Journal of Neuromuscular Diseases - Volume 3, issue 3

Authors: Savarese, Marco | Sarparanta, Jaakko | Vihola, Anna | Udd, Bjarne | Hackman, Peter

Article Type: Review Article

Abstract: The TTN gene with 363 coding exons encodes titin, a giant muscle protein spanning from the Z-disk to the M-band within the sarcomere. Mutations in the TTN gene have been associated with different genetic disorders, including hypertrophic and dilated cardiomyopathy and several skeletal muscle diseases. Before the introduction of next generation sequencing (NGS) methods, the molecular analysis of TTN has been laborious, expensive and not widely used, resulting in a limited number of mutations identified. Recent studies however, based on the use of NGS strategies, give evidence of an increasing number of rare and unique TTN …variants. The interpretation of these rare variants of uncertain significance (VOUS) represents a challenge for clinicians and researchers. The main aim of this review is to describe the wide spectrum of muscle diseases caused by TTN mutations so far determined, summarizing the molecular findings as well as the clinical data, and to highlight the importance of joint efforts to respond to the challenges arising from the use of NGS. An international collaboration through a clinical and research consortium and the development of a single accessible database listing variants in the TTN gene, identified by high throughput approaches, may be the key to a better assessment of titinopathies and to systematic genotype– phenotype correlation studies. Show more

Keywords: TTN, titin, neuromuscular disorders, Limb-girdle muscular dystrophy (LGMD), Hereditary myopathy with early respiratory failure (HMERF), Late-onset autosomal dominant tibial muscular dystrophy (TMD), Congenital centronuclear myopathy (CNM), Early-onset myopathy with fatal cardiomyopathy (EOMFC), Multi-minicore disease with heart disease (MmDHD), Childhood-juvenile onset Emery-Dreifuss-like phenotype without cardiomyopathy

DOI: 10.3233/JND-160158

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 293-308, 2016

Authors: Kalra, Spandan | Montanaro, Federica | Denning, Chris

Article Type: Review Article

Abstract: Muscular dystrophies (MDs) are clinically and molecularly a highly heterogeneous group of single-gene disorders that primarily affect striated muscles. Cardiac disease is present in several MDs where it is an important contributor to morbidity and mortality. Careful monitoring of cardiac issues is necessary but current management of cardiac involvement does not effectively protect from disease progression and cardiac failure. There is a critical need to gain new knowledge on the diverse molecular underpinnings of cardiac disease in MDs in order to guide cardiac treatment development and assist in reaching a clearer consensus on cardiac disease management in the clinic. Animal …models are available for the majority of MDs and have been invaluable tools in probing disease mechanisms and in pre-clinical screens. However, there are recognized genetic, physiological, and structural differences between human and animal hearts that impact disease progression, manifestation, and response to pharmacological interventions. Therefore, there is a need to develop parallel human systems to model cardiac disease in MDs. This review discusses the current status of cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSC) to model cardiac disease, with a focus on Duchenne muscular dystrophy (DMD) and myotonic dystrophy (DM1). We seek to provide a balanced view of opportunities and limitations offered by this system in elucidating disease mechanisms pertinent to human cardiac physiology and as a platform for treatment development or refinement. Show more

Keywords: Human embryonic stem cells, human induced pluripotent stem cells, Cas9/CRISPR genome editing, cardiomyocytes, Duchenne muscular dystrophy (DMD), myotonic dystrophy (DM1), disease modelling, exon skipping, gene therapy

DOI: 10.3233/JND-150133

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 309-332, 2016

Authors: Arvanitidis, A. | Henriksen, K. | Karsdal, M.A. | Nedergaard, A.

