Journal of Neuromuscular Diseases - Volume 6, issue 4

Authors: Lamacie, Mariana M. | Warman-Chardon, Jodi | Crean, Andrew M. | Florian, Anca | Wahbi, Karim

Article Type: Review Article

Abstract: Muscular dystrophies (MD) represent a heterogeneous group of rare genetic diseases that often lead to significant weakness due to progressive muscle degeneration. In many forms of MD, cardiac manifestations including heart failure, atrial and ventricular arrhythmias and conduction abnormalities can occur and may be a predominant feature of the disease. Cardiac magnetic resonance (CMR) can assess cardiac anatomy, global and regional ventricular function, volumes and mass as well as presence of myocardial inflammation, infiltration or fibrosis. The role for cardiac MRI has been well-established in a wide range of muscular dystrophies related cardiomyopathies. CMR is a more sensitive technique than …echocardiography for early diagnosis of cardiac involvement. It has also great potential to improve the prediction of long-term outcome, particularly the development of heart failure and arrhythmic events; however it still has to be validated by longitudinal studies including large populations. This review will outline the utility of CMR in patients with muscular dystrophies for assessment of myocardial involvement, risk stratification, and in guiding therapeutic management. Show more

Keywords: Muscular dystrophies, cardiac magnetic resonance, myocardial involvement, cardiomyopathy, sudden death

DOI: 10.3233/JND-190415

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 4, pp. 389-399, 2019

Authors: Beijer, Danique | Sisto, Angela | Van Lent, Jonas | Baets, Jonathan | Timmerman, Vincent

Article Type: Review Article

Abstract: Axonal transport is a highly complex process essential for sustaining proper neuronal functioning. Disturbances can result in an altered neuronal homeostasis, aggregation of cargoes, and ultimately a dying-back degeneration of neurons. The impact of dysfunction in axonal transport is shown by genetic defects in key proteins causing a broad spectrum of neurodegenerative diseases, including inherited peripheral neuropathies. In this review, we provide an overview of the cytoskeletal components, molecular motors and adaptor proteins involved in axonal transport mechanisms and their implication in neuronal functioning. In addition, we discuss the involvement of axonal transport dysfunction in neurodegenerative diseases with a particular …focus on inherited peripheral neuropathies. Lastly, we address some recent scientific advances most notably in therapeutic strategies employed in the area of axonal transport, patient-derived iPSC models, in vivo animal models, antisense-oligonucleotide treatments, and novel chemical compounds. Show more

Keywords: Axonal transport, inherited peripheral neuropathies, Charcot-Marie-Tooth disease, genetics, neurodegeneration, cytoskeleton, molecular motors, cargoes, therapeutics

DOI: 10.3233/JND-190427

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 4, pp. 401-419, 2019

Authors: Barthélémy, Inès | Hitte, Christophe | Tiret, Laurent

Article Type: Review Article

Abstract: Dogs have long been used as a biomedical model system and in particular as a preclinical proof of concept for innovative therapies before translation to humans. A recent example of the utility of this animal model is the promising myotubularin gene delivery in boys affected by X-linked centronuclear myopathy after successful systemic, long-term efficient gene therapy in Labrador retrievers. Mostly, this is due to unique features that make dogs an optimal system. The continuous emergence of spontaneous inherited disorders enables the identification of reliable complementary molecular models for human neuromuscular disorders (NMDs). Dogs’ characteristics including size, lifespan and unprecedented medical …care level allow a comprehensive longitudinal description of diseases. Moreover, the highly similar pathogenic mechanisms with human patients yield to translational robustness. Finally, interindividual phenotypic heterogeneity between dogs helps identifying modifiers and anticipates precision medicine issues. This review article summarizes the present list of molecularly characterized dog models for NMDs and provides an exhaustive list of the clinical and paraclinical assays that have been developed. This toolbox offers scientists a sensitive and reliable system to thoroughly evaluate neuromuscular function, as well as efficiency and safety of innovative therapies targeting these NMDs. This review also contextualizes the model by highlighting its unique genetic value, shaped by the long-term coevolution of humans and domesticated dogs. Because the dog is one of the most protected research animal models, there is considerable opposition to include it in preclinical projects, posing a threat to the use of this model. We thus discuss ethical issues, emphasizing that unlike many other models, the dog also benefits from its contribution to comparative biomedical research with a drastic reduction in the prevalence of morbid alleles in the breeding stock and an improvement in medical care. Show more

