scholarly journals Persistent neuromuscular junction transmission defects in adults with spinal muscular atrophy treated with nusinersen

2021 ◽  
Vol 3 (2) ◽  
pp. e000164
Author(s):  
W David Arnold ◽  
Steven Severyn ◽  
Songzhu Zhao ◽  
David Kline ◽  
Matthew Linsenmayer ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
T Test ◽  
Survival Motor Neuron ◽  
Repetitive Nerve Stimulation ◽  
Maximum Voluntary Isometric Contraction ◽  
Smn Protein

ObjectiveSpinal muscular atrophy (SMA) is a motor neuron disease caused by low levels of survival motor neuron (SMN) protein. Prior work in models and patients has demonstrated electrophysiological and morphological defects at the neuromuscular junction (NMJ). Therapeutic development has resulted in clinically available therapies to increase SMN protein levels in patients and improve muscle function. Here we aimed to investigate the effect of SMN restoration (via nusinersen) on NMJ transmission in adults with SMA.MethodsParticipants undergoing nusinersen treatment underwent 3 Hz repetitive nerve stimulation (RNS) of the spinal accessory nerve to assess compound muscle action potential amplitude decrement. Maximum voluntary isometric contraction (MVICT), Revised Upper Limb Module (RULM), and 6 min walk test (6MWT) were assessed for correlations with decrement.ResultsData from 13 ambulatory (7 men/6 women, mean age 40±11 years) and 11 non-ambulatory (3 men/8 women, mean age 38±12 years) participants were analysed. Cross-sectional analyses of RNS decrement were similar at 14 months of nusinersen (−14.2%±11.5%, n=17) vs baseline (−11.9%±8.3%, n=15) (unpaired t-test, p=0.5202). Longitudinal comparison of decrement in eight participants showed no change at 14 months (−13.9%±6.7%) vs baseline (−16.9%±13.4%) (paired t-test, p=0.5863). Decrement showed strong correlations with measures of MVICT, RULM and 6MWT but not age or disease duration.ConclusionAdults with SMA had significant NMJ transmission defects that were not corrected with 14 months of nusinersen treatment. NMJ defects were negatively associated with physical function, and thus may represent a promising target for additive or combinatorial treatments.

scholarly journals Utilizing gene therapy methods to probe the genetic requirements to prevent spinal muscular atrophy.

2016 ◽  
Author(s):  
◽  
Madeline R. Miller
Keyword(s):  
Neuromuscular Junction ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Downstream Effects ◽  
Smn Protein ◽  
Progressive Weakness

Spinal Muscular Atrophy is clinically recognized as a progressive weakness within the trunk and proximal limbs that will lead to breathing failure and death within infants. As a neurodegenerative genetic disease, SMA is caused by loss of motor neurons, which in turn is caused by low levels of the Survival Motor Neuron (SMN) protein. The mechanism by which a ubiquitously expressed protein such as SMN is able to cause the specific death of motor neurons is highly debated and of great interest. Work presented here focuses on understanding the biological requirements of SMN and its downstream effects on the neuromuscular junction. To this end we utilize viral based gene delivery as a powerful tool to assess the effects of genes of interest in vivo. Our findings contribute to the conversation regarding whether SMA is truly a "motor neuron" disease, suggesting that astrocytes play a meaningful role in staving off SMA. Further, we investigate the domains within SMN needed to maintain its function in a mammalian system. We take a novel and challenging approach to identify a minimal domain capable of maintaining function. Finally, we demonstrate the practical use of morophological analysis of the neuromuscular junction as a means to characterize SMA pathology.

scholarly journals Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

2016 ◽  
Vol 10 ◽  
pp. JEN.S33122 ◽  
Author(s):  
Saif Ahmad ◽  
Kanchan Bhatia ◽  
Annapoorna Kannan ◽  
Laxman Gangwani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Skeletal Muscle Atrophy ◽  
Spinal Motor Neurons ◽  
Low Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

scholarly journals Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron

2018 ◽  
Vol 29 (2) ◽  
pp. 96-110 ◽  
Author(s):  
Kelsey M. Gray ◽  
Kevin A. Kaifer ◽  
David Baillat ◽  
Ying Wen ◽  
Thomas R. Bonacci ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Protein Isoforms ◽  
Survival Motor Neuron Protein ◽  
Protein Levels ◽  
Motor Neuron Protein ◽  
Smn Protein ◽  
Oligomerization Domain

SMN protein levels inversely correlate with the severity of spinal muscular atrophy. The SCFSlmbE3 ligase complex interacts with a degron embedded within the C-terminal self-oligomerization domain of SMN. The findings elucidate a model whereby accessibility of the SMN degron is regulated by self-multimerization.

