scholarly journals Current Genetic Survey and Potential Gene-Targeting Therapeutics for Neuromuscular Diseases

2020 ◽  
Vol 21 (24) ◽  
pp. 9589
Author(s):  
Wei Chiu ◽  
Ya-Hsin Hsun ◽  
Kao-Jung Chang ◽  
Aliaksandr A. Yarmishyn ◽  
Yu-Jer Hsiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscular Dystrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Premature Termination Codon ◽  
Becker Muscular Dystrophy ◽  
Functional Impairments ◽  
Motor Neuron Diseases

Neuromuscular diseases (NMDs) belong to a class of functional impairments that cause dysfunctions of the motor neuron-muscle functional axis components. Inherited monogenic neuromuscular disorders encompass both muscular dystrophies and motor neuron diseases. Understanding of their causative genetic defects and pathological genetic mechanisms has led to the unprecedented clinical translation of genetic therapies. Challenged by a broad range of gene defect types, researchers have developed different approaches to tackle mutations by hijacking the cellular gene expression machinery to minimize the mutational damage and produce the functional target proteins. Such manipulations may be directed to any point of the gene expression axis, such as classical gene augmentation, modulating premature termination codon ribosomal bypass, splicing modification of pre-mRNA, etc. With the soar of the CRISPR-based gene editing systems, researchers now gravitate toward genome surgery in tackling NMDs by directly correcting the mutational defects at the genome level and expanding the scope of targetable NMDs. In this article, we will review the current development of gene therapy and focus on NMDs that are available in published reports, including Duchenne Muscular Dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked myotubular myopathy (XLMTM), Spinal Muscular Atrophy (SMA), and Limb-girdle muscular dystrophy Type 2C (LGMD2C).

scholarly journals A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

2021 ◽  
pp. 1-18
Author(s):  
Andre Megarbane ◽  
Sami Bizzari ◽  
Asha Deepthi ◽  
Sandra Sabbagh ◽  
Hicham Mansour ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Cohort Analysis ◽  
Becker Muscular Dystrophy ◽  
Molecular Data ◽  
Motor Neuron Diseases ◽  
Charcot Marie Tooth Disease ◽  
High Prevalence ◽  
Tooth Disease

Background: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce. Objective: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon. Methods: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999–2019) was reviewed. Results: A total of 506 patients were diagnosed with 62 different disorders encompassing 10 classes of NMDs. 103 variants in 49 genes were identified. In this cohort, 81.4%of patients were diagnosed with motor neuron diseases and muscular dystrophies, with almost half of these described with spinal muscular atrophy (SMA) (40.3%of patients). We estimate a high SMA incidence of 1 in 7,500 births in Lebanon. Duchenne and Becker muscular dystrophy were the second most frequently diagnosed NMDs (17%of patients). The latter disorders were associated with the highest number of variants (39) identified in this study. A highly heterogeneous presentation of Limb Girdle Muscular Dystrophy and Charcot-Marie-Tooth disease was notably identified. The least common disorders (5.5%of patients) involved congenital, metabolic, and mitochondrial myopathies, congenital myasthenic syndromes, and myotonic dystrophies. A review of the literature for selected NMDs in Lebanon is provided. Conclusions: Our study indicates a high prevalence and underreporting of heterogeneous forms of NMDs in Lebanon- a major challenge with many novel NMD treatments in the pipeline. This report calls for a regional NMD patient registry.

scholarly journals Assessing Cognitive Function in Neuromuscular Diseases: A Pilot Study in a Sample of Children and Adolescents

2021 ◽  
Vol 10 (20) ◽  
pp. 4777
Author(s):  
Rossella D’Alessandro ◽  
Neftj Ragusa ◽  
Martina Vacchetti ◽  
Enrica Rolle ◽  
Francesca Rossi ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Motor Impairment ◽  
Sensory Neuropathy ◽  
Becker Muscular Dystrophy ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Cross Sectional

