Diagnosis and New Treatment Avenues in Spinal Muscular Atrophy

2017 ◽  
Vol 48 (04) ◽  
pp. 273-281 ◽  
Author(s):  
Janbernd Kirschner ◽  
Astrid Pechmann
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscle Weakness ◽  
Age Of Onset ◽  
Muscular Atrophy ◽  
Multidisciplinary Treatment ◽  
Homozygous Deletion ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Proximal Muscle Weakness ◽  
Proximal Muscle

AbstractSpinal muscular atrophy (SMA) is an autosomal-recessive, neuromuscular disorder that is characterized by degeneration of the anterior horn cells of the spinal cord, resulting in muscle atrophy and proximal muscle weakness. SMA is caused by a homozygous deletion in the survival motor neuron 1 (SMN1) gene on chromosome 5q13. The SMN gene region also comprises a centromeric copy containing the SMN2 gene. The severity of the disease correlates with age of onset and SMN2 copy number and varies from a severe muscle weakness with tetraplegia in infants to a mild proximal muscle weakness in ambulant children. Due to lack of a curative treatment, the care of children with SMA consists mostly of a multidisciplinary treatment including respiratory, nutritional, and orthopaedic management. During the past years, there has been a promising approach for the development of drugs intervening the pathophysiology of SMA with the main idea of upregulating the levels of functional SMN protein. Here, we summarize recent studies regarding diagnosis and treatment avenues in SMA.

scholarly journals Spinal Muscular Atrophy Type 3: A Case Report

2020 ◽  
Vol 43 (3) ◽  
pp. 183-187
Author(s):  
Maria Kibtiar ◽  
Roksana Parvin ◽  
Manik Kumar Talukder ◽  
Choudhury Ali Kawser
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Proximal Muscle Weakness ◽  
Proximal Muscle ◽  
Spinal Muscular Atrophy Type ◽  
Genetically Determined ◽  
Type 3 ◽  
Tendon Reflexes

Spinal muscular atrophy (SMA) type 3 is a relatively stable genetically determined chronic neuromuscular disorder caused by degeneration of motor neurons of spinal cord. Patients with type 3 SMA may gradually experience decline in muscle strength and motor function. However functional progression is difficult to document and mechanisms remain poorly understood. A five years old boy presented with proximal muscle weakness, generalized hypotonia, absent deep tendon reflexes and features of neuropathy and labeled as SMA type 3. Bangladesh J Child Health 2019; VOL 43 (3) :183-187

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 Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Wiebke A. Rehorst ◽  
Maximilian P. Thelen ◽  
Hendrik Nolte ◽  
Clara Türk ◽  
Sebahattin Cirak ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Metabolic Labeling

Abstract Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is primarily considered as a motor neuron disease, recent data suggests that survival motor neuron (SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.

scholarly journals Circulating microRNAs as potential biomarkers and therapeutic targets in spinal muscular atrophy

2020 ◽  
Vol 13 ◽  
pp. 175628642097995
Author(s):  
Tai-Heng Chen
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Therapeutic Targets ◽  
Homozygous Deletion ◽  
Survival Motor Neuron ◽  
Novel Mirna ◽  
Potential Applications ◽  
Smn Protein

Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of particular groups of motor neurons (MNs) in the anterior horn of the spinal cord with progressive muscle wasting. SMA is caused by a deficiency of the survival motor neuron (SMN) protein due to a homozygous deletion or mutation of the SMN1 gene. However, the molecular mechanisms whereby the SMN complex regulates MN functions are not fully elucidated. Emerging studies on SMA pathogenesis have turned the attention of researchers to RNA metabolism, given that increasingly identified SMN-associated modifiers are involved in both coding and non-coding RNA (ncRNA) processing. Among various ncRNAs, microRNAs (miRNAs) are the most studied in terms of regulation of posttranscriptional gene expression. Recently, the discovery that miRNAs are critical to MN function and survival led to the study of dysregulated miRNAs in SMA pathogenesis. Circulating miRNAs have drawn attention as a readily available biomarker due to their property of being clinically detectable in numerous human biofluids through non-invasive approaches. As there are recent promising findings from novel miRNA-based medicines, this article presents an extensive review of the most up-to-date studies connecting specific miRNAs to SMA pathogenesis and the potential applications of miRNAs as biomarkers and therapeutic targets for SMA.

