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ObjectiveWe clinically and molecularly characterize a new family with autosomal dominant rimmed vacuolar myopathy (RVM) caused by mutations in the HSPB8 gene.MethodsWe performed whole-exome and whole-genome sequencing in the family. Western blot and immunocytochemistry were used to analyze 3 patient fibroblasts, and findings were compared with their age- and sex-matched controls.ResultsAffected patients have distal and proximal myopathy, with muscle biopsy showing rimmed vacuoles, muscle fiber atrophy, and endomysial fibrosis typical of RVM. Muscle MRI showed severe relatively symmetric multifocal fatty degenerative changes of the lower extremities. We identified a duplication of C at position 515 of the HSPB8 gene (c.515dupC) by whole-genome sequencing, which caused a frameshift with a predicted alternate stop codon p.P173SFS*43 in all affected individuals, resulting in an elongated protein product. Western blot and immunocytochemistry studies revealed reduced expression of heat shock protein beta 8 in patient fibroblasts compared with control fibroblasts, in addition to disrupted autophagy pathology.ConclusionsWe report a novel family with autosomal dominant RVM caused by the c.515dupC mutation of the HSPB8 gene, causing a translational frameshift that results in an elongated protein. Understanding the mechanism for the RVM pathology caused by mutated chaperone will permit novel targeted strategies to alter the natural history progression. As next-generation sequencing becomes more available, additional myopathic families will be identified with HSPB8 mutations.

Author(s): Woolley, Susan; Goetz, Ray; Factor-Litvak, Pam; Murphy, Jennifer; Hupf, Jonathan; Garofalo, Diana C; Lomen-Hoerth, Catherine; Andrews, Howard; Heitzman, Daragh; Bedlack, Richard; Katz, Jonathan; Barohn, Richard; Sorenson, Eric; Oskarsson, Bjorn; Filho, Americo Fernandes; Kasarskis, Edward; Mozaffar, Tahseen; Nations, Sharon; Swenson, Andrea; Koczon-Jaremko, Agnes; Christodoulou, Georgia; Mitsumoto, Hiroshi | Abstract: [This corrects the article DOI: 10.1155/2018/5969137.].

Objective To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy. Methods UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy–Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results. Results Eighty-nine patients were randomized (Ace-ER n = 45; placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER −2.25 kg vs placebo −2.99 kg; LSM difference confidence interval [CI] 0.74 [−1.61 to 3.09]; p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) −1.49 (−5.83 to 2.86); knee extension strength −0.40 (−2.38 to 1.58); and GNEM-FAS mobility domain score −0.72 (−2.01 to 0.57). Gastrointestinal events were the most common AEs. Conclusions Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy. Classification of evidence This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.

Objective We clinically and molecularly characterize a new family with autosomal dominant rimmed vacuolar myopathy (RVM) caused by mutations in the HSPB8 gene. Methods We performed whole-exome and whole-genome sequencing in the family. Western blot and immunocytochemistry were used to analyze 3 patient fibroblasts, and findings were compared with their age- and sex-matched controls. Results Affected patients have distal and proximal myopathy, with muscle biopsy showing rimmed vacuoles, muscle fiber atrophy, and endomysial fibrosis typical of RVM. Muscle MRI showed severe relatively symmetric multifocal fatty degenerative changes of the lower extremities. We identified a duplication of C at position 515 of the HSPB8 gene (c.515dupC) by whole-genome sequencing, which caused a frameshift with a predicted alternate stop codon p.P173SFS*43 in all affected individuals, resulting in an elongated protein product. Western blot and immunocytochemistry studies revealed reduced expression of heat shock protein beta 8 in patient fibroblasts compared with control fibroblasts, in addition to disrupted autophagy pathology. Conclusions We report a novel family with autosomal dominant RVM caused by the c.515dupC mutation of the HSPB8 gene, causing a translational frameshift that results in an elongated protein. Understanding the mechanism for the RVM pathology caused by mutated chaperone will permit novel targeted strategies to alter the natural history progression. As next-generation sequencing becomes more available, additional myopathic families will be identified with HSPB8 mutations.

