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https://www.readbyqxmd.com/read/29758563/pilot-study-of-population-based-newborn-screening-for-spinal-muscular-atrophy-in-new-york-state
#1
Jennifer N Kraszewski, Denise M Kay, Colleen F Stevens, Carrie Koval, Bianca Haser, Veronica Ortiz, Anthony Albertorio, Lilian L Cohen, Ritu Jain, Sarah P Andrew, Sally Dunaway Young, Nicole M LaMarca, Darryl C De Vivo, Michele Caggana, Wendy K Chung
PurposeTo determine feasibility and utility of newborn screening for spinal muscular atrophy (SMA) in New York State.MethodsWe validated a multiplex TaqMan real-time quantitative polymerase chain reaction assay using dried blood spots for SMA. From January 2016 to January 2017, we offered, consented, and screened 3,826 newborns at three hospitals in New York City and tested newborns for the deletion in exon 7 of SMN1.ResultsNinety-three percent of parents opted in for SMA screening. Overall the SMA carrier frequency was 1...
October 12, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29742241/therapeutic-advances-in-5q-linked-spinal-muscular-atrophy
#2
Umbertina Conti Reed, Edmar Zanoteli
Spinal muscular atrophy (SMA) is a severe and clinically-heterogeneous motor neuron disease caused, in most cases, by a homozygous mutation in the SMN1 gene. Regarding the age of onset and motor involvement, at least four distinct clinical phenotypes have been recognized. This clinical variability is, in part, related to the SMN2 copy number. By now, only supportive therapies have been available. However, promising specific therapies are currently being developed based on different mechanisms to increase the level of SMN protein; in particular, intrathecal antisense oligonucleotides that prevent the skipping of exon 7 during SMN2 transcription, and intravenous SMN1 insertion using viral vector...
April 2018: Arquivos de Neuro-psiquiatria
https://www.readbyqxmd.com/read/29735415/interventions-targeting-glucocorticoid-kr%C3%A3-ppel-like-factor-15-branched-chain-amino-acid-signaling-improve-disease-phenotypes-in-spinal-muscular-atrophy-mice
#3
Lisa M Walter, Marc-Olivier Deguise, Katharina E Meijboom, Corinne A Betts, Nina Ahlskog, Tirsa L E van Westering, Gareth Hazell, Emily McFall, Anna Kordala, Suzan M Hammond, Frank Abendroth, Lyndsay M Murray, Hannah K Shorrock, Domenick A Prosdocimo, Saptarsi M Haldar, Mukesh K Jain, Thomas H Gillingwater, Peter Claus, Rashmi Kothary, Matthew J A Wood, Melissa Bowerman
The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn-/- ;SMN2 and Smn2B/- mouse models...
May 4, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29712837/mechanistic-studies-of-a-small-molecule-modulator-of-smn2-splicing
#4
Jingxin Wang, Peter G Schultz, Kristen A Johnson
RG-7916 is a first-in-class drug candidate for the treatment of spinal muscular atrophy (SMA) that functions by modulating pre-mRNA splicing of the SMN2 gene, resulting in a 2.5-fold increase in survival of motor neuron (SMN) protein level, a key protein lacking in SMA patients. RG-7916 is currently in three interventional phase 2 clinical trials for various types of SMA. In this report, we show that SMN-C2 and -C3, close analogs of RG-7916, act as selective RNA-binding ligands that modulate pre-mRNA splicing...
April 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29703692/new-and-developing-therapies-in-spinal-muscular-atrophy
#5
REVIEW
Didu Kariyawasam, Kate A Carey, Kristi J Jones, Michelle A Farrar
Great progress has been made in the clinical translation of several therapeutic strategies for spinal muscular atrophy (SMA), including measures to selectively address Survival Motor Neuron (SMN) protein deficiency with SMN1 gene replacement or modulation of SMN2 encoded protein levels, as well as neuroprotective approaches and supporting muscle strength and function. This review highlights these novel therapies. This is particularly vital with the advent of the first disease modifying therapy, which has brought to the fore an array of questions surrounding who, how and when to treat, and stimulated challenges in resource limited healthcare systems to streamline access for those eligible for drug therapy...
