Journal of Neuromuscular Diseases - Volume 6, issue 2

Authors: Kanagawa, Motoi

Article Type: Review Article

Abstract: Glycosylation is a major form of post-translational modification and plays various important roles in organisms by modifying proteins or lipids, which generates functional variability and can increase their stability. Because of the physiological importance of glycosylation, defects in genes encoding proteins involved in glycosylation or glycan degradation are sometimes associated with human diseases. A number of genetic neuromuscular diseases are caused by abnormal glycan modification or degeneration. Heterogeneous and complex modification machinery, and difficulties in structural and functional analysis of glycans have impeded the understanding of how glycosylation contributes to pathology. However, recent rapid advances in glycan and genetic analyses, …as well as accumulating genetic and clinical information have greatly contributed to identifying glycan structures and modification enzymes, which has led to breakthroughs in the understanding of the molecular pathogenesis of various diseases and the possible development of therapeutic strategies. For example, studies on the relationship between glycosylation and muscular dystrophy in the last two decades have significantly impacted the fields of glycobiology and neuromyology. In this review, the basis of glycan structure and biosynthesis will be briefly explained, and then molecular pathogenesis and therapeutic concepts related to neuromuscular diseases will be introduced from the point of view of the life cycle of a glycan molecule. Show more

Keywords: Glycosylation, muscular dystrophy, neuromuscular disease, therapeutic strategy

DOI: 10.3233/JND-180369

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 175-187, 2019

Authors: Kapoor, Mahima | Rossor, Alexander M. | Laura, Matilde | Reilly, Mary M.

Article Type: Review Article

Abstract: Systemic amyloidosis can be hereditary or acquired with autosomal dominant mutations in the transthyretin gene (TTR ) being the most common cause of hereditary amyloidosis. ATTRm amyloidosis is a multi-system disorder with cardiovascular, peripheral and autonomic nerve involvement that can be difficult to diagnose due to phenotypic heterogeneity. This review will focus on the neuropathic manifestations of ATTRm, the genotype-phenotype variability, the diagnostic approach and the recent therapeutic advances in this disabling condition.

Keywords: Amyloid, TTR, polyneuropathy, treatment, gene-silencing

DOI: 10.3233/JND-180371

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 189-199, 2019

Authors: Tao, Feifei | Beecham, Gary W. | Rebelo, Adriana P. | Blanton, Susan H. | Moran, John J. | Lopez-Anido, Camila | Svaren, John | Abreu, Lisa | Rizzo, Devon | Kirk, Callyn A. | Wu, Xingyao | Feely, Shawna | Verhamme, Camiel | Saporta, Mario A. | Herrmann, David N. | Day, John W. | Sumner, Charlotte J. | Lloyd, Thomas E. | Li, Jun | Yum, Sabrina W. | Taroni, Franco | Baas, Frank | Choi, Byung-Ok | Pareyson, Davide | Scherer, Steven S. | Reilly, Mary M. | Shy, Michael E. | Züchner, Stephan | the Inherited Neuropathy Consortium

Article Type: Research Article

Abstract: Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5–Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability. Objective: We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A. Methods: We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed …in this study. Results: The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P  = 9.91×10–7 , odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P  = 2.08×10–7 , odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P  = 1.63×10–7 , odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P  = 1.14×10–7 , beta = 3.014). Conclusions: While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A. Show more

Keywords: Charcot-marie-tooth disease, type 1a; genome-wide association study; modifier gene; single nucleotide polymorphism

DOI: 10.3233/JND-190377

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 201-211, 2019

Authors: Khan, Navid | Eliopoulos, Helen | Han, Lixin | Kinane, T. Bernard | Lowes, Linda P. | Mendell, Jerry R. | Gordish-Dressman, Heather | Henricson, Erik K. | McDonald, Craig M. | on behalf of the Eteplirsen Investigators and the CINRG DNHS Investigators

Article Type: Research Article

Abstract: Background: Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. Objective: Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. Methods: Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is …evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n  = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n  = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n  = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n  = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change. Results: FVC% p annual change was greater for CINRG DNHS Exon 51 controls (– 6.00) versus patients in studies 201/202, study 204, and study 301 (– 2.19, P  < 0.001; – 3.66, P 0.004; and – 3.79, P 0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (– 5.67) and All CINRG DNHS (– 5.56) cohorts (P  < 0.05, all comparisons). Conclusions: Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls. Show more