BackgroundThis project is an effort to understand how orders for IV immunoglobulin (IVIg) are documented and prescribed by physicians, and subsequently, how they are reviewed by insurance companies for the treatment of immune neuropathies.MethodsA panel of neuromuscular specialists reviewed case records from 248 IVIg-naive patients whose in-home IVIg infusion treatment was submitted to insurance for authorization. After reviewing a case record, 1 panelist was asked to make a diagnosis and to answer several questions about the treatment. A second panelist reviewed the original record and follow-up records that were obtained for reauthorization of additional treatments and was asked to determine whether the patient had responded to the treatment.ResultsOur specialists believed that only 32.2% of 248 patients had an immune neuropathy and were appropriate candidates for IVIg therapy, whereas 46.4% had neuropathies that were not immune mediated. Only 15.3% of cases met electrodiagnostic criteria for a demyelinating neuropathy. Our specialists believed that 36.7% of 128 cases with follow-up records had responded to therapy. In cases in which the initial reviewer had predicted that there would be a response to IVIg, the second reviewer found that 54% had responded. This is compared with a 27% response rate when the first reviewer predicted that there would be no response (p = 0.019).ConclusionsOur expert review finds that the diagnosis of immune neuropathies made by providers, and subsequently approved for IVIg therapy by payers, is incorrect in a large percentage of cases. If payers include an expert in their review process, it would improve patient selection, appropriate use, and continuation of treatment with this expensive therapeutic agent.

The purpose of this review is to update the audience on the recent progress in the treatment of idiopathic inflammatory myopathies, highlighting a myriad of treatment trials aimed at slowing down progression of muscle weakness and/or skin involvement in idiopathic inflammatory myopathies. Myositis continues to be an active area of clinical and translational research. Through the work of a number of investigators, we now have a much better understanding of the pathogenesis underlying the various myositides. The role of T cells, B cells, and dendritic cells has been better defined in dermatomyositis and inclusion body myositis. The role of autoantibodies has been better elucidated, with the recognition that autoantibodies play an important role in not only establishing the diagnosis but also helping with prognostication and choosing treatment paradigms. A number of new treatment trials were designed to alter the pathogenic factors, including T cell activation, docking, and signaling, cytokines, B cell signaling, B cell depletion, as well as targeting Toll-like receptors (TLRs). Myostatin inhibitors have been developed and tried in inclusion body myositis (IBM) in hopes that they would stop muscle atrophy and improve muscle strength and function. This review will outline the progress made to date in the treatment of idiopathic inflammatory myopathies.

Summary Background Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. Methods In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov , NCT02024932 . Findings 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (–3·4% [–110 cm3]) but not in the BVS857 group (0% [2 cm3]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01–1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function. Interpretation TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. Funding Novartis Pharmaceuticals and the US National Institutes of Health.

In the article “BOLD cerebrovascular reactivity as a novel marker for crossed cerebellar diaschisis,” Sebok et al. reported similar sensitivity of blood oxygen level–dependent cerebrovascular reactivity (BOLD-CVR) in detecting crossed cerebellar diaschisis (CCD) as compared to (15O)-H2O-PET in 25 participants with symptomatic unilateral cerebrovascular steno-occlusive disease and reported that those with CCD had poorer baseline neurologic performance and 3-month neurologic outcome. In response, Reidler et al. question whether CCD was the cause of consequence of poor outcomes, noting that it may be an epiphenomenon of large-volume supratentorial strokes and citing conflicting evidence in the literature about independent association of CCD with post-stroke outcomes. They suggest accounting for lesion volume and distribution in the analyses. In their reply, Niftrik et al. agree that their finding of worse outcome in those with CCD should be cautiously interpreted and investigated in follow-up studies, but argue that supratentorial stroke volume is an inexact measurement, although stroke location would be helpful to examine. They clarify their finding of impaired supratentorial BOLD-CVR in the group with CCD and opine that hemodynamic changes may cause CCD rather than just functional disruption.

