Journal of Neuromuscular Diseases - Volume 5, issue 4

Authors: Tasfaout, Hichem | Cowling, Belinda S. | Laporte, Jocelyn

Article Type: Review Article

Abstract: Centronuclear myopathies are a group of congenital myopathies characterized by severe muscle weakness, genetic heterogeneity, and defects in the structural organization of muscle fibers. Their names are derived from the central position of nuclei on biopsies, while they are at the fiber periphery under normal conditions. No specific therapy exists yet for these debilitating diseases. Mutations in the myotubularin phosphoinositides phosphatase, the GTPase dynamin 2, or amphiphysin 2 have been identified to cause respectively X-linked centronuclear myopathies (also called myotubular myopathy) or autosomal dominant and recessive forms. Mutations in additional genes, as RYR1 , TTN , SPEG or CACNA1S …, were linked to phenotypes that can overlap with centronuclear myopathies. Numerous animal models of centronuclear myopathies have been studied over the last 15 years, ranging from invertebrate to large mammalian models. Their characterization led to a partial understanding of the pathomechanisms of these diseases and allowed the recent validation of therapeutic proof-of-concepts. Here, we review the different therapeutic strategies that have been tested so far for centronuclear myopathies, some of which may be translated to patients. Show more

Keywords: Centronuclear myopathy, myotubular myopathy, myotubularin, amphiphysin, dynamin, gene therapy, autophagy, phosphoinositides, oligonucleotide, neuropathy

DOI: 10.3233/JND-180309

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 387-406, 2018

Authors: Gordish-Dressman, Heather | Willmann, Raffaella | Dalle Pazze, Laura | Kreibich, Arati | van Putten, Maaike | Heydemann, Ahlke | Bogdanik, Laurent | Lutz, Cathleen | Davies, Kay | Demonbreun, Alexis R. | Duan, Dongsheng | Elsey, David | Fukada, So-ichiro | Girgenrath, Mahasweta | Patrick Gonzalez, J. | Grounds, Miranda D. | Nichols, Andy | Partridge, Terry | Passini, Marco | Sanarica, Francesca | Schnell, Frederick J. | Wells, Dominic J. | Yokota, Toshifumi | Young, Courtney S. | Zhong, Zhong | Spurney, Christopher | Spencer, Melissa | De Luca, Annamaria | Nagaraju, Kanneboyina | Aartsma-Rus, Annemieke

Article Type: Review Article

Abstract: A new line of dystrophic mdx mice on the DBA/2J (D2) background has emerged as a candidate to study the efficacy of therapeutic approaches for Duchenne muscular dystrophy (DMD). These mice harbor genetic polymorphisms that appear to increase the severity of the dystropathology, with disease modifiers that also occur in DMD patients, making them attractive for efficacy studies and drug development. This workshop aimed at collecting and consolidating available data on the pathological features and the natural history of these new D2/mdx mice, for comparison with classic mdx mice and controls, and to identify gaps in information …and their potential value. The overall aim is to establish guidance on how to best use the D2/mdx mouse model in preclinical studies. Show more

Keywords: Duchenne muscular dystrophy, DMD, DBA/2J, mdx

DOI: 10.3233/JND-180324

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 407-417, 2018

Authors: Buyse, Gunnar M. | Rummey, Christian | Meier, Thomas | Leinonen, Mika | Voit, Thomas | McDonald, Craig M. | Mayer, Oscar H.

