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 Bone loss in survival motor neuron (Smn −/− SMN2 ) genetic mouse model of spinal muscular atrophy

2009 ◽  
Vol 219 (1) ◽  
pp. 52-60 ◽  
Author(s):  
Srinivasan Shanmugarajan ◽  
Eichi Tsuruga ◽  
Kathryn J Swoboda ◽  
Bernard L Maria ◽  
William L Ries ◽  
...  
Keyword(s):  
Bone Loss ◽  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Genetic Mouse Model

scholarly journals Application of DNA-based tests for diagnosis of spinal muscular atrophy in Saudi Arabia

1999 ◽  
Vol 5 (6) ◽  
pp. 1225-1229
Author(s):  
S. Al Rajeh ◽  
R. Majumdar ◽  
A. Awada ◽  
M. Al Jumah
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Type I ◽  
Type Ii ◽  
Inhibitory Protein ◽  
Neuronal Apoptosis Inhibitory Protein ◽  
Smn Gene ◽  
Naip Gene ◽  
Homozygous Deletions

We examined the deletion of the survival motor neuron [SMN] and neuronal apoptosis inhibitory protein [NAIP]genes in patients with spinal muscular atrophy [SMA] using polymerase chain reaction followed by restriction site assay methods. The study included 16 Saudi patients [9 SMA type I and 7 SMA type II]and 6 healthy Saudi volunteers. The homozygous deletions of exons 7 and 8 of the telomeric SMN gene, and exon 5 of the NAIP gene were found in all SMA type I patients. Exons 7 and 8 of telomeric SMN were deleted in all SMA type II patients. However, exon 5 of NAIP was deleted in three of the seven cases. All control volunteers and all family members of the patients had normal SMN and NAIP. The incidence of NAIP deletion was higher in the more severe SMA cases and the dual deletion of the SMN and NAIP genes was more common in Saudi SMA type I patients compared with patients of other ethnic groups

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.

scholarly journals AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy

2019 ◽  
Vol 28 (22) ◽  
pp. 3742-3754 ◽  
Author(s):  
E Villalón ◽  
R A Kline ◽  
C E Smith ◽  
Z C Lorson ◽  
E Y Osman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Genetic Disorder ◽  
Premature Death ◽  
Survival Motor Neuron ◽  
Motor Neuron Diseases ◽  
Smn Protein

Abstract Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide therapy for SMA was an important milestone in SMA research; however, effective next-generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin-depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment of SMA.

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 Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA)

2021 ◽  
Vol 22 (15) ◽  
pp. 8015
Author(s):  
Zhihua Feng ◽  
Steven Lam ◽  
Elena-Marie Sandino Tenn ◽  
Arundhati Sengupta Ghosh ◽  
Sarah Cantor ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Complementary Therapy ◽  
The Body ◽  
Survival Motor Neuron ◽  
Cross Sectional ◽  
Muscle Specific Kinase ◽  
Agonist Antibody

Spinal muscular atrophy (SMA) is a motor neuron disease caused by insufficient levels of the survival motor neuron (SMN) protein. One of the most prominent pathological characteristics of SMA involves defects of the neuromuscular junction (NMJ), such as denervation and reduced clustering of acetylcholine receptors (AChRs). Recent studies suggest that upregulation of agrin, a crucial NMJ organizer promoting AChR clustering, can improve NMJ innervation and reduce muscle atrophy in the delta7 mouse model of SMA. To test whether the muscle-specific kinase (MuSK), part of the agrin receptor complex, also plays a beneficial role in SMA, we treated the delta7 SMA mice with an agonist antibody to MuSK. MuSK agonist antibody #13, which binds to the NMJ, significantly improved innervation and synaptic efficacy in denervation-vulnerable muscles. MuSK agonist antibody #13 also significantly increased the muscle cross-sectional area and myofiber numbers in these denervation-vulnerable muscles but not in denervation-resistant muscles. Although MuSK agonist antibody #13 did not affect the body weight, our study suggests that preservation of NMJ innervation by the activation of MuSK may serve as a complementary therapy to SMN-enhancing drugs to maximize the therapeutic effectiveness for all types of SMA patients.

scholarly journals Clinical and molecular analysis of spinal muscular atrophy in Brazilian patients

1999 ◽  
Vol 22 (4) ◽  
pp. 487-492 ◽  
Author(s):  
C.A. Kim ◽  
M.R. Passos-Bueno ◽  
S.K. Marie ◽  
A. Cerqueira ◽  
U. Conti ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Disease Type ◽  
Survival Motor Neuron ◽  
Type I ◽  
Type Ii ◽  
Inhibitory Protein ◽  
Type Iii ◽  
Smn Gene ◽  
Naip Gene

Spinal muscular atrophy (SMA), the second most common lethal autosomal recessive disorder, has an incidence of 1:10,000 newborns. SMA is divided into acute (Werdnig-Hoffmann disease, type I), intermediate (type II) and juvenile forms (Kugelberg-Welander disease, type III). The gene of all three forms of SMA maps to chromosome 5q 11.2-13.3. Two candidate genes, the survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene, have been identified; SMN is deleted in most SMA patients. We studied both genes in 87 Brazilian SMA patients (20 type I, 14 type II and 53 type III) from 74 unrelated families, by using PCR and single strand conformation polymorphism (SSCP). Deletions of exons 7 and/or 8 of the SMN gene were found in 69% of the families: 16/20 in type I, 9/12 in type II and 26/42 in type III. Among 51 families with deletions, 44 had both exons deleted while seven had deletions only of exon 7. Deletions of exon 5 of the NAIP gene were found in 7/20 of type I, 2/12 of type II and 1/42 of type III patients. No deletion of SMN and NAIP genes was found in 112 parents, 26 unaffected sibs and 104 normal controls. No correlation between deletions of one or both genes and phenotype severity was found.

Hydrocephalus in Spinal Muscular Atrophy: A Case Report and Review of the Literature

2020 ◽  
Author(s):  
Jeetendra P. Sah ◽  
Aaron W. Abrams ◽  
Geetha Chari ◽  
Craig Linden ◽  
Yaacov Anziska
Keyword(s):  
Spinal Muscular Atrophy ◽  
Clinical Characteristics ◽  
Clinical Presentation ◽  
Muscular Atrophy ◽  
Communicating Hydrocephalus ◽  
Type I ◽  
Review Of The Literature ◽  
Radiographic Findings ◽  
Comprehensive Review ◽  
The Relationship

AbstractIn this article, we reported a case of spinal muscular atrophy (SMA) type I noted to have tetraventricular hydrocephalus with Blake's pouch cyst at 8 months of age following intrathecal nusinersen therapy. The association of hydrocephalus with SMA is rarely reported in the literature. Development of hydrocephalus after intrathecal nusinersen therapy is also reported in some cases, but a cause–effect relationship is not yet established. The aim of this study was to describe the clinical characteristics of a patient with SMA type I and hydrocephalus, to review similar cases reported in the literature, and to explore the relationship between nusinersen therapy and development of hydrocephalus. The clinical presentation and radiographic findings of the patient are described and a comprehensive review of the literature was conducted. The adverse effect of communicating hydrocephalus related to nusinersen therapy is being reported and the authors suggest carefully monitoring for features of hydrocephalus developing during the course of nusinersen therapy.

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