scholarly journals Combining multi-omics and drug perturbation profiles to identify novel treatments that improve disease phenotypes in spinal muscular atrophy

2019 ◽  
Author(s):  
Katharina E. Meijboom ◽  
Viola Volpato ◽  
Jimena Monzón-Sandoval ◽  
Joseph M. Hoolachan ◽  
Suzan M. Hammond ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Muscle Pathology ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Disease Phenotypes ◽  
Parallel Data ◽  
Smn Protein

ABSTRACTSpinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the lead candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple, parallel data driven approaches for development of novel treatments for use in combination with SMN restoration therapies.

Novel protective modifiers in mouse models of spinal muscular atrophy

2018 ◽  
Author(s):  
◽  
Kevin Andrew Cody Kaifer
Keyword(s):  
Spinal Muscular Atrophy ◽  
Mouse Models ◽  
Muscular Atrophy ◽  
Experimental System ◽  
Homozygous Deletion ◽  
Alpha Synuclein ◽  
Survival Motor Neuron ◽  
Virus Serotype ◽  
Smn Protein

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by the homozygous deletion or mutation in the survival motor neuron-1 (SMN1) gene resulting in extremely low levels of the SMN protein. Without treatment, the majority of SMA cases progress rapidly and lead to mortality by age 2. SMA is uniquely positioned for therapy, however, as a nearly identical gene called SMN2 can be modulated to express the functional SMN protein. A recently approved, highly efficacious therapy called Spinraza adopts this strategy and has brought promise to the SMA patient community. Despite this breakthrough, it is widely hypothesized that a long-term strategy will require a combinatorial approach to address the complexity of this disease, and additional therapeutic strategies need to be established. Towards this aim, the past decade of research has led to the elucidation of key molecular events that contribute to the pathology of SMA as well as several factors that modulate disease severity. Referred to as protective modifiers, these factors represent potential targets for combinatorial therapy. In this work we establish a strategy to identify and characterize novel protective modifiers in mouse models of SMA. Our approach utilizes adenoassociated virus serotype 9 (AAV9) to express putative modifiers in mouse models, effectively allowing us to determine their effects in vivo. Using our experimental system, we confirm that a previously controversial modifier, Plastin-3, reduces severity in mouse models of SMA. We also identify miR-23a, DOK7, and [alpha]-synuclein as novel protective modifiers of SMA. These insights implicate microRNA dysregulation, neuromuscular junction organization, and synaptic transmission as disease modifying pathways that contain potential therapeutic candidates for the treatment of SMA.

scholarly journals Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

2015 ◽  
Vol 112 (43) ◽  
pp. E5863-E5872 ◽  
Author(s):  
Laurent P. Bogdanik ◽  
Melissa A. Osborne ◽  
Crystal Davis ◽  
Whitney P. Martin ◽  
Andrew Austin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Clinical Presentation ◽  
Age Of Onset ◽  
Muscular Atrophy ◽  
Severe Disease ◽  
Motor Units ◽  
Survival Motor Neuron ◽  
Clinical Electrophysiology ◽  
Type Ii

Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system.

scholarly journals Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1346
Author(s):  
Jan Lejman ◽  
Grzegorz Zieliński ◽  
Piotr Gawda ◽  
Monika Lejman
Keyword(s):  
Alternative Splicing ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Homozygous Deletion ◽  
Survival Motor Neuron ◽  
Biological Information ◽  
Survival Motor Neuron Protein ◽  
Attractive Therapeutic Target

It has been estimated that 80% of the pre-mRNA undergoes alternative splicing, which exponentially increases the flow of biological information in cellular processes and can be an attractive therapeutic target. It is a crucial mechanism to increase genetic diversity. Disturbed alternative splicing is observed in many disorders, including neuromuscular diseases and carcinomas. Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. Homozygous deletion in 5q13 (the region coding for the motor neuron survival gene (SMN1)) is responsible for 95% of SMA cases. The nearly identical SMN2 gene does not compensate for SMN loss caused by SMN1 gene mutation due to different splicing of exon 7. A pathologically low level of survival motor neuron protein (SMN) causes degeneration of the anterior horn cells in the spinal cord with associated destruction of α-motor cells and manifested by muscle weakness and loss. Understanding the regulation of the SMN2 pre-mRNA splicing process has allowed for innovative treatment and the introduction of new medicines for SMA. After describing the concept of splicing modulation, this review will cover the progress achieved in this field, by highlighting the breakthrough accomplished recently for the treatment of SMA using the mechanism of alternative splicing.

