Journal of Neuromuscular Diseases - Volume 6, issue 3

Authors: Widrick, Jeffrey J. | Kawahara, Genri | Alexander, Matthew S. | Beggs, Alan H. | Kunkel, Louis M.

Article Type: Review Article

Abstract: The recent availability and development of mutant and transgenic zebrafish strains that model human muscular dystrophies has created new research opportunities for therapeutic development. Not only do these models mimic many pathological aspects of human dystrophies, but their small size, large clutch sizes, rapid ex utero development, body transparency, and genetic tractability enable research approaches that would be inconceivable with mammalian model systems. Here we discuss the use of zebrafish models of muscular dystrophy to rapidly screen hundreds to thousands of bioactive compounds in order to identify novel therapeutic candidates that modulate pathologic phenotypes. We review the justification and …rationale behind this unbiased approach, including how zebrafish screens have identified FDA-approved drugs that are candidates for treating Duchenne and limb girdle muscular dystrophies. Not only can these drugs be re-purposed for treating dystrophies in a fraction of the time and cost of new drug development, but their identification has revealed novel, unexpected directions for future therapy development. Phenotype-driven zebrafish drug screens are an important compliment to the more established mammalian, target-based approaches for rapidly developing and validating therapeutics for muscular dystrophies. Show more

Keywords: Drug discovery, drug screening, preclinical drug evaluation, Duchenne muscular dystrophy, limb-girdle muscular dystrophy, Danio rerio

DOI: 10.3233/JND-190389

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 3, pp. 271-287, 2019

Authors: Schartner, Vanessa | Laporte, Jocelyn | Böhm, Johann

Article Type: Review Article

Abstract: Muscle contraction requires specialized membrane structures with precise geometry and relies on the concerted interplay of electrical stimulation and Ca2+ release, known as excitation-contraction coupling (ECC). The membrane structure hosting ECC is called triad in skeletal muscle and dyad in cardiac muscle, and structural or functional defects of triads and dyads have been observed in a variety of myopathies and cardiomyopathies. Based on their function, the proteins localized at the triad/dyad can be classified into three molecular pathways: the Ca2+ release complex (CRC), store-operated Ca2+ entry (SOCE), and membrane remodeling. All three are mechanistically linked, and consequently, …aberrations in any of these pathways cause similar disease entities. This review provides an overview of the clinical and genetic spectrum of triad and dyad defects with a main focus of attention on the underlying pathomechanisms. Show more

Keywords: Triad, dyad, myopathy, cardiomyopathy, excitation-contraction coupling, ECC, store-operated Ca2+ entry, SOCE, calcium, membrane remodeling

DOI: 10.3233/JND-180314

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 3, pp. 289-305, 2019

Authors: Al-Zaidy, Samiah A. | Kolb, Stephen J. | Lowes, Linda | Alfano, Lindsay N. | Shell, Richard | Church, Kathleen R. | Nagendran, Sukumar | Sproule, Douglas M. | Feltner, Douglas E. | Wells, Courtney | Ogrinc, Francis | Menier, Melissa | L’Italien, James | Arnold, W. David | Kissel, John T. | Kaspar, Brian K. | Mendell, Jerry R.

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy type 1 (SMA1) is the leading genetic cause of infant mortality for which therapies, including AVXS-101 (onasemnogene abeparvovec, Zolgensma® ) gene replacement therapy, are emerging. Objective: This study evaluated the effectiveness of AVXS-101 in infants with spinal muscular atrophy type 1 (SMA1) compared with a prospective natural history cohort and a cohort of healthy infants. Methods: Twelve SMA1 infants received the proposed therapeutic dose of AVXS-101 (NCT02122952). Where possible, the following outcomes were compared with a natural history cohort of SMA1 infants (n  = 16) and healthy infants (n  = 27) enrolled in the …NeuroNEXT (NN101) study (NCT01736553): event-free survival, CHOP-INTEND scores, motor milestone achievements, compound muscle action potential (CMAP), and adverse events. Results: Baseline characteristics of SMA1 infants in the AVXS-101 and NN101 studies were similar in age and genetic profile. The proportion of AVXS-101–treated infants who survived by 24 months of follow-up was higher compared with the NN101 study (100% vs 38%, respectively). The average baseline CHOP-INTEND score for NN101 SMA1 infants was 20.3, worsening to 5.3 by age 24 months; the average baseline score in AVXS-101–treated infants was 28.2, improving to 56.5 by age 24 months. Infants receiving AVXS-101 achieved motor milestones, such as sitting unassisted and walking. Improvements in CMAP peak area were observed in AVXS-101–treated infants at 6 and 24 months (means of 1.1 and 3.2 mV/s, respectively). Conclusions: In this study, AVXS-101 increased the probability of survival, rapidly improved motor function, and enabled motor milestone achievement in SMA1 infants. Show more