In patients with Late-Onset Pompe Disease (LOPD), progressive respiratory muscle involvement leads to reduced pulmonary function, with respiratory failure the most common cause of mortality. Early disease manifestations include sleep-disordered breathing, which can be treated with non-invasive ventilation; however, progressive diurnal deficits can require invasive ventilation. To determine if pulmonary function tests (PFTs) predict the thresholds for ventilation and wheelchair use, a systematic literature review identified cross-sectional clinical patient data (N = 174) that was classified into ventilation and wheelchair cohorts. PFTs included maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and vital capacity (VC), with vital capacities measured in the upright (-U) and supine (-S) positions. Receiver operating characteristic (ROC) curves were used to calculate cut-points (CP) and area under the curve (AUC). For all ventilation and mobility thresholds tested, ROC analyses demonstrated AUC values from 86–89% for MIP, 72–96% for MEP, and 74–96% for all vital capacity metrics. Thus, PFTs are useful in predicting the thresholds for nighttime ventilation, daytime ventilation, and wheelchair use, with MIP and VC-U having both high AUC values and consistency. The PFT mobility CPs were low (MIP CP = 0.9 kPa, MEP, CP = 2.6 kPa, VC-U CP = 19% predicted), suggesting an endurance component associated with wheelchair use.

Objectives: To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS). Methods: Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data. Results: Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range. Conclusions: This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline.

The secreted protein desert hedgehog (dhh) controls the formation of the nerve perineurium during development and is a key component of Schwann cells that ensures peripheral nerve survival. We postulated that dhh may play a critical role in maintaining myelination and investigated its role in demyelination-induced compression neuropathies by using a post-natal model of a chronic nerve injury in wildtype and dhh(-/-) mice. We evaluated demyelination using electrophysiological, morphological, and molecular approaches. dhh transcripts and protein are down-regulated early after injury in wild-type mice, suggesting an intimate relationship between the hedgehog pathway and demyelination. In dhh(-/-) mice, nerve injury induced more prominent and severe demyelination relative to their wild-type counterparts, suggesting a protective role of dhh. Alterations in nerve fiber characteristics included significant decreases in nerve conduction velocity, increased myelin debris, and substantial decreases in internodal length. Furthermore, in vitro studies showed that dhh blockade via either adenovirus-mediated (shRNA) or pharmacological inhibition both resulted in severe demyelination, which could be rescued by exogenous Dhh. Exogenous Dhh was protective against this demyelination and maintained myelination at baseline levels in a custom in vitro bioreactor to applied biophysical forces to myelinated DRG/Schwann cell co-cultures. Together, these results demonstrate a pivotal role for dhh in maintaining myelination. Furthermore, dhh signaling reveals a potential target for therapeutic intervention to prevent and treat demyelination of peripheral nerves in compression neuropathies.

Polymyositis and dermatomyositis are inflammatory myopathies that differ in their clinical features, histopathology, response to treatment, and prognosis. Although their clinical pictures differ, they both present with symmetrical, proximal muscle weakness. Treatment relies mainly upon empirical use of corticosteroids and immunosuppressive agents. A deeper understanding of the molecular pathways that drive pathogenesis, careful phenotyping, and accurate disease classification will aid clinical research and development of more efficacious treatments. In this review we address the current knowledge of the epidemiology, clinical characteristics, diagnostic evaluation, classification, pathogenesis, treatment, and prognosis of polymyositis and dermatomyositis.

More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available.A multicenter, double-blind, placebo-controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps.Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P 0.05). The average reduction, based on t tests, was 1.8 cramps per day (a reduction from 5.3 with placebo to 3.5 with mexiletine). The estimated reduction of cramp severity was 15 units on a 100-unit scale (P = 0.01) from a baseline average of 46. No effect on fasciculations was noted. One patient discontinued the study because of dizziness, and another patient discontinued the study to start open-label mexiletine therapy. No serious adverse event occurred.Mexiletine is a well tolerated and effective medication for controlling the symptom of muscle cramps in ALS. Muscle Nerve, 2018.

Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat-related adverse events or drug-related tolerability issues were identified., Pharmacological chaperones stabilize enzyme replacement in circulation, providing increased uptake of properly folded enzyme into tissues. In a phase 2a study, Kishnani et al. demonstrate a 2-fold increase in plasma and increased uptake in muscle of active recombinant human GAA following co-administration with duvoglustat HCl in patients with late onset Pompe disease.

Disease progression in Pompe Disease, a lysosomal storage disorder, occurs despite enzyme replacement therapy ERT, and is characterized by cytoplasmic accumulation of glycogen, presumably due to rupture or seepage of glycogen from lysosomes, defects in autophagy and the targeting of conventional ERT only to the lysosome. VAL-1221 is a fusion protein comprising the Fab portion of a cell-penetrating antibody utilizing the nucleoside transporter ENT-2 to gain access to the cytosol, and recombinant human acid alpha glucosidase (rhGAA), which enters lysosomes via mannose-6-phosphate receptors (M6PRs). Thus, VAL-1221 targets both cytosolic and lysosomal glycogen. 30 mg of VAL-1221 contains 20 mg of rhGAA. We performed a 3-month Phase 1/2 repeat dose, dose-escalation study of VAL-1221 with an rhGAA (Myozyme/Lumizyme) control to assess its safety and preliminary efficacy. 12 adults with late-onset Pompe disease (LOPD) treated with rhGAA for at least one year were randomized (1:3) to rhGAA (20 mg/kg qow) or to VAL-1221 (Cohort 1: 3 mg/kg, Cohort 2: 10 mg/kg, Cohort 3: 30 mg/kg). Adverse events, infusion-associated reactions, anti-VAL-1221 antibodies and PD markers were assessed. Efficacy outcomes included six-minute walk test (6MWT), pulmonary function tests, measures of muscle strength and function and patient-reported outcomes. There were no serious or unexpected adverse events all patients completed the study. All but 1 patient had anti-VAL-1221 antibodies at Baseline which increased initially but declined thereafter. Three patients, one in each cohort, experienced IARs requiring transient reduction in dose. Although there were no significant changes in PD markers, there were largely dose-dependent improvements in nearly all efficacy outcome parameters. Control patients declined by 49 meters on 6MWT while VAL-1221 patients in cohorts 2 and 3 increased by 54 meters. VAL-1221 is safe and well-tolerated in previously treated patients with LOPD and shows preliminary efficacy at doses of 10–30 mg/kg.

