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"Spinal Muscular Atrophy"

Garrett Smith, Stephanie K Bell, John T Sladky, Peter B Kang, Mehmet S Albayram
Spinal muscular atrophies are rare genetic disorders most often caused by homozygous deletion mutations in SMN1 that lead to progressive neurodegeneration of anterior horn cells. Ventral spinal root atrophy is a consistent pathological finding in post-mortem examinations of patients who suffered from various subtypes of spinal muscular atrophy; however, corresponding radiographic findings have not been previously reported. We present a patient with hypotonia and weakness who was found to have ventral spinal root atrophy in the lumbosacral region on MRI and was subsequently diagnosed with spinal muscular atrophy...
October 5, 2018: Clinical Imaging
Matthew E R Butchbach
Systems biology uses a combination of experimental and mathematical approaches to investigate the complex and dynamic interactions with a given system or biological process. Systems biology integrates genetics, signal transduction, biochemistry and cell biology with mathematical modeling. It can be used to identify novel pathways implicated in diseases as well as to understand the mechanisms by which a specific gene is regulated. This review describes the development of mathematical models for the regulation of an endogenous modifier gene, SMN2, in spinal muscular atrophy-an early-onset motor neuron disease that is a leading genetic cause of infant mortality worldwide-by cAMP signaling...
2018: Advances in Neurobiology
Sandra de la Fuente, Alba Sansa, Ambika Periyakaruppiah, Ana Garcera, Rosa M Soler
Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is caused by the loss of survival motor neuron 1 (SMN1) gene. SMA is characterized by the degeneration and loss of spinal cord motoneurons (MNs), muscular atrophy, and weakness. SMN2 is the centromeric duplication of the SMN gene, whose numbers of copies determine the intracellular levels of SMN protein and define the disease onset and severity. It has been demonstrated that elevating SMN levels can be an important strategy in treating SMA and can be achieved by several mechanisms, including promotion of protein stability...
October 16, 2018: Molecular Neurobiology
David Michelson, Emma Ciafaloni, Stephen Ashwal, Elliot Lewis, Pushpa Narayanaswami, Maryam Oskoui, Melissa J Armstrong
OBJECTIVE: To identify the level of evidence for use of nusinersen to treat spinal muscular atrophy (SMA) and review clinical considerations regarding use. METHODS: The author panel systematically reviewed nusinersen clinical trials for patients with SMA and assigned level of evidence statements based on the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed...
October 12, 2018: Neurology
Michael J Gait, Andrey A Arzumanov, Graham McClorey, Caroline Godfrey, Corinne Betts, Suzan Hammond, Matthew J A Wood
The review starts with a historical perspective of the achievements of the Gait group in synthesis of oligonucleotides (ONs) and their peptide conjugates toward the award of the 2017 Oligonucleotide Therapeutic Society Lifetime Achievement Award. This acts as a prelude to the rewarding collaborative studies in the Gait and Wood research groups aimed toward the enhanced delivery of charge neutral ON drugs and the development of a series of Arg-rich cell-penetrating peptides called Pip (peptide nucleic acid/phosphorodiamidate morpholino oligonucleotide [PNA/PMO] internalization peptides) as conjugates of such ONs...
October 16, 2018: Nucleic Acid Therapeutics
Benjamin Stolte, Andreas Totzeck, Kathrin Kizina, Saskia Bolz, Lena Pietruck, Christoph Mönninghoff, Nika Guberina, Denise Oldenburg, Michael Forsting, Christoph Kleinschnitz, Tim Hagenacker
Background: Nusinersen is an intrathecally administered antisense oligonucleotide (ASO) and the first approved drug for the treatment of spinal muscular atrophy (SMA). However, progressive neuromyopathic scoliosis and the presence of spondylodesis can impede lumbar punctures in SMA patients. Our aim was to assess the feasibility and safety of the treatment in adults with SMA. Methods: For the intrathecal administration of nusinersen, we performed conventional, fluoroscopy-assisted and computer tomography (CT)-guided lumbar punctures in adult patients with type 2 and type 3 SMA...
2018: Therapeutic Advances in Neurological Disorders
Antonio Silvinato, Wanderley M Bernardo
The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.
June 2018: Revista da Associação Médica Brasileira
Nicole Hellbach, Suzanne Peterson, Daniel Haehnke, Aditi Shankar, Samuel LaBarge, Cullen Pivaroff, Stefanie Saenger, Carolin Thomas, Kathleen McCarthy, Martin Ebeling, Monica Hayhurst Bennett, Uli Schmidt, Friedrich Metzger
Spinal muscular atrophy (SMA) is a severe genetic disorder that manifests in progressive neuromuscular degeneration. SMA originates from loss-of-function mutations of the SMN1 (Survival of Motor Neuron 1) gene. Recent evidence has implicated peripheral deficits, especially in skeletal muscle, as key contributors to disease progression in SMA. In this study we generated myogenic cells from two SMA-affected human embryonic stem cell (hESC) lines with deletion of SMN1 bearing two copies of the SMN2 gene and recapitulating the molecular phenotype of Type 1 SMA...
