Journal of Neuromuscular Diseases - Volume 5, issue 3

Authors: Behin, Anthony | Le Panse, Rozen

Article Type: Review Article

Abstract: Acquired Myasthenia Gravis (MG) is a neuromuscular disease caused by autoantibodies against components of the neuromuscular junction. It is a prototype organ-specific autoimmune disease with well-defined antigenic targets mainly the nicotinic acetylcholine receptor (AChR). Patients suffer from fluctuating, fatigable muscle weakness that worsens with activity and improves with rest. Various therapeutic strategies have been used over the years to alleviate MG symptoms. These strategies aim at improving the transmission of the nerve impulse to muscle or at lowering the immune system with steroids or immunosuppressant drugs. Nevertheless, MG remains a chronic disease and symptoms tend to persist in many …patients, some being or becoming refractory over time. In this review, based on recent experimental data on MG or based on results from clinical trials for other autoimmune diseases, we explore new potential therapeutic approaches for MG patients, going from non-specific approaches with the use of stem cells with their anti-inflammatory and immunosuppressive properties to targeted therapies using monoclonal antibodies specific for cell-surface antigens or circulating molecules. Show more

Keywords: Autoimmunity, acetylcholine receptor antibodies, thymus, thymectomy, rituximab, monoclonal antibodies

DOI: 10.3233/JND-170294

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 3, pp. 265-277, 2018

Authors: Minier, Lisa | Lignier, Baptiste | Bouvet, Cyrille | Gallais, Benjamin | Camart, Nathalie

Article Type: Review Article

Abstract: Background: The last literature review on psychopathological features in Myotonic Dystrophy type 1 had been conducted by Ambrosini and Nurnberg in 1979. Since that date, many researches had been carried out. Objective: The aim of this study is (i) to systematically obtain and evaluate the relevant literature on psychopathological features, personality, and coping in individuals with adult phenotypes of Myotonic Dystrophy type 1. (ii) To summarize current research findings and draw conclusions for future research. Methods: A systematic search was conducted on Pubmed, PubPsych, PsycInfo, Science Direct, and Scopus covering the period of January 1979 to …July 2017. Results: In view of our literature review, patients show mild psychopathological problems, such as interpersonal difficulties, lack of interest, dysphoria, concern about bodily functioning, and hypersensibility. However, they do not experience more psychiatric disorder in comparison to the general population, except for personality disorders and depression. We discussed problems concerning depression’s assessment tool. Patients also present symptoms of several personality disorders: avoidant personality disorder was the most common. Finally, coping strategies relative to limitations resulting from their disease have a negative impact on their quality of life. Conclusions: In conclusion, Myotonic Dystrophy type 1 patients did not present homogeneous psychopathological and psychological features. However, based on tendencies observed among Myotonic Dystrophy type 1 patients, elements to conceptualize their social difficulties are provided. Show more

Keywords: Myotonic dystrophy 1, psychopathology, depression, personality, emotion

DOI: 10.3233/JND-180310

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 3, pp. 279-294, 2018

Authors: Lowe, Jeovanna | Kadakia, Feni K. | Zins, Jonathan G. | Haupt, Michael | Peczkowski, Kyra K. | Rastogi, Neha | Floyd, Kyle T. | Gomez-Sanchez, Elise P. | Gomez-Sanchez, Celso E. | Elnakish, Mohammad T. | Rafael-Fortney, Jill A. | Janssen, Paul M.L.

Article Type: Research Article

Abstract: Background: Mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors have shown preclinical efficacy for both skeletal and cardiac muscle outcomes in young sedentary dystrophin-deficient mdx mice also haploinsufficient for utrophin, a Duchenne muscular dystrophy (DMD) model. The mdx genotypic DMD model has mild pathology, making non-curative therapeutic effects difficult to distinguish at baseline. Since the cardiac benefit of mineralocorticoid receptor antagonists has been translated to DMD patients, it is important to optimize potential advantages for skeletal muscle by further defining efficacy parameters. Objective: We aimed to test whether therapeutic effects of mineralocorticoid receptor antagonists added …to angiotensin converting enzyme inhibitors are detectable using three different reported methods of exacerbating the mdx phenotype. Methods: We tested treatment with lisinopril and the mineralocorticoid receptor antagonist spironolactone in: 10 week-old exercised, 1 year-old sedentary, and 5 month-old isoproterenol treated mdx mice and performed comprehensive functional and histological measurements. Results: None of the protocols to exacerbate mdx phenotypes resulted in dramatically enhanced pathology and no significant benefit was observed with treatment. Conclusions: Since endogenous mineralocorticoid aldosterone production from immune cells in dystrophic muscle may explain antagonist efficacy, it is likely that these drugs work optimally during the narrow window of peak inflammation in mdx mice. Exercised and aged mdx mice do not display prolific damage and inflammation, likely explaining the absence of continued efficacy of these drugs. Since inflammation is more prevalent in DMD patients, the therapeutic window for mineralocorticoid receptor antagonists in patients may be longer. Show more

