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Summary Background Pompe disease is a rare disorder characterised by progressive loss of muscle and respiratory function due to acid α-glucosidase deficiency. Enzyme replacement therapy with recombinant human acid α-glucosidase, alglucosidase alfa, is the first approved treatment for the disease, but some patients do not respond, and many do not show a sustained benefit. We aimed to assess the safety and efficacy of an investigational two-component therapy (cipaglucosidase alfa, a novel recombinant human acid α-glucosidase, plus miglustat, an enzyme stabiliser) for late-onset Pompe disease. Methods We did a randomised, double-blind, parallel-group, phase 3 trial at 62 neuromuscular and metabolic medical centres in 24 countries in the Americas, Asia-Pacific, and Europe. Eligible participants were aged 18 years or older with late-onset Pompe disease, and had either been receiving alglucosidase alfa for at least 2 years or were enzyme replacement therapy-naive. Participants were randomly assigned (2:1) using interactive response technology software, stratified by 6-min walk distance and previous enzyme replacement therapy status, to intravenous cipaglucosidase alfa (20 mg/kg) plus oral miglustat or to intravenous alglucosidase alfa (20 mg/kg) plus oral placebo once every 2 weeks for 52 weeks. Patients, investigators, and outcome assessors were masked to treatment assignment. The primary endpoint was change from baseline to week 52 in 6-min walk distance, assessed using a mixed-effect model for repeated measures analysis for comparison of superiority in the intention-to-treat population (all patients who received at least one dose of study drug). This study is now complete and is registered with ClinicalTrials.gov , NCT03729362 . Findings Between Dec 3, 2018, and Nov 26, 2019, 130 patients were screened for eligibility and 125 were enrolled and randomly assigned to receive cipaglucosidase alfa plus miglustat (n=85) or alglucosidase alfa plus placebo (n=40). Two patients in the alglucosidase alfa plus placebo group did not receive any dose due to absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group, five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At week 52, mean change from baseline in 6-min walk distance was 20·8 m (SE 4·6) in the cipaglucosidase alfa plus miglustat group versus 7·2 m (6·6) in the alglucosidase alfa plus placebo group using last observation carried forward (between-group difference 13·6 m [95% CI −2·8 to 29·9]). 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events were fall (25 [29%] patients in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%]) vs 5 [13%]). 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group; only one event (anaphylaxis) was deemed related to study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was deemed unrelated to study drug. There were no deaths. Interpretation Cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-min walk distance in our overall population of patients with late-onset Pompe disease. Further studies should investigate the longer-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than 2 years, as suggested by our secondary and subgroup analyses. Funding Amicus Therapeutics.

OBJECTIVES: The objective of this study was to examine the psychometric properties of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0 GCS) in Duchenne muscular dystrophy (DMD), a rare, severely debilitating, and ultimately fatal neuromuscular disease. METHODS: Patients with DMD were recruited from 20 centres across nine countries as part of the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (NCT00468832). The psychometric properties of the PedsQL 4.0 GCS were examined using Rasch analysis. RESULTS: In total, 329 patients with DMD (mean age: 9 years, range: 3–18 years; 75% ambulatory) completed the PedsQL 4.0 GCS. The most difficult instrument items, expressing the greatest loss in HRQoL, were those associated with emotional well-being (e.g., being teased by other children, feeling sad, and not making friends), as opposed to somatic disability (e.g., lifting heavy objects, participating in sports, and running). The mean item and person fit residuals were estimated at 0.301 (SD: 1.385) and −0.255 (1.504), respectively. In total, 87% (20 of 23) of items displayed disordered thresholds, and many exhibited non-trivial dependency. The overall item-trait interaction [Formula: see text] value was 178 (115 degrees of freedom, p

