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https://www.readbyqxmd.com/read/28229309/nusinersen-first-global-approval
#1
Sheridan M Hoy
Spinal muscular atrophy (SMA) is a rare autosomal recessive disorder characterized by muscle atrophy and weakness resulting from motor neuron degeneration in the spinal cord and brainstem. It is most commonly caused by insufficient levels of survival motor neuron (SMN) protein (which is critical for motor neuron maintenance) secondary to deletions or mutations in the SMN1 gene. Nusinersen (SPINRAZA™) is a modified antisense oligonucleotide that binds to a specific sequence in the intron, downstream of exon 7 on the pre-messenger ribonucleic acid (pre-mRNA) of the SMN2 gene...
February 22, 2017: Drugs
https://www.readbyqxmd.com/read/28219127/-sanger-sequencing-for-the-diagnosis-of-spinal-muscular-atrophy-patients-with-survival-motor-neuron-gene-1-compound-heterozygous-mutation
#2
L Yang, Y Y Cao, Y J Qu, J L Bai, H Wang, Y W Jin, Y L Han, F Song
Objective: To detect the subtle variant of survival motor neuron gene 1(SMN1) by Sanger sequencing, and to assess the value of Sanger sequencing for the diagnosis of spinal muscular atrophy(SMA) with compound heterozygous mutation of SMN1. Methods: Fifty-two patients suspected SMA were recruited by the Capital Institute of Pediatrics from Jan.2014 to June.2016. PCR was used for amplifying exon7 of SMN1 and SMN2 in 52 patients. Natural different base peaks on the sequencing chromatogram in the SMN1 and SMN2 within the amplified segments were identified with Sanger DNA sequencing to detect the homozygous deletion or heterozygous deletion of SMN1...
February 14, 2017: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/28214532/smn1-functions-as-a-novel-inhibitor-for-traf6-mediated-nf-%C3%AE%C2%BAb-signaling
#3
Eun Kyung Kim, Eui-Ju Choi
Survival motor neuron (SMN) is a 38-kDa protein, whose deficiency in humans develops spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disease with muscular atrophy due to motor neuron death in the spinal cord. We now report that SMN prevents the activation of TRAF6 and IκB kinase (IKK) and thereby negatively regulates the NF-κB signaling processes. SMN physically interacted with TRAF6 and with each component of the IKK complex, IKK-α, IKK-β, and IKK-γ in BV2 microglia cells. Moreover, SMN1 inhibited the E3 ubiquitin ligase activity of TRAF6 as well as the kinase activity of IKK...
February 15, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28193854/gene-activation-of-smn-by-selective-disruption-of-lncrna-mediated-recruitment-of-prc2-for-the-treatment-of-spinal-muscular-atrophy
#4
Caroline J Woo, Verena K Maier, Roshni Davey, James Brennan, Guangde Li, John Brothers, Brian Schwartz, Susana Gordo, Anne Kasper, Trevor R Okamoto, Hans E Johansson, Berhan Mandefro, Dhruv Sareen, Peter Bialek, B Nelson Chau, Balkrishen Bhat, David Bullough, James Barsoum
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by progressive motor neuron loss and caused by mutations in SMN1 (Survival Motor Neuron 1). The disease severity inversely correlates with the copy number of SMN2, a duplicated gene that is nearly identical to SMN1. We have delineated a mechanism of transcriptional regulation in the SMN2 locus. A previously uncharacterized long noncoding RNA (lncRNA), SMN-antisense 1 (SMN-AS1), represses SMN2 expression by recruiting the Polycomb Repressive Complex 2 (PRC2) to its locus...
