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Spinal muscular atrophy

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
Basil T Darras, Ioannis N Mammas, Demetrios A Spandidos
No abstract text is available yet for this article.
April 2018: Experimental and Therapeutic Medicine
Xing Chen, Detlef Wolf, Juliane Siebourg-Polster, Christian Czech, Ulrike Bonati, Dirk Fischer, Omar Khwaja, Martin Strahm
Progressive and irreversible muscle atrophy characterizes Spinal Muscular Atrophy (SMA) and other similar muscle disorder diseases. Objective assessment of muscle functions is an essential and important, although challenging, prerequisite for successful clinical trials. Current clinical rating scales restrain the movement abnormalities to certain predefined coarse-grained individual items. The Kinect 3-D sensor has emerged as a low-cost and portable motion sensing technology used to capture and track people's movement in many medical and research fields...
February 12, 2018: Journal of Visualized Experiments: JoVE
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
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
Navaneetha Santhanam, Lee Kumanchik, Xiufang Guo, Frank Sommerhage, Yunqing Cai, Max Jackson, Candace Martin, George Saad, Christopher W McAleer, Ying Wang, Andrea Lavado, Christopher J Long, James J Hickman
There are currently no functional neuromuscular junction (hNMJ) systems composed of human cells that could be used for drug evaluations or toxicity testing in vitro. These systems are needed to evaluate NMJs for diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy or other neurodegenerative diseases or injury states. There are certainly no model systems, animal or human, that allows for isolated treatment of motoneurons or muscle capable of generating dose response curves to evaluate pharmacological activity of these highly specialized functional units...
February 27, 2018: Biomaterials
Katherine B Santosa, Alexandra M Keane, Albina Jablonka-Shariff, Bianca Vannucci, Alison K Snyder-Warwick
The terminal Schwann cell (tSC), a type of nonmyelinating Schwann cell, is a significant yet relatively understudied component of the neuromuscular junction. In addition to reviewing the role tSCs play on formation, maintenance, and remodeling of the synapse, we review studies that implicate tSCs in neuromuscular diseases including spinal muscular atrophy, Miller-Fisher syndrome, and amyotrophic lateral sclerosis, among others. We also discuss the importance of these cells on degeneration and regeneration after nerve injury...
March 13, 2018: Journal of Neuroscience Research
Lilian A Martinez Carrera, Elke Gabriel, Colin Donohoe, Irmgard Hölker, Aruljothi Mariappan, Markus Storbeck, Mirka Uhlirova, Jay Gopalakrishnan, Brunhilde Wirth
BICD2 encodes a highly conserved motor adaptor protein that regulates the dynein-dynactin complex in different cellular processes. Heterozygous mutations in BICD2 cause autosomal dominant lower extremity-predominant spinal muscular atrophy-2 (SMALED2). Although, various BICD2 mutations have been shown to alter interactions with different binding partners or the integrity of the Golgi apparatus, the specific pathological effects of BICD2 mutations underlying SMALED2 remain elusive. Here, we show that the fibroblasts derived from individuals with SMALED2 exhibit stable microtubules...
March 8, 2018: Human Molecular Genetics
Frank Curmi, Ruben J Cauchi
Gemin3, also known as DDX20 or DP103, is a DEAD-box RNA helicase which is involved in more than one cellular process. Though RNA unwinding has been determined in vitro , it is surprisingly not required for all of its activities in cellular metabolism. Gemin3 is an essential gene, present in Amoeba and Metazoa. The highly conserved N-terminus hosts the helicase core, formed of the helicase- and DEAD-domains, which, based on crystal structure determination, have key roles in RNA binding. The C-terminus of Gemin3 is highly divergent between species and serves as the interaction site for several accessory factors that could recruit Gemin3 to its target substrates and/or modulate its function...
March 9, 2018: Biochemical Society Transactions
Melissa R Mandarakas, Kristy J Rose, Oranee Sanmaneechai, Manoj P Menezes, Kathryn M Refshauge, Joshua Burns
A functional outcome measure for infants (aged 0-3 years) with Charcot-Marie-Tooth disease (CMT) is needed for upcoming disease-modifying trials. A systematic review of outcome measures for infants with neuromuscular disorders was completed to determine if validated measures were available for the CMT infant population. We assessed 20,375 papers and identified seven functional outcome measures for infants with neuromuscular disorders. Six were developed and validated for Spinal Muscular Atrophy (SMA). There were no CMT-specific outcome measures identified, however one (Motor Function Measure) assessed a range of neuromuscular disorders including 13 infants and children with CMT...
