Journal of Neuromuscular Diseases - Volume 3, issue 1

Authors: Carlier, Pierre G. | Marty, Benjamin | Scheidegger, Olivier | Loureiro de Sousa, Paulo | Baudin, Pierre-Yves | Snezhko, Eduard | Vlodavets, Dmitry

Article Type: Review Article

Abstract: Recent years have seen tremendous progress towards therapy of many previously incurable neuromuscular diseases. This new context has acted as a driving force for the development of novel non-invasive outcome measures. These can be organized in three main categories: functional tools, fluid biomarkers and imagery. In the latest category, nuclear magnetic resonance imaging (NMRI) offers a considerable range of possibilities for the characterization of skeletal muscle composition, function and metabolism. Nowadays, three NMR outcome measures are frequently integrated in clinical research protocols. They are: 1/ the muscle cross sectional area or volume, 2/ the percentage of intramuscular fat and 3/ …the muscle water T2, which quantity muscle trophicity, chronic fatty degenerative changes and oedema (or more broadly, “disease activity”), respectively. A fourth biomarker, the contractile tissue volume is easily derived from the first two ones. The fat fraction maps most often acquired with Dixon sequences have proven their capability to detect small changes in muscle composition and have repeatedly shown superior sensitivity over standard functional evaluation. This outcome measure will more than likely be the first of the series to be validated as an endpoint by regulatory agencies. The versatility of contrast generated by NMR has opened many additional possibilities for characterization of the skeletal muscle and will result in the proposal of more NMR biomarkers. Ultra-short TE (UTE) sequences, late gadolinium enhancement and NMR elastography are being investigated as candidates to evaluate skeletal muscle interstitial fibrosis. Many options exist to measure muscle perfusion and oxygenation by NMR. Diffusion NMR as well as texture analysis algorithms could generate complementary information on muscle organization at microscopic and mesoscopic scales, respectively. 31 P NMR spectroscopy is the reference technique to assess muscle energetics non-invasively during and after exercise. In dystrophic muscle, 31 P NMR spectrum at rest is profoundly perturbed, and several resonances inform on cell membrane integrity. Considerable efforts are being directed towards acceleration of image acquisitions using a variety of approaches, from the extraction of fat content and water T2 maps from one single acquisition to partial matrices acquisition schemes. Spectacular decreases in examination time are expected in the near future. They will reinforce the attractiveness of NMR outcome measures and will further facilitate their integration in clinical research trials. Show more

DOI: 10.3233/JND-160145

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 1, pp. 1-28, 2016

Authors: Rodrigues, Merryl | Echigoya, Yusuke | Fukada, So-ichiro | Yokota, Toshifumi

Article Type: Review Article

Abstract: Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscle degeneration. Mutations in the DMD gene result in the absence of dystrophin, a protein required for muscle strength and stability. Currently, there is no cure for DMD. Since murine models are relatively easy to genetically manipulate, cost effective, and easily reproducible due to their short generation time, they have helped to elucidate the pathobiology of dystrophin deficiency and to assess therapies for treating DMD. Recently, several murine models have been developed by our group and others to be more representative of the human DMD mutation …types and phenotypes. For instance, mdx mice on a DBA/2 genetic background, developed by Fukada et al., have lower regenerative capacity and exhibit very severe phenotype. Cmah -deficient mdx mice display an accelerated disease onset and severe cardiac phenotype due to differences in glycosylation between humans and mice. Other novel murine models include mdx52 , which harbors a deletion mutation in exon 52, a hot spot region in humans, and dystrophin/utrophin double-deficient (dko ), which displays a severe dystrophic phenotype due the absence of utrophin, a dystrophin homolog. This paper reviews the pathological manifestations and recent therapeutic developments in murine models of DMD such as standard mdx (C57BL/10), mdx on C57BL/6 background (C57BL/6-mdx ), mdx52 , dystrophin/utrophin double-deficient (dko ), mdx β geo , Dmd-null , humanized DMD (hDMD ), mdx on DBA/2 background (DBA/2-mdx ), Cmah-mdx , and mdx/mTRKO murine models. Show more

Keywords: Duchenne muscular dystrophy (DMD), exon skipping, mdx, mdx52, hDMD, dko, C57BL/6-mdx, DBA/2-mdx, Cmah-mdx, Dmd-null

DOI: 10.3233/JND-150113

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 1, pp. 29-48, 2016

Authors: Argov, Zohar | Caraco, Yoseph | Lau, Heather | Pestronk, Alan | Shieh, Perry B. | Skrinar, Alison | Koutsoukos, Tony | Ahmed, Ruhi | Martinisi, Julia | Kakkis, Emil