Keywords: Mineralocorticoid receptors, Duchenne muscular dystrophy, spironolactone, lisinopril, mdx mice

DOI: 10.3233/JND-180323

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 3, pp. 295-306, 2018

Authors: Sagath, Lydia | Lehtokari, Vilma-Lotta | Välipakka, Salla | Udd, Bjarne | Wallgren-Pettersson, Carina | Pelin, Katarina | Kiiski, Kirsi

Article Type: Research Article

Abstract: Background: Our previous array, the Comparative Genomic Hybridisation design (CGH-array) for nemaline myopathy (NM), named the NM-CGH array, revealed pathogenic copy number variation (CNV) in the genes for nebulin (NEB ) and tropomyosin 3 (TPM3 ), as well as recurrent CNVs in the segmental duplication (SD), i.e. triplicate, region of NEB (TRI, exons 82–89, 90–97, 98–105). In the light of this knowledge, we have designed and validated an extended CGH array, which includes a selection of 187 genes known to cause neuromuscular disorders (NMDs). Objective: Our aim was to develop a reliable method for CNV detection in …genes related to neuromuscular disorders for routine mutation detection and analysis, as a much-needed complement to sequencing methods. Methods: We have developed a novel custom-made 4×180 k CGH array for the diagnostics of NMDs. It includes the same tiled ultra-high density coverage of the 12 known or putative NM genes as our 8×60 k NM-CGH-array but also comprises a selection of 175 additional genes associated with NMDs, including titin (TTN ), at a high to very high coverage. The genes were divided into three coverage groups according to known and potential pathogenicity in neuromuscular disorders. Results: The array detected known and putative CNVs in all three gene coverage groups, including the repetitive regions of NEB and TTN . Conclusions: The targeted neuromuscular disorder 4×180 k array-CGH (NMD-CGH-array v1.0) design allows CNV detection for a broader spectrum of neuromuscular disorders at a high resolution. Show more

Keywords: Array comparative genomic hybridisation (aCGH), copy number variation (CNV), nebulin, NEB , titin, TTN , NM-CGH, NMD-CGH

DOI: 10.3233/JND-170298

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 3, pp. 307-314, 2018

Authors: Lassche, Saskia | Janssen, Barbara H. | IJzermans, Ties | Fütterer, Jurgen J. | Voermans, Nicol C. | Heerschap, Arend | Küsters, Benno | Mann, Ritse M. | van Engelen, Baziel GM

Article Type: Research Article

Abstract: Background: Sampling error is a common problem in muscle biopsies. MRI-guided biopsy allows verification of biopsy site during the procedure, which may reduce sampling error in patients with focal disease. Objectives: To describe the technique for MRI-guided muscle biopsy and discuss potential applications. Methods: Axial MRI images were acquired to determine the target site for muscle biopsy. Needle trajectory was planned on 3D T1 weighted imaging and a MRI-guided biopsy of the vastus lateralis was performed in 13 FSHD patients. Results: An adequate amount of muscle tissue was obtained in all participants, and MRI-guided …biopsy succeeded in reaching focal target sites. However, symptomatic hematomas were observed in 2/13 patients Discussion: MRI-guided biopsy has a higher complication rate compared to traditional needle biopsy, most likely due to proximity to blood vessels in combination with the vacuum-assisted suction of the MRI-guided technique. We recommend that this technique is reserved for select diagnostic cases and research questions, with careful assessment of vasculature and reduced suction levels. Show more

Keywords: Muscle MRI, muscle biopsy, facioscapulohumoral muscular dystrophy, inflammatory myopathy, myositis