Keywords: Comparative genomics, laurasiatheria, euarchontoglires, domestication, animal model, comparative medicine, myology, myopathies, neurology, DMD, mdx, CNM, MTM1, SMA, gene therapy, AAV, CRISPR/Cas9, genetic testing, ethics, 3 R rule, rehoming, medical costs

DOI: 10.3233/JND-190394

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 4, pp. 421-451, 2019

Authors: Walter, Maggie C. | Wenninger, Stephan | Thiele, Simone | Stauber, Julia | Hiebeler, Miriam | Greckl, Eva | Stahl, Kristina | Pechmann, Astrid | Lochmüller, Hanns | Kirschner, Janbernd | Schoser, Benedikt

Article Type: Research Article

Abstract: Objective: Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease caused by loss of the SMN1 gene. Based on randomized clinical trials in children with SMA type 1 and 2, Nusinersen has been approved as the first treatment for all types of SMA, including adults with SMA type 3. Methods: We evaluated the safety and treatment effects of Nusinersen in longstanding adult 5q-SMA type 3. Patients were treated with intrathecal loading doses at day 1, 14, 28 and 63, followed by maintenance dose every four months up to 300 days. We monitored the patients …within SMArtCARE, a prospective open-label outcome study for disease progression, side effects and treatment efficacy, encompassing clinical examination including MRC sum score, vital capacity in sitting position (VC, VC % pred.), ALS Functional Rating Scale (ALS-FRS), 6-Minute-Walk-Test (6MWT), Revised Upper Limb Module (RULM), and Hammersmith Functional Rating Scale (HFMSE). We also measured biomarkers in the spinal fluid (phosphorylated neurofilament heavy chain pNFH, neuron-specific enolase NSE, proteins, ß-Amyloid 1–40, ß-Amyloid 1–42, tau and phospho-tau) and creatine kinase (CK). Assessments were performed at baseline, day 63 (V4), day 180 (V5) and day 300 (V6). For statistical analysis, we compared baseline to V4, V5 and V6, using the paired sample t -test. When there were significant differences, we added cohen's d and effect size r for evaluation of clinical meaningfulness. Results: 19 patients were included, 17 of them have completed the observation period of 10 months (day 300, V6). Patients were aged 18 to 59 years with disease duration ranging from 6 to 53 years. Except for the 6MWT, the RULM and the peak cough flow, there were no relevant significant changes in all functional outcome assessments at V4, V5 or V6, compared to baseline. For the 6MWT, there was a statistically significant improvement at visit 5 and at visit 6. RULM-score increased significantly at V6, and peak cough flow at visit 5. In biomarker studies, there was a significant decline in NSE and pTAU as well as a slight increase in proteins. In safety analysis, overall, Nusinersen applications were well tolerated. Eleven patients reported adverse events that were related to the study procedures, comprising back pain in seven patients and post-lumbar-puncture headache following intrathecal administration in four patients. Post-lumbar-puncture headache was reported in three females and one male, in total eleven times of 108 punctures (10%). No serious adverse events occurred. Conclusions: This prospective observational study indicates a mild treatment effect in adults with long-standing SMA3 after 10 months of treatment with Nusinersen, which had never occurred in the natural history of the disease. In our cohort, the most significant outcome measures were the 6MWT with statistically significant changes after day 180 and day 300, RULM after day 300 and peak cough flow after day 180. Show more

Keywords: Nusinersen, spinal muscular atrophy, treatment, safety, prospective observational study

DOI: 10.3233/JND-190416

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 4, pp. 453-465, 2019

Authors: Waldrop, Megan | Amornvit, Jakkrit | Pierson, Christopher R. | Boue, Daniel R. | Sahenk, Zarife