scholarly journals Detection of Spinal Muscular Atrophy Patients Using Dried Saliva Spots

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1621
Author(s):  
Yogik Onky Silvana Wijaya ◽  
Hisahide Nishio ◽  
Emma Tabe Eko Niba ◽  
Kentaro Okamoto ◽  
Haruo Shintaku ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Dried Blood Spots ◽  
Gene Replacement ◽  
Homozygous Deletion ◽  
Survival Motor Neuron ◽  
Screening System ◽  
Emerging Treatments ◽  
The Right

Spinal muscular atrophy (SMA) is a lower motor neuron disease, once considered incurable. The main symptoms are muscle weakness and muscular atrophy. More than 90% of cases of SMA are caused by homozygous deletion of survival motor neuron 1 (SMN1). Emerging treatments, such as splicing modulation of SMN2 and SMN gene replacement therapy, have improved the prognoses and motor functions of patients. However, confirmed diagnosis by SMN1 testing is often delayed, suggesting the presence of diagnosis-delayed or undiagnosed cases. To enable patients to access the right treatments, a screening system for SMA is essential. Even so, the current newborn screening system using dried blood spots is still invasive and cumbersome. Here, we developed a completely non-invasive screening system using dried saliva spots (DSS) as an alternative DNA source to detect SMN1 deletion. In this study, 60 DSS (40 SMA patients and 20 controls) were tested. The combination of modified competitive oligonucleotide priming-polymerase chain reaction and melting peak analysis clearly distinguished DSS samples with and without SMN1. In conclusion, these results suggest that our system with DSS is applicable to SMA patient detection in the real world.

scholarly journals Managing pregnancy in a spinal muscular atrophy type III patient in Indonesia: a case report

2022 ◽  
Vol 16 (1) ◽  
Author(s):  
Cempaka Thursina Srie Setyaningrum ◽  
Indra Sari Kusuma Harahap ◽  
Dian Kesumapramudya Nurputra ◽  
Irwan Taufiqur Rachman ◽  
Nur Imma Fatimah Harahap
Keyword(s):  
Genetic Counseling ◽  
Genetic Testing ◽  
Spinal Muscular Atrophy ◽  
Clinical Decision Making ◽  
Age Of Onset ◽  
Muscular Atrophy ◽  
Genetic Disorder ◽  
Survival Motor Neuron ◽  
Collaborative Management ◽  
Asian Woman

Abstract Background Spinal muscular atrophy is a genetic disorder characterized by degeneration of lower motor neurons, leading to progressive muscular atrophy and even paralysis. Spinal muscular atrophy usually associated with a defect of the survival motor neuron 1 (SMN-1) gene. Classification of spinal muscular atrophy is based on the age of onset and maximum motor function milestone achieved. Although spinal muscular atrophy can be screened for in newborns, and even confirmed earlier genetically, this remains difficult in Third World countries such as Indonesia. Case presentation A 28-year-old Asian woman in the first trimester of her second pregnancy, was referred to the neurology department from the obstetric department. Her milestone history showed she was developmentally delayed and the ability to walk independently was reached at 26 months old. At 8 years old, she started to stumble and lose balance while walking. At this age, spinal muscular atrophy was suspected because of her clinical presentations, without any molecular genetic testing. She was married at the age of 25 years and was soon pregnant with her first child. At the gestational age of 32 weeks, her first pregnancy was ended by an emergency caesarean section because of premature rupture of the membranes. In this second pregnancy, she was referred early to the general hospital from the district hospital to receive multidisciplinary care. She and her first daughter underwent genetic testing for spinal muscular atrophy, which has been readily available in our institution since 2018, to confirm the diagnosis and prepare for genetic counseling. Conclusions Managing pregnancy in a patient with spinal muscular atrophy should be performed collaboratively. In this case, genetic testing of spinal muscular atrophy and the collaborative management of this patient allowed the clinical decision making and genetic counseling throughout her pregnancy and delivery.

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