Keywords: Gene therapy, spinal muscular atrophy, natural history, neuromuscular diseases, ClinicalTrials.gov NCT02122952 (https://clinicaltrials.gov/ct2/show/NCT02122952) and NCT01736553(https://clinicaltrials.gov/ct2/show/NCT01736553)

DOI: 10.3233/JND-190403

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 3, pp. 307-317, 2019

Authors: Servais, Laurent

Article Type: Article Commentary

DOI: 10.3233/JND-199001

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 3, pp. 319-320, 2019

Authors: van der Plas, Ellen | Hamilton, Mark J. | Miller, Jacob N. | Koscik, Timothy R. | Long, Jeffrey D. | Cumming, Sarah | Povilaikaite, Julija | Farrugia, Maria Elena | McLean, John | Jampana, Ravi | Magnotta, Vincent A. | Gutmann, Laurie | Monckton, Darren G. | Nopoulos, Peggy C.

Article Type: Research Article

Abstract: Background: Few adequately-powered studies have systematically evaluated brain morphology in adult-onset myotonic dystrophy type 1 (DM1). Objective: The goal of the present study was to determine structural brain differences between individuals with and without adult-onset DM1 in a multi-site, case-controlled cohort. We also explored correlations between brain structure and CTG repeat length. Methods: Neuroimaging data was acquired in 58 unaffected individuals (29 women) and 79 individuals with DM1 (50 women). CTG repeat length, expressed as estimated progenitor allele length (ePAL), was determined by small pool PCR. Statistical models were adjusted for age, sex, site, and intracranial …volume (ICV). Results: ICV was reduced in DM1 subjects compared with controls. Accounting for the difference in ICV, the DM1 group exhibited smaller volume in frontal grey and white matter, parietal grey matter as well as smaller volume of the corpus callosum, thalamus, putamen, and accumbens. In contrast, volumes of the hippocampus and amygdala were significantly larger in DM1. Greater ePAL was associated with lower volumes of the putamen, occipital grey matter, and thalamus. A positive ePAL association was observed for amygdala volume and cerebellar white matter. Conclusions: Smaller ICV may be a marker of aberrant neurodevelopment in adult-onset DM1. Volumetric analysis revealed morphological differences, some associated with CTG repeat length, in structures with plausible links to key DM1 symptoms including cognitive deficits and excessive daytime somnolence. These data offer further insights into the basis of CNS disease in DM1, and highlight avenues for further work to identify therapeutic targets and imaging biomarkers. Show more

Keywords: Myotonic dystrophy, magnetic resonance imaging, neuroanatomy

DOI: 10.3233/JND-190397

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 3, pp. 321-332, 2019

Authors: Gillespie, Meredith K. | McMillan, Hugh J. | Kernohan, Kristin D. | Pena, Izabella A. | Meyer-Schuman, Rebecca | Care4Rare Canada Consortium | Antonellis, Anthony | Boycott, Kym M.

