Journal of Neuromuscular Diseases - Volume 3, issue 4

Authors: Marty, Isabelle | Fauré, Julien

Article Type: Review Article

Abstract: During the complex series of events leading to muscle contraction, the initial electric signal coming from motor neurons is transformed into an increase in calcium concentration that triggers sliding of myofibrils. This process, referred to as excitation–contraction coupling, is reliant upon the calcium-release complex, which is restricted spatially to a sub-compartment of muscle cells (“the triad”) and regulated precisely. Any dysfunction in the calcium-release complex leads to muscle impairment and myopathy. Various causes can lead to alterations in excitation–contraction coupling and to muscle diseases. The latter are reviewed and classified into four categories: (i) mutation in a protein of the calcium-release complex; …(ii) alteration in triad structure; (iii) modification of regulation of channels; (iv) modification in calcium stores within the muscle. Current knowledge of the pathophysiologic mechanisms in each category is described and discussed. Show more

Keywords: RyR1, DHPR, triad, sarcoplasmic reticulum, calcium, congenital myopathies

DOI: 10.3233/JND-160172

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 443-453, 2016

Authors: Alameddine, Hala S. | Morgan, Jennifer E.

Article Type: Review Article

Abstract: In skeletal muscles, levels and activity of Matrix MetalloProteinases (MMPs) and Tissue Inhibitors of MetalloProteinases (TIMPs) have been involved in myoblast migration, fusion and various physiological and pathological remodeling situations including neuromuscular diseases. This has opened perspectives for the use of MMPs’ overexpression to improve the efficiency of cell therapy in muscular dystrophies and resolve fibrosis. Alternatively, inhibition of individual MMPs in animal models of muscular dystrophies has provided evidence of beneficial, dual or adverse effects on muscle morphology or function. We review here the role played by MMPs/TIMPs in skeletal muscle inflammation and fibrosis, two major hurdles that limit …the success of cell and gene therapy. We report and analyze the consequences of genetic or pharmacological modulation of MMP levels on the inflammation of skeletal muscles and their repair in light of experimental findings. We further discuss how the interplay between MMPs/TIMPs levels, cytokines/chemokines, growth factors and permanent low-grade inflammation favor cellular and molecular modifications resulting in fibrosis. Show more

Keywords: MMPs, TIMPs, skeletal muscle, diseases, inflammation, fibrosis

DOI: 10.3233/JND-160183

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 455-473, 2016

Authors: Ylikallio, Emil | Auranen, Mari | Mahjneh, Ibrahim | Lamminen, Antti | Kousi, Maria | Träskelin, Ann-Liz | Muurinen, Tiina | Löfberg, Mervi | Salmi, Tapani | Paetau, Anders | Lehesjoki, Anna-Elina | Piirilä, Päivi | Kiuru-Enari, Sari

Article Type: Research Article

Abstract: Background: Anoctaminopathies are muscle diseases caused by recessive mutations in the ANO5 gene. The effects of anoctaminopathy on oxidative capacity have not previously been studied in a controlled setting. Objective: To characterize oxidative capacity in a clinically and genetically well-defined series of patients with anoctaminopathy. Methods: We sequenced the ANO5 gene in 111 Finnish patients with suspected LGMD2. Patients with positive findings underwent close clinical examination, including electromyography, muscle MRI, and, in selected cases, muscle biopsy. Oxidative capacity was analyzed using spiroergometry and compared to age-matched healthy controls. Results: We characterized …12 newly identified and 2 previously identified patients with ANO5 mutations from 11 families. Our material was genetically homogeneous with most patients homozygous for the Finnish founder variant c.2272C>T (p.Arg758Cys). In one family, we found a novel p.Met470Arg variant compound heterozygous with p.Arg758Cys. Lower limb muscle MRI revealed progressive fatty degeneration of specific posterior compartment muscles. Patients’ spiroergometric profiles showed that anoctaminopathy significantly impaired oxidative capacity with increasing ventilation. Conclusions: Our findings support earlier reports that anoctaminopathy progresses slowly and demonstrate that the disease impairs the capacity for aerobic exercise. Show more

Keywords: Muscular dystrophies, limb-girdle, muscular diseases, inborn genetic diseases, aerobic exercise

DOI: 10.3233/JND-160186

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 475-485, 2016

Authors: Grotto, Sarah | Cuisset, Jean-Marie | Marret, Stéphane | Drunat, Séverine | Faure, Patricia | Audebert-Bellanger, Séverine | Desguerre, Isabelle | Flurin, Vincent | Grebille, Anne-Gaëlle | Guerrot, Anne-Marie | Journel, Hubert | Morin, Gilles | Plessis, Ghislaine | Renolleau, Sylvain | Roume, Joëlle | Simon-Bouy, Brigitte | Touraine, Renaud | Willems, Marjolaine | Frébourg, Thierry | Verspyck, Eric | Saugier-Veber, Pascale