February 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28159932/modeling-the-differential-phenotypes-of-spinal-muscular-atrophy-with-high-yield-generation-of-motor-neurons-from-human-induced-pluripotent-stem-cells
#5
Xiang Lin, Jin-Jing Li, Wen-Jing Qian, Qi-Jie Zhang, Zhong-Feng Wang, Ying-Qian Lu, En-Lin Dong, Jin He, Ning Wang, Li-Xiang Ma, Wan-Jin Chen
Spinal muscular atrophy (SMA) is a devastating motor neuron disease caused by mutations of the survival motor neuron 1 (SMN1) gene. SMN2, a paralogous gene to SMN1, can partially compensate for the loss of SMN1. On the basis of age at onset, highest motor function and SMN2 copy numbers, childhood-onset SMA can be divided into three types (SMA I-III). An inverse correlation was observed between SMN2 copies and the differential phenotypes of SMA. Interestingly, this correlation is not always absolute. Using SMA induced pluripotent stem cells (iPSCs), we found that the SMN was significantly decreased in both SMA III and SMA I iPSCs derived postmitotic motor neurons (pMNs) and γ-aminobutyric acid (GABA) neurons...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28152480/securinine-enhances-smn2-exon-7-inclusion-in-spinal-muscular-atrophy-cells
#6
Yu-Chia Chen, Jan-Gowth Chang, Ting-Yuan Liu, Yuh-Jyh Jong, Wei-Lin Cheng, Chung-Yee Yuo
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron gene (SMN1) on chromosome 5q13. A second copy of the SMN gene (SMN2) also exists on chromosome 5, and both genes can produce functional protein. However, due to alternative splicing of the exon 7, the majority of SMN protein produced by SMN2 is truncated and unable to compensate for the loss of SMN1...
January 30, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28132687/neurocalcin-delta-suppression-protects-against-spinal-muscular-atrophy-in-humans-and-across-species-by-restoring-impaired-endocytosis
#7
Markus Riessland, Anna Kaczmarek, Svenja Schneider, Kathryn J Swoboda, Heiko Löhr, Cathleen Bradler, Vanessa Grysko, Maria Dimitriadi, Seyyedmohsen Hosseinibarkooie, Laura Torres-Benito, Miriam Peters, Aaradhita Upadhyay, Nasim Biglari, Sandra Kröber, Irmgard Hölker, Lutz Garbes, Christian Gilissen, Alexander Hoischen, Gudrun Nürnberg, Peter Nürnberg, Michael Walter, Frank Rigo, C Frank Bennett, Min Jeong Kye, Anne C Hart, Matthias Hammerschmidt, Peter Kloppenburg, Brunhilde Wirth
Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss. However, rarely individuals with homozygous absence of SMN1 and only three to four SMN2 copies are fully asymptomatic, suggesting protection through genetic modifier(s)...
February 2, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28125085/the-next-generation-of-population-based-spinal-muscular-atrophy-carrier-screening-comprehensive-pan-ethnic-smn1-copy-number-and-sequence-variant-analysis-by-massively-parallel-sequencing
#8
Yanming Feng, Xiaoyan Ge, Linyan Meng, Jennifer Scull, Jianli Li, Xia Tian, Tao Zhang, Weihong Jin, Hanyin Cheng, Xia Wang, Mari Tokita, Pengfei Liu, Hui Mei, Yue Wang, Fangyuan Li, Eric S Schmitt, Wei V Zhang, Donna Muzny, Shu Wen, Zhao Chen, Yaping Yang, Arthur L Beaudet, Xiaoming Liu, Christine M Eng, Fan Xia, Lee-Jun Wong, Jinglan Zhang
PURPOSE: To investigate pan-ethnic SMN1 copy-number and sequence variation by hybridization-based target enrichment coupled with massively parallel sequencing or next-generation sequencing (NGS). METHODS: NGS reads aligned to SMN1 and SMN2 exon 7 were quantified to determine the total combined copy number of SMN1 and SMN2. The ratio of SMN1 to SMN2 was calculated based on a single-nucleotide difference that distinguishes the two genes. SMN1 copy-number results were compared between the NGS and quantitative polymerase chain reaction and/or multiplex ligation-dependent probe amplification...
January 26, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28120840/non-invasive-prenatal-diagnosis-of-spinal-muscular-atrophy-by-relative-haplotype-dosage
#9
Michael Parks, Samantha Court, Benjamin Bowns, Siobhan Cleary, Samuel Clokie, Julie Hewitt, Denise Williams, Trevor Cole, Fiona MacDonald, Mike Griffiths, Stephanie Allen
Although technically possible, few clinical laboratories across the world have implemented non-invasive prenatal diagnosis (NIPD) for selected single-gene disorders, mostly owing to the elevated costs incurred. Having previously proven that NIPD for X-linked disorders can be feasibly implemented in clinical practice, we have now developed a test for the NIPD of an autosomal-recessive disorder, spinal muscular atrophy (SMA). Cell-free DNA was extracted from maternal blood and prepared for massively parallel sequencing on an Illumina MiSeq by targeted capture enrichment of single-nucleotide polymorphisms across a 6 Mb genomic window on chromosome 5 containing the SMN1 gene...