Article Type: Research Article

Abstract: Background: GNE Myopathy (GNEM) is a progressive adult-onset myopathy likely caused by deficiency of sialic acid (SA) biosynthesis. Objective: Evaluate the safety and efficacy of SA (delivered by aceneuramic acid extended-release [Ace-ER]) as treatment for GNEM. Methods: A Phase 2, randomized, double-blind, placebo-controlled study evaluating Ace-ER 3 g/day or 6 g/day versus placebo was conducted in GNEM subjects (n  = 47). After the first 24 weeks, placebo subjects crossed over to 3 g/day or 6 g/day for 24 additional weeks (dose pre-assigned during initial randomization). Assessments included serum SA, muscle strength by dynamometry, functional assessments, clinician- and patient-reported outcomes, and …safety. Results: Dose-dependent increases in serum SA levels were observed. Supplementation with Ace-ER resulted in maintenance of muscle strength in an upper extremity composite (UEC) score at 6 g/day compared with placebo at Week 24 (LS mean difference +2.33 kg, p  = 0.040), and larger in a pre-specified subgroup able to walk ≥200 m at Screening (+3.10 kg, p  = 0.040). After cross-over, a combined 6 g/day group showed significantly better UEC strength than a combined 3 g/day group (+3.46 kg, p  = 0.0031). A similar dose-dependent response was demonstrated within the lower extremity composite score, but was not significant (+1.06 kg, p  = 0.61). The GNEM-Functional Activity Scale demonstrated a trend improvement in UE function and mobility in a combined 6 g/day group compared with a combined 3 g/day group. Patients receiving Ace-ER tablets had predominantly mild-to-moderate AEs and no serious adverse events. Conclusions: This is the first clinical study to provide evidence that supplementation with SA delivered by Ace-ER may stabilize muscle strength in individuals with GNEM and initiating treatment earlier in the disease course may lead to better outcomes. Show more

Keywords: Sialic acid, hereditary inclusion body myopathy, GNE Myopathy, distal myopathy with rimmed vacuoles, myopathy therapy

DOI: 10.3233/JND-159900

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 1, pp. 49-66, 2016

Authors: Price, Mark A. | Barghout, Victoria | Benveniste, Olivier | Christopher-Stine, Lisa | Corbett, Alastair | de Visser, Marianne | Hilton-Jones, David | Kissel, John T. | Lloyd, Thomas E. | Lundberg, Ingrid E. | Mastaglia, Francis | Mozaffar, Tahseen | Needham, Merrilee | Schmidt, Jens | Sivakumar, Kumaraswamy | DeMuro, Carla | Tseng, Brian S.

Article Type: Research Article

Abstract: Background: There is a paucity of data on mortality and causes of death (CoDs) in patients with sporadic inclusion body myositis (sIBM), a rare, progressive, degenerative, inflammatory myopathy that typically affects those aged over 50 years. Objective: Based on patient records and expertise of clinical specialists, this study used questionnaires to evaluate physicians’ views on clinical characteristics of sIBM that may impact on premature mortality and CoDs in these patients. Methods: Thirteen physicians from seven countries completed two questionnaires online between December 20, 2012 and January 15, 2013. Responses to the first questionnaire were collated …and presented in the second questionnaire to seek elaboration and identify consensus. Results: All 13 physicians completed both questionnaires, providing responses based on 585 living and 149 deceased patients under their care. Patients were reported to have experienced dysphagia (60.2%) and injurious falls (44.3%) during their disease. Over half of physicians reported that a subset of their patients with sIBM had a shortened lifespan (8/13), and agreed that bulbar dysfunction/dysphagia/oropharyngeal involvement (12/13), early-onset disease (8/13), severe symptoms (8/13), and falls (7/13) impacted lifespan. Factors related to sIBM were reported as CoDs in 40% of deceased patients. Oropharyngeal muscle dysfunction was ranked as the leading feature of sIBM that could contribute to death. The risk of premature mortality was higher than the age-matched comparison population. Conclusions: In the absence of data from traditional sources, this study suggests that features of sIBM may contribute to premature mortality and may be used to inform future studies. Show more

Keywords: Myositis, inclusion body, cause of death, mortality, deglutition disorder, neuromuscular disease, myositis, morbidity

DOI: 10.3233/JND-150138

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 1, pp. 67-75, 2016

Authors: Hulsker, Margriet | Verhaart, Ingrid | van Vliet, Laura | Aartsma-Rus, Annemieke | van Putten, Maaike