April 5, 2018: Paediatric Respiratory Reviews
https://www.readbyqxmd.com/read/29649521/modelling-motor-neuron-disease-in-fruit-flies-lessons-from-spinal-muscular-atrophy
#6
Beppe Aquilina, Ruben J Cauchi
Motor neuron disease (MND) is characterised by muscle weakness and paralysis downstream of motor neuron degeneration. Genetic factors play a major role in disease pathogenesis and progression. This is best underscored by spinal muscular atrophy (SMA), the most common MND affecting children. Although SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene, partial compensation by the paralogous SMN2 gene and/or genetic modifiers influence age of onset and disease severity. SMA is also the first MND that is treatable thanks to the recent development of a molecular-based therapy...
April 9, 2018: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/29614705/identification-of-a-resilient-mouse-facial-motoneuron-population-following-target-disconnection-by-injury-or-disease
#7
Deborah O Setter, Melissa M Haulcomb, Taylor Beahrs, Rena M Meadows, Nicole D Schartz, Sara K Custer, Virginia M Sanders, Kathryn J Jones
BACKGROUND: When nerve transection is performed on adult rodents, a substantial population of neurons survives short-term disconnection from target, and the immune system supports this neuronal survival, however long-term survival remains unknown. Understanding the effects of permanent axotomy on cell body survival is important as target disconnection is the first pathological occurrence in fatal motoneuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA)...
March 25, 2018: Restorative Neurology and Neuroscience
https://www.readbyqxmd.com/read/29614695/treatment-algorithm-for-infants-diagnosed-with-spinal-muscular-atrophy-through-newborn-screening
#8
Jacqueline Glascock, Jacinda Sampson, Amanda Haidet-Phillips, Anne Connolly, Basil Darras, John Day, Richard Finkel, R Rodney Howell, Katherine Klinger, Nancy Kuntz, Thomas Prior, Perry B Shieh, Thomas Crawford, Doug Kerr, Jill Jarecki
BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity. OBJECTIVE: To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number...
March 26, 2018: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/29610000/critical-period-of-neuromuscular-development-importance-for-a-new-treatment-of-sma
#9
REVIEW
Gerta Vrbová, Urszula Sławińska
Findings from mice that had their Smn gene deleted and some copies of the human SMN2 gene introduced to produce SMN protein are summarized. Symptoms due to this manipulation can be corrected only by restoring the SMN protein expression in neurones and not in muscle. The changes in muscle and neuromuscular junction (NMJ) in these mutant mice are probably due to the malfunction of the neuronal component of the NMJ i.e. the nerve terminal. The reduction of transmitter release by nerve terminals in animals with reduced SMN protein supports this notion...
March 13, 2018: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/29598153/seamless-genetic-conversion-of-smn2-to-smn1-via-crispr-cpf1-and-single-stranded-oligodeoxynucleotides-in-spinal-muscular-atrophy-patient-specific-ipscs
#10
Miaojin Zhou, Zhiqing Hu, Liyan Qiu, Tao Zhou, Mai Feng, Qian Hu, Baitao Zeng, Zhuo Li, Qianru Sun, Yong Wu, Xionghao Liu, Lingqian Wu, Desheng Liang
Spinal muscular atrophy (SMA) is a kind of neuromuscular disease characterized by progressive motor neuron loss in the spinal cord. It is caused by mutations in the survival motor neuron 1 (SMN1) gene. SMN1 has a paralogous gene, survival motor neuron 2 (SMN2), in humans that is present in almost all SMA patients. The generation and genetic correction of SMA patient specific induced pluripotent stem cells (iPSCs) is a viable, autologous therapeutic strategy for the disease. Here, we generated c-Myc-free and non-integrating iPSCs from the urine cells of an SMA patient using an episomal iPSC reprogramming vector and designed a unique crRNA that does not have similar sequences (≤3 mismatches) anywhere in the human reference genome...