Article Type: Review Article

Abstract: For several decades, serological biomarkers of neuromuscular diseases as dystrophies, myopathies and myositis have been limited to routine clinical biochemistry panels. Gauging the pathological progression is a prerequisite for proper treatment and therefore identifying accessible, easy to monitor biomarkers that can predict the disease progression would be an important advancement. Most muscle diseases involve accelerated muscle fiber degradation, inflammation, fatty tissue substitution and/or fibrosis. All these pathological traits have been shown to give rise to serological peptide biomarkers in other tissues, underlining the potential application of existing biomarkers of such traits in muscle disorders. A significant quantity of tissue is …involved in these pathological mechanisms alongside with qualitative changes in protein turnover in myofibrillar, extra-cellular matrix and immunological cell protein fractions accompanied by alterations in body fluids. We propose that protein and peptides can leak out of the afflicted muscles and can be of use in diagnosis, prediction of pathology trajectory and treatment efficacy. Proteolytic cleavage systems are especially modulated during a range of muscle pathologies, thereby giving rise to peptides that are differentially released during disease manifestation. Therefore, we believe that pathology-specific post-translational modifications like cleavages can give rise to neoepitope peptides that may represent a promising class of peptides for discovery of biomarkers pertaining to neuromuscular diseases. Show more

Keywords: Muscular dystrophies, myopathies, biomarkers, prognosis

DOI: 10.3233/JND-160150

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 333-346, 2016

Authors: Walklet, Elaine | Muse, Kate | Meyrick, Jane | Moss, Tim

Article Type: Review Article

Abstract: Quality of life and well-being are frequently restricted in adults with neuromuscular disorders. As such, identification of appropriate interventions is imperative. The objective of this paper was to systematically review and critically appraise quantitative studies (RCTs, controlled trials and cohort studies) of psychosocial interventions designed to improve quality of life and well-being in adults with neuromuscular disorders. A systematic review of the published and unpublished literature was conducted. Studies meeting inclusion criteria were appraised using a validated quality assessment tool and results presented in a narrative synthesis. Out of 3,136 studies identified, ten studies met criteria for inclusion within the …review. Included studies comprised a range of interventions including: cognitive behavioural therapy, dignity therapy, hypnosis, expressive disclosure, gratitude lists, group psychoeducation and psychologically informed rehabilitation. Five of the interventions were for patients with Amyotrophic Lateral Sclerosis (ALS). The remainder were for patients with post-polio syndrome, muscular dystrophies and mixed disorders, such as Charcot-Marie-Tooth disease, myasthenia gravis and myotonic dystrophy. Across varied interventions and neuromuscular disorders, seven studies reported a short-term beneficial effect of intervention on quality of life and well-being. Whilst such findings are encouraging, widespread issues with the methodological quality of these studies significantly compromised the results. There is no strong evidence that psychosocial interventions improve quality of life and well-being in adults with neuromuscular disorders, due to a paucity of high quality research in this field. Multi-site, randomised controlled trials with active controls, standardised outcome measurement and longer term follow-ups are urgently required. Show more

Keywords: Neuromuscular diseases, adult, quality of life, psychology, review

DOI: 10.3233/JND-160155

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 347-362, 2016

Authors: Bartsakoulia, Marina | Mϋller, Juliane S. | Gomez-Duran, Aurora | Yu-Wai-Man, Patrick | Boczonadi, Veronika | Horvath, Rita

Article Type: Research Article

Abstract: Background: Mitochondrial encephalomyopathies are severe, relentlessly progressive conditions and there are very few effective therapies available to date. We have previously suggested that in two rare forms of reversible mitochondrial disease (reversible infantile respiratory chain deficiency and reversible infantile hepatopathy) supplementation with L-cysteine can improve mitochondrial protein synthesis, since cysteine is required for the 2-thiomodification of mitochondrial tRNAs. Objectives: We studied whether supplementation with L-cysteine or N-acetyl-cysteine (NAC) results in any improvement of the mitochondrial function in vitro in fibroblasts of patients with different genetic forms of abnormal mitochondrial translation. Methods: We studied in …vitro in fibroblasts of patients carrying the common m.3243A>G and m.8344A>G mutations or autosomal recessive mutations in genes affecting mitochondrial translation, whether L-cysteine or N-acetyl-cysteine supplementation have an effect on mitochondrial respiratory chain function. Results: Here we show that supplementation with L-cysteine, but not with N-acetyl-cysteine partially rescues the mitochondrial translation defect in vitro in fibroblasts of patients carrying the m.3243A>G and m.8344A>G mutations. In contrast, N-acetyl-cysteine had a beneficial effect on mitochondrial translation in TRMU and MTO1 deficient fibroblasts. Conclusions: Our results suggest that L-cysteine or N-acetyl-cysteine supplementation may be a potential treatment for selected subgroups of patients with mitochondrial translation deficiencies. Further studies are needed to explore the full potential of cysteine supplementation as a treatment for patients with mitochondrial disease. Show more