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1 /1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. Objective: The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. Methods: SMA patients with the 0SMN1 /1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database. …Results: Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. Conclusion: Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis. Show more

Keywords: Spinal muscular atrophy, human SMN2 protein, prenatal ultrasonography, congenital heart defect, fetal akinesia deformation sequence

DOI: 10.3233/JND-160177

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 487-495, 2016

Authors: Ziat, Esma | Mamchaoui, Kamel | Beuvin, Maud | Nelson, Isabelle | Azibani, Feriel | Spuler, Simone | Bonne, Gisèle | Bertrand, Anne T.

Article Type: Research Article

Abstract: Background: Emery-Dreifuss muscular dystrophy (EDMD) is associated with mutations in EMD and LMNA genes, encoding for the nuclear envelope proteins emerin and lamin A/C, indicating that EDMD is a nuclear envelope disease. We recently reported mutations in FHL1 gene in X-linked EDMD. FHL1 encodes FHL1A, and the two minor isoforms FHL1B and FHL1C. So far, none have been described at the nuclear envelope. Objective: To gain insight into the pathophysiology of EDMD, we focused our attention on the poorly characterized FHL1B isoform. Methods: The amount and the localisation of FHL1B were evaluated …in control and diseased human primary myoblasts using immunofluorescence and western blotting. Results: We found that in addition to a cytoplasmic localization, this isoform strongly accumulated at the nuclear envelope of primary human myoblasts, like but independently of lamin A/C and emerin. During myoblast differentiation, we observed a major reduction of FHL1B protein expression, especially in the nucleus. Interestingly, we found elevated FHL1B expression level in myoblasts from an FHL1 -related EDMD patient where the FHL1 mutation only affects FHL1A, as well as in myoblasts from an LMNA -related EDMD patient. Conclusions: Altogether, the specific localization of FHL1B and its modulation in disease-patient’s myoblasts confirmed FHL1 -related EDMD as a nuclear envelope disease. Show more

Keywords: FHL1B, emerin, lamin A/C, nuclear envelope, Emery-Dreifuss muscular dystrophy

DOI: 10.3233/JND-160169

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 497-510, 2016

Authors: Edwards, Jonathan D. | Butchbach, Matthew E. R.

Article Type: Research Article

Abstract: Spinal muscular atrophy (SMA) is an early-onset motor neuron disease that leads to loss of muscle function. Butyrate (BA)-based compounds markedly improve the survival and motor phenotype of SMA mice. In this study, we examine the protective effects of the BA prodrug pivaloyloxymethyl butyrate (AN9) on the survival of SMNΔ 7 SMA mice. Oral administration of AN9 beginning at PND04 almost doubled the average lifespan of SMNΔ 7 SMA mice. AN9 treatment also increased the growth rate of SMNΔ 7 SMA mice when compared to vehicle-treated SMNΔ 7 SMA mice. In conclusion, BA prodrugs like AN9 have ameliorative effects on …SMNΔ 7 SMA mice. Show more

Keywords: Motor neuron disease, spinal muscular atrophy, preclinical drug trial, neonatal mouse, AN9

DOI: 10.3233/JND-160187

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 511-515, 2016

Authors: Vry, Julia | Gramsch, Kathrin | Rodger, Sunil | Thompson, Rachel | Steffensen, Birgit F. | Rahbek, Jes | Doerken, Sam | Tassoni, Adrian | Beytía, María de los Angeles | Guergueltcheva, Velina | Chamova, Teodora | Tournev, Ivailo | Kostera-Pruszczyk, Anna | Kaminska, Anna | Lusakowska, Anna | Mrazova, Lenka | Pavlovska, Lenka | Strenkova, Jana | Vondráček, Petr | Garami, Marta | Karcagi, Veronika | Herczegfalvi, Ágnes | Bushby, Katherine | Lochmüller, Hanns | Kirschner, Janbernd

Article Type: Research Article

Abstract: Background: Publication of comprehensive clinical care guidelines for Duchenne muscular dystrophy (DMD) in 2010 was a milestone for DMD patient management. Our CARE-NMD survey investigates the neuromuscular, medical, and psychosocial care of DMD patients in Europe, and compares it to the guidelines. Methods: A cross-sectional survey of 1677 patients contacted via the TREAT-NMD patient registries was conducted using self-report questionnaires in seven European countries. Results: Survey respondents were 861 children and 201 adults. Data describe a European DMD population with mean age of 13.0 years (range 0.8–46.2) of whom 53% had lost ambulation (at 10.3 …years of age, median). Corticosteroid medication raised the median age for ambulatory loss from 10.1 years in patients never medicated to 11.4 years in patients who received steroids (p  < 0.0001). The majority of patients reported receiving care in line with guidelines, although we identified significant differences between countries and important shortcomings in prevention and treatment. Summarised, 35% of patients aged≥ nine years received no corticosteroid medication, 24% of all patients received no regular physiotherapy, echocardiograms were not performed regularly in 22% of patients, pulmonary function was not regularly assessed in 71% of non-ambulatory patients. Patients with regular follow-up by neuromuscular specialists were more likely to receive care according to guidelines, were better satisfied, and experienced shorter unplanned hospitalization periods. Show more

