, magnetic resonance imaging demonstrating abnormal enhancement of extraocular muscles, muscle biopsy showing necrotic myofibers, and positive anti-HMGCR antibodies. Patient 1 also had weakly positive anti-PM/Scl antibodies. Immunomodulatory therapies led to resolution of oculobulbar weakness and normalization of CK levels in both patients, while limb weakness resolved completely in patient 1 and partially in patient 2. These cases expand the phenotypic spectrum of anti-HMGCR antibody-associated myopathies to include subacute ophthalmoparesis with limb-girdle weakness and markedly elevated CK. [ABSTRACT FROM AUTHOR]

Muscle involvement in sarcoidosis is common by pathologic analysis, but symptomatic disorders are less frequent. Sarcoidosis-related muscle pathology includes non-caseating granulomas, muscle fiber changes that are diffuse or anatomically related to granulomas, and perimysial connective tissue with histiocyte-associated damage. The mechanisms by which granulomas form, enlarge and damage muscle tissues are incompletely understood. Sarcoidosis-related clinical syndromes with muscle involvement include: chronic myopathies with proximal weakness; nodular disorders; subacute onset disorders involving proximal or eye muscles; myalgia or fatigue syndromes; and, possibly, inclusion body myositis-like disorders. Corticosteroid treatment may benefit some syndromes, but clinical trials are necessary. [Display omitted] • Sarcoidosis involvement of muscle with granulomas is common on pathology analysis. • Some granulomas form by invasion and replacement of intact myofibers by histiocytes. • Muscle pathology, other than granulomas, includes muscle fiber and connective tissue damage. • Clinical "myopathy" syndromes are uncommon in sarcoidosis, but are well recognized. • Different clinical "myopathies" in sarcoidosis may include weakness, myalgias or nodules. [ABSTRACT FROM AUTHOR]

Summary: Background: Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis. Methods: In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11·5 h at increasing doses (0·15 mg, 0·50 mg, 1·50 mg, 3·00 mg) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov, number NCT01041222. Findings: Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated. Interpretation: This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders. Funding: The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals. [Copyright &y& Elsevier]

Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38β MAPK) for the treatment of facioscapulohumeral muscular dystrophy. We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18–65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2–4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov , number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4 - driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI –1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. Fulcrum Therapeutics. [ABSTRACT FROM AUTHOR]

Highlights • MYH2 mutations cause dominant and recessive myopathies with ophthalmoplegia. • Dominant mutations cause progressive proximal weakness with rimmed vacuoles. • Recessive mutations cause congenital myopathy with reduced MyHCIIa expression. • We describe a recessive MYH2 mutation associated with a dominant phenotype. Abstract Mutations in MYH2 that encodes myosin heavy chain IIa cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with ophthalmoplegia and progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, patients with recessive MYH2 mutations have early onset, non-progressive, diffuse weakness and ophthalmoplegia. Muscle biopsy reveals near or complete absence of type 2A fibers with no vacuole or inclusion pathology. We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient's disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246His homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies. [ABSTRACT FROM AUTHOR]

The International Clinical Outcome Study for Dysferlinopathy (COS) was the first multi-country natural history study in dysferlinopathy with the aim to characterise disease presentation and improve clinical trial readiness. In the absence of validated disease specific motor assessment scales, The North Star Assessment for limb girdle type muscular dystrophies (NSAD), was developed and validated in the COS I cohort. The Performance of upper limb (PUL 2.0), originally developed for DMD was assessed in COS I and found to be suitable to measure upper limb function in dysferlinopathy. The extension study, COS II, recruited 203 participants (119 new) from 16 sites in nine countries with the aim to validate the findings from COS I in an expanded cohort. We now examine the psychometric performance of the NSAD and PUL in the new COS II participants using Rasch Unidimensional Measurement Model (RUMM). Psychometric evaluation of 117 available assessments evaluated NSAD and PUL performance in seven areas: targeting, response categories, fit, reliability, dependency, stability and unidimensionality using RUMM2030 software. NSAD and PUL demonstrated unidimensional construct of functional motor performance and upper limb motor performance respectively, high reliability with a PSI of 0.96 and 0.95 respectively. A potential ceiling effect still existed for the strongest/ asymptomatic subjects in both scales. 27/29 items of the NSAD and 19/22 items of the PUL demonstrated ordered response categories, meaning the scoring categories for each item are logical and appropriate for dysferlinopathy. No items of NSAD with fit residuals outside ±2.5 but three on the PUL. The items fit well together to make use of the total score appropriate. Differential item functioning analysis, which indicates if a person factor influences the probability of scoring on an item was not present for gender on either scale. This study validated previous data from COS, confirming that the NSAD and PUL are suitable measurements for use in dysferlinopathy. Ongoing analysis is underway to examine the psychometric properties of these scales and responsiveness to change in functional ability over time. [ABSTRACT FROM AUTHOR]