Keywords: Cysteine supplementation, mitochondrial translation, mt-tRNA modification, mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy ragged red fibres (MERRF)

DOI: 10.3233/JND-160178

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 363-379, 2016

Authors: Carver, Michael P. | Charleston, Jay S. | Shanks, Courtney | Zhang, Jianbo | Mense, Mark | Sharma, Alok K. | Kaur, Harjeet | Sazani, Peter

Article Type: Research Article

Abstract: Background: Phosphorodiamidate morpholino oligomers (PMOs) are a class of exon skipping drugs including eteplirsen, which has shown considerable promise for treatment of the degenerative neuromuscular disease, Duchenne musculardystrophy (DMD). Objective: Toxicity studies in non-human primates (NHPs) of 12 weeks duration with two new PMOs for DMD, SRP-4045 and SRP-4053, along with results from a chronic study in NHPs of 39 weeks duration for eteplirsen, are described here. Methods: PMOs were administered once-weekly by bolus intravenous (IV) injections to male NHPs. Endpoints evaluated included plasma exposures, clinical observations, body weight/food consumption, eye exams, electrocardiograms, male reproductive …hormones/endpoints, complement alternative pathway, clinical pathology, urinalysis, and macroscopic/light microscopic pathology. Results: Findings in these studies were limited to the kidneys, with a common presentation of tubular basophilia, vacuolation, and/or minimal degeneration that was considered non-adverse. No necrosis, glomerular lesions, or effects on renal function tests such as serum creatinine or urea nitrogen were observed, suggesting that PMO-related kidney findings are not likely to develop into frank nephrotoxicity. There were no adverse effects on other potential target organs after repeated IV injections at the highest dose levels tested, 320 mg/kg. Conclusions: Nonclinical results in NHPs for these three PMOs, together with the excellent clinical safety established for eteplirsen to date, suggest that once-weekly IV administration of PMOs for lifetime durations at therapeutic doses will be well tolerated by patients with DMD. Show more

Keywords: Duchenne muscular dystrophy, eteplirsen, AVI-4658, phosphorodiamidate morpholino oligomers, exon skipping, splice switching oligonucleotides, toxicity studies, non-human primates, kidney toxicity

DOI: 10.3233/JND-160157

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 381-393, 2016

Authors: Lowe, Jeovanna | Floyd, Kyle T. | Rastogi, Neha | Schultz, Eric J. | Chadwick, Jessica A. | Swager, Sarah A. | Zins, Jonathan G. | Kadakia, Feni K. | Smart, Suzanne | Gomez-Sanchez, Elise P. | Gomez-Sanchez, Celso E. | Raman, Subha V. | Janssen, Paul M.L. | Rafael-Fortney, Jill A.

Article Type: Research Article

Abstract: Background: Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor. Objective: The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril. Methods: Three groups of n  = 18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus …spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls. In vivo measurements included cardiac magnetic resonance imaging, conscious electrocardiography, and grip strength. From each mouse in the study, diaphragm, extensor digitorum longus , and cardiac papillary muscle force was measured ex vivo , followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles. Results: Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment. Conclusions: These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy. Show more

Keywords: Spironolactone, eplerenone, lisinopril, Duchenne muscular dystrophy, mineralocorticoid receptors

DOI: 10.3233/JND-160173

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 395-404, 2016

Authors: Prasad, Madhavi | Hicks, Rhiannon | MacKay, Melissa | Nguyen, Cam-Tu | Campbell, Craig