DOI: 10.3233/JND-180318

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 3, pp. 315-319, 2018

Authors: Hébert, Luc J. | Vial, Christophe | Hogrel, Jean-Yves | Puymirat, Jack

Article Type: Research Article

Abstract: Background: In Myotonic Dystrophy type 1 (DM1) patients, ankle muscles are affected early and this impairment is reported to be a good biological marker for longitudinal studies. Objective: To characterize the ankle dorsiflexion (DF) and eversion (EV) maximal isometric muscle strength changes in adult DM1 patients over 5 years using a standardized handheld dynamometer protocol and the Myoankle method, compare the changes measured with both methods and to the standard error of measurement, and verify the relationship between ankle muscle strength and gait performance. Methods: The maximal isometric muscle strength of ankle DF and EV in …DM1 patients from Quebec and Lyon was assessed at baseline, 18, 36 and 60 months using a handheld dynamometer (HHD) protocol and the MyoAnkle method. Results: There was a decrease of torque in DF/EV of 36.0% /31.3% and 27.7% /35.5% for the Quebec and Lyon cohorts respectively (p ≤0.01), but not in a linear way. In most cases (82.5%), the changes observed were greater than the standard error of measurement. DF torque measures taken by the two methods (HHD and MyoAnkle) were highly correlated (rp = 0.97–0.98, p < 0.001). Conclusion: Muscle strength ankle impairments are clinically meaningful in DM1 and can be accurately monitored using quantitative testing to measure the efficacy of therapeutic trials. Show more

Keywords: Muscle strength, myotonic dystrophy, muscle strength dynamometer, multicenter studies

DOI: 10.3233/JND-180311

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 3, pp. 321-330, 2018

Authors: Zapata-Aldana, Eugenio | Ceballos-Sáenz, Delia | Hicks, Rhiannon | Campbell, Craig

Article Type: Research Article

Abstract: Background: Congenital myotonic dystrophy (CDM) is the neonatal onset and most severe presentation of Myotonic Dystrophy type 1. Since it first description, perinatal complications have been detailed including prolonged hospital stay, respiratory and feeding therapy during the neonatal period, although long-term complications are less documented. Objective: Present a prospective cohort of CDM and compare it to the literature of other CDM case series, to adequately describe and contrast the prenatal, neonatal and infancy features of CDM. Methods: A 5-year cohort of CDM eligible cases was conducted via the Canadian Pediatric Surveillance Program. 38 patients met the …inclusion criteria. Comparison to other CDM case series published in the literature between 1992 and 2016 about perinatal and infancy morbidity. Result: From a total of 118 cases, the most frequent features were Polyhydramnios (58%), feeding therapy (77%), intubation and ventilation (58%); neonatal death was reported in 16% of the cases; the most frequent long-term morbidity were respiratory tract infections. Conclusions: We performed a detailed description of the main perinatal features of CDM and precise documentation of the mortality and morbidity during the first five years of life. This is an essential step in the knowledge of the natural history of CDM. Show more

Keywords: Congenital myotonic dystrophy, myotonic dystrophy type 1, DM1, DMPK, polyhydramnios, neonatal hypotonia, ventilation therapy

DOI: 10.3233/JND-170277

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 3, pp. 331-340, 2018

Authors: Jones, Kelly M. | O’Grady, Gina | Rodrigues, Miriam J. | Ranta, Anna | Roxburgh, Richard H. | Love, Donald R. | Theadom, Alice | on behalf of the MD-PREV study group

Article Type: Research Article

Abstract: Background: Genetic muscle disorders, including muscular dystrophies, congenital myopathies, and ion channel muscle diseases can be associated with significant disability. Objective: This study aimed to explore child and parent perspectives of the impact of living with a genetic muscle disorder. Methods: Eighty-three children (<16 years) with a clinical or molecular diagnosis were identified as part of a national prevalence study. Parents’ experiences and needs were assessed using a study-specific questionnaire. Additional outcome measures included parent and child self-report versions of the Behavior Assessment System for Children and the Pediatric Quality of Life Inventory. Parents also completed …the Hospital Anxiety and Depression Scale and Activlim. Results: Sixty-four percent of families had a combined annual household income below $60,000 NZD ($43,650 USD), being less than the national median income of $73,000 NZD ($53,112 USD). Parents reported needing more support than they were currently receiving (40%), particularly with household chores (23%) and transportation (17%). Few parents (13%) or children (4%) reported significant child behavioral difficulties. Risks of impaired quality of life were high (parent proxy 71%, child report 70%), and associated with co-morbid health conditions (p = 0.008), functional status (p = 0.001), wheelchair use (p = 0.001) and mechanical ventilation (p = 0.01). Conclusions: Findings are relevant to those involved in the care and support of children, and their families, who are impacted by genetic muscle disorders. Targeted guidelines are required to inform the provision of services, alongside promotion of existing community services to improve access to financial support, and assistance with day-to-day functioning. Future research should examine intervention and treatment options aimed at maximising affected children’s quality of life. Show more