Keywords: Duchenne muscular dystrophy, standards of care, corticosteroid treatment, functional status

DOI: 10.3233/JND-160185

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 517-527, 2016

Authors: West, Sophie D. | Lochmüller, Hanns | Hughes, Joan | Atalaia, Antonio | Marini-Bettolo, Chiara | Baudouin, Simon V. | Anderson, Kirstie N.

Article Type: Research Article

Abstract: Objective: We conducted prospective assessments in people with myotonic dystrophy type 1 (DM1) with daytime sleepiness, provided targeted therapies and assessed response. Methods: Patients had overnight sleep assessments. Treatment with continuous positive airway pressure (CPAP) for OSA, non-invasive ventilation (NIV) for respiratory failure, modafinil for excessive daytime sleepiness were commenced. Results: 120 people were studied: mean age 46.9 years (SD 13.2, range 18–74), body mass index 27.9 kg/m2 (7.2, 16–53), Epworth Sleepiness Score (ESS) 13.1 (4.7, 2–24). Twenty one people (18% of group) had OSA: mean age 49.6, BMI 31.1, ESS 14.3, ODI 22, pO2 …11.3, pCO2 5.4. All were offered CPAP; seven continued with benefit but 14 had intolerance or no benefit. Thirty-three people (27%) had respiratory failure and abnormal sleep study: mean age 51.5, BMI 31.3, ESS 13.9, ODI 22.9, pO2 8.7, pCO2 6.8. All were offered NIV; 12 continued with benefit but 18 had intolerance or no benefit, 1 died and 2 declined commencement. Thirty-six people (30%) had predominantly sleepiness: mean age 44.8, BMI 24.6, ESS 14.1, ODI 9.2, pO2 11.7, pCO2 5.4. All were offered modafinil; 12 continued this with benefit but 10 had intolerance or no benefit, one was unkeen to start, 11 did not attend further clinic and two had other sleep disorders. Comparing means of treatment responders to non-responders showed no significant difference in any variable, except ESS: 15.9 vs.11.9 respectively, p  < 0.0001. Conclusions: Causes of sleepiness are variable in DM1, but include obstructive sleep apnoea, respiratory failure and sleepiness with a normal sleep study; 29% of this studied cohort benefited from targeted sleep therapies. Show more

Keywords: Assisted ventilation, respiratory muscles, respiratory monitoring, sleep apnoea

DOI: 10.3233/JND-160191

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 529-537, 2016

Authors: van Groenestijn, Annerieke C. | Verschuren, Olaf | Schröder, Carin D. | van den Berg, Leonard H. | Visser-Meily, Johanna M.A.

Article Type: Research Article

Abstract: Background: Ambulatory patients with Amyotrophic Lateral Sclerosis (ALS) show a decreased aerobic capacity which may hamper the ability to perform activities of daily living. A standardized measure, however, for assessing aerobic capacity in patients with ALS during the disease course, is lacking. Objective: To examine the feasibility of the Åstrand-Ryhming (ÅR) test protocol longitudinally in ambulatory patients with amyotrophic lateral sclerosis (ALS). Methods: Seven ambulatory male patients with spinal ALS onset were assessed at baseline and at 4, 7 and 10 months’ follow-up. Feasibility of the ÅR test protocol was analysed using percentage of: a) …completed ÅR tests; b) achieved steady states; and c) predefined heart rates. Results: Test completion decreased from 7/7 at baseline to 10/21 at follow-up due to ALS-related symptoms as fatigue, muscle weakness and cramps. Steady states and predefined heart rates were achieved in 12/17 and 17/17 of the completed tests, respectively. Overall, the feasibility of the ÅR test protocol declines from 5/7 at baseline to 7/21 at follow-up. Conclusions: The results suggest that changes in aerobic capacity in ambulatory patients with ALS could not be successfully monitored due to a diminished feasibility of the ÅR test protocol. Show more

Keywords: Amyotrophic Lateral Sclerosis, exercise test, physical fitness, aerobic capacity, outcome measure

DOI: 10.3233/JND-160182

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 539-544, 2016

Article Type: Other

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 4, pp. 545-550, 2016