Central nervous system (CNS) involvement has been variously studied in pediatric neuromuscular disorders (NMDs). The primary goal of this study was to assess cognitive functioning in NMDs, and secondary aims were to investigate possible associations of cognitive impairment with motor impairment, neurodevelopmental delay, and genotype. This was a cross-sectional study of 43 pediatric patients, affected by six NMDs. Myotonic dystrophy type 1 (DM1) and glycogen storage disease type 2 (GSD2) patients had a delay on the Bayley-III scales. On Wechsler scales, DMD and DM1 patients showed lower FSIQ scores, with an intellectual disability (ID) in 27% and 50%, respectively. FSIQ was normal in Becker muscular dystrophy (BMD), GSD2, and hereditary motor sensory neuropathy (HMSN) patients, while higher individual scores were found in the spinal muscular atrophy (SMA) group. In the DM1 cohort, lower FSIQ correlated with worse motor performance (ρ = 0.84, p < 0.05), and delayed speech acquisition was associated with ID (p = 0.048), with worse cognitive impairment in the congenital than in the infantile form (p = 0.04). This study provides further evidence of CNS in some NMDs and reinforces the need to include cognitive assessment in protocols of care of selected pediatric NMDs.

scholarly journals Barriers and facilitators to clinical trial participation among parents of children with pediatric neuromuscular disorders

2018 ◽  
Vol 15 (2) ◽  
pp. 139-148 ◽  
Author(s):  
Holly L Peay ◽  
Barbara B Biesecker ◽  
Benjamin S Wilfond ◽  
Jill Jarecki ◽  
Kendall L Umstead ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Muscular Dystrophy ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Becker Muscular Dystrophy ◽  
Barriers And Facilitators ◽  
Trial Participation ◽  
Clinical Trial Participation ◽  
Parental Interest

Background/aims: Pediatric rare disease presents a challenging situation of high unmet need and a limited pool of potential clinical trial participants. Understanding perspectives of parents of children who have not participated in trials may facilitate approaches to optimize participation rates. The objective of this study was to explore factors associated with parental interest in enrolling children with pediatric neuromuscular disorders in clinical trials. Methods: Parents of individuals with Duchenne or Becker muscular dystrophy and spinal muscular atrophy were recruited through advocacy organizations, a registry, and clinics. These parents ( N = 203) completed a questionnaire including assessments of barriers and facilitators to clinical trial participation, parents’ interest in trial participation, and their perceptions of others’ views about participation in a clinical trial. Results: Trial interest in participating parents was high (64% combined group). The most highly endorsed barrier to participation was the possibility of receiving placebo, followed by not having enough information on risks and trial procedures. Compared to parents of children with Duchenne or Becker muscular dystrophy, parents of children with spinal muscular atrophy endorsed significantly more information and knowledge barriers. The greatest facilitators of participation were (1) confidence in improving disease understanding and (2) guarantee to receive the treatment after a successful trial. A logistic regression model, χ2 (4, n = 188) = 80.64, p < .001, indicated that higher perceived barriers and more frequent trial communication by the provider were associated with lower interest, while positive trial perceptions by the child’s providers and concordance in trial perceptions among those close to the decision-maker were associated with higher interest. Conclusion: We found high parental interest in pediatric neuromuscular trials that was tempered by concerns about the potential for randomization to a placebo arm. Participants perceived that their trial participation would be facilitated by additional education and guidance from their clinicians. Yet, intentions were negatively associated with frequency of provider communication, perhaps reflecting waning parental interest with a greater understanding of limitations in trial access, increased sophistication in their understanding of trial design, and appreciation of potential burden. To support parents’ informed decisions, it is important to educate them to evaluate the quality of research, as well as providing lay information explaining the use of placebo, trial processes, and potential barriers to long-term drug access. Our findings should inform the development of targeted educational content, clinician training, and decision support tools.

The Dystrophinopathies

2010 ◽  
Author(s):  
Veronica J. Hinton
Keyword(s):  
Muscular Dystrophy ◽  
Clinical Investigation ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Becker Muscular Dystrophy ◽  
Severe Form ◽  
Creatine Kinase Activity ◽  
Behavioral Abnormalities ◽  
Behavioral Attributes

