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Aziza Alrafiah, Evangelia Karyka, Ian Coldicott, Kayleigh Iremonger, Katherin E Lewis, Ke Ning, Mimoun Azzouz
Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease. SMA is caused by mutations in the survival motor neuron gene ( SMN1 ), leading to reduced levels of SMN protein in the CNS. The actin-binding protein plastin 3 (PLS3) has been reported as a modifier for SMA, making it a potential therapeutic target. Here, we show reduced levels of PLS3 protein in the brain and spinal cord of a mouse model of SMA. Our study also revealed that lentiviral-mediated PLS3 expression restored axonal length in cultured Smn-deficient motor neurons...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
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
Philippe Corcia, Patrick Vourc'h, Helene Blasco, Philippe Couratier, Audrey Dangoumau, Remi Bellance, Claude Desnuelle, Fausto Viader, Vivien Pautot, Stephanie Millecamps, Salah Bakkouche, FranÇois Salachas, Christian R Andres, Vincent Meininger, William Camu
BACKGROUND: Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family. OBJECTIVES: To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients...
March 1, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
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
Christine E Beattie, Stephen J Kolb
Spinal muscular atrophy is caused by deletions or mutations in the SMN1 gene that result in reduced expression of the SMN protein. The SMN protein is an essential molecular chaperone that is required for the biogenesis of multiple ribonucleoprotein (RNP) complexes including spliceosomal small nuclear RNPs (snRNPs). Reductions in SMN expression result in a reduced abundance of snRNPs and to downstream RNA splicing alterations. SMN is also present in axons and dendrites and appears to have important roles in the formation of neuronal mRNA-protein complexes during development or neuronal repair...
February 17, 2018: Brain Research
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
Emma Tabe Eko Niba, Mawaddah Ar Rochmah, Nur Imma Fatimah Harahap, Hiroyuki Awano, Ichiro Morioka, Kazumoto Iijima, Toshio Saito, Kayoko Saito, Atsuko Takeuchi, Poh San Lai, Yoshihiro Bouike, Hisahide Nishio, Masakazu Shinohara
BACKGROUND: Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders. The symptoms are caused by defects of lower motor neurons in the spinal cord. More than 95% of SMA patients are homozygous for survival motor neuron 1 (SMN1) deletion. We previously developed a screening system for SMN1 deletion based on a modified competitive oligonucleotide priming-PCR (mCOP-PCR) technique using dried blood spot (DBS) on filter paper. This system is convenient for mass screening in the large population and/or first-tier diagnostic method of the patients in the remote areas...
December 18, 2017: Kobe Journal of Medical Sciences
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
Masakazu Shinohara, Mawaddah Ar Rochmah, Kenta Nakanishi, Nur Imma Fatimah Harahap, Emma Tabe Eko Niba, Toshio Saito, Kayoko Saito, Atsuko Takeuchi, Yoshihiro Bouike, Hisahide Nishio
BACKGROUND: Spinal muscular atrophy (SMA) is a frequent autosomal recessive disorder, characterized by lower motor neuron loss in the spinal cord. More than 95% of SMA patients show homozygous survival motor neuron 1 (SMN1) deletion. We previously developed a screening system for SMN1 deletion based on a modified competitive oligonucleotide priming-PCR (mCOP-PCR) technique. However, non-specific amplification products were observed with mCOP-PCR, which might lead to erroneous interpretation of the screening results...
September 7, 2017: Kobe Journal of Medical Sciences
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...
January 11, 2018: Neuromuscular Disorders: NMD
Ewout J N Groen, Kevin Talbot, Thomas H Gillingwater
Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease-modifying therapy for SMA by US and European authorities - the antisense oligonucleotide nusinersen...
February 9, 2018: Nature Reviews. Neurology
Hannah K Shorrock, Thomas H Gillingwater, Ewout J N Groen
Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily characterized by a loss of spinal motor neurons, leading to progressive paralysis and premature death in the most severe cases. SMA is caused by homozygous deletion of the survival motor neuron 1 (SMN1) gene, leading to low levels of SMN protein. However, a second SMN gene (SMN2) exists, which can be therapeutically targeted to increase SMN levels. This has recently led to the first disease-modifying therapy for SMA gaining formal approval from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)...
January 29, 2018: Drugs
Gamze Bora, Şulenur Subaşı-Yıldız, Ayşe Yeşbek-Kaymaz, Numan Bulut, İpek Alemdaroğlu, Öznur Tunca-Yılmaz, Haluk Topaloğlu, Aynur Ayşe Karaduman, Hayat Erdem-Yurter
Exercise studies in neuromuscular diseases like spinal muscular atrophy (SMA), a devastating disease caused by survival of motor neuron 1 ( SMN1) gene mutations, are drawing attention due to its beneficial effects. In this study, we presented a constructed arm cycling exercise protocol and evaluated the benefits on SMA patients. Five SMA type II patients performed 12 weeks of supervised arm cycling exercise. The physical functions were evaluated together with the SMN2 copy numbers, SMN protein levels, insulin-like growth factor 1(IGF1) and binding protein 3 (IGFBP3) levels...
