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"Spinal Muscular Atrophy"

Zhongmin Xia, Yulin Zhou, Dongmei Fu, Zengge Wang, Yunsheng Ge, Jun Ren, Qiwei Guo
Carrier screening of spinal muscular atrophy (SMA) can provide reproductive options for carriers and prevent the birth defects. Here, we developed a simple screening test based on melting analysis. The test comprises a duplex PCR with two primer pairs and three probes to simultaneous amplify SMN1, SMN2, and CFTR. By analyzing the melting profiles, we were able to determine the SMN1/SMN2 ratio and SMN1 + SMN2 copy number to subsequently determine the copy number of SMN1. Samples with one copy of SMN1 were considered as "high risk for carrier," while samples with ≥2 copies of SMN1 were considered as "low risk for carrier...
February 15, 2019: Journal of Human Genetics
Kyle A Beauchamp, Katherine A Johansen Taber, Dale Muzzey
PURPOSE: Carrier screening identifies couples at high risk for conceiving offspring affected with serious heritable conditions. Minimal guidelines recommend offering testing for cystic fibrosis and spinal muscular atrophy, but expanded carrier screening (ECS) assesses hundreds of conditions simultaneously. Although medical societies consider ECS an acceptable practice, the health economics of ECS remain incompletely characterized. METHODS: Preconception screening was modeled using a decision tree comparing minimal screening and a 176-condition ECS panel...
February 14, 2019: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Dongxue Mao, Guang Lin, Burak Tepe, Zhongyuan Zuo, Kai Li Tan, Mumine Senturk, Sheng Zhang, Benjamin R Arenkiel, Marco Sardiello, Hugo J Bellen
Mutations in the ER-associated VAPB/ALS8 protein cause amyotrophic lateral sclerosis and spinal muscular atrophy. Previous studies have argued that ER stress may underlie the demise of neurons. We find that loss of VAP proteins (VAPs) leads to an accumulation of aberrant lysosomes and impairs lysosomal degradation. VAPs mediate ER to Golgi tethering and their loss may affect phosphatidylinositol-4-phosphate (PtdIns4P) transfer between these organelles. We found that loss of VAPs elevates PtdIns4P levels in the Golgi, leading to an expansion of the endosomal pool derived from the Golgi...
February 11, 2019: Autophagy
Chenyi Wan, Yuyao Wang, Qian Zhou, Yanyan Yu, Daojun Hong, Min Zhu
Heterozygous variants in the bicaudal D homolog 2 gene ( BICD2 ) are associated with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). This disease is usually characterized by congenital or early-onset muscle weakness and atrophy of the lower extremities with benign or slow progression. We herein described an autosomal dominant inherited pedigree with SMALED2 in which the affected individuals presented with late adult-onset muscle weakness and wasting in the lower extremities...
February 10, 2019: Clinical Neuropathology
Bart Bartels, Laura E Habets, Marloes Stam, Renske I Wadman, Camiel A Wijngaarde, Marja A G C Schoenmakers, Tim Takken, Erik H J Hulzebos, W Ludo van der Pol, Janke F de Groot
BACKGROUND: Fatigability has emerged as an important dimension of physical impairment in patients with Spinal Muscular Atrophy (SMA). At present reliable and valid outcome measures for both mildly and severely affected patients are lacking. Therefore the primary aim of this study is the development of clinical outcome measures for fatigability in patients with SMA across the range of severity. METHODS: We developed a set of endurance tests using five methodological steps as recommended by the 'COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN)...
February 9, 2019: BMC Neurology
E Y Osman, A Rietz, R A Kline, J J Cherry, K J Hodgetts, C L Lorson, E J Androphy
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that causes progressive muscle weakness and is the leading genetic cause of infant mortality worldwide. SMA is caused by the loss of survival motor neuron 1 (SMN1). In humans, a nearly identical copy gene is present, called SMN2. Although SMN2 maintains the same coding sequence, this gene cannot compensate for the loss of SMN1 because of a single silent nucleotide difference in SMN2 exon 7. SMN2 primarily produces an alternatively spliced isoform lacking exon 7, which is critical for protein function...
February 7, 2019: Scientific Reports
Agnieszka Stępień, Maria Jędrzejowska, Katarzyna Guzek, Witold Rekowski, Jolanta Stępowska
BACKGROUND: The majority of individuals with spinal muscular atrophy (SMA) experience progressive skeletal deformities which may affect the quality of life and mobility. To date, no studies have evaluated the reliability of tests assessing body posture and joint mobility in SMA patients. The purpose of this study was to assess the reliability of Cervical Rotation test (CR), Supine Angle of Trunk Rotation test (SATR), Hip Extension test (HE) and Pelvic Obliquity test (PO) developed to evaluate the musculoskeletal system in SMA individuals...