The dystrophinopathies, including Duchenne and Becker muscular dystrophies, are X-linked, developmental neuromuscular disorders. The dystrophinopathies are so named because of their effect on the production of the protein dystrophin, and are known primarily as muscle diseases in males that present with progressive weakness that is eventually fatal. To date, there is no cure for the dystrophinopathies, and treatment focuses on slowing the disease progression. Medical management is complex and multifaceted. It includes care for neuromuscular, orthopedic, rehabilitative, nutritional, respiratory, cardiac, gastrointestinal, psychological, and palliative aspects of the disease. The devastating physical toll of the diseases is well known. In contrast, the associated cognitive and behavioral abnormalities are less familiar to most clinicians. Nonetheless, the cognitive and behavioral attributes of the dystrophinopathies impact on the affected individual’s and his family’s functioning in far-ranging ways. More importantly, identifying any associated cognitive and behavioral abnormalities early, and providing appropriate interventions, can contribute substantially to an affected individual’s quality of life. The dystrophinopathies are the most common neuromuscular diseases of childhood, affect all ethnic groups, and have an estimated overall prevalence of 63 per million (Emery 1991; Emery 1992). Positive diagnosis for the Duchenne muscular dystrophy (DMD, the more severe form) is based on the following criteria: (a) male; (b) onset of weakness before age 5; (c) initial proximal muscle weakness; (d) muscle hypertrophy, most prominent in the calves; (e) elevated creatine kinase activity of at least 10 times above the upper limit of normal; and either (f) positive histopathological confirmation by muscle biopsy or (g) molecular characterization of a mutation within the gene for dystrophin. Approximately 1 in 3,500 live male births meet these criteria (Emery 1992). The diagnosis of Becker muscular dystrophy (BMD, the less severe form) is clinically determined by those children who remain walking at age 12. Individuals with BMD have a slower course and considerably longer lifespan than those with DMD. Natural history studies have been conducted to characterize the course of the disease. The Clinical Investigation of Duchenne Dystrophy group (CIDD) followed more than 200 individuals affected with DMD for more than 10 years (Brooke et al. 1983; Hyser et al. 1987; Mendell et al. 1987).

scholarly journals Neuromuscular Ultrasound: Clinical Applications and Diagnostic Values

2018 ◽  
Vol 45 (6) ◽  
pp. 605-619 ◽  
Author(s):  
Jean K. Mah ◽  
Nens van Alfen
Keyword(s):  
Peripheral Nerve ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Clinical Applications ◽  
Motor Neuron Diseases ◽  
Nerve Tumor ◽  
Diagnostic Certainty ◽  
Diagnostic Values ◽  
Peripheral Nerve Trauma

AbstractAdvances in high-resolution ultrasound have provided clinicians with unique opportunities to study diseases of the peripheral nervous system. Ultrasound complements the clinical and electrophysiology exam by showing the degree of abnormalities in myopathies, as well as spontaneous muscle activities in motor neuron diseases and other disorders. In experienced hands, ultrasound is more sensitive than MRI in detecting peripheral nerve pathologies. It can also guide needle placement for electromyography exam, therapeutic injections, and muscle biopsy. Ultrasound enhances the ability to detect carpal tunnel syndrome and other focal nerve entrapment, as well as pathological nerve enlargements in genetic and acquired neuropathies. Furthermore, ultrasound can potentially be used as a biomarker for muscular dystrophy and spinal muscular atrophy. The combination of electromyography and ultrasound can increase the diagnostic certainty of amyotrophic lateral sclerosis, aid in the localization of brachial plexus or peripheral nerve trauma and allow for surveillance of nerve tumor progression in neurofibromatosis. Potential limitations of ultrasound include an inability to image deeper structures, with lower sensitivities in detecting neuromuscular diseases in young children and those with mitochondrial myopathies, due to subtle changes or early phase of the disease. As well, its utility in detecting critical illness neuromyopathy remains unclear. This review will focus on the clinical applications of neuromuscular ultrasound. The diagnostic values of ultrasound for screening of myopathies, neuropathies, and motor neuron diseases will be presented.

scholarly journals Carrier detection of duchenne and becker muscular dystrophy using muscle dystrophin immunohistochemistry

1992 ◽  
Vol 50 (4) ◽  
pp. 478-485 ◽  
Author(s):  
Acary S. Bulle Oliveira ◽  
Alberto A. Gabbai ◽  
Beny Schmidt ◽  
Beatriz Hitomi Kiyomoto ◽  
G. Camargo Lima ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Genetic Analysis ◽  
Spinal Muscular Atrophy ◽  
Muscle Biopsy ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Becker Muscular Dystrophy ◽  
Carrier State ◽  
Carrier Detection ◽  
Muscle Biopsies