Author(s): Ikenaga, Chiseko; Findlay, Andrew R; Goyal, Namita A; Robinson, Sarah; Cauchi, Jonathan; Hussain, Yessar; Wang, Leo H; Kershen, Joshua C; Beson, Brent A; Wallendorf, Michael; Bucelli, Robert C; Mozaffar, Tahseen; Pestronk, Alan; Weihl, Conrad C | Abstract: ObjectiveTo define the clinicopathologic features and diagnostic utility associated with anti-cytosolic 5'-nucleotidase 1A (NT5C1A) antibody seropositivity in idiopathic inflammatory myopathies (IIMs).MethodsAnti-NT5C1A antibody status was clinically tested between 2014 and 2019 in the Washington University neuromuscular clinical laboratory. Using clinicopathologic information available for 593 patients, we classified them as inclusion body myositis (IBM), dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy (IMNM), nonspecific myositis, or noninflammatory muscle diseases.ResultsOf 593 patients, anti-NT5C1A antibody was found in 159/249 (64%) IBM, 11/53 (21%) dermatomyositis, 7/27 (26%) antisynthetase syndrome, 9/76 (12%) IMNM, 20/84 (24%) nonspecific myositis, and 6/104 (6%) noninflammatory muscle diseases patients. Among patients with IBM, anti-NT5C1A antibody seropositive patients had more cytochrome oxidase-negative fibers compared with anti-NT5C1A antibody seronegative patients. Among 14 IBM patients initially negative for anti-NT5C1A antibody, three patients (21%) converted to positive. Anti-NT5C1A antibody seropositivity did not correlate with malignancy, interstitial lung disease, response to treatments in dermatomyositis, antisynthetase syndrome, and IMNM, or survival in IIMs.InterpretationAnti-NT5C1A antibody is associated with IBM. However, the seropositivity can also be seen in non-IBM IIMs and it does not correlate with any prognostic factors or survival.

Background Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administratio...

Myopathies during chronic graft-versus-host disease (cGvHD) are syndromes for which tissue targets and mechanisms of muscle damage remain incompletely defined. This study reviewed, and pathologically analyzed, 14 cGvHD myopathies, comparing myopathology to other immune myopathies. Clinical features in cGvHD myopathy included symmetric, proximal weakness, associated skin, gastrointestinal and lung disorders, a high serum aldolase (77%), and a 38% 2-year survival. Muscle showed noninflammatory pathology involving all 3 tissue components. Perimysial connective tissue had damaged structure and histiocytic cells. Vessel pathology included capillary loss, and reduced α-l-fucosyl and chondroitin sulfate moieties on endothelial cells. Muscle fibers often had surface pathology. Posttranslational glycosylation moieties on α-dystroglycan had reduced staining and abnormal distribution in 86%. Chondroitin-SO4 was reduced in 50%, a subgroup with 3-fold longer times from transplant to myopathy, and more distal weakness. cGvHD myopathies have noninflammatory pathology involving all 3 tissue components in muscle, connective tissue, small vessels, and myofibers. Abnormal cell surface glycosylation moieties are common in cGvHD myopathies, distinguishing them from other immune myopathies. This is the first report of molecular classes that may be immune targets in cGvHD. Disordered cell surface glycosylation moieties could produce disease-related tissue and cell damage, and be biomarkers for cGvHD features and activity.

We asked whether myopathology features of immune or inflammatory myopathies (IIM), without reference to clinical or laboratory attributes, correlate with serum autoantibodies. Retrospective study included 148 muscle biopsies with: B-cell inflammatory foci (BIM), myovasculopathy, perimysial pathology (IMPP), myofiber necrosis without perimysial or vessel damage or inflammation (MNec), inflammation and myofiber vacuoles or mitochondrial pathology (IM-VAMP), granulomas, chronic graft-versus-host disease, or none of these criteria. 18 IIM-related serum autoantibodies were tested. Strong associations between myopathology and autoantibodies included: BIM with PM/Scl-100 (63%; odds ratio [OR] = 72); myovasculopathies with TIF1-γ or NXP2 (70%; OR = 72); IMPP with Jo-1 (33%; OR = 28); MNec with SRP54 (23%; OR = 37); IM-VAMP with NT5C1a (95%; OR = 83). Hydroxymethylglutaryl-CoA reductase (HMGCR) antibodies related to presence of myofiber necrosis across all groups (82%; OR = 9), but not to one IIM pathology group. Our results validate characterizations of IIM by myopathology features, showing strong associations with some serum autoantibodies, another objective IIM-related marker. BIM with PM/Scl-100 antibodies can be described pathologically as polymyositis. Tif1-γ and NXP2 antibodies are both common in myovasculopathies. HMGCR antibodies associate with myofiber necrosis, but not one IIM pathology subtype. Relative association strengths of IIM-related autoantibodies to IIM myopathology features versus clinical characteristics require further study.