Article Type: Research Article

Abstract: Background: Loss of pulmonary function is a main cause of early morbidity and mortality in patients with Duchenne muscular dystrophy (DMD). Standard of care guidelines recommend regular assessment of pulmonary function by hospital-based spirometry to detect onset and monitor progression of pulmonary function decline. Objective: To assess the feasibility of home-based monitoring of pulmonary function by a hand-held device (HHD) in adolescent and adult patients with DMD over a period of 12 months. Methods: In the phase III randomized placebo-controlled DELOS trial in 10–18 year old DMD patients, peak expiratory flow (PEF) measurements were collected weekly …at home by the patient (assisted by parent/caregiver) using a peak flow meter HHD. Adherence to the use of the HHD was assessed and 12-month changes in PEF as percent of predicted (PEF% p) for the idebenone (N = 31) and the placebo treatment groups (N = 33) from HHD-derived data were compared to results from hospital-based spirometry. Results: A total of 2689 individual HHD assessments were analysed. Overall adherence to the use of the HHD over the course of the 12-month study duration was good (75.9%, SD 21.5%) and PEF% p data obtained at the same day by HHD and standard spirometry correlated well (Spearman’s rho 0.80; p  < 0.001). Several analysis methods of HHD-derived data for PEF% p consistently demonstrate that idebenone treatment slowed the decline in PEF% p compared to placebo, which supports the statistically significant difference in favour of idebenone for PEF% p measured by standard spirometry. Conclusions: This study demonstrates that home-based monitoring of pulmonary function in adolescent patients with DMD using a HHD is feasible, provides reliable data compared to hospital-based spirometry and is therefore suitable for use in clinical practice and for clinical trials. Show more

Keywords: Pulmonary function, respiration, idebenone, Duchenne muscular dystrophy, peak expiratory flow

DOI: 10.3233/JND-180338

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 419-430, 2018

Authors: Tilanus, T.B.M. | Groothuis, J.T. | ten Broek-Pastoor, J.M.C. | Doorduin, J. | van Engelen, B.G.M. | Kampelmacher, M.J. | Raaphorst, J.

Article Type: Research Article

Abstract: Background and objective: Non-invasive ventilation (NIV) is an established treatment for respiratory failure in patients with amyotrophic lateral sclerosis (ALS). Several studies have shown room for improvement with regard to respiratory care for ALS patients, including latency of referral. These studies focused on the time period starting at the moment of referral to a home ventilation service (HVS) onwards. In the current study we performed a nationwide survey to gain insight in the trajectory before referral. We questioned the assessment of respiratory impairment by ALS physicians/care teams, including criteria for referral to an HVS. Methods: We requested 40 …ALS care teams in the Netherlands to fill in an online questionnaire on respiratory management in ALS patients. Results: Thirty-two ALS care teams (80%) responded. Forced vital capacity was the most frequently used test at each outpatient visit (72%) and often served as a criterion (78%) for referral to an HVS. Other respiratory function measurements that were performed less often included peak cough flow (50%), maximum inspiratory/expiratory pressure (31% /28%) and sniff nasal inspiratory pressure (13%). Morning headache was the most frequently questioned complaint (94%), followed by daytime sleepiness (91%). Dyspnoea and orthopnoea were reported by 38% and 59% as important complaints. Out of all patients under the care of the ALS care teams, the mean estimated proportion of patients that was referred to an HVS was 69% (range 20-100%). When physicians refrained from referral, the most often cited reasons were patient’s decision to withhold NIV (94%) and cognitive impairment (50%). Sixteen percent of the respondents stated bulbar impairment as a reason to refrain from referral. Conclusion: Despite findings in previous studies on the superiority of SNIP and PCF as compared to FVC, our study shows that a majority of ALS care teams still prefers to use FVC for the assessment of respiratory dysfunction and for the timing of referral to an HVS. Another finding is that bulbar impairment is not an obstacle for referral for NIV. Show more

Keywords: ALS, respiratory function tests, non-invasive ventilation

DOI: 10.3233/JND-180302

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 431-438, 2018

Authors: Sandstedt, Petter | Littorin, Susanne | Johansson, Sverker | Gottberg, Kristina | Ytterberg, Charlotte | Kierkegaard, Marie

Article Type: Research Article

Abstract: Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by muscle weakness and wasting. Observational natural history studies can give information on body function/structure impairments, activity limitations and participation restrictions, i.e. disability. Information needed to plan and develop care and support. Objective: To describe and explore disease severity and impairments, activity limitations, participation restrictions and contextual factors over time. In specific, to explore concurrent presence of cognitive impairment, fatigue, anxiety, depression and pain, and whether these impairments were related to disease severity. Methods: In this three-year observational study, 60 patients with ALS were included …at baseline. Follow-ups were performed every 6 months unless participants had deceased or declined participation. Data was collected from medical records, and by study-specific and standardized questionnaires administrated during home visits. Results: Regardless of disease severity; fatigue, anxiety, depression and pain were present in patients with ALS at each data collection. Approximately one-third experienced two or more of these impairments concurrently, i.e. at the same time point. Cognitive impairment could not be assessed in many patients due to their physical impairments. Disease severity was not associated with fatigue, anxiety, depression or pain. Conclusions: Patients with ALS need, throughout the course of the disease, to be regularly screened for commonly present impairments, activity limitations and participation restrictions so that person-centered interventions can be applied at the right time. Show more