Keywords: Neuromuscular diseases, muscular diseases, quality of life, child behavior

DOI: 10.3233/JND-170287

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 3, pp. 341-352, 2018

Authors: Kouwenberg, C.V. | Voermans, N.C. | Quinlivan, R. | van den Engel-Hoek, L.

Article Type: Research Article

Abstract: Background: Exertional myalgia and cramps of the limb and trunk muscles are typical in McArdle disease, but mastication and oral motor limitations have not been systematically investigated before. Objective: Determine the reported prevalence and characteristics of limitations on oral motor activities, mastication, swallowing, and other oral motor activities in patients with McArdle disease. Methods: An observational study was carried out in 28 patients using a standardised questionnaire on mastication and oral motor function. Results: 57% of the participants reported difficulties with mastication. Muscle cramps during mastication occurred in 57% of the patients. A feeling …that food remains in the throat occurred in 32%. Adaptations during mastication were needed in 42% of the patients. Mastication difficulties, muscle cramps during mastication and mastication adjustments were inversely correlated with age (r2  = – 0.445, p  < 0.05; r2  = – 0.509, p  < 0.01; r2  = – 0.456, p  < 0.05). Feeling of food remaining in throat, cramps during mastication and during other oral motor muscle activities, were correlated with disease severity (r2  = 0.476, p  < 0.01; r2  = 0.463, p  < 0.01; r2  = 0.461, p  < 0.01; r2  = 0.432, p  < 0.05). Conclusions: In short, reported mastication difficulties are prevalent in people with McArdle disease, most frequently in younger people. Therefore, awareness of mastication and oral motor problems is required. Show more

Keywords: McArdle disease, glycogen storage disease type V, mastication, oral motor function

DOI: 10.3233/JND-180320

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 3, pp. 353-357, 2018

Authors: Heutinck, Lotte | Jansen, Merel | van den Elzen, Yolanda | van der Pijl, Dick | de Groot, Imelda J.M.

Article Type: Research Article

Abstract: Background: In boys with Duchenne muscular dystrophy (DMD), loss of upper limb function becomes more evident after the onset of wheelchair-dependency, because of the inability to lift the arms against gravity. With an increasing population of older wheelchair-dependent boys with DMD it is worthwhile to know whether training can delay the loss of upper limb functions. Dynamic arm supports may enable boys with impaired arm function to train their muscles without becoming exhausted by providing external mechanical compensation for muscle weakness. Objective: This study investigated the effect of gravity-compensated 3D-training for the arms on the functional abilities in …boys with DMD. Methods: An explorative RCT was conducted among boys with DMD with impaired arm function (n = 16). Boys in the intervention group (n = 7) trained their arms by playing virtual reality games while using dynamic arm support during 20 weeks. The primary endpoint was the difference in change in Performance of the Upper Limb (PUL) score between the intervention and control group (n = 9) after 20 weeks. Secondary outcome measures were at the different ICF-CY levels. Results: No significant group differences were found for the PUL. Elbow range of motion (p = 0.018) and extension strength (p = 0.038) improved in the intervention group and worsened in the control group. Conclusions: Although this study did not show a significant effect of training on the primary outcome measure, there are indications that training may decline the loss of range of motion and strength. This may prolong the functional abilities on long-term. Trial registration: Netherlands Trial Register 3857. Show more

Keywords: Duchenne muscular dystrophy, neuromuscular diseases, training, exercise, upper limb, dynamic arm support

DOI: 10.3233/JND-180307

Citation: Journal of Neuromuscular Diseases, vol. 5, no. 3, pp. 359-372, 2018