Introduction Causes of small-fiber peripheral neuropathies (SFN) are often undefined. In this study we investigated associations of serum autoantibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor-3 (FGFR-3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS-HDS) in cryptogenic SFN. Methods One hundred fifty-five patients with biopsy-proven SFN and no identified cause for their neuropathy were blindly tested for serum IgM vs TS-HDS and IgG vs FGFR-3. Results Forty-eight percent of SFN patients had serum antibodies, 37% with IgM vs TS-HDS and 15% with IgG vs FGFR-3. TS-HDS antibodies were more frequent in SFN patients than in controls (P = .0012). Both antibodies were more common in females, and with non-length-dependent nerve pathology. Nintey-two percent of patients with acute-onset SFN had serum IgM vs TS-HDS. Discussion Autoantibodies directed against TS-HDS and FGFR-3 suggest an immune disorder in otherwise idiopathic SFN. Serum IgM vs TS-HDS may be a marker for SFN with an acute onset.

OBJECTIVE: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression. RESULTS: Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: −16.8, −11.9) in the placebo group and 13.4% (95% CI: −15.3, −11.6) in the tirasemtiv group (p = 0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p = 0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups. CONCLUSIONS: Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898). ispartof: AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION vol:20 issue:7-8 pages:584-594 ispartof: location:England status: published

ObjectiveTo describe the features of a new, pathologically distinctive, acquired myopathy with an unusual pattern of scattered necrotic muscle fibers that are neighbored, surrounded, or invaded, by large, often multinucleated, histiocytic cells.MethodsRetrospective review of records and muscle pathology of 4 patients.ResultsClinical features common to our patients included muscle pain and proximal, symmetric, moderate to severe, weakness in the arms and legs progressing over 1–4 weeks. Patients had other associated systemic disorders, including anemia in all, and hemophagocytic lymphohistiocytosis, hepatic disease, Raynaud phenomenon, metastatic cancer, and cardiomyopathy, in 1 patient each. Serum creatine kinase (CK) levels at presentation were very high, ranging from 10,000 to 102,000 U/L. Three patients improved within 3 months after treatment. Muscle pathology included scattered necrotic muscle fibers with cytoplasm that stained for C5b-9 complement, especially around fiber peripheries, pale on nicotinamide adenine dinucleotide and often dark on hematoxylin & eosin. Large, often multinucleated, cells with features of histiocytes, including anatomical features on electron microscopy and immunostaining for major histocompatibility complex Class I and histiocyte markers (HAM56, CD68, CD163, and S100), were usually closely apposed to the surface of, or invaded, necrotic myofibers.ConclusionsPatients with large-histiocyte-associated myopathy (LHIM) had a subacute onset of proximal predominant weakness, associated systemic disorders, very high serum CK, and a pathologically distinctive pattern of large histiocyte-associated muscle fiber necrosis. LHIM may be caused by an autoimmune, histiocyte-mediated attack directed against muscle fibers.

Objective To assess the intraepidermal nerve fiber density in patients diagnosed with fibromyalgia (FM) and to evaluate the role of IgM binding to trisulfated heparin disaccharide (TS-HDS) in these patients. Methods FM is a poorly understood pain disorder with several proposed pathophysiologic mechanisms. It is characterized by widespread pain, fatigue, and sleep abnormalities. Small fiber neuropathy (SFN) has been proposed as an underlying mechanism, and patients with FM have been shown to have a reduction in the intraepidermal nerve fiber density. An underlying inflammatory process that could be a result of autoimmune phenomena has also been suggested. Non-length-dependent SFN (NLDSFN) has been shown to have a higher incidence of autoimmune disease. Twenty-two patients with established diagnosis of FM underwent skin biopsy at 2 sites; 10 cm above the lateral malleolus and 10 cm above the patella. Serum IgM binding to TS-HDS was assayed using an ELISA method. Results A total of 5/22 patients had positive TS-HDS antibodies; of these, 4 had NLDSFN (P = 0.0393). Comparison with a control group at Washington University showed no significant difference in percentage with TS-HDS antibodies (P = 0.41). When compared with Washington University database of skin biopsy, there was a trend for an increased percentage of NLDSFN in patients with FM (P = 0.06). Conclusions This study further supports the hypothesis that a subgroup of patients with FM has SFN. We suggest a correlation between the presence of NLDSFN and TS-HDS antibodies.

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 (t1/2z∼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. ispartof: NEUROMUSCULAR DISORDERS vol:29 issue:3 pages:167-186 ispartof: location:England status: published

Web-based Electronic data capture (EDC) has become the preferred method for capture of key-entered data in clinical studies. This chapter reviews the considerations for selecting an EDC system including evaluation of systems and vendors, user requirements, an process change, as well as initial implementation of systems within organizations. The goal of system selection is to assure that organizational needs are identified and documented and ultimately that the desired functionality is available and appropriately supports clinical studies conducted by the organization. Multiple roles on study teams use the EDC system and should be involved in software selection and initial implementation.

