Journal of Neuromuscular Diseases - Volume 4, issue 3

Authors: Sochala, Maximilien | Wahbi, Karim | Sorbets, Emmanuel | Lazarus, Arnaud | Bécane, Henri-Marc | Stojkovic, Tanya | Fayssoil, Abdallah | Laforêt, Pascal | Béhin, Anthony | Sroussi, Marjorie | Eymard, Bruno | Duboc, Denis | Meune, Christophe

Article Type: Research Article

Abstract: Background: Pacemakers (PM) and implantable cardioverter defibrillators (ICD) may be indicated for sudden death prevention in myotonic dystrophy type 1 (DM1), however the risk of complications after the placement of these devices is unknown. Objective: To compare the rate of device-related complications between PM and ICD implantations in patients with DM1. Methods: Among 914 patients with DM1 included in the DM1 Heart Registry between January 2000 and January 2010, we retrospectively selected 23 patients who were implanted with an ICD and matched them to 46 controls with a PM on age, gender, and year of device …placement. Results: Over a 6 years follow-up period, we observed device-related complications in 9 ICD recipients (inappropriate shocks in 5, lead dysfunction in 5, infection in 2) and in 3 PM recipients (lead dysfunction in 3). Patients with an ICD had, compared to those with a PM, higher rates of complications (39.1% vs. 6.5%, p  = 0.0006) and more frequent complications requiring hospitalisation and/or re-intervention (respectively 30.4% and 21.7% vs. 0%). Conclusion: Our study shows a higher risk of device-related complications after the implantation of an ICD than for a PM in patients presenting with DM1. Show more

Keywords: Myotonic dystrophy 1, complications, implantable cardioverter-defibrillator, pacemaker

DOI: 10.3233/JND-170232

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 175-181, 2017

Authors: Rodrigues, Miriam J. | O’Grady, Gina L. | Hammond-Tooke, Graeme | Kidd, Alexa | Love, Donald O. | Baker, Ronelle K. | Roxburgh, Richard H.

Article Type: Research Article

Abstract: The New Zealand Neuromuscular Disease Patient Registry has been recruiting for five years. Its primary aim is to enable people with neuromuscular disease to participate in research including clinical trials. It has contributed data to large anonymised cohort studies and many feasibility studies, and has provided practical information and advice to researchers wanting to work with people with neuromuscular conditions. 1019 people have enrolled since the Registry’s launch in August 2011 with over 70 different diagnoses. Of these; 8 patients have been involved in clinical trials, 134 in other disease-specific research and 757 have contributed anonymised data to cohort studies. …As a result the Registry is now effectively facilitating almost all neuromuscular research currently taking place in New Zealand. Show more

DOI: 10.3233/JND-170240

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 183-188, 2017

Authors: Mayer, Oscar H. | Leinonen, Mika | Rummey, Christian | Meier, Thomas | Buyse, Gunnar M. | for the DELOS Study Group

Article Type: Research Article

Abstract: Background: Patients with DMD experience progressive restrictive respiratory disease and eventual respiratory failure. Standard of care guidelines command changes in disease management when forced vital capacity percent of predicted (FVC% p) falls below clinically relevant thresholds. The Phase 3 DELOS trial in patients with DMD demonstrated that idebenone reduces the loss of peak expiratory flow and FVC compared to placebo (Buyse GM, et al.; Lancet 2015; 385 : 1748-57). Objective: Post-hoc analyses were conducted to assess whether treatment with idebenone could reduce the risk of patients dropping below clinically meaningful thresholds of FVC% p. Methods: The DELOS …trial enrolled DMD patients 10–18 years of age not using glucocorticoids to receive idebenone (N = 31) or placebo (N = 33) for 12 months. Change from baseline in FVC and FVC% p was assessed by hospital spirometry and analyzed by mixed model of repeated measures and slope analysis and proportions of patients falling below clinically meaningful thresholds of FVC% p were compared. Results: The change over 1 year in FVC and FVC% p showed a consistent pattern in favor of idebenone treatment across multiple analysis methods and fewer patients in the idebenone group declined by a margin of 10% or more in FVC and FVC% p compared to placebo. There were also fewer patients in the idebenone group (15%) with a decline below FVC% p of 50% compared to the placebo group (25%) and fewer patients in the idebenone group (28%) showed a decline below FVC% p of 50% or 40% or 30% compared to the placebo group (43%). Conclusions: These data added to the consistency and clinical meaningfulness of findings from the DELOS trial showing that idebenone can slow the loss of pulmonary function in patients with DMD. Show more

Keywords: Pulmonary function, respiration, idebenone, Duchenne muscular dystrophy, forced vital capacity

DOI: 10.3233/JND-170245

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 189-198, 2017

Authors: Wein, Nicolas | Vulin, Adeline | Findlay, Andrew R. | Gumienny, Felecia | Huang, Nianyuan | Wilton, Steve D. | Flanigan, Kevin M.