Although cerebrovascular accident (CVA) is a relatively infrequent complication of acute myocardial infarction (AMI), the occurrence of CVA in patients with AMI is associated with increased morbidity and mortality. We wanted to assess post-AMI CVA rate in the United States and identify the associated patient characteristics, comorbidities, type of AMI, and utilization of invasive procedures.This is an observational study from the Nationwide Inpatient Sample, 2006-2008. Using multivariate regression models, we assessed predictive risk factors for post-AMI CVA among patients admitted for AMI.Among the 1,924,413 patients admitted for AMI, the overall rate of CVA was 2% (ischemic stroke: 1.47%, transient ischemic attack [TIA]: 0.35% and hemorrhagic stroke: 0.21%). In this sample of AMI patient, higher incidence of CVA was associated with: CHF (adjusted odds ratio [AOR] 1.71; 95% confidence interval [CI], 1.58-1.84,), age over 65 AOR, 1.65; 95% CI, 1.60-1.70, alcohol abuse AOR, 1.60; 95% CI, 1.49-1.73, cocaine use AOR, 1.48; 95% CI, 1.29-1.70, atrial fibrillation AOR, 1.43; 95% CI, 1.39-1.46, Black race AOR, 1.35; 95% CI, 1.30-1.40, female gender AOR, 1.32; 95% CI, 1.29-1.35, peripheral vascular disease [PVD] AOR, 1.26; 95% CI, 1.22-1.30, coronary artery bypass graft (CABG) AOR, 1.22; 95% CI, 1.17-1.27, P0.0001, STEMI AOR, 1.17; 95% CI, 1.14-1.20 and teaching hospitals AOR, 1.09; 95% CI, 1.06-1.12.Female gender, older age (age≥65), black ethnicity, comorbidities including CHF, PVD, atrial fibrillation as well as STEMI and undergoing CABG were associated with the highest risk of CVA post-AMI.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects roughly 2 subjects per 100,000 in the United States; however, given the rapid decline and mortality, there are low prevalence rates. Although ALS is considered a single disease, it, in truth, probably represents a series of disorders with different clinical patterns and different pathophysiologic mechanisms that eventually coalesce into a single entity. The challenge has been to target these different pathophysiologic abnormalities, and so far, most drug studies have focused on only one or two different pathways. Over 50 well-designed clinical trials have been conducted in ALS over the last 25 years and with the exception of the Riluzole trial, all have failed.In this review, the authors highlight some of the recently concluded, ongoing or planned Phase II and Phase III studies in ALS. Furthermore, they summarize the progress in the recently initiated stem-cell therapy trials in ALS.The challenge remains for developing effective targeted therapeutic interventions for ALS. However, with improved recognition of the complex interplay of several factors that may contribute to ALS pathogenesis, in addition to improved patient selection criteria, outcome measures and biomarkers for drug development, advancements may be made in the future.

Background: Pompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alpha-glucosidase ( GAA ) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement. Methods: We report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22–74 years (mean 53.7 years) and were diagnosed at an age range of 11–65 years (mean 43.6 years), often after a history of progressive muscle disease of several years’ duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies. Results: Genetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves’ disease and testicular cancer. Conclusions: Our study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies.

In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods utilize an extensive structured telephone interview ascertaining environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3-6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Three hundred and fifty-five patients were recruited. Subjects were enrolled over a 36-month period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Results showed that demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, the only difference being type of health insurance among enrolled patients. Sites were divided into three groups by the number of enrolled subjects. Comparing these three groups, the Columbia site had fewer 'definite ALS' diagnoses. This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and has been accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized.

Valosin-containing protein (VCP)-associated disease caused by mutations in the VCP gene includes combinations of a phenotypically heterogeneous group of disorders such as hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis. Currently, there are no effective treatments for VCP myopathy or dementia. VCP mouse models carrying the common R155H mutation include several of the features typical of the human disease. In our previous investigation, VCP(R155H/R155H) homozygous mice exhibited progressive weakness and accelerated pathology prior to their early demise. Herein, we report that feeding pregnant VCP(R155H/+) heterozygous dams with a lipid-enriched diet (LED) results in the reversal of the lethal phenotype in VCP(R155H/R155H) homozygous offspring. We examined the effects of this diet on homozygous and wild-type mice from birth until 9 months of age. The LED regimen improved survival, motor activity, muscle pathology and the autophagy cascade. A targeted lipidomic analysis of skeletal muscle and liver revealed elevations in tissue levels of non-esterified palmitic acid and ceramide (d18:1/16:0), two lipotoxic substances, in the homozygous mice. The ability to reverse lethality, increase survival, and ameliorate myopathy and lipids deficits in the VCP(R155H/R155H) homozygous animals suggests that lipid supplementation may be a promising therapeutic strategy for patients with VCP-associated neurodegenerative diseases.