Article Type: Research Article

Abstract: Background: The phenotypic spectrum of the skeletal muscle voltage-gated sodium channel gene (SCN4A ) mutations has been expanding dramatically with advancements in genetic testing. Previously only known to cause autosomal dominant myotonia or periodic paralysis, now recessive mutations have been found causing congenital myopathies and congenital myasthenic syndromes. Case presentation: A 27-year-old woman who was born with Arnold-Chiari malformation, hydrocephalus, high-arched palate, bilateral hip dysplasia, and severe scoliosis presented for evaluation of episodic muscle stiffness and weakness. Electrodiagnostic studies revealed myopathy and widespread myotonia. Muscle histopathology showed marked fiber size variability, type I fiber predominance with minimal scattered …necrosis and regeneration which was typical of a congenital myopathy with an additional finding of a lobulated structural pattern in type I fibers. Sequential individual gene testing revealed a novel de novo heterozygous c.2386 C > G, p.Leu796Val missense mutation in the SCN4A gene. Discussion: To the best of our knowledge, this is the first report of a dominant, heterozygous mutation in SCN4A causing a complex phenotype of congenital myopathy and myotonia with multiple congenital anomalies and unique muscle pathology findings. This case is another addition to the ever expanding phenotype of SCN4A mutations. Show more

Keywords: SCN4A, myotonia, congenital myopathy, Arnold-Chiari malformation, bilateral hip dysplasia, scoliosis

DOI: 10.3233/JND-190425

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 4, pp. 467-473, 2019

Authors: Hu, Ying | Mohassel, Payam | Donkervoort, Sandra | Yun, Pomi | Bolduc, Véronique | Ezzo, Daniel | Dastgir, Jahannaz | Marshall, Jamie L. | Lek, Monkol | MacArthur, Daniel G. | Foley, A. Reghan | Bönnemann, Carsten G.

Article Type: Research Article

Abstract: Calpainopathy, also known as limb girdle muscular dystrophy (LGMD) type 2A (LGMD2A) or LGMD R1 Calpain3-related, is one of the most common genetically characterized forms of limb-girdle muscular dystrophy with a wide range of phenotypic severity. We evaluated a consanguineous family with a clinical phenotype consistent with calpainopathy in whom conventional sequencing did not detect any mutations in the CAPN3 gene. Using whole exome sequencing paired with haplotype analysis, we identified a homozygous deep intronic single base pair deletion in CAPN 3 (c.946-29delT). Familial segregation studies were consistent with recessive inheritance. Immunoblotting of muscle tissue from the patient showed …complete absence of calpain 3. In silico analysis predicted the deletion to disrupt the branch point and subsequently alter splicing of exon 7. Studies of patient fibroblasts and muscle tissue confirmed altered splicing, resulting in an inclusion of a 389-bp intronic sequence upstream of exon 7, originating from a cryptic splice acceptor site in intron 6. This out-of-frame insertion results in a premature stop codon, leading to an apparent absence of protein likely due to degradation of the transcript via nonsense-mediated decay. We then designed phosphorodiamidate morpholino oligomers (PMOs) as splice modulators to block the new splice acceptor site. This approach successfully prevented the aberrant splicing – reverting the majority of the splice to the wildtype transcript. These results confirm the pathogenicity of this novel deep intronic mutation and provide a mutation-specific therapeutic strategy. Thus, deep intronic mutations in CAPN3 may be pathogenic and should be considered in the appropriate clinical setting. The identification of mutations which may be missed by traditional Sanger sequencing is essential as they may be excellent targets for individualized therapeutic strategies using RNA-directed splice modulation. Show more

Keywords: Calpainopathy, LGMD2A, deep intronic mutation, phosphorodiamidate morpholino oligomer (PMO)

DOI: 10.3233/JND-190414

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 4, pp. 475-483, 2019

Authors: Shelton, G. Diane | Minor, Katie M. | Li, Kefeng | Naviaux, Jane C. | Monk, Jon | Wang, Lin | Guzik, Elizabeth | Guo, Ling T. | Porcelli, Vito | Gorgoglione, Ruggiero | Lasorsa, Francesco M. | Leegwater, Peter J. | Persico, Antonio M. | Mickelson, James R. | Palmieri, Luigi | Naviaux, Robert K.