January 25, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28069797/oligodendrocyte-development-and-cns-myelination-are-unaffected-in-a-mouse-model-of-severe-spinal-muscular-atrophy
#10
Ryan W O'Meara, Sarah E Cummings, Yves De Repentigny, Emily McFall, John-Paul Michalski, Marc-Olivier Deguise, Sabrina Gibeault, Rashmi Kothary
The childhood neurodegenerative disease spinal muscular atrophy (SMA) is caused by loss-of-function mutations or deletions in the Survival Motor Neuron 1 (SMN1) gene resulting in insufficient levels of survival motor neuron (SMN) protein. Classically considered a motor neuron disease, increasing evidence now supports SMA as a multi-system disorder with phenotypes discovered in cortical neuron, astrocyte, and Schwann cell function within the nervous system. In this study, we sought to determine whether Smn was critical for oligodendrocyte (OL) development and central nervous system myelination...
January 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28026041/emerging-therapies-and-challenges-in-spinal-muscular-atrophy
#11
REVIEW
Michelle A Farrar, Susanna B Park, Steve Vucic, Kate A Carey, Bradley J Turner, Thomas H Gillingwater, Kathryn J Swoboda, Matthew C Kiernan
Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease-modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized...
December 27, 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27939059/treatment-of-infantile-onset-spinal-muscular-atrophy-with-nusinersen-a-phase-2-open-label-dose-escalation-study
#12
Richard S Finkel, Claudia A Chiriboga, Jiri Vajsar, John W Day, Jacqueline Montes, Darryl C De Vivo, Mason Yamashita, Frank Rigo, Gene Hung, Eugene Schneider, Daniel A Norris, Shuting Xia, C Frank Bennett, Kathie M Bishop
BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy...
17, 2016: Lancet
https://www.readbyqxmd.com/read/27917293/alternative-splicing-of-a-cryptic-exon-embedded-in-intron-6-of-smn1-and-smn2
#13
Satomi Yoshimoto, Nur Imma Fatimah Harahap, Yuko Hamamura, Mawaddah Ar Rochmah, Ai Shima, Naoya Morisada, Masakazu Shinohara, Toshio Saito, Kayoko Saito, Poh San Lai, Masafumi Matsuo, Hiroyuki Awano, Ichiro Morioka, Kazumoto Iijima, Hisahide Nishio
Both survival of motor neuron (SMN) genes are associated with spinal muscular atrophy; mutations in SMN1 cause the disease, and SMN2 modulates its severity. It is established that different alternative splicing of exon 7 occurs for SMN1 and SMN2, and a cryptic exon was recently found in intron 6 of both genes. Here, we characterize this cryptic exon and clarify its alternative splicing pattern in control and spinal muscular atrophy cells.
2016: Human Genome Variation
https://www.readbyqxmd.com/read/27911332/type-0-spinal-muscular-atrophy-further%C3%A2-delineation-of-prenatal-and%C3%A2-postnatal-features-in-16-patients
#14
Sarah Grotto, Jean-Marie Cuisset, Stéphane Marret, Séverine Drunat, Patricia Faure, Séverine Audebert-Bellanger, Isabelle Desguerre, Vincent Flurin, Anne-Gaëlle Grebille, Anne-Marie Guerrot, Hubert Journel, Gilles Morin, Ghislaine Plessis, Sylvain Renolleau, Joëlle Roume, Brigitte Simon-Bouy, Renaud Touraine, Marjolaine Willems, Thierry Frébourg, Eric Verspyck, Pascale Saugier-Veber
BACKGROUND: Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. OBJECTIVE: The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. METHODS: SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database...