March 29, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29580671/intron-retained-transcripts-of-the-spinal-muscular-atrophy-genes-smn1-and-smn2
#11
Nur Imma Fatimah Harahap, Emma Tabe Eko Niba, Mawaddah Ar Rochmah, Yogik Onky Silvana Wijaya, Toshio Saito, Kayoko Saito, Hiroyuki Awano, Ichiro Morioka, Kazumoto Iijima, Poh San Lai, Masafumi Matsuo, Hisahide Nishio, Masakazu Shinohara
BACKGROUND: The SMN genes, SMN1 and SMN2, are highly homologous genes which are related to the development or clinical severity of spinal muscular atrophy. Some alternative splicing patterns of the SMN genes have been well documented. In 2007, an SMN1 transcript with a full sequence of intron 3 was reported as the first intron-retained SMN transcript. METHODS: Intron-retained SMN transcripts in various cells and tissues were studied using reverse transcription (RT)-PCR...
March 23, 2018: Brain & Development
https://www.readbyqxmd.com/read/29556256/spinal-muscular-atrophy-type-i-and-the-dual-role-of-viruses-an-interview-with-professor-basil-t-darras-professor-of-neurology-pediatrics-at-harvard-medical-school
#12
Ioannis N Mammas, Demetrios A Spandidos
According to Professor Basil T. Darras, Professor of Neurology (Pediatrics) at Harvard Medical School and Director of the Spinal Muscular Atrophy (SMA) Program at Boston Children's Hospital in Boston (MA, USA), the diagnosis of SMA type I is clinical and is based on detailed general physical and neurological examinations. SMA type I remains the most common genetic disease resulting in death in infancy and is really devastating for the child, the parents, as well as the medical professionals with the privilege of caring for patients with SMA and their parents...
April 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29549190/nusinersen-for-sma-expanded-access-programme
#13
Michelle A Farrar, Hooi Ling Teoh, Kate A Carey, Anita Cairns, Robin Forbes, Karen Herbert, Sandra Holland, Kristi J Jones, Manoj P Menezes, Margot Morrison, Kate Munro, Daniella Villano, Richard Webster, Ian R Woodcock, Eppie M Yiu, Hugo Sampaio, Monique M Ryan
BACKGROUND: Spinal muscular atrophy (SMA) is a devastating motor neuron disorder causing progressive muscle weakness and respiratory insufficiency. We present the initial Australian experiences implementing the expanded access programme (EAP) to enable preapproval access to nusinersen, the first disease-modifying therapy, for SMA type 1. METHODS: An Australian multicentre, open-label EAP for nusinersen enrolled patients with infantile-onset SMA type 1 from November 2016 to September 2017...
March 16, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/29504374/a-versatile-method-for-gene-dosage-quantification-multiplex-pcr-and-single-base-extension-for-copy-number-and-gene-conversion-identification-of-smn-genes
#14
S Radovic, G Dubsky De Wittenau, N Mandl, E Betto, F Curcio, M Morgante, I R Lonigro
A comparison of the individual genomes within a species demonstrates that structural variation, including copy number variation (CNV), is a major contributor to phenotypic diversity and evolutionary adaptation. CNVs lead to the under/over-expression of a gene, according to the changes in the gene dosage, which account for the development of a number of genomic disorders. Thus, the development of efficient, rapid and accurate CNV screening is of fundamental importance. We report a method that enables the simultaneous determination of the copy numbers of several different targets as well as the discrimination among highly similar/almost identical targets that differ by only one single nucleotide variant, which establishes their copy numbers...