Background and Objectives We investigated the prevalence of late-onset Pompe disease (LOPD) in patients presenting to 13 academic, tertiary neuromuscular practices in the United States and Canada. Methods All successive patients presenting with proximal muscle weakness or isolated hyperCKemia and/or neck muscle weakness to these 13 centers were invited to participate in the study. Whole blood was tested for acid alpha-glucosidase (GAA) assay through the fluorometric method, and all cases with enzyme levels of ≤10 pmoL/punch/h were reflexed to molecular testing for mutations in the GAA gene. Clinical and demographic information was abstracted from their clinical visit and, along with study data, entered into a purpose-built REDCap database, and analyzed at the University of California, Irvine. Results GAA enzyme assay results were available on 906 of the 921 participants who consented for the study. LOPD was confirmed in 9 participants (1% prevalence). Another 9 (1%) were determined to have pseudodeficiency of GAA, whereas 19 (1.9%) were found to be heterozygous for a pathogenic GAA mutation (carriers). Of the definite LOPD participants, 8 (89%) were Caucasian and were heterozygous for the common leaky (IVS1) splice site mutation in the GAA gene (c -32-13T>G), with a second mutation that was previously confirmed to be pathogenic. Discussion The prevalence of LOPD in undiagnosed patients meeting the criteria of proximal muscle weakness, high creatine kinase, and/or neck weakness in academic, tertiary neuromuscular practices in the United States and Canada is estimated to be 1%, with an equal prevalence rate of pseudodeficiency alleles. Trial Registration Information Clinical trial registration number: NCT02838368.

The Jain COS Consortium., [Objective] Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD., [Methods] We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories., [Results] The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline., [Interpretation] The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967–978, The estimated US $4 million needed to fund this study was provided by the Jain Foundation. (www.jain-foundation.org) The Jain COS consortium would like to thank the study participants and their families for their invaluable contribution. The John Walton Centre Muscular Dystrophy Research Centre is part of the MRC Centre for Neuromuscular Diseases (Grant number MR/K000608/1).

The Jain COS Consortium., This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments., The estimated $4 million USD needed to fund this study was provided by the Jain Foundation. Volker Straub was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1.

ObjectivesTo approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families.DesignRetrospective cohort study.SettingClinics across North America.ParticipantsThe study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis.MethodsPhenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed.ResultsAmong 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members.DiscussionThe familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.

Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1) gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1 coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validation.

The Jain COS Consortium., Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined as no activity, minimal, moderate, or intensive activity by using metabolic equivalents and patient reported frequency of sports undertaken between the ages of 10 and 18. We used ANCOVA and linear modeling to compare the mean Lamminen-Mercuri score for the pelvis, thigh, and leg between exercise groups, controlling for age at assessment and symptom duration. Intensive exercisers showed greater fatty replacement in the muscles of the pelvis than moderate exercisers, but no significant differences of the thigh or leg. Within the pelvis, Psoas was the muscle most strongly associated with this exercise effect. In patients with a short symptom duration of, The estimated $4 million USD needed to fund this study was provided by the Jain Foundation. VS was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1.

We describe changes in pulmonary function measures across time in Duchenne muscular dystrophy patients treated with glucocorticoids (GCs) 1 year compared to GC naïve patients in the Cooperative International Research Group Duchenne Natural History Study, a multicenter prospective cohort study. 397 participants underwent 2799 pulmonary function assessments over a period up to 10 years. Fifty-three GC naïve participants ( 1 month exposure) were compared to 322 subjects with 1 year cumulative GC treatment. Forced vital capacity (FVC), peak expiratory flow rate (PEFr), maximal inspiratory and expiratory pressures were performed and calculated as a percent predicted (%p). GC treatment slowed the rate of pulmonary decline as measured by FVC%p, in patients aged 7-9.9 years. GC treatment slowed 12 and 24-month progression of percent predicted spirometry to a greater degree in those with baseline FVC%p from 80-34%. GC treatment resulted in higher peak absolute FVC and PEFr values with later onset of decline. Progression to an absolute FVC 1 liter was delayed by GC treatment. Patients who reached a FVC below 1 L were 4.1 times more likely to die (p = 0.017). Long-term glucocorticoid treatment slows pulmonary disease progression in Duchenne dystrophy throughout the lifespan.