Article Type: Case Report

Abstract: Charcot-Marie-Tooth disease is a phenotypically and genetically heterogeneous group of disorders affecting both motor and sensory neurons. Exome sequencing has driven discovery of genes responsible for Charcot-Marie-Tooth disease with more than 70 genes now associated with this neuromuscular disease. The MARS gene was recently reported as the cause of Charcot-Marie-Tooth 2U, a slowly progressive axonal sensorimotor polyneuropathy with adult-onset reported in six patients. We report here a patient with a progressive, early childhood-onset, motor-predominant form of Charcot-Marie-Tooth disease. Exome sequencing identified a novel MARS variant (c.1189G>A; p.Ala397Thr) that was not present in her unaffected mother; her unaffected father …was unavailable. Further studies using structural modeling and a yeast humanization assay support pathogenicity of the variant. Our study expands the phenotype of Charcot-Marie-Tooth 2U, while highlighting the utility of functional assays to evaluate variant pathogenicity. Show more

Keywords: MARS, early-onset neuropathy, exome sequencing, Charcot-Marie-Tooth disease type 2U, CMT2U

DOI: 10.3233/JND-190404

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 3, pp. 333-339, 2019

Authors: Prasad, Madhavi | Glueck, Michael | Ceballos-Saenz, Delia | Zapata-Aldana, Eugenio | Johnson, Nicholas | Campbell, Craig | Nguyen, Cam-Tu Emilie

Article Type: Research Article

Abstract: Background: Congenital Myotonic Dystrophy (CDM1) is a rare neuromuscular condition caused by a triplet repeat expansion in the DMPK gene. Despite there being a well-recognized clinical syndrome, there has not been an effort to use a standardized ontology system to describe the disease characteristics in existing literature. Thus, comparing or contrasting different cohorts from the literature can be challenging, and coding disease features for clinical research or for registry data items is not uniform. PhenoStacks is a visualization analytics tool which helps graphically illustrate phenotypes of patients with genetic disorders using Human Phenotype Ontology (HPO) terms and can sort phenotypes …by different disease characteristics. Objective: To demonstrate the efficacy of PhenoStacks and the HPO system as clinical research tools when describing CDM1 cohorts. Methods: Health Endpoints and Longitudinal progression in congenital myotonic dystrophy (HELP-CDM) is an ongoing study which longitudinally follows patients with CDM1. Items from the HELP-CDM data sheet were matched to corresponding HPO terms and analyzed using PhenoStacks. Results: In total 40 subjects’ phenotypes were visualized through PhenoStacks and 73 HPO terms were used for the analysis. Frequent phenotypic features included “high narrow palate”, “facial palsy”, “ptosis”, “hyporeflexia”, and “weak voice”. Contractures were associated with higher repeat sizes. Hypoplastic muscles and infantile axial hypotonia were more frequently observed in infants. Conclusions: PhenoStacks is a valuable clinical and scientific tool as it identifies variability within cohorts and highlights significant phenotypic features. Show more

Keywords: Myotonic dystrophy, Human Phenotype Ontology, PhenoStacks, congenital

DOI: 10.3233/JND-180345

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 3, pp. 341-347, 2019

Authors: Annexstad, Ellen Johanne | Fagerheim, Toril | Holm, Inger | Rasmussen, Magnhild

Article Type: Research Article

Abstract: Background: As new gene-related treatment options for Duchenne muscular dystrophy (DMD) are being developed, precise information about the patients’ genetic diagnosis and knowledge about the diversities of natural history in DMD is vital. Objective: To obtain detailed insight into the genetic and clinical characteristics of paediatric DMD in Norway. Methods: 94 boys with DMD, aged 0–18 years, were identified over a period of 3.5 years, yielding a national prevalence of 13.5×10–5 boys. 73 boys (78%) were recruited to full genetic and clinical or limited (genetic only) evaluation. Results: Molecular analysis disclosed 64% deletions, …18% duplications and 18% point mutations. The mean age of diagnosis was 3.9±2.0 years. 78% were treated with glucocorticoids from age 5.8±1.5 years. 23 boys (35%) had lost ambulation at an age of 10.7±2.0 years. 17% were treated for left ventricular dysfunction from age 12.1±3.0 years and 12% had received night-time non-invasive positive pressure ventilation from age 13.0±2.5 years. Conclusions: The distribution of mutation types and sites was similar to previous studies but with more duplications and fewer point mutations. Any genotype-phenotype correlations were not uncovered. The boys were diagnosed early but there is still diagnostic delay among boys presenting with late motor development. Glucocorticoid treatment was widespread, especially among the younger boys. The clinical results of this comprehensive nationwide study highlight the large variability of disease progression in DMD. Show more