Article Type: Research Article

Abstract: Background: Inflammatory myopathies are characterized by infiltration of inflammatory cells into muscle. Typically, immune-mediated disorders such as polymyositis, dermatomyositis and inclusion body myositis are diagnosed. Objective: A small family of dogs with early onset muscle weakness and inflammatory muscle biopsies were investigated for an underlying genetic cause. Methods: Following the histopathological diagnosis of inflammatory myopathy, mutational analysis including whole genome sequencing, functional transport studies of the mutated and wild-type proteins, and metabolomic analysis were performed. Results: Whole genome resequencing identified a pathological variant in the SLC25A12 gene, resulting in a leucine to proline …substitution at amino acid 349 in the mitochondrial aspartate-glutamate transporter known as the neuron and muscle specific aspartate glutamate carrier 1 (AGC1). Functionally reconstituting recombinant wild-type and mutant AGC1 into liposomes demonstrated a dramatic decrease in AGC1 transport activity and inability to transfer reducing equivalents from the cytosol into mitochondria. Targeted, broad-spectrum metabolomic analysis from affected and control muscles demonstrated a proinflammatory milieu and strong support for oxidative stress. Conclusions: This study provides the first description of a metabolic mechanism in which ablated mitochondrial glutamate transport markedly reduced the import of reducing equivalents into mitochondria and produced a highly oxidizing and proinflammatory muscle environment and an inflammatory myopathy. Show more

Keywords: Canine, myopathy, SLC25A12, mitochondrial transporter, metabolomics

DOI: 10.3233/JND-190421

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 4, pp. 485-501, 2019

Authors: Vill, Katharina | Kölbel, Heike | Schwartz, Oliver | Blaschek, Astrid | Olgemöller, Bernhard | Harms, Erik | Burggraf, Siegfried | Röschinger, Wulf | Durner, Jürgen | Gläser, Dieter | Nennstiel, Uta | Wirth, Brunhilde | Schara, Ulrike | Jensen, Beate | Becker, Marc | Hohenfellner, Katharina | Müller-Felber, Wolfgang

Article Type: Research Article

Abstract: Objective: Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. The study was conducted to assess the impact of early detection of SMA by newborn screening (NBS) on the clinical course of the disease. Methods: Screening was performed in two federal states of Germany, Bavaria and North Rhine Westphalia, between January 2018 and February 2019. The incidence in the screening population was calculated as number of detected patients with a homozygous deletion in the SMN1 -gene per number of screened patients. To get an idea about the incidence of newly diagnosed SMA in the year …prior to screening a survey covering all neuropediatric centers in the state of Bavaria was conducted, identifying all SMA-cases in 2017 and 2018. Following positive NBS and confirmatory diagnostic test, treatment was advised according to the recommendations of the “American SMA NBS Multidisciplinary Working Group”. Immediate treatment with Nusinersen was recommended in children with 2 and 3 SMN2 copies and a conservative strict follow-up strategy in children with ≥4 copies. All children underwent regular standardized neuropediatric examination, CHOP INTEND and HINE-2 testing as well as electrophysiological exams every 2-3 months. Results: 165,525 children were screened. 22 cases of SMA were identified, meaning an incidence rate of 1:7524. SMN2 copy number analysis showed 2 SMN2 copies in 45% of patients, 3 SMN2 copies in 19 % and 4 SMN2 copies in 36%. These findings are confirmed in the most recent statistical data-cut from 31st August 2019 (incidence 1:7089, 2 SMN2 copies in 44%, 3 in 15% and 4 in 38%). Comparison with up-to-date German data on SMA incidence and the Bavarian survey give evidence that NBS did not lead to a relevant increase in incidence. 10 patients with 2 or 3 SMN2 copies were treated with Nusinersen, starting between 15– 39 days after birth, in 7/10 patients before onset of symptoms. Presymptomatically treated patients (age at last examination: 1– 12 months, median 8 months) showed no muscle weakness by the age of one month to one year. One child with 4 SMN2 copies became symptomatic at the age of 8 months. Conclusions: Newborn screening, resulting in presymptomatic treatment, improves outcome in children with genetically proven SMA. Newborn screening for SMA should be introduced in all countries where therapy is available. An immediate therapy in cases with 4 SMN2 copies should be considered. Show more

Keywords: Spinal muscular atrophy, newborn screening, SMA treatment, Nusinersen, prognosis