Article Type: Research Article

Abstract: Background: Exon skipping strategies in Duchenne muscular dystrophy (DMD) have largely been directed toward altering splicing of exons flanking out-of-frame deletions, with the goal of restoring an open mRNA reading frame that leads to production of an internally deleted but partially functional dystrophin protein. Objective: We sought to apply exon skipping to duplication mutations, assuming that the inherently limited efficiency of antisense oligonucleotide-induced exon skipping would more frequently skip a single copy of a duplicated exon, rather than both and result in significant amounts of wild-type DMD mRNA. Methods: We tested this hypothesis in fibroblast …cell lines derived from patients with a variety of single or multiple exon duplications that have been modified to allow transdifferentiation into a myogenic lineage. Results: Using a variety of 2’O-methyl antisense oligonucleotides, significant skipping was induced for each duplication leading to a wild-type transcript as a major mRNA product. Conclusions: This study provides another proof of concept for the feasibility of therapeutic skipping in patients carrying exon duplications in order to express wild-type, full-length mRNA, although careful evaluation of the skipping efficiency should be performed as some exons are easier to skip than others. Such a personalized strategy is expected to be highly beneficial for this subset of DMD patients, compared to inducing expression of an internally-deleted dystrophin. Show more

Keywords: Duchenne muscular dystrophy, duplications, exon skipping, dystrophin, antisense oligonucleotide

DOI: 10.3233/JND-170233

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 199-207, 2017

Authors: Lanza, Giuseppe | Kosac, Ana | Trajkovic, Goran | Whittaker, Roger G.

Article Type: Research Article

Abstract: Background: Clinical nerve conduction studies (NCS) are often used as a secondary outcome measure in therapeutic trials, but show a high degree of inter-trial variability even when technical factors known to affect the recorded responses are minimised. This raises the intriguing possibility that some of the observed variability may reflect true changes in nerve activity. Objectives: Our aim was determine how much variability these factors might produce, and how this might affect the results of commonly used neuropathy rating scales. Methods: A standardised protocol was repeated over forty consecutive trials by the same operators in two …healthy subjects. The protocol included recordings that shared either a stimulating or a recording electrode position, such that changes due to electrode position could be excluded, and hand temperature was closely controlled. Results: Despite controlling for inter-operator differences, electrode position, and hand temperature, the variability in sensory nerve action potential (SNAP) amplitude was extremely high (Range 23 μV, CoV = 10.7–18.8). This variability was greater than the change in amplitude needed to move a subject from point 0 to point 4 on the CMT neuropathy rating scale. Neither temperature or electrode position accounted for all of this variability, suggesting that additional as yet unidentified factors are responsible. Conclusion: Even under closely controlled conditions and sophisticated laboratory methods, test-to-test variability can be significant. The factors responsible for this variability may be difficult to control, limiting the utility of single nerve recordings as a trial outcome measure. Show more

Keywords: Nerve conduction studies, reproducibility, serial measurements, technical variability, nerve excitability

DOI: 10.3233/JND-170243

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 209-215, 2017

Authors: Hendriksen, Ruben G.F. | Lionarons, Judith M. | Hendriksen, Jos G.M. | Vles, Johan S.H. | McAdam, Laura C. | Biggar, W. Douglas