2018: PloS One
Stefan Sturm, Andreas Günther, Birgit Jaber, Paul Jordan, Nada Al Kotbi, Nikhat Parkar, Yumi Cleary, Nicolas Frances, Tobias Bergauer, Katja Heinig, Heidemarie Kletzl, Anne Marquet, Hasane Ratni, Agnès Poirier, Lutz Müller, Christian Czech, Omar Khwaja
AIMS: Risdiplam (RG7916, RO7034067) is an orally administered, centrally and peripherally distributed, survival of motor neuron 2 (SMN2) mRNA splicing modifier for the treatment of spinal muscular atrophy (SMA). The objectives of this entry-into-human study were to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of risdiplam, and the effect of the strong CYP3A inhibitor itraconazole on the PK of risdiplam in healthy male volunteers. METHODS: Part 1 had a randomized, double-blind, adaptive design with 25 subjects receiving single ascending oral doses of risdiplam (ranging from 0...
October 10, 2018: British Journal of Clinical Pharmacology
Elisa Longinetti, Amanda Regodón Wallin, Kristin Samuelsson, Rayomand Press, Anne Zachau, Lars-Olof Ronnevi, Marie Kierkegaard, Peter M Andersen, Jan Hillert, Fang Fang, Caroline Ingre
OBJECTIVE: We set up the Swedish Motor Neuron Disease (MND) Quality Registry to assure early diagnosis and high-quality health care for all MND patients (mainly amyotrophic lateral sclerosis, ALS), and to create a research base by prospectively following the entire MND population in Sweden. METHODS: Since 2015, the MND Quality Registry continuously collects information about a wide range of clinical measures, biological samples, and quality of life outcomes from all MND patients recruited at the time of MND diagnosis in Sweden and followed at each clinic visit approximately every 12 weeks...
October 9, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Anna Ambrosini, Daniela Calabrese, Francesco Maria Avato, Felice Catania, Guido Cavaletti, Maria Carmela Pera, Antonio Toscano, Giuseppe Vita, Lucia Monaco, Davide Pareyson
BACKGROUND: The worldwide landscape of patient registries in the neuromuscular disease (NMD) field has significantly changed in the last 10 years, with the international TREAT-NMD network acting as strong driver. At the same time, the European Medicines Agency and the large federations of rare disease patient organizations (POs), such as EURORDIS, contributed to a great cultural change, by promoting a paradigm shift from product-registries to patient-centred registries. In Italy, several NMD POs and Fondazione Telethon undertook the development of a TREAT-NMD linked patient registry in 2009, with the referring clinical network providing input and support to this initiative through the years...
October 4, 2018: Orphanet Journal of Rare Diseases
Kyle H Cichos, Eva J Lehtonen, Gerald McGwin, Brent A Ponce, Elie S Ghanem
INTRODUCTION: Orthopaedic surgeons are wary of patients with neuromuscular (NM) diseases as a result of perceived poor outcomes and lack of data regarding complication risks. We determined the prevalence of patients with NM disease undergoing total joint arthroplasty (TJA) and characterized its relationship with in-hospital complications, prolonged length of stay, and total charges. METHODS: Data from the Nationwide Inpatient Sample from 2005 to 2014 was used for this retrospective cohort study to identify 8,028,435 discharges with total joint arthroplasty...
October 2, 2018: Journal of the American Academy of Orthopaedic Surgeons
Alan R Bielsky, Peter G Fuhr, Julie A Parsons, Myron Yaster
INTRODUCTION: Spinal muscular atrophy is characterized by loss of motor neurons in the anterior horn of the spinal cord with resultant proximal muscle weakness. Intrathecal nusinersen has revolutionized the treatment of spinal muscular atrophy. We reviewed the perioperative care of 61 anesthetics performed on eight patients with spinal muscular atrophy type 2 who received nusinersen over 30 months in conjunction with nusinersen's phase 3 clinical trials. METHODS: Anesthesia was induced in all patients with sevoflurane, nitrous oxide, and oxygen (30%) via facemask...
October 4, 2018: Paediatric Anaesthesia
Dunhui Li, Frank L Mastaglia, Sue Fletcher, Steve D Wilton
Clinical implementation of two recently approved antisense RNA therapeutics - Exondys51® to treat Duchenne muscular dystrophy (Duchenne MD) and Spinraza® as a treatment for spinal muscular atrophy (SMA) - highlights the therapeutic potential of antisense oligonucleotides (ASOs). As shown in the Duchenne and Becker cases, the identification and specific removal of 'dispensable' exons by exon-skipping ASOs could potentially bypass lethal mutations in other genes and bring clinical benefits to affected individuals carrying amenable mutations...