Article Type: Research Article

Abstract: Duchenne muscular dystrophy (DMD) is a progressive muscle–wasting disorder primarily affecting males. This disorder is caused by mutations in the DMD gene that abolish dystrophin protein function. Many therapeutic approaches for DMD aim at recovery of the dystrophin protein in muscle fibers of affected patients, rendering accurate dystrophin quantification important. Several methods have been reported to detect and quantify dystrophin restoration in preclinical and clinical trials. We here evaluated the applicability of dystrophin specific enzyme-linked immunosorbent assays (ELISA) and a TaqMan protein assay, benchmarking them against Western blotting analysis. Despite numerous optimization attempts, in our hands the background signals …in the ELISA and TaqMan protein assays were too high to allow dystrophin quantification. By contrast, the Western blot approach was able to detect dystrophin levels as low as 0.2% in a reproducible manner. We provide a Western blot protocol that allows sensitive and accurate dystrophin quantification in preclinical studies. Show more

Keywords: Duchenne muscular dystrophy, dystrophin, TaqMan protein assay, Trans-Blot Turbo transfer system, protein quantification

DOI: 10.3233/JND-150126

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 1, pp. 77-90, 2016

Authors: Posner, Andrew D. | Soslow, Jonathan H. | Burnette, W. Bryan | Bian, Aihua | Shintani, Ayumi | Sawyer, Douglas B. | Markham, Larry W.

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle and cardiac dysfunction. While skeletal muscle dysfunction precedes cardiomyopathy, the relationship between the progressive decline in skeletal and cardiac muscle function is unclear. This relationship is especially important given that the myocardial effects of many developing DMD therapies are largely unknown. Objective: Our objective was to assess the relationship between progression of skeletal muscle weakness and onset of cardiac dysfunction in DMD. Methods: A total of 77 DMD subjects treated at a single referral center were included. Demographic information, quantitative muscle testing (QMT), subjective …muscle strength, cardiac function, and current and retrospective medications were collected. A Spearman rank correlation was used to evaluate for an association between subjective strength and fractional shortening. The effects of total QMT and arm QMT on fractional shortening were examined in generalized least square with and without adjustments for age, ambulatory status, and duration of corticosteroids and cardiac specific medications. Results: We found a significant correlation between maintained subjective skeletal muscle arm and leg strength and maintained cardiac function as defined by fractional shortening (rho = 0.47, p  = 0.004 and rho = 0.48, p  = 0.003, respectively). We also found a significant association between QMT and fractional shortening among non-ambulatory DMD subjects (p  = 0.03), while this association was not significant in ambulatory subjects. Conclusions: Our findings allow us to conclude that in this population, there exists a significant relationship between skeletal muscle and cardiac function in non-ambulatory DMD patients. While this does not imply a causal relationship, a possible association between skeletal and cardiac muscle function suggests that researchers should carefully monitor cardiac function, even when the primary outcome measures are not cardiac in nature. Show more

Keywords: Duchenne muscular dystrophy, cardiac dysfunction, cardiomyopathy, skeletal muscle dysfunction, ambulation

DOI: 10.3233/JND-150132

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 1, pp. 91-99, 2016

Authors: van der Sluijs, B.M. | Raz, V. | Lammens, M. | van den Heuvel, L.P. | Voermans, N.C. | van Engelen, B.G.M.

Article Type: Research Article

Abstract: Background: Oculopharyngeal muscular dystrophy (OPMD) has long been characterized by a combination of bilateral ptosis and dysphagia and subsequent limb girdle weakness. The role of the typical intranuclear inclusion in the pathophysiology is unresolved. Objective: The aim of this study was to describe the clinical and histopathological features of oculopharyngeal muscular dystrophy (OPMD). We examined this in a Dutch cohort including presymptomatic Ala-expanded-PABPN1 carriers and late symptomatic patients. Methods: We performed a prospective, observational study in OPMD patients and adult children of genetically confirmed OPMD patients. The study includes a structured history, a detailed …neurological examination, muscle histology and biochemical analysis. Forty patients and 18 adult children participated in this study, among whom were six presymptomatic mutation carriers. One patient died during the study and had given permission to autopsy. Results: In addition to the characteristic OPMD symptoms including ptosis and dysphagia, other symptoms such as limb girdle and axial weakness, and external ophthalmoplegia were frequently observed. Intranuclear aggregates were observed in the biopsies of presymptomatic carriers. Biochemical analysis of the biopsies of the presymptomatic carriers showed no mitochondrial dysfunction. The autopsy showed that muscle weakness correlated with histopathological findings in five different muscles in an individual patient. Conclusions: The main findings of this nationwide study are the presence of intranuclear aggregates before clinical onset and the absence of mitochondrial changes in Ala-expanded-PABPN1 carriers. This indicates that the expression of Ala-expanded-PABPN1 causes the formation of nuclear aggregates before the onset of muscle weakness. Normal results of biochemical analysis in presymptomatic carriers suggest that possible mitochondrial dysfunction occurs later. Furthermore we confirmed that limb girdle weakness occurs frequently in Dutch OPMD patients. This study thus expands the OPMD research towards characterization of presymptomatic carriers. Show more

