المؤلفون: Jessika Johannsen, Jonas Denecke, Roberto Colombo, Tatjana Bierhals, Marta Bertoli, Franziska Degenhardt, Eva Wohlleber, Tim M. Strom, Alexander M. Zink, Jessica Becker, Davor Lessel, Elisabeth Mangold, Dagmar Wieczorek, Laura M Yates, Kirsten Cremer, Hartmut Engels, Kerstin U. Ludwig, Sophia Peters, Theresia Herget, Maja Hempel, Isabelle C Windheuser, Hela Hundertmark

المصدر: Am. J. Med. Genet. A 182, 1021-1031 (2020)

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Microcephaly, Adolescent, Medizin, Nerve Tissue Proteins, Haploinsufficiency, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, Short stature, Young Adult, 03 medical and health sciences, Intellectual Disability, Exome Sequencing, Intellectual disability, Genetics, medicine, Humans, Point Mutation, Genetic Predisposition to Disease, Obesity, Child, Genetics (clinical), Exome sequencing, Point mutation, Macrocephaly, Microarray Analysis, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, Chromosomes, Human, Pair 2, Female, Chromosomal Microarray, Microdeletion 2p25, 3, Myt1l, Whole Exome Sequencing, Chromosome Deletion, medicine.symptom, Transcription Factors

الوصف: Both point mutations and deletions of the MYT1L gene as well as microdeletions of chromosome band 2p25.3 including MYT1L are associated with intellectual disability, obesity, and behavioral problems. Thus, MYT1L is assumed to be the-at least mainly-causative gene in the 2p25.3 deletion syndrome. Here, we present comprehensive descriptions of nine novel individuals bearing MYT1L mutations; most of them single nucleotide variants (SNVs). This increases the number of known individuals with causative deletions or SNVs of MYT1L to 51. Since eight of the nine novel patients bear mutations affecting MYT1L only, the total number of such individuals now nearly equals the number of individuals with larger microdeletions affecting additional genes, allowing for a comprehensive phenotypic comparison of these two patient groups. For example, 55% of the individuals with mutations affecting MYT1L only were overweight or obese as compared to 86% of the individuals with larger microdeletions. A similar trend was observed regarding short stature with 5 versus 35%, respectively. However, these differences were nominally significant only after correction for multiple testing, further supporting the hypothesis that MYT1L haploinsufficiency is central to the 2p25.3 deletion phenotype. Most importantly, the large number of individuals with MYT1L mutations presented and reviewed here allowed for the delineation of a more comprehensive clinical picture. Seizures, postnatal short stature, macrocephaly, and microcephaly could be shown to be over-represented among individuals with MYT1L mutations.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d6687b40b1f36cdad3881b0200ff57d0Test
https://doi.org/10.1002/ajmg.a.61515Test

المؤلفون: Silvia Maitz, Elisa Rahikkala, Wayne Lam, Pedro A. Sanchez-Lara, Katherine Lachlan, Melissa Lees, Katherine L. Nathanson, Chey Loveday, Lionel Van Maldergem, Shane McKee, Dragana Josifova, Sally Ann Lynch, Katrina Tatton-Brown, Michael Parker, Ana Beleza-Meireles, Andrew G. L. Douglas, Sarina G. Kant, Philip J. Ostrowski, Tyler Mark Pierson, Yvonne Hilhorst-Hofstee, Sofia Douzgou, Kay Metcalfe, Marta Bertoli, Charlotte W. Ockeloen, Usha Kini, Diana Johnson, John Dean, Alice Spano, Trevor Cole, Alison Foster, Jennifer Hague, John M. Graham, Ian O. Ellis, Anna Zachariou, Mariëtte J.V. Hoffer

المصدر: American Journal of Medical Genetics Part C : Seminars in Medical Genetics, 181, 4, pp. 557-564
American Journal of Medical Genetics Part C : Seminars in Medical Genetics, 181, 557-564
American Journal of Medical Genetics Part C: Seminars in Medical Genetics. WILEY
American Journal of Medical Genetics Part C: Seminars in Medical Genetics

مصطلحات موضوعية: Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Scoliosis, macrocephaly, Young Adult, CHD8, Intellectual disability, Genetics, medicine, Humans, Child, overgrowth, Genetics (clinical), Growth Disorders, business.industry, Macrocephaly, Infant, Syndrome, medicine.disease, Cadherins, Umbilical hernia, Neonatal hypotonia, Phenotype, intellectual disability, Overgrowth syndrome, Child, Preschool, Autism, Female, Differential diagnosis, medicine.symptom, business, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]

الوصف: Item does not contain fulltext CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference >/=2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (

وصف الملف: text

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3264e73bb704ac5d8c7608f78ec2c1b6Test
https://doi.org/10.1002/ajmg.c.31749Test