September 30, 2018: Trends in Pharmacological Sciences
Antonella LoMauro, Paolo Banfi, Chiara Mastella, Katia Alberti, Giovanni Baranello, Andrea Aliverti
The involvement of the respiratory muscular pump makes SMA children prone to frequent hospitalization and morbidity, particularly in type 1. Progressive weakness affects ribcage muscles resulting in bell-shaped chest that was never quantified. The aims of the present work were: (1) to quantify the presence of bell-shaped chest in SMA infants and children and to correlate it with the action of ribcage muscles, assessed by the contribution of pulmonary ribcage to tidal volume (ΔVRC, p ); (2) to verify if and how the structure of the ribcage and ΔVRC, p change after 1-year in SMA type 2...
2018: Frontiers in Neurology
Diane V Murrell, Claire A Crawford, Chanti T Jackson, Timothy E Lotze, Constance M Wiemann
STUDY PURPOSE: The purpose of this qualitative study was to understand, from the parent perspective, the experience of the family whose child has Type 1 spinal muscular atrophy (Type 1 SMA), in the emergency center, hospital, and clinical care settings to identify opportunities for improved family-centered care (FCC). DESIGN AND METHODS: This study used a qualitative descriptive design with individual or small group interviews guided by a semi-structured questionnaire...
September 25, 2018: Journal of Pediatric Nursing
M Repko, M Filipovič, M Leznar, A Šprláková-Puková, J Heger
PURPOSE OF THE STUDY Neuromuscular deformities of the spine represent surgically uneasy to solve problems as well as serious handicaps causing sitting instability, pressure ulcers as well as pain. The aim of our study is to conduct a retrospective clinical analysis of the results of surgical correction of these deformities. This paper presents the use of a recent technique of sacral-alar-iliac (S2AI) screws and its comparison with other techniques of pelvic stabilisation. MATERIAL AND METHODS The group of 41 patients treated surgically with S2AI screws technique and transpedicular or hybrid instrumentation of the spine consisted of patients with the primary diagnosis of muscular dysthrophy, spinal muscular atrophy, cerebral palsy and some other neuromuscular diseases...
2018: Acta Chirurgiae Orthopaedicae et Traumatologiae Cechoslovaca
Maggie C Walter, Anne Julia Stauber
Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease with an incidence of 1:10,000 live births, caused by loss of the survival motor neuron 1 gene (SMN1), and represents the most frequent neurodegenerative disorder in children. With greater understanding of the molecular basis of SMA in the past two decades, a major focus of therapeutic developments has been on increasing the fulllength SMN protein by increasing the inclusion of exon 7 in SMN2 transcripts, enhancing SMN2 gene expression, stabilizing the SMN protein or replacing the SMN1 gene...
September 2018: Fortschritte der Neurologie-Psychiatrie
Giorgia Querin, Timothée Lenglet, Rabab Debs, Tanya Stojkovic, Anthony Behin, François Salachas, Nadine Le Forestier, Maria Del Mar Amador, Lucette Lacomblez, Vincent Meininger, Gaelle Bruneteau, Pascal Laforêt, Sophie Blancho, Véronique Marchand-Pauvert, Peter Bede, Jean-Yves Hogrel, Pierre-François Pradat
OBJECTIVE: Objective of this study is the comprehensive characterisation of motor unit (MU) loss in type III and IV Spinal Muscular Atrophy (SMA) using motor unit number index (MUNIX), and evaluation of compensatory mechanisms based on MU size indices (MUSIX). METHODS: Nineteen type III and IV SMA patients and 16 gender- and age-matched healthy controls were recruited. Neuromuscular performance was evaluated by muscle strength testing and functional scales. Compound motor action potential (CMAP), MUNIX and MUSIX were studied in the abductor pollicis brevis (APB), abductor digiti minimi (ADM), deltoid, tibialis anterior and trapezius muscles...
September 13, 2018: Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology
Marianna Maretina, Anna Egorova, Vladislav Baranov, Anton Kiselev
Methylation profiles of CpG islands within the SLC23A2, CDK2AP1, and DYNC1H1 genes and their association with spinal muscular atrophy (SMA) severity were studied. High clinical heterogeneity of SMA suggests the existence of different factors modifying SMA phenotype with gene methylation as a plausible one. The genes picked up in our earlier genome-wide methylation studies of SMA patients demonstrated obvious differences in their methylation patterns, thus suggesting the likely involvement of their protein products in SMA development...
September 24, 2018: Annals of Human Genetics
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