Nephropathic cystinosis is an autosomal recessive lysosomal disease in which cystine cannot exit the lysosome to complete its degradation in the cytoplasm, thus accumulating in tissues. Some patients develop a distal myopathy involving mainly hand muscles. Myopathology descriptions from only 5 patients are available in the literature. We present a comprehensive clinical, pathological and genetic description of 3 patients from 2 families with nephropathic cystinosis. Intrafamiliar variability was detected in one family in which one sibling developed a severe distal myopathy while the other sibling did not show any signs of skeletal muscle involvement. One of the patients was on treatment with Cysteamine for over 12 years but still developed the usual complications of nephropathic cystinosis in his twenties. Novel pathological findings consisting in sarcoplasmic deposits reactive for slow myosin were identified. Three previously known and one novel mutation are reported. Nephropathic cystinosis should be included in the differential diagnosis of distal myopathies in those with early renal failure. Novel clinical and pathological features are reported here contributing to the characterization of the muscle involvement in nephropathic cystinosis.

Objective: We studied mitochondrial impairment as a factor in the pathologic equivalent of sarcopenia, muscle fiber atrophy associated with increased age. Methods: Mitochondrial oxidative enzyme activities and coenzyme Q10 levels were measured in frozen human proximal limb muscles with combined age and atrophy, age alone, atrophy alone, denervation, immune myopathies, and mitochondrial disorders with ophthalmoplegia. Results: Sarcopenia (age and atrophy) had reduced mean activities of mitochondrial Complexes I, II, and II+III, with severe reduction of Complex I activity in 54% of patients. Atrophy, and specific denervation atrophy, had similar patterns of changes. Age alone had moderately reduced Complex I activity. Mitochondrial myopathies had mildly lower Complex IV activity. Immune myopathies had unchanged enzyme activities. Interpretation: Mitochondrial oxidative enzyme activities, especially Complex I, but also Complexes II and II+III, are reduced in muscles with the pathologic equivalent of sarcopenia. Individually, atrophy and age have different patterns of oxidative enzyme changes. This article is protected by copyright. All rights reserved.

Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial ...

Jain COS Consortium., [Objective] To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year., [Methods] One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis., [Results] The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint., [Conclusion] Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials., [ClinicalTrials.gov identifier] NCT01676077., The estimated US $4 million needed to fund this study is being provided by the Jain Foundation. The John Walton Centre Muscular Dystrophy Research Centre is part of the MRC Centre for Neuromuscular Diseases (grant MR/K000608/1).

Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). We examined the effectiveness of ataluren + standard of care (SoC) in the registry versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), DMD genotype–phenotype/–ataluren benefit correlations and ataluren safety. Patients & methods: Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established disease progression predictors (registry cut-off date, 9 July 2018). Results & conclusion: Kaplan–Meier analyses demonstrated that ataluren + SoC significantly delayed age at loss of ambulation and age at worsening performance in timed function tests versus SoC alone (p ≤ 0.05). There were no DMD genotype–phenotype/ataluren benefit correlations. Ataluren was well tolerated. These results indicate that ataluren + SoC delays functional milestones of DMD progression in patients with nmDMD in routine clinical practice. ClinicalTrials.gov identifier: NCT02369731. ClinicalTrials.gov identifier: NCT02369731.

Objective: To assess safety and efficacy of deflazacort (DFZ) and prednisone (PRED) vs placebo in Duchenne muscular dystrophy (DMD). Methods: This phase III, double-blind, randomized, placebo-controlled, multicenter study evaluated muscle strength among 196 boys aged 5–15 years with DMD during a 52-week period. In phase 1, participants were randomly assigned to receive treatment with DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, PRED 0.75 mg/kg/d, or placebo for 12 weeks. In phase 2, placebo participants were randomly assigned to 1 of the 3 active treatment groups. Participants originally assigned to an active treatment continued that treatment for an additional 40 weeks. The primary efficacy endpoint was average change in muscle strength from baseline to week 12 compared with placebo. The study was completed in 1995. Results: All treatment groups (DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, and PRED 0.75 mg/kg/d) demonstrated significant improvement in muscle strength compared with placebo at 12 weeks. Participants taking PRED had significantly more weight gain than placebo or both doses of DFZ at 12 weeks; at 52 weeks, participants taking PRED had significantly more weight gain than both DFZ doses. The most frequent adverse events in all 3 active treatment arms were Cushingoid appearance, erythema, hirsutism, increased weight, headache, and nasopharyngitis. Conclusions: After 12 weeks of treatment, PRED and both doses of DFZ improved muscle strength compared with placebo. Deflazacort was associated with less weight gain than PRED. Classification of evidence: This study provides Class I evidence that for boys with DMD, daily use of either DFZ and PRED is effective in preserving muscle strength over a 12-week period.