To ascertain whether dystrophin immunohistochemistry could improve DMD/ BMD carrier detection, we analyzed 14 muscle biopsies from 13 DMD and one BMD probable and possible carriers. All women were also evaluated using conventional methods, including genetic analysis, clinical and neurological evaluation, serum CK levels, KMG, and muscle biopsy. In 6 cases, there was a mosaic of dystrophin-positive and dystrophin-deficient fibers that allowed to make the diagnosis of a carrier state. Comparing dystrophin immunohistochemistry to the traditional methods, it was noted that this method is less sensitive than serum CK measuremens, but is more sensitive than EMG and muscle biopsy. The use of dystrophin immunohistochemistry in addition to CK, EMG and muscle biopsy improved the accuracy of carrier detection. This method is also helpful to distinguish manifesting DMD carriers from patients with other neuromuscular diseases like limb-girdle muscular dystrophy and spinal muscular atrophy.

scholarly journals Becker muscular dystrophy associated with sarcomeric hypertrophic cardiomyopathy in a paediatric patient: a case report

2019 ◽  
Vol 3 (3) ◽  
Author(s):  
Paola Dolader ◽  
Ella Field ◽  
Anna Sarkozy ◽  
Juan Pablo Kaski
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Muscular Dystrophy ◽  
Neuromuscular Disorders ◽  
Elevated Serum ◽  
Becker Muscular Dystrophy ◽  
Neuromuscular Disorder ◽  
Chain Gene ◽  
Septal Hypertrophy ◽  
History Of ◽  
Myocardial Involvement

Abstract Background  Becker muscular dystrophy (BMD) is a neuromuscular disorder associated with myocardial involvement. The most frequent presentation is dilated cardiomyopathy. There have been isolated reports of hypertrophic cardiomyopathy (HCM) in association with BMD, but it is unclear whether these patients had an additional aetiology. Case summary  A 10-year-old boy was diagnosed with BMD having presented with a history of muscular pain during exercise and elevated serum creatine kinase levels. A cardiac screening was arranged and the echocardiogram confirmed an asymmetric septal hypertrophy. Given the unusual finding of HCM in this patient with BMD, we performed genetic testing for HCM-causing mutations and identified a likely pathogenic variant in heterozygosis in the beta-myosin heavy chain gene. Discussion  This case highlights the importance of considering additional aetiologies of cardiac disease in the presence of infrequent phenotypic expressions in neuromuscular disorders.

Motor Neuron Diseases

2014 ◽  
Author(s):  
Elena Ratti ◽  
Merit E. Cudkowicz ◽  
James D Berry
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Muscular Atrophy ◽  
Experimental Therapy ◽  
Rapid Progression ◽  
Motor Neuron Diseases ◽  
Efficacy Outcome ◽  
Single Disease Entity

The motor neuron diseases (MNDs) are a family of diseases commonly categorized by their propensity to affect upper or lower motor neurons and by their mode of inheritance. The chapter provides some content on infectious MNDs caused by viral infections affecting the motor neurons in the anterior horn of the spinal cord. However, the chapter devotes most of its attention to the inherited and sporadically occurring MNDs. The majority of research into adult MND focuses on amyotrophic lateral sclerosis (ALS) due to its high prevalence, rapid progression, and phenotypical similarities between its inherited form and its sporadic form. As our knowledge of genetic mechanisms underlying ALS pathology has grown, common themes have emerged. These include abnormalities in RNA biology, axonal transport, protein folding, and inflammatory responses. These themes currently drive much of the direction in ALS experimental therapy development. It is clear that MND is complex and involves several different molecular pathways. Given this complexity, ALS might not be a single disease entity, and if this is the case, treatment approaches may need to be targeted to specific pathologies rather than all ALS patients on a broad scale. Chapter content is enhanced by tables outlining the types of MNDs, criteria for supporting a diagnosis, first-line workup, the genes associated with ALS, ALS efficacy outcome measures, symptom management of ALS, and spinal muscular atrophy classification. Mechanisms of ALS are illustrated, and clinical photographs demonstrate symptoms. This chapter contains 252 references. 

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