Journal of Neuromuscular Diseases - Volume 1, issue 2

Authors: Kaufmann, Petra

Article Type: Research Article

DOI: 10.3233/JND-140029

Citation: Journal of Neuromuscular Diseases, vol. 1, no. 2, pp. 117-118, 2014

Authors: Sommerville, Ewen W. | Chinnery, Patrick F. | Gorman, Gráinne S. | Taylor, Robert W.

Article Type: Review Article

Abstract: Background: Progressive external ophthalmoplegia (PEO) is an eye movement disorder characterised by paresis of the extra ocular muscles and muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Classification of patients is particularly difficult due to overlapping phenotypes and a poor genotype-phenotype relationship. Despite the identification of several nuclear encoded genes causing PEO, over half of patients with clinically confirmed PEO do not have a genetic diagnosis. Objective: To systematically review genotypic and phenotypic correlates of published cases of adult-onset PEO. Methods: Patients were identified from interrogation of articles from Scopus, Medline via PubMed, and Genetic Abstracts databases using electronic searches (1st …January 1970 to 8th November 2013). Reference lists and UniProt entries were also manually checked for additional articles. Results: Twelve nuclear encoded genes were identified (TYMP, SLC25A4, POLG, C10ORF2, OPA1, POLG2, RRM2B, TK2, DGUOK, MPV17, MGME1, and DNA2) systematically from 583 patients. At the time of writing, mutations in SPG7 and AFG3L2 genes were reported to be associated with ophthalmoparesis and multiple mtDNA deletions in fourteen additional adult-onset PEO patients, bringing the total number of known genes to fourteen. Conclusions: Diagnostic yield is still critically dependent on the meticulous clinical and biochemical characterisation of patients. Understanding the intimate relationship between genotype and phenotype remains a fundamental challenge. The results of this systematic review provide guidance to both patients and clinician about future prognosis, and will serve, in future, to assess methods of disease prevention and evaluation of targeted therapeutic strategies. Show more

Keywords: Mitochondria, ophthalmoplegia, genotype, phenotype

DOI: 10.3233/JND-140041

Citation: Journal of Neuromuscular Diseases, vol. 1, no. 2, pp. 119-133, 2014

Authors: Lek, Monkol | MacArthur, Daniel

Article Type: Review Article

Abstract: New genomic technologies, such as exome, whole-genome and transcriptome sequencing, are transforming the genetic diagnosis of neuromuscular diseases and dramatically accelerating the discovery of new disease-associated genes. The increasingly widespread availability of these technologies creates both opportunities and challenges for neuromuscular disease researchers. Here we survey the current literature on the application of new genomic technologies to the diagnosis of severe muscle diseases, with a focus on assessment of the approaches used for data processing, analysis and interpretation. We also highlight several key areas requiring improvement.

Keywords: exome sequencing, neurogenetics, muscle disease, next generation sequencing

DOI: 10.3233/JND-140032

Citation: Journal of Neuromuscular Diseases, vol. 1, no. 2, pp. 135-149, 2014

Authors: Montes, Jacqueline | Garber, Carol Ewing | Kramer, Samantha S. | Montgomery, Megan J. | Dunaway, Sally | Kamil-Rosenberg, Shirit | Carr, Brendan | Strauss, Nancy E. | Sproule, Douglas | De Vivo, Darryl C.

Article Type: Research Article

Abstract: Background: Spinal Muscular Atrophy (SMA) is a recessively-inherited neuromuscular disease characterized by weakness and muscle atrophy. Although anecdotal benefits from exercise have been noted, and despite promising pre-clinical and pilot reports, the effect of exercise has not been addressed in a controlled trial in SMA. Objective: To assess the effects of exercise on measures of function, strength, and exercise capacity in ambulatory SMA patients. Methods/Design: An evaluator-blinded, randomized, controlled trial of aerobic and strengthening exercise in 14 ambulatory SMA patients aged 8–50 years. Patients will be randomized to either the exercise or control arm after the 1 month lead in …period. During the first 6-months, the exercise group will receive the intervention while the other group serves as a control. After those 6 months, both groups will receive the intervention. The last 6-months of the study are designed to mimic real-world conditions where all participants are encouraged to continue on their own. Participants will be monitored throughout this 19 month study and will have in-person visits every three months. The primary outcome measure is the change in the total distance walked over 6-months on the six minute walk test (6MWT). Secondary outcome measures include maximal oxygen uptake (VO2 max), functional and strength assessments, pulmonary function, fatigue, and quality of life. Discussion: The result of this prospective, single blinded, randomized and controlled clinical trial of exercise on an established functional outcome measure will have impact on clinical practice by providing important guidance to clinical management of SMA patients. Show more