To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS).Sixty participants with SALS from 10 centers were randomized 1:1:1 to placebo, mexiletine 300 mg/d, or mexiletine 900 mg/d and followed for 12 weeks. The primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetic study from plasma and CSF, ALS Functional Rating Scale-Revised (ALSFRS-R) score, slow vital capacity (SVC), and muscle cramp frequency and severity.The only serious adverse event among active arm participants was one episode of imbalance. Thirty-two percent of participants receiving 900 mg of mexiletine discontinued study drug vs 5% on placebo (p = 0.026). Pharmacokinetic study demonstrated a peak plasma concentration 2 hours postdose and strong correlation between plasma and CSF (p0.001). Rates of decline of ALSFRS-R and SVC did not differ from placebo. Analysis of all randomized patients demonstrated significant reductions of muscle cramp frequency (300 mg: rate = 31% of placebo, p = 0.047; 900 mg: 16% of placebo, p = 0.002) and cramp intensity (300 mg: mean = 45% of placebo, p = 0.08; 900 mg: 25% of placebo, p = 0.005).Mexiletine was safe at both doses and well-tolerated at 300 mg/d but adverse effects at 900 mg/d led to a high rate of discontinuation. Mexiletine treatment resulted in large dose-dependent reductions in muscle cramp frequency and severity. No effect on rate of progression was detected, but clinically important differences could not be excluded in this small and short-duration study.This study provides Class I evidence that mexiletine is safe when given daily to patients with amyotrophic lateral sclerosis at 300 and 900 mg and well-tolerated at the lower dose.

Introduction: The radial nerve and posterior interosseous nerve (PIN) are prone to injury at multiple sites. Electrodiagnostic (EDx) studies may only identify the most proximal lesion. Nerve ultrasound could augment EDx by visualizing additional pathology. Methods: This investigation was a retrospective examination of ultrasound and EDx from 26 patients evaluated for posterior cord/radial/PIN lesions. Results: Eighteen of 26 patients had abnormalities on EDx (15 radial, 2 PIN, 1 posterior cord). Ultrasound identified 15 of 18 (83%) of the EDx abnormalities and provided additional diagnostic information. In 6 of 15 (40%) patients with EDx evidence of radial neuropathy, ultrasound identified both radial nerve enlargement and additional, unsuspected PIN enlargement (53% to 339% enlarged vs. unaffected side). Ultrasound also identified: nerve (dis)continuity at the trauma site (n = 8); and nerve tumor (n = 2; 1 with normal EDx). Conclusion: In radial neuropathy, ultrasound often augments EDx studies and identifies a second lesion in the PIN. Further studies are required to determine the etiology and significance of this additional distal pathology. Muscle Nerve 53: 379–383, 2016

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.

INTRODUCTION CANOMAD/CANDA are syndromes characterized by ataxic neuropathy, ophthalmoplegia, monoclonal gammopathy, cold agglutinins and disialosyl antibodies. METHODS A retrospective review of our neuromuscular autoantibody panel database was performed. Anti-GD1b seropositive patients with ataxia were included. RESULTS Eleven patients were identified. Median age at onset was 56 years. Median disease duration was 6 years. All patients had gait disorders. Nine had ocular motility abnormalities. Most had a monoclonal protein and all had elevated serum IgM. Electrodiagnostic studies showed a mixed axonal/demyelinating pattern (6), an axonal pattern (4), or a pure demyelinating pattern (1). Ultrasounds showed nerve enlargement patterns consistent with acquired demyelination. A nerve biopsy showed near complete loss of myelinated axons with preservation of smaller axons. Rituximab was the most effective immunotherapy. CONCLUSION CANOMAD/CANDA are rare and debilitating disorders with characteristic clinical and diagnostic findings. In our cohort, nerve ultrasound showed regional nerve enlargement and rituximab was the most effective immunomodulatory therapy.

Background and objectiveDysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests.MethodsWe present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed.ResultsIn 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment.ConclusionsThe information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials.Clinical trial registrationNCT01676077.