November 29, 2016: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/27907179/correction-cervical-spinal-cord-atrophy-profile-in-adult-smn1-linked-sma
#15
Mohamed-Mounir El Mendili, Timothée Lenglet, Tanya Stojkovic, Anthony Behin, Raquel Guimarães-Costa, François Salachas, Vincent Meininger, Gaelle Bruneteau, Nadine Le Forestier, Pascal Laforêt, Stéphane Lehéricy, Habib Benali, Pierre-François Pradat
[This corrects the article DOI: 10.1371/journal.pone.0152439.].
2016: PloS One
https://www.readbyqxmd.com/read/27907033/normalization-of-patient-identified-plasma-biomarkers-in-smn%C3%AE-7-mice-following-postnatal-smn-restoration
#16
W David Arnold, Sandra Duque, Chitra C Iyer, Phillip Zaworski, Vicki L McGovern, Shannon J Taylor, Katharine M von Herrmann, Dione T Kobayashi, Karen S Chen, Stephen J Kolb, Sergey V Paushkin, Arthur H M Burghes
INTRODUCTION AND OBJECTIVE: Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function...
2016: PloS One
https://www.readbyqxmd.com/read/27894243/spinal-muscular-atrophy-more-than-a-disease-of-motor-neurons
#17
L A Nash, J K Burns, J W Chardon, R Kothary, R J Parks
Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e...
November 28, 2016: Current Molecular Medicine
https://www.readbyqxmd.com/read/27893852/a-comparative-study-of-smn-protein-and-mrna-in-blood-and-fibroblasts-in-patients-with-spinal-muscular-atrophy-and-healthy-controls
#18
Renske I Wadman, Marloes Stam, Marc D Jansen, Yana van der Weegen, Camiel A Wijngaarde, Oliver Harschnitz, Peter Sodaar, Kees P J Braun, Dennis Dooijes, Henny H Lemmink, Leonard H van den Berg, W Ludo van der Pol
BACKGROUND: Clinical trials to test safety and efficacy of drugs for patients with spinal muscular atrophy (SMA) are currently underway. Biomarkers that document treatment-induced effects are needed because disease progression in childhood forms of SMA is slow and clinical outcome measures may lack sensitivity to detect meaningful changes in motor function in the period of 1-2 years of follow-up during randomized clinical trials. OBJECTIVE: To determine and compare SMN protein and mRNA levels in two cell types (i...
2016: PloS One
https://www.readbyqxmd.com/read/27891608/compensatory-axon-sprouting-for-very-slow-axonal-die-back-in-a-transgenic-model-of-spinal-muscular-atrophy-type-iii
#19
Esther Udina, Charles T Putman, Luke R Harris, Neil Tyreman, Victoria E Cook, Tessa Gordon
KEY POINTS: Smn(+/-) transgenic mouse is a model of the mildest form of spinal muscular atrophy. Although there is a loss of spinal motoneurons in 11-month-old animals, muscular force is maintained. This maintained muscular force is mediated by reinnervation of the denervated fibres by surviving motoneurons. The spinal motoneurons in these animals do not show an increased susceptibility to death after nerve injury and they retain their regenerative capacity. We conclude that the hypothesized immaturity of the neuromuscular system in this model cannot explain the loss of motoneurons by systematic die-back...
November 28, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27843464/molecular-genetic-analysis-of-survival-motor-neuron-gene-in-460-turkish-cases-with-suspicious-spinal-muscular-atrophy-disease
#20
Afrooz Rashnonejad, Huseyin Onay, Tahir Atik, Ozlem Atan Sahin, Sarenur Gokben, Hasan Tekgul, Ferda Ozkinay
OBJECTIVE: To describe 12 yr experience of molecular genetic diagnosis of Spinal Muscular Atrophy (SMA) in 460 cases of Turkish patients. MATERIALS & METHODS: A retrospective analysis was performed on data from 460 cases, referred to Medical Genetics Laboratory, Ege University's Hospital, Izmir, Turkey, prediagnosed as SMA or with family history of SMA between 2003 and 2014. The PCR-restriction fragment length polymorphism (RFLP) and the Multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect the survival motor neuron (SMN)1 deletions and to estimate SMN1 and SMN2 gene copy numbers...
2016: Iranian Journal of Child Neurology
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