scholarly journals Spinal Muscular Atrophy Type B Awareness and Symptoms Prediction Using 3D Segmentation Process in MRI Images

2019 ◽  
pp. 312-318
Author(s):  
V. Manochithra ◽  
G. Sumithra
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Homozygous Deletion ◽  
Survival Motor Neuron ◽  
Molecular Testing ◽  
Prevention Measures ◽  
Neuron Loss ◽  
Motor Neuron Loss ◽  
Smn Protein

Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produce reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that the understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early phase clinical trials. This proposed model investigates the symptoms and scans readings from the initial MRI scan images of babies with mutation progress and SMN proteins formation benchmark values for this particular disorder SMA and further this segmented parameters are acquitted into the K-means clustering technique that predict the report with the disorder symptoms with MSE (mean square error) values that helps the babies in future to take prevention measures to overcome this problem.

scholarly journals Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy

2020 ◽  
Vol 4 (1) ◽  
pp. e202000889
Author(s):  
Anne Rietz ◽  
Kevin J Hodgetts ◽  
Hrvoje Lusic ◽  
Kevin M Quist ◽  
Erkan Y Osman ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Potential Drug ◽  
Transgenic Mouse Models ◽  
Fda Approval ◽  
Smn Protein

Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. SMA results from insufficient survival motor neuron (SMN) protein due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models mimicking milder cases that manifest post-infancy have proven challenging to develop. We established a titratable model of mild and moderate SMA using the splicing compound NVS-SM2. Administration for 30 d prevented development of the SMA phenotype in severe SMA mice, which typically show rapid weakness and succumb by postnatal day 11. Furthermore, administration at day eight resulted in phenotypic recovery. Remarkably, acute dosing limited to the first 3 d of life significantly enhanced survival in two severe SMA mice models, easing the burden on neonates and demonstrating the compound as suitable for evaluation of follow-on therapies without potential drug–drug interactions. This pharmacologically tunable SMA model represents a useful tool to investigate cellular and molecular pathogenesis at different stages of disease.

scholarly journals New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges

2020 ◽  
Vol 9 (7) ◽  
pp. 2222 ◽  
Author(s):  
Sonia Messina ◽  
Maria Sframeli
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Respiratory Muscles ◽  
Gene Replacement ◽  
Survival Motor Neuron ◽  
Significant Disability ◽  
New Challenges ◽  
Smn Protein ◽  
New Treatments

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases with progressive weakness of skeletal and respiratory muscles, leading to significant disability. The disorder is caused by mutations in the survival motor neuron 1 (SMN1) gene and a consequent decrease in the SMN protein leading to lower motor neuron degeneration. Recently, Food and Drug Administration (FDA) and European Medical Agency (EMA) approved the antisense oligonucleotide nusinersen, the first SMA disease-modifying treatment and gene replacement therapy by onasemnogene abeparvovec. Encouraging results from phase II and III clinical trials have raised hope that other therapeutic options will enter soon in clinical practice. However, the availability of effective approaches has raised up ethical, medical and financial issues that are routinely faced by the SMA community. This review covers the available data and the new challenges of SMA therapeutic strategies.

scholarly journals Metabolic Dysfunction in Spinal Muscular Atrophy

2021 ◽  
Vol 22 (11) ◽  
pp. 5913
Author(s):  
Marc-Olivier Deguise ◽  
Lucia Chehade ◽  
Rashmi Kothary
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Hormonal Regulation ◽  
Muscular Atrophy ◽  
Genetic Disorder ◽  
Survival Motor Neuron ◽  
Potential Contribution ◽  
Metabolic Dysfunction ◽  
History Of ◽  
Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense oligonucleotide treatment and gene therapy have made it possible for SMA patients to benefit from improvements in many aspects of the once devastating natural history of the disease. How the depletion of survival motor neuron (SMN) protein, the product of the gene implicated in the disease, leads to the consequent pathogenic changes remains unresolved. Over the past few years, evidence toward a potential contribution of gastrointestinal, metabolic, and endocrine defects to disease phenotype has surfaced. These findings ranged from disrupted body composition, gastrointestinal tract, fatty acid, glucose, amino acid, and hormonal regulation. Together, these changes could have a meaningful clinical impact on disease traits. However, it is currently unclear whether these findings are secondary to widespread denervation or unique to the SMA phenotype. This review provides an in-depth account of metabolism-related research available to date, with a discussion of unique features compared to other motor neuron and related disorders.

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