Article Type: Research Article

Abstract: Background: There is no cure for Duchenne Muscular Dystrophy (DMD); treatment is symptomatic and corticosteroids slow the progression. Side effects of corticosteroids – especially the physical effects – have been described, however patients’ and caregivers perception on chronic corticosteroid treatment and their side effects is less well known, in particular with regards to cognition, behaviour, and emotional functioning. Objective: The primary aim of this pilot study was to (i) construct a self-report questionnaire to assess the perceived benefits and side effects of corticosteroids for patients with DMD and their parents. Furthermore we aimed to (ii) investigate the psychometric …qualities of this questionnaire, (iii) whether there was a difference between parents’ and patient’s perceptions, and finally (iv) to what extent reported side effects may alter over time. Methods: A 23-item questionnaire (SIDECORT: side effect of corticosteroids ) was constructed to assess the perception of these benefits and side effects in a systematic manner. Results: In total, 86 patients (aged 5 – 28 years) and 125 of their parents completed the questionnaire. Internal consistency was good. Using factor analyses on the side effect items as reported by parents, two underlying factors were found, with the first factor describing cognitive, behavioural and emotional functioning, and the second factor describing physical functioning. The potential benefits of corticosteroids were highly rated among both parents and patients, although parents rated the importance of the benefits higher than their sons (p  = 0.002). Similarly, parents rated the severity of the side effects generally higher than their sons (p  = 0.011), especially with regards to the physical side effects (p  = 0.014). Based on the parent’s perception, the neurodevelopmental side effects generally appeared to decline the longer corticosteroids were used. Conclusions: To our knowledge, this is the first explicit study on perceived cognitive-, behavioural-, and emotional side effects and the allocation of benefits to corticosteroids in DMD. On the basis of our research we suggest a short form questionnaire, which proves to be reliable and valid for research- and clinical practice. This questionnaire could provide useful insights for the care of boys and men with DMD. Show more

Keywords: Duchenne muscular dystrophy, corticosteroids, side effects, benefits, questionnaire-study

DOI: 10.3233/JND-170223

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 217-236, 2017

Authors: Osman, Erkan Y. | Washington III, Charles W. | Simon, Madeline E. | Megiddo, Dalia | Greif, Hagar | Lorson, Christian L.

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is a neurodegenerative autosomal recessive disorder characterized by the loss of α-motor neurons. A variety of molecular pathways are being investigated to elevate SMN protein expression in SMA models and in the clinic. One of these approaches involves stabilizing the SMNΔ 7 protein by inducing translational read-through. Previous studies have demonstrated that functionality and stability are partially restored to the otherwise unstable SMNΔ 7 by the addition of non-specific C-terminal peptide sequences, or by inducing a similar molecular event through the use of read-through inducing compounds such as aminoglycosides. Objective: The objective was …to determine the efficacy of the macrolide Azithromycin (AZM), an FDA approved read-through-inducing compound, in the well-established severe mouse model of SMA. Methods: Initially, dosing regimen following ICV administrations of AZM at different post-natal days and concentrations was determined by their impact on SMN levels in disease-relevant tissues. Selected dose was then tested for phenotypic parameters changes as compared to the appropriate controls and in conjugation to another therapy. Results: AZM increases SMN protein in disease relevant tissues, however, this did not translate into similar improvements in the SMA phenotype in a severe mouse model of SMA. Co-administration of AZM and a previously developed antisense oligonucleotide that increases SMN2 splicing, resulted in an improvement in the SMA phenotype beyond either AZM or ASO alone, including a highly significant extension in survival with improvement in body weight and movement. Conclusions: It is important to explore various approaches for SMA therapeutics, hence compounds that specifically induce SMNΔ 7 read-through, without having prohibitive toxicity, may provide an alternative platform for a combinatorial treatment. Here we established that AZM activity at a low dose can increase SMN protein in disease-relevant animal model and can impact disease severity. Show more

Keywords: Spinal muscular atrophy (SMA), neurodegeneration, Survival Motor Neuron (SMN), Pre-mRNA splicing, Azithromycin (AZM)

DOI: 10.3233/JND-170230

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 237-249, 2017

Authors: Russell, Angela | Yaraskavitch, Megan | Fok, Daniel | Chhibber, Sameer | Street, Lesley | Korngut, Lawrence

Article Type: Case Report

Abstract: Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, characterized by fatigable weakness of the extraocular, bulbar, and limb musculature; prevalence is estimated at 14 to 32 per 100,000 in North America. Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, resulting from clonal expansion of B-cells in blood, marrow, and secondary lymphoid tissues. The simultaneous presentation of MG and CLL is exceedingly rare. This article presents the case of 71-year-old man diagnosed simultaneously with MG and CLL. His MG was severe and refractory to treatment; therefore, a strategy of treating his coexisting CLL …with obinutuzumab and chlorambucil was pursued. Following 6 cycles of obinutuzumab and chlorambucil, his CLL is in remission and his MG is almost entirely undetectable. This is the first case report describing the use of obinutuzumab, a novel anti-CD20 monoclonal antibody, in a patient with concurrent MG and CLL. Show more

Keywords: Myasthenia gravis, chronic lymphocytic leukemia, obinutuzumab, rituximab, autoimmune, immunotherapy

DOI: 10.3233/JND-170211

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 251-257, 2017