Keywords: Oculopharyngeal muscular dystrophy, nuclear aggregates, presymptomatic carrier, mitochondria

DOI: 10.3233/JND-150118

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 1, pp. 101-109, 2016

Authors: Garibaldi, Matteo | Böhm, Johann | Fattori, Fabiana | Koch, Catherine | Surace, Cecilia | Ottaviani, Pierfrancesco | Laschena, Francesco | Laporte, Jocelyn | Bertini, Enrico | Antonini, Giovanni | Romero, Norma B.

Article Type: Research Article

Abstract: We present the clinical, morphological and molecular data of an Italian family with centronuclear myopathy, carrying a novel pathogenic mutation of BIN1 gene in heterozygous state, consistent with autosomal dominant inheritance. The proband, a 56-years-old man suffered of lower limbs myalgia and slight CK elevation. Clinical examination revealed no muscle weakness, short stature, mild symmetric eyelid ptosis, scapular winging, ankle retraction and well-developed muscles. Muscle biopsy showed nuclear centralization and clustering, deep sarcolemmal invaginations and type 1 fibers hypotrophy. Muscle MRI revealed fatty infiltration of posterior legs compartments, lumbar paraspinal and serratus muscles. By sequencing BIN1 , we identified …a heterozygous pathogenic mutation [c.107C>A (p.A36E)], and we demonstrate that the mutation strongly impairs the membrane tubulation property of the protein. One affected sister with similar phenotype carried the same mutation. Our findings expand the clinical, morphological and genetic spectrum of the autosomal dominant CNM associated with BIN1 mutations. Show more

Keywords: Congenital myopathies, centronuclear myopathies (CNM), autosomal dominant BIN1 mutation, myalgias, CK elevation, late-onset

DOI: 10.3233/JND-150125

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 1, pp. 111-114, 2016

Authors: Butala, Brian N. | Kang, Audry | Guron, Jasmeen | Brandom, Barbara W.

Article Type: Research Article

Abstract: This case report describes a female with p.Lys4876Arg amino acid change in the ryanodine receptor type 1 (RYR1) and a sibling who died of malignant hyperthermia (MH) during anesthesia. After her diagnosis as MH susceptible, this patient was administered low-dose dantrolene daily for greater than 25 years for treatment of chronic muscle spasm and pain in her lower extremities and back limiting sleep. Her creatine phosphokinase (CPK) was as high as 2390 IU/L during labor and 900 IU at rest. With 25 mg dantrolene daily, muscle cramps were eliminated, and sleep was improved. Gait instability was noted with dantrolene in the …morning, but not when taken at bedtime. There was no evidence of liver injury. This case suggests that low dose dantrolene by mouth could be considered for the treatment of chronic muscle pain in individuals with MH susceptibility. Show more

Keywords: Skeletal muscle ryanodine receptor (RYR1) gene, malignant hyperthermia (MH) susceptibility, myalgia, dantrolene

DOI: 10.3233/JND-150130

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 1, pp. 115-119, 2016

Authors: Lanman, Tyler A. | Bakar, Dara | Badders, Nisha M. | Burke, Ailbhe | Kokkinis, Angela | Shrader, Joseph A. | Joe, Galen O. | Schindler, Alice B. | Bott, Laura C. | Harmison, George G. | Taylor, J. Paul | Fischbeck, Kenneth H. | Grunseich, Christopher

Article Type: Short Communication

Abstract: Spinal and bulbar muscular atrophy is caused by polyglutamine expansion in the androgen receptor. As an X-linked disease dependent on androgens, symptoms and findings are only fully manifest in males. Here we describe a 40-year-old male-to-female transgender SBMA patient who developed full disease manifestations despite undetectable levels of androgens. We used cell culture and animal models to show that spironolactone, the anti-androgen she had taken for 15 years, promotes nuclear localization and toxicity of the mutant protein, which may explain the disease manifestations in this patient.

Keywords: Motor neuron disease, bulbo-spinal atrophy, X-Linked, spironolactone, receptors, androgen

DOI: 10.3233/JND-150128

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 1, pp. 121-125, 2016