Article Type: Research Article

Abstract: Background: Congenital myotonic dystrophy (CDM) is a neuromuscular disorder caused by a CTG triplet repeat expansion in the DMPK gene. In addition to the expected motor delay, affected children often have significant developmental disability in language and cognitive realms, which ultimately impacts on quality of life. Objective: In a prospective cohort of children with CDM to 1) present the profile of language and motor developmental milestones, and 2) describe their early childhood health related quality of life (HRQOL). Methods: A five year cohort study of eligible incident cases of CDM was performed via the Canadian …Pediatric Surveillance Program (CPSP). Consenting subjects were then followed from infancy in a prospective cohort study. Caregivers were contacted every 3 months for the first year of life, and then twice yearly in order to obtain data concerning language skills, motor development and parent proxy HRQOL from the PedsQL and Infant and Toddler Quality of life (ITQOL) questionnaires. Results: Milestones were achieved at later ages in patients when compared to healthy children. Girls appeared to be more delayed than boys in both language and motor skills. HRQOL scores remained stable in this cohort, for both the PedsQL and ITQOL. Conclusions: Understanding developmental milestones and quality of life are important parameters when judging a child’s overall health. For CDM patients delineating developmental milestones and QOL have important clinical care and research implications. Show more

Keywords: Myotonic dystrophy, congenital, QOL, developmental milestones

DOI: 10.3233/JND-160165

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 405-412, 2016

Authors: Rodolico, Carmelo | Parisi, Daniela | Portaro, Simona | Biasini, Fiammetta | Sinicropi, Stefano | Ciranni, Annamaria | Toscano, Antonio | Messina, Sonia | Musumeci, Olimpia | Vita, Giuseppe | Girlanda, Paolo

Article Type: Research Article

Abstract: Background: Myasthenia gravis (MG) is an autoimmune disorder presenting with fluctuating, fatigable muscle weakness. Initial symptoms classically involve ocular and proximal limb muscles. Rarely, MG may onset with unusual features, so it can be misdiagnosed with other neuromuscular diseases. Objective: To describe unusual and atypical presentations of MG in a large cohort of patients, considering and discussing diagnostic difficulties and pitfalls. Methods: We report on 21 out of 508 MG patients, coming to our department in the last 27 years and presenting with atypical or unusual features. The diagnosis was achieved performing a careful clinical …examination, a proper neurophysiological assessment, the neostigmine test, the AChR and MuSK antibodies assay and chest CT-scan. Results: Patients with atypical/unusual MG onset were the 4.4% of all MG patients population. We describe seven different clinical categories: asymmetric distal upper limbs weakness, foot drop, isolated triceps brachii weakness and foot drop, post exertional axial weakness with dropped head, acute facial dyplegia, limb-girdle MG and MG with sudden lower limbs weakness and recurrent falls. Conclusions: Atypical and unusual presentations may increase the risk to misdiagnose or delay MG diagnosis. Isolated limb-girdle presentation is the most frequent atypical form in our series. Show more

Keywords: Myasthenia gravis, limb girdle myasthenia, distal myasthenia, foot drop

DOI: 10.3233/JND-160148

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 413-418, 2016

Authors: Mulroy, Eoin | Gleeson, Sarah | Furlong, Michael James

Article Type: Short Communication

Abstract: Ketoacidosis is an important but under-recognized complication of neuromuscular disease, in particular spinal muscular atrophy. This easily treatable condition is largely overlooked in best practice guidelines, and lack of awareness contributes to adverse outcomes in this patient population. Neuromyopathy associated ketosis should be considered in all patients with severe muscle wasting presenting with an elevated anion gap metabolic ketoacidosis. Treatment is simple, effective, and should be instituted early. Our report of a 50-year-old patient with type 2 spinal muscular atrophy who presents with recurrent ketoacidosis aims to increase awareness of neuromyopathy associated ketosis as a clinical entity, and to enhance …its early recognition and timely treatment in order to improve patient outcomes. Show more

Keywords: Myopathy, ketosis, acidosis, acid-base equilibrium, muscular atrophy, spinal

DOI: 10.3233/JND-160171

Citation: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 419-423, 2016