Keywords: Duchenne muscular dystrophy, genotype-phenotype correlation, glucocorticoid, ambulation, cardiopulmonary, disease progression

DOI: 10.3233/JND-190402

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 3, pp. 349-359, 2019

Authors: van der Heul, A.M.B. | Wijngaarde, C.A. | Wadman, R.I. | Asselman, F. | van den Aardweg, M.T.A. | Bartels, B. | Cuppen, I. | Gerrits, E. | van den Berg, L.H. | van der Pol, W.L. | van den Engel-Hoek, L.

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is hereditary motor neuron disorder, characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by the homozygous loss of function of the survival motor neuron (SMN) 1 gene. SMA shows a wide variability of disease severity. Objective: To investigate self-reported bulbar problems in patients with SMA, and their relationship to age, functional motor scores and active maximum mouth opening. Methods: We used the Diagnostic List of Dysphagia and Dysarthria in (pediatric) patients and relevant recent clinical data from the national SMA database. Results: …The 118 included patients with SMA frequently reported jaw problems (34%), fatigue associated with mastication (44%), choking (56%) and intelligibility problems (27%). Jaw, mastication and swallowing problems frequently occurred in combination with each other. There was an increase of reported bulbar problems in patients with SMA type 3a, older than 30 years of age, compared to younger patients of this SMA type. The Hammersmith Functional Motor Scale Expanded scores showed a negligible correlation with jaw and mastication problems, a low negative correlation with swallowing problems and a moderate negative correlation with intelligibility problems. Reduced mouth opening showed a significant, but low correlation with bulbar complaints in patients with SMA type 2. Conclusions: Fatigue associated with mastication and swallowing problems were frequently reported complaints. Patients 30 years and older with milder forms of SMA showed an increase of self-reported bulbar problems. Show more

Keywords: Feeding and swallowing problems, dysphagia, bulbar function, spinal muscular atrophy.

DOI: 10.3233/JND-190379

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 3, pp. 361-368, 2019

Authors: de Meel, Robert H.P. | Raadsheer, Wouter F. | van Zwet, Erik W. | Tannemaat, Martijn R. | Verschuuren, Jan J.G.M.

Article Type: Research Article

Abstract: Introduction: In this study we quantitatively describe ocular weakness patterns in myasthenia gravis (MG) to help neurologists in making the clinical diagnosis and to investigate how the current outcome measures reflect ocular weakness in MG. Methods: We investigated ptosis and diplopia patterns in a retro- and prospective cohort of 306 MG patients. Diplopia was systematically examined by testing extra-ocular muscle (EOM) fatigability in two horizontal and four oblique directions for 60 seconds. Results: Of patients with initial symmetric ptosis, 40% developed asymmetric ptosis at the second visit. Changes in form of ptosis occurred less often in …seronegative MG patients (50%) than in patients with acetylcholine receptor (AChR) antibodies (70%) or muscle-specific kinase (MuSK) antibodies (69%) (p  = 0.038). Of patients with diplopia on the first visit, double vision contained both a vertical and horizontal component in 95%. At the second visit, 83% manifested diplopia in other gaze directions. The mean time (in seconds) to diplopia was 11.6±14.0 and the mean time to ptosis was 27.6±19.8. Diplopia or ptosis manifested within 30 seconds in 87% and 58%, respectively. Patients who manifested diplopia after 30 seconds, reported no limitations due to diplopia. Discussion: Changes in the gaze directions in which diplopia occurs or ptosis side occur frequently in MG. In diagnostically challenging cases, we recommend testing ptosis and diplopia in multiple gaze directions for 30–60 seconds during at least two follow-up visits to maximize the chance of observing changes in ocular weakness patterns. Show more

Keywords: Myasthenia gravis, ocular weakness, ptosis, diplopia, fluctuations

DOI: 10.3233/JND-190407

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 3, pp. 369-376, 2019