Introduction Different disease patterns result from loss of myelinated and unmyelinated axons, but quantitation to define their loss has been difficult. Methods We measured large and small endoneurial axons in axonal neuropathies by staining them with peripherin and comparing their area to that of nonmyelinating Schwann cells stained with neural cell adhesion molecule (NCAM). Results Loss of myelinated and unmyelinated axons was typically proportional, with predominant myelinated or unmyelinated axon loss in a few patients. Myelinated axon loss was associated with loss of distal vibration sense and sensory potentials (P

The role of autoimmune mechanisms in idiopathic small fiber neuropathy (SFN) is not completely understood. Serum IgM binding to trisulfated disaccharide IdoA2S-GlcNS-6S (TS-HDS) and IgG to fibroblast growth factor receptor 3 were associated with sensory motor polyneuropathies and sensory neuronopathy among others. In this retrospective case review, we describe the clinical and laboratory findings of idiopathic SFN in a small cohort of pediatric patients. Eight children were diagnosed with SFN clinically and confirmed by reduced epidermal nerve fiber density. No involvement of large fibers was confirmed by clinical examination and electrophysiological tests. Possible triggering factors were infectious mononucleosis in 4 patients and human papilloma virus vaccination in 1 patient. Tilt table test was positive in 1 patient, and clinical autonomic dysfunctions were noted in 6 patients. Five patients had positive IgM against TS-HDS, 3 of whom had lower extremity predominant paresthesia. In conclusion, a high proportion of patients with idiopathic SFN in our cohort had a positive IgM TS-HDS antibody.

Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy.For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832.440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501).In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death.US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.

ImportanceUnderstanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population.ObjectiveTo establish an updated natural history of ALSSOD1.Design, setting and participantsRetrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.Main outcomes and measuresAge of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis.ResultsMean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p

Introduction: Nerves are often enlarged in chronic inflammatory demyelinating polyneuropathy (CIDP). In this investigation we studied changes with treatment over time. Methods: We retrospectively compared serial ultrasound measurements of median and ulnar nerve size with clinical and electrodiagnostic evaluations in 23 CIDP subjects. We defined remission as stable clinical improvement on low or decreasing amounts of medication. Results: Nerves were normal at last follow-up more often in subjects who achieved remission than in those who did not (10 of 13 vs. 0 of 10, P = 0.0001). Nerves were normal or smaller (>30% reduction) more often in subjects whose grip strength improved or remained strong compared those whose grip strength weakened (12 of 16 vs. 0 of 3, P = 0.04), and in subjects whose demyelinating electrodiagnostic features resolved compared with those whose demyelination persisted (7 of 7 vs. 6 of 12, P = 0.04). Over time, nerve size decreased more in subjects with baseline nerve enlargement who achieved remission than in those who did not (−41% vs. 7%, P = 0.04). Conclusion: In CIDP, enlarged nerves normalized or decreased with remission. Muscle Nerve 50: 733–738, 2014

Introduction: Ipilimumab, a monoclonal anti–CTLA-4 antibody, is used to treat melanoma. Neuromuscular side effects, possibly autoimmune, may occur. Methods: In this investigation we undertook a retrospective review of patient records. Results: After 3 doses of ipilimumab, a 31-year-old man developed asymmetric, severe weakness involving all limbs, respiration, and cranial nerves, which was progressive over 2 weeks. EMG/NCS showed an axonal polyradiculoneuropathy with multifocal motor conduction blocks. CSF protein was 749 mg/dl. Nerve pathology showed inflammation around the endoneurial microvessels and subperineurial edema and inflammation. Spine MRI showed leptomeningeal and anterior and posterior root enhancement. Strength improved slowly over months after ipilimumab discontinuation and immunomodulating treatment. Conclusions: Ipilimumab toxicity presented as a monophasic, multifocal, asymmetric polyradiculoneuropathy involving roots and peripheral and cranial nerves. Ipilimumab may produce a polyradiculoneuropathy with disruption of the blood–nerve barrier due to a microvasculopathy. Muscle Nerve 48: 440–444, 2013

Introduction: Muscle cramps are a common complaint and are thought to arise from spontaneous discharges of the motor nerve terminal. Polyneuropathy is often causative, but small-fiber neuropathy (SFN) has not been assessed. Methods: We performed skin biopsies on consecutive patients with cramps but without neuropathic complaints. Twelve patients were biopsied, 8 with normal small-fiber sensation. Results: Seven patients had decreased intraepidermal nerve fiber density (IENFD), 2 with non–length-dependent loss. A cause for neuropathy was found in 1 patient with cramp–fasciculation syndrome. Creatine kinase was elevated in 8 patients, 4 with decreased IENFD. Muscle biopsy, performed in 8 patients, but was diagnostic in only 1, with McArdle disease. Conclusions: Our data show that 60% of patients with muscle cramps who lack neuropathic complaints have SFN, as documented by decreased IENFD. Cramps may originate as local mediators of inflammation released by damaged small nerve that excite intramuscular nerves. Muscle Nerve, 48: 252–255, 2013