DOI: 10.3233/JND-190428

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 4, pp. 503-515, 2019

Authors: Fernndez, Shirley Steffany Muñoz | Ribeiro, Sandra Maria Lima

Article Type: Research Article

Abstract: Background: People suffering from spinal cord injury (SCI) undergo metabolic and physical disturbances that target the skeletal muscle, causing a progressive loss of muscle mass. Objective: To estimate the appendicular lean mass index (ALMI) in athletes with traumatic (T-group) and non-traumatic (NT-group) SCI, and its association with metabolic and demographic parameters. Methods: Wheelchair athletes with SCI aged 18 to 52 years old were included (n  = 62). From DEXA assessment, we estimated the ALM index (ALMI = appendicular lean mass/height2 ) and classified participants according to the degree of muscle loss (ALMI < 2 SD from the reference populations). Fasting blood …was assayed for glycaemia, insulin, cortisol, and IGF-1 serum levels. Data were compared by T -test and Fisher’s Exact Test; predictors of ALMI were investigated by linear regression models. Results: The frequency of low ALMI was 63% in overall sample, 55% T-group and 71% NT-group. Low ALMI had no significant association with the origin of injury (X2  = 1.1, p  = 0.29). Linear regression analyses showed significant association, in the whole sample, between ALMI and serum levels of IGF-1 (Beta = 0.69; p  < 0.001), age (Beta=–5.8; p  < 0.001), percentage fat mass (Beta=–0.26; p  = 0.001), and energy intake (Beta = 0.32; p  = 0.02). These significances were not maintained in the NT-group sub-analyses. Conclusions: Low ALMI was very frequent in our SCI participants, despite exercising and independently of the type of injury. Metabolic and demographic variables associated with low ALMI were different according to the origin of injury, which possibly relies on physiopathology particularities. More studies are necessary to clarify our findings. Show more

Keywords: Muscular Atrophy, Metabolism, Body Composition, Exercise, Spinal Cord Injuries

DOI: 10.3233/JND-190409

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 4, pp. 517-525, 2019

Authors: Kurauchi, Go | Endo, Makiko | Odaira, Kaori | Ono, Ryohei | Koseki, Atsushi | Goto, Momoko | Sato, Yumi | Kon, Seiko | Watanabe, Norio | Sugawara, Norio | Kimura, En | Takada, Hiroto

Article Type: Research Article

Abstract: Background: Multi-systemic symptoms of varying severity in myotonic dystrophy type 1 (DM1) may pose difficulties in caregiving. However, the factors which affect their care burden are yet to be sufficiently understood. Objective: We investigated care burden and its correlates among caregivers of patients with DM1. Methods: General demographic information was obtained from patients with DM1, as well as Barthel index (ADL), body mass index, and genetic information. Patients completed SF-36v2 (health-related quality of life), CES-D (depressive symptoms), and ESS (daytime sleepiness) questionnaires. Caregivers reported their perception of patient’s status through these questionnaires, and completed Zarit Caregiver …Burden Interview (ZBI). Correlation analysis of these variables were performed, and regression analysis was utilized to assess the relationship between caregiver burden and other variables. Results: Forty-three patient-caregiver dyads participated. Mean ZBI score was 20.7±17.4, and 32.6% reported a significant care burden. ZBI correlated with caregiver-reported CES-D, but not with patient-reported CES-D. Both patient-reported and caregiver-reported physical QoL of patients correlated with patient ADL. Multiple regression analysis revealed that the combination of caregiver-reported CES-D, caregiver-reported mental QoL, and genetic characteristics predicted caregiver burden. Conclusions: Caregiver burden was felt although patients were relatively well-functioning. Patients’ and caregivers’ assessment of patients’ physical condition were similar. However, they did not agree on the evaluation of the patients’ psychological state. Cognitive characteristic of the patients and the caregivers’ perception of the patients’ state may have affected the results. Future DM1 care strategies need to work on improvement of patient-caregiver communication and provide support for the caregiver’s psychological health. Show more

Keywords: Caregivers, burden of illness, activities of daily living, mental health, trinucleotide repeats, psychosocial support systems

DOI: 10.3233/JND-190386

Citation: Journal of Neuromuscular Diseases, vol. 6, no. 4, pp. 527-536, 2019