An important requirement for interventional studies and clinical management is the identification of minimal clinically important differences (MCID) in outcomes of interest. This is lacking for many neuromuscular diseases; however, the Dysferlinopathy Clinical Outcome Study (COS) has given us the opportunity to assess the meaningful change in several outcomes in individuals with dysferlinopathy. We identified 378 12-month observation intervals in 240 COS participants to calculate several MCID values. We utilized both distribution-based and anchor-based methods to calculate MCIDs for three outcomes, the ACTIVLIM patient reported activity questionnaire, forced vital capacity (FVC), and forced expiratory volume in first second (FEV1). We chose two different anchors, a ≥3 point decrease in total NSAD score and a ≥1 point decrease in NSAD item 29 (timed 10-meter walk/run), along with several different methods of MCID calculation to determine consensus values. 12-month MCID estimates using all methods for the ACTIVLIM ranged from a decrease of 0.4 to 1.7 points, a decrease of 1.0 to 4.4 % points for % predicted FEV1, and a decrease of 0.9 to 4.8 % points for % predicted FVC. Anchor-based MCID values based on total NSAD change and NSAD item 29 change were very similar using the multiple methods. However, the distribution-based methods produced MCID values that were either greater decreases than anchor-based values or smaller decreases than anchor-based values. Anchor-based MCID values for the ACTIVLIM show a decrease of 1.0 point is associated with a 3+ point drop in the NSAD and a 0.9-point decrease is associated with a 1+ point decrease in NSAD item 29. A decrease of 1.5 and 1.8 for FEV1, and 2.0 and 3.0 for FVC, respectively, were calculated. To better refine these, we plan to evaluate MCID values in sex-stratified cohorts alongside other factors that may mediate the 12-month observed changes in outcomes. [ABSTRACT FROM AUTHOR]

Highlights • Avalglucosidase alfa (neoGAA) had a well-tolerated safety profile in LOPD patients. • Respiratory and functional capacities were stable or improved in most patients. • Postinfusion, avalglucosidase alfa in plasma fell monoexponentially (t 1/2z ∼1.0 h). • AUC for avalglucosidase alfa in plasma was 5–6 × higher for the 20 vs 5 mg/kg group. • Safety/exploratory efficacy data support further avalglucosidase alfa development. Abstract This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t 1/2z ∼1.0 h). AUC was 5–6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development. [ABSTRACT FROM AUTHOR]

Abstract: Necrotizing myopathy is an unusual and severe form of paraneoplastic myopathy in which inflammation is minimal or absent. We report two cases of necrotizing myopathy which demonstrated significant response to intravenous immunoglobulin (IVIG) (one in spite of tumor progression). A third case represents the first association of anti-signal recognition particle (anti-SRP) syndrome with large-cell lung cancer. These cases highlight the role of histopathologic diagnosis in directing the treatment of paraneoplastic myopathy, and the role for IVIG in treatment of the syndrome. [Copyright &y& Elsevier]

We have previously reported a new autosomal dominant inclusion body myopathy clinically resembling limb girdle muscular dystrophy, associated with Paget disease of bone in the majority and frontotemporal dementia in a third of individuals. The critical locus for this unique disorder now termed IBMPFD is 9p21.1–p12, spans 5.5 Mb and contains the gene responsible for the recessive quadriceps-sparing inclusion body myopathy (IBM2). Mutation analysis of the GNE gene associated with IBM2 in affected individuals from four IBMPFD families did not identify any mutations, indicating that the two disorders are not allelic. Expression studies indicate that GNE has a tissue-specific splice pattern, with four splice variants. Mutation analysis in three other candidate genes (β-tropomyosin, NDUFB6 and SMU1) did not identify any mutations. [Copyright &y& Elsevier]

Complement deposition and macrophages are common in biopsies of children with muscular dystrophy. While the presumed roles of complement and macrophages have been those of scavenger to remove and clear necrotic fibers, there is some evidence that they play a primary role in the pathogenesis of these diseases. Here, we explore the role of complement in the pathogenesis of the most severe animal model of congenital dystrophy, the dy−/− mouse, which is laminin α2-deficient. We generated animals deficient in both C3 and laminin α2. C3 is the third component of the complement cascade and is required for activation of either the classical or alternative pathways. Thirty-three percent of the dy−/−:C3+ mice (n=59) died before 24 weeks while only 14% of the dy−/−:C3−/− (n=29) mice died (p=0.04). Absolute forepaw strength was 25–30% greater for the dy−/−:C3−/− mice up to 20 weeks of age (p<0.05 compared to complement-sufficient). Forepaw strength adjusted for weight also showed significant differences with C3−/− mice being stronger up to 20 weeks (p<0.05). However, by 24 weeks, the two groups did not differ for strength. Next, we treated 20 mice with twice weekly oral prednisolone. Survival at 24 weeks for the prednisolone treated dy−/− mice (C3−/− or C3+) was 90% (p=0.04). This work shows that complement insufficiency and weekly prednisone prolong survival and improve strength of the laminin α2-deficient mouse. This work suggests that the complement system may contribute directly to the pathogenesis of this form of dystrophy. Because complement activity may be modified pharmacologically, this work may have implications for treatment of children with congenital muscular dystrophy secondary to laminin α2 deficiency. [Copyright &y& Elsevier]

Abstract: We present a case of juvenile dermatomyositis with unusual histopathologic findings. The child presented with a course consistent with dermatomyositis, a diagnosis confirmed by finding reticulotubular aggregates in endothelial cells on electron microscopy. However, histopathology of his muscle biopsy revealed a striking pattern of glycogen accumulation, to an extent similar to that seen in glycogen storage diseases; this degree of accumulation could potentially confound histopathologic diagnosis. [Copyright &y& Elsevier]