January 2018: Journal of Biological Regulators and Homeostatic Agents
https://www.readbyqxmd.com/read/29478602/spinal-muscular-atrophy
#15
Eveline S Arnold, Kenneth H Fischbeck
Autosomal-recessive proximal spinal muscular atrophy (Werdnig-Hoffmann, Kugelberg-Welander) is caused by mutation of the SMN1 gene, and the clinical severity correlates with the number of copies of a nearly identical gene, SMN2. The SMN protein plays a critical role in spliceosome assembly and may have other cellular functions, such as mRNA transport. Cell culture and animal models have helped to define the disease mechanism and to identify targets for therapeutic intervention. The main focus for developing treatment has been to increase SMN levels, and accomplishing this with small molecules, oligonucleotides, and gene replacement has been quite...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29443664/nusinersen-versus-sham-control-in-later-onset-spinal-muscular-atrophy
#16
RANDOMIZED CONTROLLED TRIAL
Eugenio Mercuri, Basil T Darras, Claudia A Chiriboga, John W Day, Craig Campbell, Anne M Connolly, Susan T Iannaccone, Janbernd Kirschner, Nancy L Kuntz, Kayoko Saito, Perry B Shieh, Már Tulinius, Elena S Mazzone, Jacqueline Montes, Kathie M Bishop, Qingqing Yang, Richard Foster, Sarah Gheuens, C Frank Bennett, Wildon Farwell, Eugene Schneider, Darryl C De Vivo, Richard S Finkel
BACKGROUND: Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274...
February 15, 2018: New England Journal of Medicine
https://www.readbyqxmd.com/read/29434670/advances-in-spinal-muscular-atrophy-therapeutics
#17
REVIEW
Valeria Parente, Stefania Corti
Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families...
2018: Therapeutic Advances in Neurological Disorders
https://www.readbyqxmd.com/read/29434173/gender-effects-on-the-clinical-phenotype-in-japanese-patients-with-spinal-muscular-atrophy
#18
Mawaddah Ar Rochmah, Ai Shima, Nur Imma Fatimah Harahap, Emma Tabe Eko Niba, Naoya Morisada, Shinichiro Yanagisawa, Toshio Saito, Kaori Kaneko, Kayoko Saito, Ichiro Morioka, Kazumoto Iijima, Poh San Lai, Yoshihiro Bouike, Hisahide Nishio, Masakazu Shinohara
BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a mutation in SMN1. SMA is classified into three subtypes (types 1, 2, 3) based on achieved motor milestones. Although NAIP and SMN2 are widely accepted as SMA-modifying factors, gender-related modifying factors or gender effects on the clinical phenotype are still controversial. METHODS: A total of 122 Japanese patients with SMA, of which SMN1 was homozygously deleted, were analyzed from the perspective of the achieved motor milestone, NAIP status and SMN2 copy number...
October 16, 2017: Kobe Journal of Medical Sciences
https://www.readbyqxmd.com/read/29433793/correlation-between-sma-type-and-smn2-copy-number-revisited-an-analysis-of-625-unrelated-spanish-patients-and-a-compilation-of-2834-reported-cases
#19
Maite Calucho, Sara Bernal, Laura Alías, Francesca March, Adoración Venceslá, Francisco J Rodríguez-Álvarez, Elena Aller, Raquel M Fernández, Salud Borrego, José M Millán, Concepción Hernández-Chico, Ivon Cuscó, Pablo Fuentes-Prior, Eduardo F Tizzano
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss or mutations in SMN1. According to age of onset, achieved motor abilities, and life span, SMA patients are classified into type I (never sit), II (never walk unaided) or III (achieve independent walking abilities). SMN2, the highly homologous copy of SMN1, is considered the most important phenotypic modifier of the disease. Determination of SMN2 copy number is essential to establish careful genotype-phenotype correlations, predict disease evolution, and to stratify patients for clinical trials...
March 2018: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/29405035/protective-effects-of-long-term-lithium-administration-in-a-slowly-progressive-sma-mouse-model
#20
Francesca Biagioni, Michela Ferrucci, Larisa Ryskalin, Federica Fulceri, Gloria Lazzeri, Maria Teresa Calierno, Carla L Busceti, Riccardo Ruffoli, Francesco Fornai
In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course...
December 1, 2017: Archives Italiennes de Biologie
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