February 7, 2019: BMC Musculoskeletal Disorders
María Angélica Palomino, Claudia Castiglioni
Spinal muscular atrophy (SMA) is the first inherited cause of mortality in infants, with four subtypes: SMA0 prenatal onset, SMA1 babies less than 3 months non sitters, SMA2 sitters and SMA3 walkers. Pneumonia and respiratory insufficiency are the most severe complications. Informed parental de cisions are relevant. Respiratory management includes cough assistance, prevention of lung under development due to chest deformity, prompt treatment of respiratory infections, hypoventilation, swallow problems, gastro esophageal reflux and malnutrition...
December 2018: Revista Chilena de Pediatría
Kazuki Ohuchi, Michinori Funato, Shiori Ando, Satoshi Inagaki, Arisu Sato, Chizuru Kawase, Junko Seki, Shinsuke Nakamura, Masamitsu Shimazawa, Hideo Kaneko, Hideaki Hara
Survival motor neuron (SMN) deficiency indicates that various cellular processes are impaired in spinal muscular atrophy (SMA). Previous reports have shown that SMN deficiency causes motor neuron degeneration, whereas the numbers of astrocytes and microglia are significantly increased or activated in SMA model systems. Only a few groups have studied the role of oligodendrocyte (OL) lineages such as OL precursor cell and nerve/glial antigen 2 (NG2)-glia in SMA pathology. Our aim in this study was to investigate whether OL lineages are impaired in SMA model systems...
February 4, 2019: Neuroreport
Joseph E Kaserman, Andrew A Wilson
PIZZ alpha-1 antitrypsin deficiency (AATD) is an autosomal recessive disease affecting approximately 100,000 individuals in the United States and one of the most common hereditary causes of liver disease.1 The most common form of the disease results from a single base pair mutation (Glu342Lys), known as the "Z" mutation, that encodes a mutant protein (Z alpha-1 antritypsin [AAT]) that is prone to misfolding and is retained in the endoplasmic reticulum (ER) rather than appropriately secreted. Some of the retained mutant protein attains an unusual aggregated or polymerized conformation...
September 15, 2018: Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation
Steven Lehrer, Peter H Rheinstein
NSAIDs may prevent Alzheimer's disease (AD) but have failed as a treatment, possibly because only 1-2% of an oral NSAID dose reaches the brain. This minuscule dose is enough to have a preventative effect on Alzheimer's disease but not to treat it. We propose a new route of administration for drugs to treat AD: transspinal delivery by transdermal patch over the back-of-neck/cervical spine. The drug would diffuse from the patch through the intervertebral spaces, penetrate the dura, enter the CSF, and reach the brain...
January 2019: Discovery Medicine
Santiago Zuluaga-Sanchez, Megan Teynor, Christopher Knight, Robin Thompson, Thomas Lundqvist, Mats Ekelund, Annabelle Forsmark, Adrian D Vickers, Andrew Lloyd
BACKGROUND: Spinal muscular atrophy is a rare neuromuscular disorder with a spectrum of severity related to age at onset and the number of SMN2 gene copies. Infantile-onset (≤ 6 months of age) is the most severe spinal muscular atrophy and is the leading monogenetic cause of infant mortality; patients with later-onset (> 6 months of age) spinal muscular atrophy can survive into adulthood. Nusinersen is a new treatment for spinal muscular atrophy. OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of nusinersen for the treatment of patients with infantile-onset spinal muscular atrophy and later-onset spinal muscular atrophy in Sweden...
February 4, 2019: PharmacoEconomics
Maarten J Fischer, Fay-Lynn Asselman, Esther T Kruitwagen-van Reenen, Marjolein Verhoef, Renske I Wadman, Johanna M A Visser-Meily, W Ludo van der Pol, Carin D Schröder
PURPOSE: Patients with spinal muscular atrophy (SMA) suffer from slowly progressive weakness of axial, respiratory and proximal muscles, leading to restrictions in activity and participation. This study aims to investigate patients' level of psychological well-being, using the International Classification of Functioning model and self-determination theory as theoretical frameworks. MATERIALS AND METHODS: In this cross-sectional study, adults with SMA were invited to complete a questionnaire...
January 29, 2019: Disability and Rehabilitation
Maria Carmela Pera, Giorgia Coratti, Elena S Mazzone, Jacqueline Montes, Mariacristina Scoto, Roberto De Sanctis, Marion Main, Anna Mayhew, Robert Muni Lofra, Sally Dunaway Young, Allan M Glanzman, Tina Duong, Amy Pasternak, Danielle Ramsey, Basil Darras, John W Day, Richard S Finkel, Darryl C De Vivo, Maria Pia Sormani, Francesca Bovis, Volker Straub, Francesco Muntoni, Marika Pane, Eugenio Mercuri
INTRODUCTION: The aim of the study was to assess 12 month changes in upper limb function in patients affected by spinal muscular atrophy type 2 and 3. METHODS: Longitudinal 12 month data was collected in 114 patients, 60 type 2 and 54 type 3, using the Revised Upper Limb Module. RESULTS: The 12 month changes ranged between -7 and 9 (mean: -0.41; SD: 2.93). The mean changes were not significantly different between the three spinal muscular atrophy groups (-0...
