Journal of Neuromuscular Diseases - Volume 4, issue 1

Authors: Batonnet-Pichon, Sabrina | Behin, Anthony | Cabet, Eva | Delort, Florence | Vicart, Patrick | Lilienbaum, Alain

Article Type: Review Article

Abstract: Myofibrillar myopathies (MFMs) are muscular disorders involving proteins that play a role in the structure, maintenance processes and protein quality control mechanisms closely related to the Z-disc in the muscular fibers. MFMs share common histological characteristics including progressive disorganization of the interfibrillar network and protein aggregation. Currently no treatment is available. In this review, we describe first clinical symptoms associated with mutations of the six genes (DES, CRYAB, MYOT, ZASP, FLNC and BAG3 ) primary involved in MFM and defining the origin of this pathology. As mechanisms determining the aetiology of the disease remain unclear yet, several research teams …have developed animal models from invertebrates to mammalians species. Thus we describe here these different models that often recapitulate human clinical symptoms. Therefore they are very useful for deeper studies to understand early molecular and progressive mechanisms determining the pathology. Finally in the last part, we emphasize on the potential therapeutic approaches for MFM that could be conducted in the future. In conclusion, this review offers a link from patients to future therapy through the use of MFMs animal models. Show more

Keywords: Myofibrillar myopathies, MFM animal models, therapeutics

DOI: 10.3233/JND-160203

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 1, pp. 1-15, 2017

Authors: Fayssoil, Abdallah | Abasse, Soumeth | Silverston, Katy

Article Type: Review Article

Abstract: Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. The clinical picture included peripheral muscle weakness, cardiomyopathy and chronic respiratory insufficiency. In this paper, the authors review cardiac involvement in patients with DMD, propose a cardiac impairment classification and discuss therapeutic management options.

Keywords: Duchenne muscular dystrophy, cardiomyopathy, echocardiography, classification, CMR

DOI: 10.3233/JND-160194

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 1, pp. 17-23, 2017

Authors: Jimenez-Moreno, Aura Cecilia | Newman, Jane | Charman, Sarah J. | Catt, Michael | Trenell, Michael I. | Gorman, Grainne S. | Hogrel, Jean-Yves | Lochmüller, Hanns

Article Type: Research Article

Abstract: Background: Free-living or habitual physical activity (HPA) refers to someone’s performance in his or her free-living environment. Neuromuscular disorders (NMD) manifest through HPA, and the observation of HPA can be used to identify clinical risks and to quantify outcomes in research. This review summarizes and analyses previous studies reporting the assessment of HPA in NMD, and may serve as the basis for evidence-based decision-making when considering assessing HPA in this population. Methods: A systematic review was performed to identify all studies related to HPA in NMD, followed by a critical appraisal of the assessment methodology and a …final review of the identified HPA tools. Results: A total of 22 studies were selected, reporting on eight different direct tools (or activity monitors) and ten structured patient-reported outcomes. Overall, HPA patterns in NMD differ from healthy control populations. There was a noticeable lack of validation studies for these tools and outcome measures in NMD. Very little information regarding feasibility and barriers for the application of these tools in this population have been published. Conclusions: The variety and heterogeneity of tools and methods in the published literature makes the comparison across different studies difficult, and methodological guidelines are warranted. We propose a checklist of considerations for the assessment and reporting of HPA in NMD. Show more

Keywords: Physical activity, daily activity, exercise, activity monitor, neuromuscular disorders, muscular dystrophy

DOI: 10.3233/JND-160195

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 1, pp. 25-52, 2017

Authors: Doorenweerd, Nathalie | Hooijmans, Melissa | Schubert, Stephanie A. | Webb, Andrew G. | Straathof, Chiara S.M. | van Zwet, Erik W. | van Buchem, Mark A. | Verschuuren, Jan J.G.M. | Hendriksen, Jos G.M. | Niks, Erik H. | Kan, Hermien E.

