scholarly journals A Novel De Novo Variant in DYNC1H1 Causes Spinal Muscular Atrophy Lower Extremity Predominant in Identical Twins: A Case Report

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110274
Author(s):  
Alexa Derksen ◽  
Amytice Mirchi ◽  
Luan T. Tran ◽  
Lei Cao-Lei ◽  
Maryam Oskoui ◽  
...  
Keyword(s):  
Lower Extremity ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
De Novo ◽  
Muscular Atrophy ◽  
Monozygotic Twins ◽  
Neuromuscular Disorder ◽  
Predominant Type ◽  
De Novo Variant

Mutations in DYNC1H1 have been shown to cause spinal muscular atrophy lower extremity predominant type 1 (SMALED1), an autosomal dominant genetic neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in muscle weakness. Here, we describe monozygotic twins, one with a more severe upper motor neuron phenotype as a result of a suspected perinatal hypoxic-ischemic event and the other presenting a typical lower motor neuron phenotype. Using exome sequencing, we identified the novel de novo variant c.752G>T; p.Arg251Leu in DYNC1H1. We thereby add this variant to the growing list of mutations in DYNC1H1 that cause SMALED1.

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 Ultrastructural characterization of peripheral denervation in a mouse model of Type III spinal muscular atrophy

2021 ◽  
Author(s):  
Federica Fulceri ◽  
Francesca Biagioni ◽  
Fiona Limanaqi ◽  
Carla L. Busceti ◽  
Larisa Ryskalin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Disease Onset ◽  
Muscle Spindles ◽  
Neuromuscular Disorder ◽  
Type Iii ◽  
Smn Protein

AbstractSpinal muscular atrophy (SMA) is a heritable, autosomal recessive neuromuscular disorder characterized by a loss of the survival of motor neurons (SMN) protein, which leads to degeneration of lower motor neurons, and muscle atrophy. Despite SMA being nosographically classified as a motor neuron disease, recent advances indicate that peripheral alterations at the level of the neuromuscular junction (NMJ), involving the muscle, and axons of the sensory-motor system, occur early, and may even precede motor neuron loss. In the present study, we used a mouse model of slow progressive (type III) SMA, whereby the absence of the mouse SMN protein is compensated by the expression of two human genes (heterozygous SMN1A2G, and SMN2). This leads to late disease onset and prolonged survival, which allows for dissecting slow degenerative steps operating early in SMA pathogenesis. In this purely morphological study carried out at transmission electron microscopy, we extend the examination of motor neurons and proximal axons towards peripheral components, including distal axons, muscle fibers, and also muscle spindles. We document remarkable ultrastructural alterations being consistent with early peripheral denervation in SMA, which may shift the ultimate anatomical target in neuromuscular disease from the spinal cord towards the muscle. This concerns mostly mitochondrial alterations within distal axons and muscle, which are quantified here through ultrastructural morphometry. The present study is expected to provide a deeper knowledge of early pathogenic mechanisms in SMA.

scholarly journals Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Tai-Heng Chen ◽  
Jun-An Chen
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Cell Types ◽  
Spinal Motor Neurons ◽  
Potential Applications ◽  
The Central Nervous System

Two crucial questions in neuroscience are how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. In the central nervous system, spinal motor neurons serve as one of the best-characterized cell types for addressing these two questions. In this review, we dissect these questions by evaluating the emerging role of regulatory microRNAs in motor neuron generation in developing embryos and their potential contributions to neurodegenerative diseases such as spinal muscular atrophy (SMA). Given recent promising results from novel microRNA-based medicines, we discuss the potential applications of microRNAs for clinical assessments of SMA disease progression and treatment.

scholarly journals Genomic analysis of a spinal muscular atrophy (SMA) discordant family identifies a novel mutation in TLL2, an activator of growth differentiation factor 8 (myostatin): a case report

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Jianping Jiang ◽  
Jinwei Huang ◽  
Jianlei Gu ◽  
Xiaoshu Cai ◽  
Hongyu Zhao ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
De Novo ◽  
Muscular Atrophy ◽  
Novel Mutation ◽  
Genomic Analysis ◽  
Neuromuscular Disorder ◽  
De Novo Mutation ◽  
Compound Heterozygous ◽  
Mice Model ◽  
Compound Heterozygous Mutations