Keywords: spinal muscular atrophy, exercise, six minute walk test, strength

DOI: 10.3233/JND-140004

Citation: Journal of Neuromuscular Diseases, vol. 1, no. 2, pp. 151-161, 2014

Authors: Gosavi, Tushar D. | Huang, G.Z. | Fook-Chong, S. | Lo, Yew Long

Article Type: Research Article

Abstract: Objective: Single fibre electromyography (SFEMG) and repetitive nerve stimulation (RNS) are routinely performed investigations in evaluation of patients with myasthenia gravis (MG). Significant number of MG patients have a thymic pathology. We aimed to explore the relationship between the SFEMG and RNS findings with the presence of thymic pathology. Methods: We studied 159 consecutive patients with MG over a 10 year period. The SFEMG parameters – mean jitter (MJ) and percentage of abnormal fibres (POAF) and the RNS result were correlated with the thymic findings. Results: As compared to patients with normal thymus (MJ:58.3 μsec; POAF:63.5%), patients with thymic pathology …had a significantly higher MJ (80.9 μsec; p < 0.0005) and POAF (83.5%; p < 0.0005). MG patients with thymic hyperplasia had the highest MJ (87.6 μsec) and POAF (84.4%) followed by patients with thymoma (MJ:78.6 μsec; POAF:83.2%). The MJ and POAF did not correlate with the stage of thymoma. Mean jitter values above 34.9 μsec and POAF above 31% had 100% sensitivity for the presence of thymic pathology. A positive RNS increased the risk of thymic pathology (OR = 3.9, CI = 1.8–8.5) and thymoma. (OR = 3.5; CI = 1.5–8.1). Conclusion: Electrophysiology could be valuable complimentary tool to identify MG patients at high risk for thymic pathology. However, it does not aid us to identify the exact thymic pathology and does not correlate with the stage of thymoma. All OMG patients with higher MJ and PAOF values should also be screened for thymoma. The results reinforce the immunological role of thymic pathology in neuromuscular transmission interference. Show more

Keywords: Myasthenia gravis, thymic pathology, thymoma, single fibre electromyography, mean jitter, percentage of abnormal fibres, repetitive nerve stimulation

DOI: 10.3233/JND-140020

Citation: Journal of Neuromuscular Diseases, vol. 1, no. 2, pp. 163-168, 2014

Authors: Oliveira, Jorge | Gonçalves, Ana | Oliveira, Márcia E. | Fineza, Isabel | Pavanello, Rita C.M. | Vainzof, Mariz | Bronze-da-Rocha, Elsa | Santos, Rosário | Sousa, Mário

Article Type: Research Article

Abstract: Background: Congenital muscular dystrophy (CMD) type 1A (MDC1A) is caused by recessive mutations in laminin-α2 (LAMA2) gene. Laminin-211, a heterotrimeric glycoprotein that contains the α2 chain, is crucial for muscle stability establishing a bond between the sarcolemma and the extracellular matrix. More than 215 mutations are listed in the locus specific database (LSDB) for LAMA2 gene (May 2014). Objective: A limited number of large deletions/duplications have been reported in LAMA2. Our main objective was the identification of additional large rearrangements in LAMA2 found in CMD patients and a systematic review of cases in the literature and LSDB. Methods: In four …of the fifty-two patients studied over the last 10 years, only one heterozygous mutation was identified, after sequencing and screening for a frequent LAMA2 deletion. Initial screening of large mutations was performed by multiplex ligation-dependent probe application (MLPA). Further characterization implied several techniques: long-range PCR, cDNA and Southern-blot analysis. Results: Three novel large deletions in LAMA2 and the first pathogenic large duplication were successfully identified, allowing a definitive molecular diagnosis, carrier screening and prenatal diagnosis. A total of fifteen deletions and two duplications previously reported were also reviewed. Two possible mutational “hotspots” for deletions may exist, the first encompassing exons 3 and 4 and second in the 3′ region (exons 56 to 65) of LAMA2. Conclusions: Our findings show that this type of mutation is fairly frequent (18.4% of mutated alleles) and is underestimated in the literature. It is important to include the screening of large deletions/duplications as part of the genetic diagnosis strategy. Show more

Keywords: LAMA2, congenital muscular dystrophy, large deletion, large duplication, review

DOI: 10.3233/JND-140031

Citation: Journal of Neuromuscular Diseases, vol. 1, no. 2, pp. 169-179, 2014

Authors: Statland, Jeffrey | Donlin-Smith, Colleen M. | Tapscott, Stephen J. | van der Maarel, Silvère M. | Tawil, Rabi