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin. DMD is associated with specific learning and behavioural disabilities. In the brain, dystrophin is associated with GABAA receptors and aquaporin-4 in neurons and astrocytes, respectively, but little is known about its function. Objective and Methods: In this study we aimed to compare the biochemical composition between patients and healthy controls in brain regions that are naturally rich in dystrophin using magnetic resonance spectroscopy. Given previous conflicting results obtained at clinical field strengths, we obtained data using a 7 Tesla system with associated higher signal-to-noise …ratio and spectral resolution. Results: Results indicated unchanged biochemical composition in all regions investigated, and increased variance in glutamate in the frontal cortex. Show more

Keywords: Duchenne muscular dystrophy, brain, magnetic resonance spectroscopy, metabolites

DOI: 10.3233/JND-160201

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 1, pp. 53-58, 2017

Authors: Iyer, Chitra | Wang, Xueqian | Renusch, Samantha R. | Duque, Sandra I. | Wehr, Allison M. | Mo, Xiaokui-Molly | McGovern, Vicki L. | Arnold, W. David | Burghes, Arthur H.M. | Kolb, Stephen J.

Article Type: Research Article

Abstract: Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease that results in loss of spinal motor neurons, muscular weakness and, in severe cases, respiratory failure and death. SMA is caused by a deletion or mutation of the SMN1 gene and retention of the SMN2 gene that leads to low SMN expression levels. The measurement of SMN mRNA levels in peripheral blood samples has been used in SMA clinical studies as a pharmacodynamic biomarker for response to therapies designed to increase SMN levels. We recently developed a postnatal porcine model of SMA by the …viral delivery of a short-hairpin RNA (shRNA) targeting porcine SMN (pSMN ). scAAV9-mediated knockdown of pSMN mRNA at postnatal day 5 results in denervation, weakness and motor neuron and ventral root axon loss that begins 3-4 weeks after viral delivery, and this phenotype can be ameliorated by subsequent viral delivery of human SMN (hSMN ). Objective: To determine if the effect of modulating SMN levels using gene therapy can be measured in blood. Methods: We measured expression of pSMN mRNA and hSMN mRNA by quantitative droplet digital PCR (ddPCR). Results: We found that the endogenous expression of pSMN mRNA in blood increases in the first month of life. However, there were no significant differences in blood levels of pSMN mRNA after knock-down or of human SMN mRNA after gene therapy. Conclusions: Our results, obtained in a large animal model of SMA that is similar in size and anatomy to human infants, suggest that measurement of SMN mRNA levels in blood may not be informative in SMA clinical trials involving intrathecal delivery of SMN-modulating therapies. Show more

Keywords: ddPCR, gene-therapy, scAAV9-shRNA, scAAV9-SMN, SMA, SMN

DOI: 10.3233/JND-170209

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 1, pp. 59-66, 2017

Authors: Samões, Raquel | Oliveira, Jorge | Taipa, Ricardo | Coelho, Teresa | Cardoso, Márcio | Gonçalves, Ana | Santos, Rosário | Melo Pires, Manuel | Santos, Manuela

Article Type: Research Article

Abstract: Background: Pathogenic variants in ryanodine receptor type 1 (RYR1 ) gene are an important cause of congenital myopathy. The clinical, histopathologic and genetic spectrum is wide. Objective: Review a group of the patients diagnosed with ryanodinopathy in a tertiary centre from North Portugal, as an attempt to define some phenotypical patterns that may help guiding future diagnosis. Methods: Patients were identified from the database of the reference centre for Neuromuscular Disorders in North Portugal. Their data (clinical, histological and genetic) was retrospectively accessed. Results: Seventeen RYR1-related patients (including 4 familial cases) were …identified. They were divided in groups according to three distinctive clinical characteristics: extraocular muscle (EOM) weakness (N  = 6), disproportionate axial muscle weakness (N  = 2) and joint laxity (N  = 5). The fourth phenotype includes patients with mild tetraparesis and no distinctive clinical features (N  = 4). Four different histopathological patterns were found: centronuclear (N  = 5), central core (N  = 4), type 1 fibres predominance (N  = 4) and congenital fibre type disproportion (N  = 1) myopathies. Each index case, except two patients, had a different RYR1 variant. Four new genetic variants were identified. All centronuclear myopathies were associated with autosomal recessive inheritance and EOM weakness. All central core myopathies were caused by pathogenic variants in hotspot 3 with autosomal dominant inheritance. Three genetic variants were reported to be associated to malignant hyperthermia susceptibility. Conclusions: Distinctive clinical features were recognized as diagnostically relevant: extraocular muscle weakness (and centronuclear pattern on muscle biopsy), severe axial weakness disproportionate to the ambulatory state and mild tetraparesis associated with (proximal) joint laxity. There was a striking genetic heterogeneity, including four new RYR1 variants. Show more

Keywords: Central core, centronuclear, congenital myopathies, joint laxity, malignant hyperthermia, myopathy, ryanodine receptor 1, RYR1

DOI: 10.3233/JND-160199

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 1, pp. 67-76, 2017

Authors: Hou, Tieying | Li, Yilan | Chen, Weiwei | Heffner, Reid R. | Vladutiu, Georgirene D.