Keywords: Dystrophin, Exondys 51, forced expiratory volume, vital capacity

DOI: 10.3233/JND-180351

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 213-225, 2019

Authors: Yong, Jonathan | Moffett, Megan | Lucas, Sam

Article Type: Short Communication

Abstract: Nusinersen is the first disease-modifying therapy approved for the treatment of spinal muscular atrophy (SMA), a rare genetic disorder characterized by severe progressive muscular atrophy and weakness. An expanded access program (EAP) provides investigational treatment to patients without other treatment options. An EAP providing nusinersen treatment to individuals with the most severe form of SMA, infantile-onset SMA (consistent with SMA Type I), has enrolled over 800 participants as of September 2018, making it one of the largest in rare disease history. The successes, challenges experienced and opportunities for future consideration during the implementation of the nusinersen EAP are discussed.

Keywords: Compassionate use, spinal muscular atrophy, expanded access trial, rare disease, antisense oligodeoxyribonucleotides, drug therapy, orphan drug, antisense oligonucleotides, neuromuscular disease

DOI: 10.3233/JND-190387

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 227-231, 2019

Authors: Roussel, Marie-Pier | Hébert, Luc J. | Duchesne, Elise

Article Type: Research Article

Abstract: Background: Myotonic dystrophy type 1 (DM1) is the most prevalent degenerative neuromuscular disease in adults. Knee extensor (KE) maximal strength loss is a strong indicator of physical limitations in DM1. A reliable, precise and accessible maximal strength evaluation method needs to be validated for this slowly progressive disease. Objective: This paper aims to assess the intra-rater reliability, the standard error of measurement (SEM), the minimal detectable change (MDC), and the concurrent validity of quantified muscle testing (QMT) using a handheld dynamometer with a gold standard: the Biodex isokinetic device. Methods: Nineteen men with the adult form …of DM1 participated in this study by attending 2 visits spaced by one week. The evaluation of KE muscle strength with QMT was completed on the first visit and the same QMT evaluation in addition to the maximal muscle strength evaluation using an isokinetic device were performed on the second visit. Results: The intra-rater reliability was excellent with an intraclass correlation coefficient (ICC) of 0.98 (0.96–0.99 : 95% confidence interval). SEM and MDC values were 1.05 Nm and 2.92 Nm, respectively. Concurrent validity of QMT of KE muscle group with the Biodex was also excellent with a Spearman’s correlation of ρ = 0.98. Conclusions: The excellent concurrent validity and intra-rater reliability, and the small SEM and MDC of the QMT make this test a method of choice, in either a clinical or research setting, to precisely evaluate muscle strength impairments of the KE in men with DM1. Show more

Keywords: Myotonic dystrophy type 1, muscle strength, quantified muscle testing, isokinetic device, intra-rater reliability, concurrent validity

DOI: 10.3233/JND-190388

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 233-240, 2019

Authors: Westra, Dineke | Schouten, Meyke I. | Stunnenberg, Bas C. | Kusters, Benno | Saris, Christiaan G.J. | Erasmus, Corrie E. | van Engelen, Baziel G. | Bulk, Saskia | Verschuuren-Bemelmans, Corien C. | Gerkes, E.H. | de Geus, Christa | van der Zwaag, P.A. | Chan, Sophelia | Chung, Brian | Barge-Schaapveld, Daniela Q.C.M. | Kriek, Marjolein | Sznajer, Yves | van Spaendonck-Zwarts, Karin | van der Kooi, Anneke J. | Krause, Amanda | Schönewolf-Greulich, Bitten | de Die-Smulders, Christine | Sallevelt, Suzanne C.E.H. | Krapels, Ingrid P.C. | Rasmussen, Magnhild | Maystadt, Isabelle | Kievit, Anneke J.A. | Witting, Nanna | Pennings, Maartje | Meijer, Rowdy | Gillissen, Christian | Kamsteeg, Erik-Jan | Voermans, Nicol C.