Hereditary Inclusion Body Myopathy (HIBM, IBM2, MIM:600737) is an autosomal recessive adult onset progressive muscle wasting disorder. It is associated with the degeneration of distal and proximal muscles, while often sparing the quadriceps. The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK), encoded by the GNE gene, catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneunaminic acid (sialic acid). Affected individuals have been identified with mutations in the GNE gene. In the present study, the GNE coding region of 136 symptomatic patients were sequenced. A total of 41 patients were found to have GNE mutations. Eight novel mutations were discovered among seven patients. Of the eight novel mutations, seven were missense (p.I150V, p.Y186C, p.M265T, p.V315T, p.N317D, p.G669R, and p.S699L) and one was nonsense (p.W495X), all of which span the epimerase, kinase, and allosteric domains of GNE. In one patient, one novel mutation was found in the allosteric region and kinase domain of the GNE gene. Mutations in the allosteric region lead to a different disease, sialuria; however, this particular mutation has not been described in patients with sialuria. The pathological significance of this variation with GNE function remains unknown and further studies are needed to identify its connection with HIBM. These findings further expand the clinical and genetic spectrum of HIBM.

Purpose Nerve repair after a segmental defect injury remains a challenge for surgeons. Fibrin glue can be used to expedite surgical procedures and maintain proper nerve spatial orientation to potentially optimize recovery, yet surgeons hesitate to use it owing to concerns about fibrin's inhibiting regeneration and increasing scar formation. The purpose of these experiments was to evaluate whether fibrin glue impedes nerve regeneration. Methods A critical-size defect of 10 mm was created in 32 Sprague-Dawley rats with 4 different forms of repair: a collagen type-I conduit (n = 8), a collagen type-I conduit filled with fibrin glue (n = 8), an autologous nerve graft (n=8), and an autologous nerve graft with fibrin glue (n = 8). Behavioral tests, including sciatic functional indices, were used to evaluate functional recovery. Neurophysiology, immunohistochemistry, and nerve morphometry were used to critically analyze nerve regeneration. Results Multiple outcome parameters for nerve regeneration, remyelination, behavior, and electrophysiology were used to determine that the addition of fibrin did not influence recovery for the autograft groups. Similarly, within the conduit group, behavioral tests showed comparable functional recovery and indistinguishable results in compound motor action potential and nerve morphometry. Immunohistochemistry revealed identical degrees of Wallerian degeneration and scarring between conduit groups. Conclusions The addition of fibrin to either the conduit or the autograft group did not result in any meaningful differences in recovery. Our data demonstrate that fibrin glue does not impede nerve regeneration or functional recovery after surgical repair of a segmental nerve defect in a rat model. Clinical relevance The clinical use of fibrin glue as an adjunct with peripheral nerve repair may be considered safe because it does not impair nerve regeneration with critical size defects in an animal model.

Introduction: Complement activation at the neuromuscular junction is a primary cause of acetylcholine receptor loss and failure of neuromuscular transmission in myasthenia gravis (MG). Eculizumab, a humanized monoclonal antibody, blocks the formation of terminal complement complex by specifically preventing the enzymatic cleavage of complement 5 (C5). Methods: This study was a randomized, double-blind, placebo-controlled, crossover trial involving 14 patients with severe, refractory generalized MG (gMG). Results: Six of 7 patients treated with eculizumab for 16 weeks (86%) achieved the primary endpoint of a 3-point reduction in the quantitative myasthenia gravis (QMG) score. Examining both treatment periods, the overall change in mean QMG total score was significantly different between eculizumab and placebo (P = 0.0144). After assessing data obtained from all visits, the overall change in mean QMG total score from baseline was found to be significantly different between eculizumab and placebo (P

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

Spasticity is a velocity-dependent increase in muscle tone and uncontrolled, repetitive, involuntary contractions of skeletal muscles. Spasticity presents as upper motor neuron symptoms in patients with central nervous system pathology such as stroke, spinal cord injury, brain injury, or multiple sclerosis. As a result, a patient can have significant pain and limited mobility, which can lead to decreased quality of life and difficulty maintaining personal care. In this article we discuss mechanisms, indications, efficacy, and side effects of the most accepted current treatments. Currently available treatment options include oral medications and interventional procedures. Oral medications comprise centrally acting agents, such as baclofen, clonidine, and tizanidine, as well as anticonvulsants such as benzodiazepines and gabapentin and peripherally acting dantrolene. Interventional procedures include focal injections of botulinum toxin, phenol or alcohol, and an intrathecal baclofen pump. Surgical treatments include selective dorsal rhizotomy and neurectomy. We found that there are several treatments available with data to support their use, but many still need further research to prove their efficacy and develop optimal utilization.