March 9, 2018: Journal of the Peripheral Nervous System: JPNS
Jeong-Ki Kim, Umrao R Monani
Spinal muscular atrophy (SMA) is a common and oft-fatal pediatric neuromuscular disorder caused by insufficient SMN protein. Now, two clinical trials (Mendell et al., 2017; Finkel et al., 2017) demonstrate that restoring the protein is therapeutic, offering new treatment options and renewed hope to SMA patients.
March 7, 2018: Neuron
Veronika Boczonadi, Martin S King, Anthony C Smith, Monika Olahova, Boglarka Bansagi, Andreas Roos, Filmon Eyassu, Christoph Borchers, Venkateswaran Ramesh, Hanns Lochmüller, Tuomo Polvikoski, Roger G Whittaker, Angela Pyle, Helen Griffin, Robert W Taylor, Patrick F Chinnery, Alan J Robinson, Edmund R S Kunji, Rita Horvath
PurposeTo understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.MethodsWe identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.ResultsThe patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy...
March 8, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Hidekazu Ito, Kazuya Sobue
No abstract text is available yet for this article.
March 6, 2018: Pediatrics International: Official Journal of the Japan Pediatric Society
Michael Briese, Lena Saal-Bauernschubert, Changhe Ji, Mehri Moradi, Hanaa Ghanawi, Michael Uhl, Silke Appenzeller, Rolf Backofen, Michael Sendtner
Disturbed RNA processing and subcellular transport contribute to the pathomechanisms of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. RNA-binding proteins are involved in these processes, but the mechanisms by which they regulate the subcellular diversity of transcriptomes, particularly in axons, are not understood. Heterogeneous nuclear ribonucleoprotein R (hnRNP R) interacts with several proteins involved in motoneuron diseases. It is located in axons of developing motoneurons, and its depletion causes defects in axon growth...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Luke W Thompson, Kim D Morrison, Sally L Shirran, Ewout J N Groen, Tom H Gillingwater, Catherine H Botting, Judith E Sleeman
Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative condition caused by reduction in functional Survival Motor Neurones Protein (SMN). SMN has been implicated in transport of mRNA in neural cells for local translation. We previously identified microtubule-dependant mobile vesicles rich in SMN and SmB, a member of the Sm family of snRNP-associated proteins, in neural cells. By comparing the interactomes of SmB and SmN, a neural-specific Sm protein, we now show that the essential neural protein neurochondrin (NCDN) interacts with Sm proteins and SMN in the context of mobile vesicles in neurites...
March 5, 2018: Journal of Cell Science
Yasuhiro Hijikata, Masahisa Katsuno, Keisuke Suzuki, Atsushi Hashizume, Amane Araki, Shinichiro Yamada, Tomonori Inagaki, Daisuke Ito, Akihiro Hirakawa, Fumie Kinoshita, Masahiko Gosho, Gen Sobue
BACKGROUND: Although spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness. OBJECTIVE: The present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA...
March 5, 2018: JMIR Research Protocols
Nisha M Badders, Ane Korff, Helen C Miranda, Pradeep K Vuppala, Rebecca B Smith, Brett J Winborn, Emmanuelle R Quemin, Bryce L Sopher, Jennifer Dearman, James Messing, Nam Chul Kim, Jennifer Moore, Brian D Freibaum, Anderson P Kanagaraj, Baochang Fan, Heather Tillman, Ping-Chung Chen, Yingzhe Wang, Burgess B Freeman, Yimei Li, Hong Joo Kim, Albert R La Spada, J Paul Taylor
Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies...
March 5, 2018: Nature Medicine
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
Koji Abe
The present review focuses an early history of Japanese amyotrophic lateral sclerosis (ALS)-related diseases and the current development. In relation to foreign previous reports, five topics are introduced and discussed on ALS with dementia, ALS/Parkinsonism dementia complex (ALS/PDC), familial ALS (FALS), spinal bulbar muscular atrophy (SBMA), and multisystem involvement especially in cerebellar system of ALS including ALS/SCA (spinocerebellar ataxia) crossroad mutation Asidan. This review found the great contribution of Japanese reports on the above five topics, and confirmed the great development of ALS-related diseases over the past 120 years...
February 28, 2018: Rinshō Shinkeigaku, Clinical Neurology
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