Article Type: Research Article

Abstract: Background: Statins have well-known benefits in the prevention of cardiovascular disease, however, 7–29% of patients develop muscle side effects and up to 0.5% develop severe symptoms. Mitochondrial dysfunction has been associated with severe statin-induced myopathy (SM); however, there is a paucity of systematic studies in affected individuals. Objectives: The goal of this study was to combine clinical and laboratory features with quantitative biochemical and histopathologic studies of skeletal muscle biopsies from SM cases to determine what proportion could be attributed to mitochondrial dysfunction and how many of these had primary respiratory chain defects. Methods: A …retrospective analysis was performed on patient records derived from 279 SM patients whose muscle biopsies were referred to our clinical diagnostic laboratory for analysis. Clinical, histopathologic and biochemical features were compared with two myopathic control groups unexposed to statins: individuals with idiopathic mitochondrial myopathy (MMP; n  = 94) and with unknown metabolic myopathy (UMP; n  = 86); normal controls were unavailable for this record review study. Results: More SM patients had significantly elevated plasma CK than in the other two groups (p  < 0.01). A subset of SM patients (67 of 279; 24%) had histopathologic and/or electron microscopic (EM) evidence for mitochondrial dysfunction in skeletal muscle; more cases were identified by EM than by histochemical analysis. Of 279 cases, 29 (10%) were confirmed to have respiratory chain defects by biochemical analysis; 4 of these had mitochondrial abnormalities by EM. An additional 20 cases had mitochondrial abnormalities by EM without a biochemical diagnosis. Conclusions: Both primary and secondary mitochondrial dysfunction was found in subsets of SM patients. The fact that respiratory chain defects were not found in most cases with histopathologic mitochondrial abnormalities does not rule out primary mitochondrial disease in these cases, however, it is more likely that secondary effects on mitochondrial structure and function have occurred; molecular analysis may be helpful only in a small number of cases. Show more

Keywords: Statin myopathy, respiratory chain defect, mitochondrial dysfunction, electron microscopy

DOI: 10.3233/JND-160184

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 1, pp. 77-87, 2017

Authors: Rakocevic-Stojanovic, V. | Peric, S. | Dujmovic, I. | Drulovic, J. | Pesovic, J. | Savic-Pavicevic, D.

Article Type: Research Article

Abstract: Introduction: The aim of this study was to present a family co-segregating myotonic dystrophy type 1 (DM1) and 2 (DM2), and one member affected with neuromyelitis optica (NMO). Case report: Index case underwent cataract surgery at age 39. Although she had no muscle symptoms, genetic testing revealed a DM2 mutation and a DM1 protomutation. The patient noticed difficulties in climbing stairs at age 47. Clinical examination showed mild muscle weakness, calf hypertrophy, mild myotonia and several multisystem signs. Patient’s mother had DM1 protomutation and clinically exhibited only cataract. Two proband’s sisters, one with DM2 mutation and another …with DM2 mutation and DM1 protomutation, had a clinical presentation similar to the index case. In addition, the latter also developed NMO. Conclusion: Our findings suggest that screening for both DM1 and DM2 should be done and a positive result in either gene should not be an indication to stop screening, but to move to the other gene. Show more

Keywords: Myotonic dystrophy type 1, myotonic dystrophy type 2, autoimmune diseases, neuromyelitis optica

DOI: 10.3233/JND-160192

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 1, pp. 89-92, 2017

Authors: Oz Tuncer, Gokcen | Teber, Serap | Kutluk, Muhammed Gültekin | Albayrak, Pelin | Deda, Gülhis

Article Type: Case Report

DOI: 10.3233/JND-160188

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 1, pp. 93-95, 2017

Authors: Bartsakoulia, Marina | Müller, Juliane S. | Gomez-Duran, Aurora | Yu-Wai-Man, Patrick | Boczonadi, Veronika | Horvath, Rita

Article Type: Other

DOI: 10.3233/JND-179001

Citation: Journal of Neuromuscular Diseases, vol. 4, no. 1, pp. 97-97, 2017