Abstract Background Spinal muscular atrophy (SMA) is a rare neuromuscular disorder threating hundreds of thousands of lives worldwide. And the severity of SMA differs among different clinical types, which has been demonstrated to be modified by factors like SMN2, SERF1, NAIP, GTF2H2 and PLS3. However, the severities of many SMA cases, especially the cases within a family, often failed to be explained by these modifiers. Therefore, other modifiers are still waiting to be explored. Case presentation In this study, we presented a rare case of SMA discordant family with a mild SMA male patient and a severe SMA female patient. The two SMA cases fulfilled the diagnostic criteria defined by the International SMA Consortium. With whole exome sequencing, we confirmed the heterozygous deletion of exon7 at SMN1 on the parents’ genomes and the homozygous deletions on the two patients’ genomes. The MLPA results confirmed the deletions and indicated that all the family members carry two copies of SMN2, SERF1, NAIP and GTF2H2. Further genomic analysis identified compound heterozygous mutations at TLL2 on the male patient’s genome, and compound heterozygous mutations at VPS13A and the de novo mutation at AGAP5 on female patient’s genome. TLL2 is an activator of myostatin, which negatively regulates the growth of skeletal muscle tissue. Mutation in TLL2 has been proved to increase muscular function in mice model. VPS13A encodes proteins that control the cycling of proteins through the trans-Golgi network to endosomes, lysosomes and the plasma membrane. And AGAP5 was reported to have GTPase activator activity. Conclusions We reported a case of SMA discordant family and identified mutations at TLL2, VPS13A and AGAP5 on the patients’ genomes. The mutations at TLL2 were predicted to be pathogenic and are likely to alleviate the severity of the male SMA patient. Our finding broadens the spectrum of genetic modifiers of SMA and will contribute to accurate counseling of SMA affected patients and families.

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 De novo variant in KIF26B is associated with pontocerebellar hypoplasia with infantile spinal muscular atrophy

2018 ◽  
Vol 176 (12) ◽  
pp. 2623-2629 ◽  
Author(s):  
Monica H. Wojcik ◽  
Kyoko Okada ◽  
Sanjay P. Prabhu ◽  
Dan W. Nowakowski ◽  
Keri Ramsey ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
De Novo ◽  
Muscular Atrophy ◽  
Pontocerebellar Hypoplasia ◽  
De Novo Variant

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 Distal Spinal Muscular Atrophy: An Overlooked Etiology of Weaning Failure in Children with Respiratory Insufficiency

2018 ◽  
Vol 07 (03) ◽  
pp. 159-162 ◽  
Author(s):  
Asgar Eghbalkhah ◽  
Kamyar Kamrani ◽  
Nahid Khosroshahi ◽  
Hossein Yousefimanesh ◽  
Zahra Eskandarizadeh ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Respiratory Insufficiency ◽  
Muscular Atrophy ◽  
Pediatric Intensive Care ◽  
Neuromuscular Disorder ◽  
Weaning Failure ◽  
Life Threatening

AbstractSpinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder that involves the anterior horn motor neurons. It is a disease with a poor prognosis presenting with progressive distal motor weakness and respiratory insufficiency from diaphragmatic paralysis followed by distal muscle weakness before 6 months of age. With the intent to spread the awareness of this rare and life-threatening disease, we report a 2.5-month-old female infant with a subsequent diagnosis of SMARD1, who was admitted in our pediatric intensive care unit with chief complaint of progressive respiratory distress and poor feeding.

scholarly journals Central and peripheral delivery of AAV9-SMN target different pathomechanisms in a mouse model of spinal muscular atrophy

2021 ◽  
Author(s):  
Aoife N Reilly ◽  
Marco Deguise ◽  
Ariane Beauvais ◽  
Rebecca Yaworski ◽  
Simon Thebault ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Liver Toxicity ◽  
Muscular Atrophy ◽  
Intrathecal Administration ◽  
High Titre ◽  
High Dose ◽  
Peripheral Tissues ◽  
Liver And Pancreas

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of the SMN1 gene. Although lower motor neurons are a primary target, there is evidence that peripheral organ defects contribute to SMA. Current SMA gene therapy uses a single, high titre intravenous bolus of AAV9-SMN resulting in impressive, yet limited amelioration of the clinical phenotype. However, risks of this treatment include liver toxicity. Intrathecal administration is under clinical trial but was interrupted due to safety concerns in a concomitant animal study. As there is no direct comparison between the different delivery strategies while avoiding high dose toxicity, we injected SMA mice with low dose scAAV9-cba-SMN either intravenously (IV) for peripheral SMN restoration or intracerebroventricularly (ICV) for CNS-focused SMN restoration. Here, IV injections restored SMN in peripheral tissues but not CNS, while ICV injections mildly increased SMN in the periphery and the CNS. Consequently, only ICV treatment rescued motor neuron degeneration. Surprisingly, both treatments resulted in an impressive rescue of survival, weight, motor function, and peripheral phenotypes including liver and pancreas pathology. Our work highlights independent contributions of peripheral organs to SMA pathology and suggests that treatments should not be restricted to the motor neuron.

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.

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