We present a case of a 65-year-old woman who was previously diagnosed with idiopathic granulomatous myositis and treated with immunosuppressive therapy for the next 10 years before a clinical diagnosis of inclusion body myositis was made. A review of the previously performed muscle biopsy showed most of the cardinal myopathologic features of sporadic inclusion body myositis, in addition to the granuloma. Her clinical course was strongly suggestive of inclusion body myositis with selective asymmetric weakness of forearm flexor muscles and quadriceps. This report highlights the importance of correlating clinical picture with muscle pathology changes along with judicious use of magnetic resonance imaging and serological studies to establish a definite diagnosis.

Objective Traumatic peripheral nerve injuries often produce permanent functional deficits despite optimal surgical and medical management. One reason for the impaired target organ reinnervation is degradation of motor endplates during prolonged denervation. Here we investigate the effect of preserving agrin on the stability of denervated endplates. Because matrix metalloproteinase 3 (MMP3) is known to degrade agrin, we examined the changes in endplate structure following traumatic nerve injury in MMP3 knockout mice. Methods After creation of a critical size nerve defect to preclude reinnervation, we characterized receptor area, receptor density, and endplate morphology in denervated plantaris muscles in wild-type and MMP3 null mice. The level of agrin and muscle-specific kinase (MuSK) was assessed at denervated endplates. In addition, denervated muscles were subjected to ex vivo stimulation with acetylcholine. Finally, reinnervation potential was compared after long-term denervation. Results In wild-type mice, the endplates demonstrated time-dependent decreases in area and receptor density and conversion to an immature receptor phenotype. In striking contrast, all denervation-induced changes were attenuated in MMP3 null mice, with endplates retaining their differentiated form. Agrin and MuSK were preserved in endplates from denervated MMP3 null animals. Furthermore, denervated muscles from MMP3 null mice demonstrated greater endplate efficacy and reinnervation. Interpretation These results demonstrate a critical role for MMP3 in motor endplate remodeling, and reveal a potential target for therapeutic intervention to prevent motor endplate degradation following nerve injury. ANN NEUROL 2013;73:210–223

VCP disease associated with Inclusion body myopathy, Paget disease of the bone and frontotemporal dementia is a progressive autosomal dominant disorder caused by mutations in Valosin containing protein gene. To establish genotype-phenotype correlations we analyzed clinical and biochemical markers from a database of 190 members in 27 families harboring ten missense mutations. Individuals were grouped into three categories: symptomatic, presymptomatic carriers and non-carriers. The symptomatic families were further divided into ten groups based on their VCP mutations. There was marked intra and inter-familial variation; and significant genotype-phenotype correlations were difficult because of small numbers. Nevertheless when comparing the two most common mutations, R155C mutation was found to be more severe, with earlier onset of myopathy and Paget (p=0.03).Survival analysis of all subjects revealed an average life span after diagnosis of myopathy and Paget of 18 and 19 years respectively, and after dementia only 6 years. R155C had a reduced survival compared to the R155H mutation (p=0.03). We identified amyotrophic lateral sclerosis (ALS) in thirteen individuals (8.9%) and Parkinson’s disease in five individuals (3%); however there was no genotypic correlation. This study represents the largest dataset of patients with VCP disease and expands our understanding of natural history and provides genotype-phenotype correlations in this unique disease.