Keywords: Amyotrophic lateral sclerosis, longitudinal studies, anxiety, depression, fatigue, pain, rehabilitation

DOI: 10.3233/JND-180322

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 439-449, 2018

Authors: Babačić, Haris | Goldina, Olga | Stahl, Kristina | Montagnese, Federica | Jurinović, Vindi | Schoser, Benedikt | Wenninger, Stephan

Article Type: Research Article

Abstract: Background/Aim: Pulmonary function tests are used for screening respiratory insufficiency in patients with myotonic dystrophy (DM). We analysed the agreement between two different approaches in assessment of abnormal findings of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP), in DM patients. Methods: We used Cohen’s κ - and Bangdiwala’s B- statistic to compare the agreement between different cut-off values recommended by experts (ENMC) and the cut-off values based on the reference range (RR). We further analysed their sensitivity (Sn) and specificity (Sp) in …detecting symptoms associated with respiratory insufficiency. Results: The observed agreement was: 1) for FVC: κ = –0.002, B = 0.406; 2) for FEV1: κ = 0.944, B = 0.946; 3) for MIP: κ = 0.625, B = 0.674; and 4) for MEP: κ = 0.241, B = 0.373. Overall, RR cut-off values showed higher sensitivity, whereas the ENMC values showed higher specificity in detecting symptoms of respiratory involvement. Conclusions: The two approaches showed perfect agreement in assessment of FEV1, substantial agreement for MIP, and weak agreement for FVC and MEP. RR is an established method of assessment for spirometry and should be favoured because it takes variability within the population into account. Further development and validation of regression equations for RR calculations of predicted maximal respiratory pressures, with corresponding lower limits of normal, is required. The B statistic is more robust in assessing agreement between two diagnostic methods, resolving the issue of the κ paradox. Show more

Keywords: Myotonic dystrophy, pulmonary function tests, spirometry, maximal respiratory pressures, reference values, Interrater reliability, Cohen’s kappa statistics, Bangdiwala B statistics, respiratory insufficiency

DOI: 10.3233/JND-180331

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 451-459, 2018

Authors: Bozovic, Ivo | Peric, Stojan | Pesovic, Jovan | Bjelica, Bogdan | Brkusanin, Milos | Basta, Ivana | Bozic, Marija | Sencanic, Ivan | Marjanovic, Ana | Brankovic, Marija | Savic-Pavicevic, Dusanka | Rakocevic-Stojanovic, Vidosava

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 2 (DM2) is a multisystem disorder, mostly presented with mild but heterogeneous spectrum of symptoms. Objective: The aim of this research was to provide detailed sociodemographic, clinical and laboratory data of a large DM2 cohort from the Serbian registry. Methods: In 2008, we started to prospectively enter data of all DM patients. We also retrospectively collected data of patients hospitalized from 1990 until 2008. Results: At the end of 2017, registry comprised 87 (68%) of 128 genetically confirmed DM2 patients in Serbia, i.e. 1.2 registered cases per 100,000 inhabitants. Female …subjects were more prevalent (63%). The diagnostic delay was 11.8±11.3 years. The most common first symptoms in our patients were lower limb weakness, handgrip myotonia and limb pain, although some percentage of patients presented with cataracts or extrapyramidal symptoms and signs. Lens opacities were present in 75% of patients. Severe ECG abnormalities were noted in 8% and pacemaker was implanted in 5% of DM2 subjects. Pulmonary restriction was observed in 10% of DM2 patients. Insulin resistance and diabetes mellitus were frequent in our cohort (21% and 17%, respectively). Male subjects more frequently had snoring, baldness, sterility, polyneuropathy, lower HDL and higher glycaemia, while waddling gait and increased muscle reflexes were more common in females. Conclusions: This registry offers a spectrum of different features presented in Serbian DM2 population, which could be at service of earlier diagnosis and better treatment. Show more