Article Type: Research Article

Abstract: Background: Recent studies have proposed a unified genetic model for Facioscapulohumeral muscular dystrophy (FSHD), identifying potential therapeutic targets for future clinical trials. Serum biomarkers related to disease activity will be important for proof of concept or early phase clinical studies. Objective: To identify potential serum biomarkers in FSHD for possible use in future clinical trials. Methods: We performed a prospective cross-sectional study of serum biomarkers in 22 FSHD patients (19 FSHD1, 3 FSHD2) compared to 23 age and gender-matched healthy controls using a commercial multiplex, microsphere-based immune-fluorescent assay of 243 markers (Myriad, Human Discovery MAP 250, v2.0). Results: 169 markers …had values sufficient for analysis. Correction for multiple testing identified 7 biomarkers below a 5% false discovery rate: creatine kinase MB fraction (CKMB, 6.52 fold change, P < 0.0001), tissue-type plasminogen activator (PLAT, 1.64 fold change, P < 0.0001), myoglobin (2.23 fold change, P = 0.0001), epidermal growth factor (EGF, 2.33 fold change, P = 0.0004), chemokine (C-C motif) ligand 2 (1.48 fold change, P = 0.0004), CD 40 ligand (1.89 fold change, P = 0.001), and vitronectin (VTN, 1.28 fold change, P = 0.001). Moderate correlations to measures of FSHD disease were seen for CKMB, PLAT, and EGF. Markers in the plasminogen pathway (PLAT and VTN) were correlated with each other in FSHD but not healthy controls. Conclusions: Commercial multiplex immune-fluorescent screening is a potentially powerful tool for identifying biomarkers for future FSHD therapeutic trials. Biomarkers identified in this study warrant further study in a larger prospective validation study. Show more

Keywords: Muscle Disease, facioscapulohumeral muscular dystrophy, DUX4, biomarker, proteomics

DOI: 10.3233/JND-140034

Citation: Journal of Neuromuscular Diseases, vol. 1, no. 2, pp. 181-190, 2014

Authors: Miller, James A.L. | Spyropoulos, Achillefs | Jaros, Evelyn | Galban-Horcajo, Francesc | Whittaker, Roger G. | Willison, Hugh J.

Article Type: Research Article

Abstract: Background: Miller Fisher syndrome is a regional variant of Guillain-Barre syndrome with a characteristic clinical triad of ophthalmoplegia, areflexia and ataxia and occasionally distal limb sensory loss. 90% of patients have associated antibodies to the GQ1b ganglioside. The pathophysiology of antibody-mediated peripheral nerve impairment remains uncertain. This report includes the first description of a peripheral sensory nerve biopsy in Miller Fisher syndrome. Results: A single case report is described of a 46 year old woman who presented with 2 weeks of distal glove and stocking sensory loss to both deep and superficial sensory modalities, areflexia and weight loss. This was …followed by rapid onset of ataxia, ophthalmoplegia, and bulbar impairment. Peripheral neurophysiology showed reduced sensory nerve amplitudes with preserved conduction velocities in keeping with an axonal pattern of impairment. Clinical concerns of a systemic inflammatory disorder led to a diagnostic peripheral nerve biopsy from the sensory branch of the radial nerve. However she subsequently made a complete recovery over 5 weeks. Combinatorial glycoarrays confirmed restricted serum binding for GQ1b in acute serum which later resolved in a convalescent sample. The nerve biopsy showed lengthening of nodes of Ranvier, myelin splitting and macrophage internodal axonal invasion without any features of demyelination. Conclusions: The pathological features were strikingly similar to those found in acute motor axonal neuropathy and indicate the region of the node of Ranvier to be a primary focus of GQ1b induced damage in Miller Fisher syndrome, at least in this particular overlap syndrome with prominent sensory nerve involvement. Show more

Keywords: Nerve biopsy, Miller Fisher syndrome, GQ1b ganglioside, node of Ranvier, pathophysiology

DOI: 10.3233/JND-140039

Citation: Journal of Neuromuscular Diseases, vol. 1, no. 2, pp. 191-195, 2014

Authors: Wyatt, Eugene J. | Sweeney, H. Lee | McNally, Elizabeth M.

Article Type: Research Article

Abstract: New Directions in Biology and Disease of Skeletal Muscle is a scientific meeting, held every other year, with the stated purpose of bringing together scientists, clinicians, industry representatives and patient advocacy groups to disseminate new discovery useful for the treatment of inherited forms of neuromuscular disease, primarily the muscular dystrophies. This meeting originated as a response to the Muscular Dystrophy Care Act in order to provide a venue for the free exchange of information, with the emphasis on unpublished or newly published data. Highlights of this years' meeting included results from early phase clinical trials for Duchenne Muscular Dystrophy, progress …in understanding the epigenetic defects in Fascioscapulohumeral Muscular Dystrophy and new mechanisms of muscle membrane repair. The following is a brief report of the highlights from the conference. Show more

Keywords: Muscular Dystrophy, spinal muscular atrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy

DOI: 10.3233/JND-149003

Citation: Journal of Neuromuscular Diseases, vol. 1, no. 2, pp. 197-206, 2014

Article Type: Other

Citation: Journal of Neuromuscular Diseases, vol. 1, no. 2, pp. 207-209, 2014