The American population weighs too much. That is so well documented; it does not even need a citation. And for all the millions of pages of research and gray literature devoted to the topic and all the complex reasons for American obesity, we know that Americans tend to eat too much, and too much of the wrong things, while not exercising nearly enough. With the girth of America growing, taking off fatty pounds and, more importantly, keeping them off will go a long way toward mitigating personal and family health catastrophes and future health care costs. Our propensityforexcessweightis,tobesure,relatedtodecisions by individuals. But these decisions are shaped and guided by what we encounter in the places where we work, learn, and play. A new environment around each of us, one less blessed with empty calories and more encouraging to movement and activity, will become us. In the past few years, policy attempts to influence the inputs have been highly visible, from the recent success in reducing sodium in processed foods to the Affordable Care Act’s requirement to place calories on menu boards and the 2010 Healthy Hunger-Free Kids Act, which promoted healthier meals in schools and in childcare centers. While the output side of the equation has not been ignored in research or in our culture, the role of policy in affecting physical activity is nowhere near as visible as the policy focus on nutrition. This issue of the Journal of Public Health Management and Practice is a welcome examination of policy’s role in altering the output side of the equation.

Objective: To compare accuracy of ultrasound and MRI for detecting focal peripheral nerve pathology, excluding idiopathic carpal or cubital tunnel syndromes. Methods: We performed a retrospective review of patients referred for neuromuscular ultrasound to identify patients who had ultrasound and MRI of the same limb for suspected brachial plexopathy or mononeuropathies, excluding carpal/cubital tunnel syndromes. Ultrasound and MRI results were compared to diagnoses determined by surgical or, if not performed, clinical/electrodiagnostic evaluation. Results: We identified 53 patients who had both ultrasound and MRI of whom 46 (87%) had nerve pathology diagnosed by surgical (n = 39) or clinical/electrodiagnostic (n = 14) evaluation. Ultrasound detected the diagnosed nerve pathology (true positive) more often than MRI (43/46 vs 31/46, p 2 cm) and only occasionally (2/13) outside the MRI field of view. MRI missed multifocal pathology identified with ultrasound in 6 of 7 patients, often (5/7) because pathology was outside the MRI field of view. Conclusions: Imaging frequently detects peripheral nerve pathology and contributes to the differential diagnosis in patients with mononeuropathies and brachial plexopathies. Ultrasound is more sensitive than MRI (93% vs 67%), has equivalent specificity (86%), and better identifies multifocal lesions than MRI. In sonographically accessible regions ultrasound is the preferred initial imaging modality for anatomic evaluation of suspected peripheral nervous system lesions.

Background GNE Myopathy (GNEM) is a progressive adult-onset myopathy likely caused by deficiency of sialic acid (SA) biosynthesis. Objective Evaluate the safety and efficacy of SA (delivered by aceneuramic acid extended-release [Ace-ER]) as treatment for GNEM. Methods A Phase 2, randomized, double-blind, placebo-controlled study evaluating Ace-ER 3 g/day or 6 g/day versus placebo was conducted in GNEM subjects (n = 47). After the first 24 weeks, placebo subjects crossed over to 3 g/day or 6 g/day for 24 additional weeks (dose pre-assigned during initial randomization). Assessments included serum SA, muscle strength by dynamometry, functional assessments, clinician- and patient-reported outcomes, and safety. Results Dose-dependent increases in serum SA levels were observed. Supplementation with Ace-ER resulted in maintenance of muscle strength in an upper extremity composite (UEC) score at 6 g/day compared with placebo at Week 24 (LS mean difference +2.33 kg, p = 0.040), and larger in a pre-specified subgroup able to walk ≥200 m at Screening (+3.10 kg, p = 0.040). After cross-over, a combined 6 g/day group showed significantly better UEC strength than a combined 3 g/day group (+3.46 kg, p = 0.0031). A similar dose-dependent response was demonstrated within the lower extremity composite score, but was not significant (+1.06 kg, p = 0.61). The GNEM-Functional Activity Scale demonstrated a trend improvement in UE function and mobility in a combined 6 g/day group compared with a combined 3 g/day group. Patients receiving Ace-ER tablets had predominantly mild-to-moderate AEs and no serious adverse events. Conclusions This is the first clinical study to provide evidence that supplementation with SA delivered by Ace-ER may stabilize muscle strength in individuals with GNEM and initiating treatment earlier in the disease course may lead to better outcomes.

MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration. © 2014 Nature America, Inc. All rights reserved.