Keywords: Myotonic dystrophy type 2, registry, gender, cataracts, cardiac conduction defects

DOI: 10.3233/JND-180328

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 461-469, 2018

Authors: Remiche, Gauthier | Lukacs, Zoltan | Kasper, David C. | Abramowicz, Marc | Pandolfo, Massimo

Article Type: Research Article

Abstract: Background: Late-onset glycogen storage disease type II is associated with variable muscle phenotypes. Epidemiological data suggest that its prevalence is lower in Belgium than in bordering countries like The Netherlands. Objective: We investigated whether such low estimated prevalence is due to missed diagnoses. Methods: We screened 100 patients with muscle phenotypes of undetermined origin using a dried blood spot test for alpha-acid glucosidase (GAA) activity. Patients with low activity at screening were re-tested by the same method and, if low activity was confirmed, GAA gene analysis was performed. Results: The screening test revealed …lower than normal GAA activity in 15 patients, but in only two of them it was low enough to be considered in the disease range. Retesting confirmed lower than normal GAA activity in five patients, but in all of them it was above the disease range. A single patient carried a heterozygous known pathogenic GAA mutation, whose significance in this case remains undetermined. Conclusions: We conclude that reported low prevalence estimates in Belgium are not likely to be due to an underdiagnosis bias. Lower prevalence compared to neighbouring The Netherlands may be due to different ethnic stratification of our patients. Diagnostic strategies should keep into account the expected prevalence of a disease in specific populations. Show more

Keywords: Glycogen storage disease type II (GSDII), epidemiology, screening, dried blood spot, assay

DOI: 10.3233/JND-180336

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 471-480, 2018

Authors: Andrews, Jennifer G. | Lamb, Molly M. | Conway, Kristin | Street, Natalie | Westfield, Christina | Ciafaloni, Emma | Matthews, Dennis | Cunniff, Christopher | Pandya, Shree | Fox, Deborah J. | MD STARnet

Article Type: Research Article

Abstract: Dystrophinopathies are caused by mutations in DMD resulting in progressive muscle weakness. They are historically divided into the more severe Duchenne (DMD) and milder Becker (BMD) muscular dystrophy phenotypes. Classification is important for research and clinical care. The purpose of this study was to describe a multi-variable approach to classifying cases from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet ) and to assess the accuracy of the diagnostic classification scheme. We used age at loss of mobility, molecular testing results, and age at symptom onset to classify cases as having DMD or BMD and to assess …sensitivity and specificity. Mobility status showed low sensitivity and high specificity for predicting DMD (65.5% and 99.3%, respectively) and BMD (62.8% and 97.7%, respectively) phenotypes. Molecular testing showed 90.9% sensitivity and 66.4% specificity for DMD; 76.3% sensitivity and 90.0% specificity for BMD. Age of onset predicted DMD with sensitivity of 73.9% and specificity of 69.0%; BMD had 99.7% specificity and 36.7% sensitivity. Mobility status, molecular test results, and age at symptom onset are important but inconsistent measures for accurately classifying individuals into DMD or BMD phenotypes. These results have implications for prognosis in newly diagnosed individuals and for classifying phenotype in clinical trials. Show more

Keywords: Muscular dystrophies, Duchenne, Becker, phenotype, diagnostic accuracy, dystrophinopathy

DOI: 10.3233/JND-180306

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 481-495, 2018

Authors: Weber, David R. | Thomas, Shiny | Erickson, Stephen W. | Fox, Deborah | Oleszek, Joyce | Pandya, Shree | Venkatesh, Yedatore | Westfield, Christina | Ciafaloni, Emma | for the Muscular Dystrophy Tracking and Research Network (MD STAR)