January 24, 2019: Muscle & Nerve
Ye Seul Son, Kwangman Choi, Hana Lee, Ohman Kwon, Kwang Bo Jung, Sunwha Cho, Jiyeon Baek, Bora Son, Sung-Min Kang, Mingu Kang, Jihee Yoon, Haihong Shen, Sangku Lee, Jung-Hwa Oh, Hyang-Ae Lee, Mi-Ok Lee, Hyun-Soo Cho, Cho-Rok Jung, Janghwan Kim, Sungchan Cho, Mi-Young Son
Spinal muscular atrophy (SMA) is caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene. Only approximately 10 % of the products of SMN2, a paralogue of SMN1, are functional full-length SMN proteins, whereas SMN2 primarily produces alternatively spliced transcripts lacking exon 7. Reduced SMN protein levels in SMA patients lead to progressive degeneration of spinal motor neurons (MNs). Here, we report an advanced platform based on an SMN2 splicing-targeting approach for SMA drug screening and validation by using an SMN2 splicing reporter cell line and an in vitro human SMA model via induced pluripotent stem cell (iPSC) technology...
January 22, 2019: Stem Cells and Development
Astrid Pechmann, Kirsten König, Günther Bernert, Kristina Schachtrup, Ulrike Schara, David Schorling, Inge Schwersenz, Sabine Stein, Adrian Tassoni, Sibylle Vogt, Maggie C Walter, Hanns Lochmüller, Janbernd Kirschner
BACKGROUND: Survival and quality of life for patients affected by spinal muscular atrophy (SMA) are thought to have improved over the last decade due to changes in care. In addition, targeted treatments for SMA have been developed based on a better understanding of the molecular pathology. In 2016 and 2017, nusinersen was the first drug to be approved for treatment of all types of SMA in the United States and in Europe based on well-controlled clinical trials in a small subgroup of pediatric SMA patients...
January 21, 2019: Orphanet Journal of Rare Diseases
Arnaud Jacquier, Valérie Risson, Laurent Schaeffer
Neurodegeneration of spinal motoneurons (MNs) is implicated in a large spectrum of neurological disorders including amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, and spinal muscular atrophy, which are all associated with muscular atrophy. Primary cultures of spinal MNs have been used widely to demonstrate the involvement of specific genes in such diseases and characterize the cellular consequences of their mutations. This protocol models a primary MN culture derived from the seminal work of Henderson and colleagues more than twenty years ago...
January 7, 2019: Journal of Visualized Experiments: JoVE
K R Valetdinova, M A Maretina, M L Kuranova, E V Grigor'eva, Y M Minina, E A Kizilova, A V Kiselev, S P Medvedev, V S Baranov, S M Zakian
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletion or mutation in SMN1 gene. SMA human induced pluripotent stem cells (iPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. We generated iPSCs from a SMA type I patient and SMA type II patient by using non-integrating episomal plasmid vectors. The resulting iPSCs are episomal-free, express pluripotency markers, display a normal karyotype, retain the mutation (homozygous deletion of SMN1) and are able to differentiate into the three germ layers...
January 11, 2019: Stem Cell Research
Afshin Saffari, Stefan Kölker, Georg F Hoffmann, Markus Weiler, Andreas Ziegler
In recent years, disease-modifying and life-prolonging therapies for spinal muscular atrophy (SMA) have been developed. However, patients are currently diagnosed with significant delay and therapies are often administered in advanced stages of motor neuron degeneration, showing limited effects. Methods to identify children in presymptomatic stages are currently evaluated in newborn screening programs. Yet, not all children develop symptoms shortly after birth raising the question whom to treat and when to initiate therapy...
January 2019: Annals of Clinical and Translational Neurology
Federica Rizzo, Monica Nizzardo, Shikha Vashisht, Erika Molteni, Valentina Melzi, Michela Taiana, Sabrina Salani, Pamela Santonicola, Elia Di Schiavi, Monica Bucchia, Andreina Bordoni, Irene Faravelli, Nereo Bresolin, Giacomo Pietro Comi, Uberto Pozzoli, Stefania Corti
Spinal muscular atrophy is a motor neuron disorder caused by mutations in SMN1. The reasons for the selective vulnerability of motor neurons linked to SMN (encoded by SMN1) reduction remain unclear. Therefore, we performed deep RNA sequencing on human spinal muscular atrophy motor neurons to detect specific altered gene splicing/expression and to identify the presence of a common sequence motif in these genes. Many deregulated genes, such as the neurexin and synaptotagmin families, are implicated in critical motor neuron functions...
January 15, 2019: Brain: a Journal of Neurology
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