Article Type: Research Article

Abstract: Background: Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous. Accurate molecular genetic diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and allows potential therapeutic trials. Objective: To establish the clinical utility of panel-based whole exome sequencing (WES) in NMDs in a population with children and adults with various neuromuscular symptoms. Methods: Clinical exome sequencing, followed by diagnostic interpretation of variants in genes associated with NMDs, was performed in a cohort of 396 patients suspected of having a genetic cause with a variable age of onset, neuromuscular phenotype, and inheritance pattern. Many …had previously undergone targeted gene testing without results. Results: Disease-causing variants were identified in 75/396 patients (19%), with variants in the three COL6 -genes (COL6A1, COL6A2 and COL6A3 ) as the most common cause of the identified muscle disorder, followed by variants in the RYR1 gene. Together, these four genes account for almost 25% of cases in whom a definite genetic cause was identified. Furthermore, likely pathogenic variants and/or variants of uncertain significance were identified in 95 of the patients (24%), in whom functional and/or segregation analysis should be used to confirm or reject the pathogenicity. In 18% of the cases with a disease-causing variant of which we received additional clinical information, we identified a genetic cause in genes of which the associated phenotypes did not match that of the patients. Hence, the advantage of panel-based WES is its unbiased approach. Conclusion: Whole exome sequencing, followed by filtering for NMD genes, offers an unbiased approach for the genetic diagnostics of NMD patients. This approach could be used as a first-tier test in neuromuscular disorders with a high suspicion of a genetic cause. With uncertain results, functional testing and segregation analysis are needed to complete the evidence. Show more

Keywords: Neuromuscular diseases, exome sequencing, genetics, neurology, myopathies

DOI: 10.3233/JND-180376

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 241-258, 2019

Authors: Lin, Hsin-Pin | Ho, Kwo Wei David | Jerath, Nivedita U.

Article Type: Case Report

Abstract: Mutations in MFN2 cause a range of Charcot–Marie–Tooth disease (CMT) phenotypes with different inheritance patterns and underlying pathogenic mechanisms. Recently, a family with a dominantly inherited CMT harboring c.2222T>G (p.Leu741Trp) mutation in MFN2 has been reported for the first time. Here, we report a second family also with a dominantly inherited CMT harboring the same mutation, thereby confirming the pathogenicity of this mutation. Interestingly, the disease onset of this second family is much later than the previously reported cases.

Keywords: Neuromuscular diseases, hereditary sensory and motor neuropathy, Charcot-Marie-Tooth disease, type 2A, MFN2 protein, human, genetic variation, pathogenicity, phenotype

DOI: 10.3233/JND-190384

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 259-261, 2019

Authors: Wittenbach, Jason D. | Cocanougher, Benjamin T. | Yun, Pomi | Foley, A. Reghan | Bönnemann, Carsten G.

Article Type: Short Communication

Abstract: Muscle strength testing is routine in clinical practice. Here we provide an aid to the documentation and visual conceptualization of those results – MuscleViz: a free, open-source application for visualizing the results of muscle strength testing. Its use in clinical settings streamlines the communication of physical examination findings. The tool is also useful for presenting patient data in case reports or case series. A push towards free, open-source software has benefitted other areas of science; we believe a similar effort dedicated to the development of clinical tools is worth pursuing.

DOI: 10.3233/JND-190385

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 263-266, 2019

Authors: Carr, A.S. | Shah, S. | Choi, D. | Blake, J. | Phadke, R. | Gilbertson, J. | Whelan, C.J. | Wechalekar, A.D. | Gillmore, J.D. | Hawkins, P.N. | Reilly, M.M.

Article Type: Case Report

Abstract: Here we describe a patient with genetically confirmed ATTR, a family history of the disease and histological confirmation following carpal tunnel release surgery but no other manifestations. The first major neurological or systemic manifestation was cauda equina syndrome with ATTR deposits contributing to lumbar spinal stenosis. Recent gene therapy trials showed improvement in the neuropathy in TTR amyloidosis. This case highlights the need for awareness of the heterogeneous neurological phenotype seen in ATTR to aid earlier diagnosis especially now that disease modifying therapies are available.

Keywords: Transthyretin amyloidosis, amyloid neuropathy, spinal surgery

DOI: 10.3233/JND-180348

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 2, pp. 267-270, 2019