January 1, 2018: Journal of Child Neurology
Agnese Ramirez, Sebastiano G Crisafulli, Mafalda Rizzuti, Nereo Bresolin, Giacomo P Comi, Stefania Corti, Monica Nizzardo
Spinal muscular atrophy (SMA) is an autosomal-recessive childhood motor neuron disease and the main genetic cause of infant mortality. SMA is caused by deletions or mutations in the survival motor neuron 1 ( SMN1 ) gene, which results in SMN protein deficiency. Only one approved drug has recently become available and allows for the correction of aberrant splicing of the paralogous SMN2 gene by antisense oligonucleotides (ASOs), leading to production of full-length SMN protein. We have already demonstrated that a sequence of an ASO variant, Morpholino (MO), is particularly suitable because of its safety and efficacy profile and is both able to increase SMN levels and rescue the murine SMA phenotype...
January 6, 2018: International Journal of Molecular Sciences
Melissa Bowerman, Lyndsay M Murrray, Frédérique Scamps, Bernard L Schneider, Rashmi Kothary, Cédric Raoul
Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the two most common motoneuron disorders, which share typical pathological hallmarks while remaining genetically distinct. Indeed, SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene whilst ALS, albeit being mostly sporadic, can also be caused by mutations within genes, including superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS), TAR DNA-binding protein 43 (TDP-43) and chromosome 9 open reading frame 72 (C9ORF72)...
December 4, 2017: European Journal of Medical Genetics
Eugenio Mercuri, Richard S Finkel, Francesco Muntoni, Brunhilde Wirth, Jacqueline Montes, Marion Main, Elena S Mazzone, Michael Vitale, Brian Snyder, Susana Quijano-Roy, Enrico Bertini, Rebecca Hurst Davis, Oscar H Meyer, Anita K Simonds, Mary K Schroth, Robert J Graham, Janbernd Kirschner, Susan T Iannaccone, Thomas O Crawford, Simon Woods, Ying Qian, Thomas Sejersen
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder due to a defect in the survival motor neuron 1 (SMN1) gene. Its incidence is approximately 1 in 11,000 live births. In 2007, an International Conference on the Standard of Care for SMA published a consensus statement on SMA standard of care that has been widely used throughout the world. Here we report a two-part update of the topics covered in the previous recommendations. In part 1 we present the methods used to achieve these recommendations, and an update on diagnosis, rehabilitation, orthopedic and spinal management; and nutritional, swallowing and gastrointestinal management...
November 23, 2017: Neuromuscular Disorders: NMD
Mieko Yoshioka, Naoya Morisada, Daisaku Toyoshima, Hajime Yoshimura, Hisahide Nishio, Kazumoto Iijima, Yasuhiro Takeshima, Tomoko Uehara, Kenjiro Kosaki
INTRODUCTION: The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogenous and largely remain to be elucidated. We present a father and son with atrophy and weakness of the lower leg muscles since infancy. Genetic studies in this family revealed a novel BICD2 mutation causing autosomal dominant lower extremity-predominant SMA type 2. PATIENTS: The proband was the father, aged 30, and the son was aged 3...
December 19, 2017: Brain & Development
Antonio Piras, Lorenzo Schiaffino, Marina Boido, Valeria Valsecchi, Michela Guglielmotto, Elena De Amicis, Julien Puyal, Ana Garcera, Elena Tamagno, Rosa M Soler, Alessandro Vercelli
Spinal muscular atrophy (SMA) is a recessive autosomal neuromuscular disease, due to homozygous mutations or deletions in the telomeric survival motoneuron gene 1 (SMN1). SMA is characterized by motor impairment, muscle atrophy, and premature death following motor neuron (MN) degeneration. Emerging evidence suggests that dysregulation of autophagy contributes to MN degeneration. We here investigated the role of autophagy in the SMNdelta7 mouse model of SMA II (intermediate form of the disease) which leads to motor impairment by postnatal day 5 (P5) and to death by P13...
December 20, 2017: Cell Death & Disease
Mai Feng, Cong Liu, Yan Xia, Bo Liu, Miaojin Zhou, Zhuo Li, Qianru Sun, Zhiqing Hu, Yanchi Wang, Lingqian Wu, Xionghao Liu, Desheng Liang
Spinal muscular atrophy (SMA) is primarily a neurodegenerative disease caused by the homozygous deletion of the survival motor neuron 1 (SMN1) gene, thereby reducing SMN protein expression. Mesenchymal stem cells (MSCs) have been implicated in the treatment of SMA. In the present study, we overexpressed exogenous SMN1 at the ribosomal DNA (rDNA) locus of induced pluripotent stem cells (iPSCs) generated from a SMA patient using an rDNA-targeting vector. The gene-targeted patient iPSCs differentiated into MSCs (SMN1-MSCs)...
February 2018: Journal of Molecular Histology
Eric W Ottesen, Joonbae Seo, Natalia N Singh, Ravindra N Singh
Humans carry two nearly identical copies of Survival Motor Neuron gene: SMN1 and SMN2. Mutations or deletions of SMN1 , which codes for SMN, cause spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Aberrant expression or localization of SMN has been also implicated in other pathological conditions, including male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. SMN2 fails to compensate for the loss of SMN1 due to skipping of exon 7, leading to the production of SMNΔ7, an unstable protein...
2017: Frontiers in Microbiology
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