Author(s): Lin, Michael Y; Frieboes, Laura S; Forootan, Maryam; Palispis, Winnie A; Mozaffar, Tahseen; Jafari, Matiar; Steward, Oswald; Gall, Christine M; Gupta, Ranjan | Abstract: ObjectiveChronic nerve compression (CNC) injuries occur when peripheral nerves are subjected to sustained mechanical forces, with increasing evidence implicating Schwann cells as key mediators. Integrins, a family of transmembrane adhesion molecules that are capable of intracellular signaling, have been implicated in a variety of biological processes such as myelination and nerve regeneration. In this study, we seek to define the physical stimuli mediating demyelination and to determine whether integrin plays a role in the demyelinating response.MethodsWe used a previously described in vitro model of CNC injury where myelinating neuron-Schwann cell cocultures were subjected to independent manipulations of hydrostatic pressure, hypoxia, and glucose deprivation in a custom bioreactor. We assessed whether demyelination increased in response to applied manipulation and determined whether integrin-associated signaling cascades are upregulated.ResultsBiophysical stimulation of neural tissue induced demyelination and Schwann cell proliferation without neuronal or glial cytotoxicity or apoptosis. Although glucose deprivation and hypoxia independently had minor effects on myelin stability, together they potentiated the demyelinating effects of hydrostatic compression, and in combination, significantly destabilized myelin. Biophysical stimuli transiently increased phosphorylation of the integrin-associated tyrosine kinase Src within Schwann cells. Silencing this integrin signaling cascade blocked Src activation and prevented pressure-induced demyelination. Colocalization analysis indicated that Src is localized within Schwann cells.InterpretationThese results indicate that myelin is sensitive to CNC injury and support the novel concept that myelinating cocultures respond directly to mechanical loading via activating an integrin signaling cascade.

Late-onset Pompe disease (LOPD) is a rare lysosomal storage disorder characterized by progressive loss of muscle and respiratory function resulting from acid α-glucosidase (GAA) deficiency, for which recombinant human GAA enzyme replacement therapy (rhGAA ERT: alglucosidase alfa) is currently available. Here, we report the 12-month interim results from ATB200-02 (NCT02675465), a first-in-human, open-label, phase 1/2 trial evaluating a next-generation rhGAA/chaperone regimen AT-GAA (ATB200/AT2221) in adults with LOPD. The study enrolled 20 patients in 3 cohorts: ERT-switch ambulatory (n=11), ERT-switch nonambulatory (n=4), and ERT-naive ambulatory (n=5). 6-minute walk test (meters) improved in ambulatory ERT-switch patients (n=10 mean change [SD]: month 6, 23.9 [52.2] month 9, 24.5 [40.8] month 12, 42.2 [46.5]) and ERT-naive patients (n=5 month 6, 41.8 [29.4] month 9, 63.5 [23.1] month 12, 63.1 [29.1]). Other motor function tests were generally consistent with these results. Nonambulatory ERT-switch patients demonstrated increases in upper extremity strength at months 6, 9, and 12 as assessed by quantitative and manual muscle testing. Forced vital capacity (% predicted) increased in ERT-naive patients (n=5, mean change: month 6, 4.2 month 9, 6.2 month 12, 4.4), and was generally stable in ambulatory ERT-switch patients (n=9, month 6, -1.3 month 9, -1.7 month 12, -3.3). AT-GAA (ATB200/AT2221) was associated with reductions in creatine kinase and urine hexose tetrasaccharide. The most common treatment-emergent adverse events were upper and lower abdominal pain, diarrhea, and nasopharyngitis. Three events of infusion-associated reactions (skin discoloration, erythema, pruritus) occurred in ≥550 infusions. Data from this interim analysis show clinical benefits of AT-GAA (ATB200/AT2221) in ERT-naive patients and both ambulatory and nonambulatory ERT-experienced patients, suggesting that ATB200/AT2221 can be an effective and well-tolerated treatment for adults with LOPD. Updated 24-month efficacy/safety data will be included in the presentation.