Article Type: Research Article

Abstract: Background: Patients with Duchenne muscular dystrophy (DMD) are at high risk of endocrine and bone health complications resulting from the high glucocorticoid (GC) doses used to treat this condition. There are limited data characterizing the clinical management of these complications. Objective: To determine the frequency of bone health screening, endocrinologist evaluation, and use of endocrine and bone health pharmacotherapy in the clinical care of males with DMD. Methods: A population based cohort study using data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet ) was conducted. Clinical data was abstracted from the medical …records of 683 males with DMD at five surveillance sites across the US. Results: A DXA scan had been documented in 24% of cases; the percentage of cases with DXA varied across surveillance sites from 13% to 43%, p  < 0.001. History of fracture and greater disease duration were associated with greater odds of having a DXA. Only 4.7% of cases had documentation of an endocrinologist evaluation. The frequency of documented endocrine and bone health pharmacotherapy use included calcium (42.8%), vitamin D (36.6%), bisphosphonates (13.3%), growth hormone (1.9%), testosterone (1.7%), insulin (1.2%), and metformin (0.3%) Conclusions: A low percentage of DMD males had record of DXA scan, endocrinologist evaluation, or treatment with endocrine or bone health pharmacotherapy. Endocrine and bone health care may represent an unmet need in the DMD population. Show more

Keywords: Muscular dystrophy, duchenne, osteoporosis, glucocorticoids, bisphosphonates, hypogonadism

DOI: 10.3233/JND-180317

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 497-507, 2018

Authors: Krosschell, Kristin J. | Bosch, Michael | Nelson, Leslie | Duong, Tina | Lowes, Linda P. | Alfano, Lindsay N. | Benjamin, Danielle | Carry, Terri B. | Devine, Ginger | Kelley, Carolyn | Gadekan, Rebecca | Malkus, Elizabeth C. | Pasternak, Amy | Provance-Orr, Stephanie | Roemeiser-Logan, Lynne | Nicorici, Alina | Trussell, Donata | Young, Sally Dunaway | Fetterman, Jennifer R. | Montes, Jacqueline | Powers, Penny J. | Quinones, Rebecca | Quigley, Janet | Coffey, Christopher S. | Yankey, Jon W. | Bartlett, Amy | Kissel, John T. | Kolb, Stephen J. | the NeuroNEXT Clinical Trial Network and on behalf of the NN101 SMA Biomarker Investigators

Article Type: Research Article

Abstract: Background: The NeuroNEXT SMA Infant Biomarker Study, a two year, longitudinal, multi-center study of infants with SMA type 1 and healthy infants, presented a unique opportunity to assess multi-site rater reliability on three infant motor function tests (MFTs) commonly used to assess infants with SMA type 1. Objective: To determine the effect of prospective MFT rater training and the effect of rater experience on inter-rater and intra-rater reliability for the Test of Infant Motor Performance Screening Items (TIMPSI), the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Alberta Infant Motor Scale (AIMS). …Methods: Training was conducted utilizing a novel set of motor function test (MFT) videos to optimize accurate MFT administration and reliability for the study duration. Inter- and intra-rater reliability of scoring for the TIMPSI and inter-rater reliability of scoring for the CHOP INTEND and the AIMS was assessed using intraclass correlation coefficients (ICC). Effect of rater experience on reliability was examined using ICC. Agreement with ‘expert’ consensus scores was examined using Pearson’s correlation coefficients. Results: Inter-rater reliability on all MFTs was good to excellent. Intra-rater reliability for the primary MFT, the TIMPSI, was excellent for the study duration. Agreement with ‘expert’ consensus was within predetermined limits (≥85%) after training. Evaluator experience with SMA and MFTs did not affect reliability. Conclusions: Reliability of scores across evaluators was demonstrated for all three study MFTs and scores were reproducible on repeated administration. Evaluator experience had no effect on reliability. Show more

Keywords: Spinal muscular atrophy, motor function testing, outcome measures, neuromuscular diseases, TIMPSI, CHOP-INTEND, AIMS, clinical evaluator, NeuroNEXT, reliability

DOI: 10.3233/JND-180327

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 509-521, 2018

Authors: Gagnon, Cynthia | Heatwole, Chad | Hébert, Luc J. | Hogrel, Jean-Yves | Laberge, Luc | Leone, Mario | Meola, Giovanni | Richer, Louis | Sansone, Valeria | Kierkegaard, Marie

Article Type: Meeting Report

Keywords: Myotonic dystrophy, outcome assessment (Health Care), metrological properties

DOI: 10.3233/JND-180329

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 523-537, 2018

Authors: Chardon, Jodi Warman | Jasmin, Bernard J. | Kothary, Rashmi | Parks, Robin J.

Article Type: Meeting Report

DOI: 10.3233/JND-180353

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 4, pp. 539-552, 2018