المؤلفون: Paul Maddison, L. Phillips, Anna Kostera-Pruszczyk, Anna Łusakowska, Ana Töpf, L. Xu, Daniel G. MacArthur, Marta Bertoli, Kristl G. Claeys, Monkol Lek, Ela Akay, Katherine Johnson, Alexandra Bastian, Volker Straub, Stojan Peric, Vidosava Rakocevic Stojanovic, Andreas Hahn

المصدر: Orphanet Journal of Rare Diseases, Vol 12, Iss 1, Pp 1-11 (2017)
Orphanet journal of rare diseases 12(1), 173 (2017). doi:10.1186/s13023-017-0722-1
Orphanet Journal of Rare Diseases

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Weakness, Candidate gene, Adolescent, lcsh:Medicine, Biology, Compound heterozygosity, Bioinformatics, Sequence variants, Frameshift mutation, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Glycogen storage disease type II, medicine, Humans, Pharmacology (medical), Child, Genetics (clinical), Exome sequencing, Aged, Aged, 80 and over, Muscle Weakness, Glycogen Storage Disease Type II, Genetic heterogeneity, Research, lcsh:R, Whole exome sequencing, Genetic Variation, Muscle weakness, Pompe disease, alpha-Glucosidases, General Medicine, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, Child, Preschool, Female, medicine.symptom, 030217 neurology & neurosurgery

الوصف: BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb-girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants. RESULTS: A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c.-13 T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease. CONCLUSIONS: Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders. ispartof: Orphanet Journal of Rare Diseases vol:12 issue:1 pages:173-184 ispartof: location:England status: published

وصف الملف: Electronic; application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::11a5bb4bbf80ab971616404ecc7b297cTest
http://link.springer.com/article/10.1186/s13023-017-0722-1Test

المؤلفون: Mark Busby, Rita Barresi, L. Phillips, Tiziana Mongini, Hacer Durmus, Jonathan Baets, Fiona Norwood, Judith N Hudson, James Miller, Peter De Jonghe, Shahriar Nafissi, Katherine Johnson, Ana Töpf, Monkol Lek, Stojan Peric, Daniel G. MacArthur, Marta Bertoli, Willem De Ridder, Shirin Jamal-Omidi, Vidosava Rakocevic Stojanovic, Volker Straub, Tine Deconinck, Anna Łusakowska

المصدر: Journal of neurology, neurosurgery and psychiatry

مصطلحات موضوعية: Adult, Male, Pathology, medicine.medical_specialty, Myopathy, Ubiquitin-Protein Ligases, Nonsense mutation, Population, Ethnic Groups, Muscle disorder, Muscular Dystrophies, Frameshift mutation, Tripartite Motif Proteins, 03 medical and health sciences, Limb-Girdle, 0302 clinical medicine, Muscular Diseases, Missense mutation, Medicine, Humans, Muscular dystrophy, education, Exome sequencing, Muscle disease, education.field_of_study, Neuromuscular, Female, Magnetic Resonance Imaging, Middle Aged, Muscle, Skeletal, Muscular Dystrophies, Limb-Girdle, Mutation, Transcription Factors, business.industry, Skeletal, medicine.disease, 3. Good health, Psychiatry and Mental health, Muscle, Surgery, Neurology (clinical), Human medicine, medicine.symptom, business, 030217 neurology & neurosurgery

الوصف: Introduction TRIM32-related myopathies represent a phenotypic spectrum of a rare autosomal recessive muscle disorder. The disease is described as a mild and progressive myopathy without characteristic clinical features. Originally classified as limb-girdle muscular dystrophy (LGMD) 2H (OMIM #254110), the disorder was first identified in the Hutterite population and the homozygous TRIM32 founder mutation, p.Asp487Asn, was identified as the cause of this disease.1 Only seven patients with definite non-Hutterite TRIM32-related myopathy have been reported in the literature. Apart from two missense mutations residing in the NHL repeats of TRIM32, only deletions, frameshift and nonsense mutations have been reported.2 Having applied next generation sequencing technologies to over 1000 patients with suspected genetic muscle disorders, we present nine patients with TRIM32-related myopathies and three patients with a homozygous TRIM32 variant of unknown significance (VUS). Subjects and methods DNA samples from 1000 patients with unexplained limb-girdle muscle weakness and/or elevated serum creatine kinase (CK) levels were gathered through the MYO-SEQ project. Samples were processed and whole exome sequencing (WES) performed as described previously.3 Additional patients with TRIM32-related myopathy were diagnosed by the Northern Molecular Genetics Service (NMGS) diagnostic laboratory through panel sequencing of 32 LGMD genes. Variants were classified according to ACMG guidelines.4 MRI imaging was performed for eight patients on a 1.5T MRI platform. Muscle biopsies for all patients were analysed following standard histological techniques. Results Genetic findings Of the 1000 MYO-SEQ patients, we identified 36 with rare coding variants in TRIM32 (minor allele frequency

وصف الملف: pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::28cfdfc1be3263ac26ee02f4f736fa0bTest
http://hdl.handle.net/2318/1786348Test

المؤلفون: Shirin Jamal-Omidi, L. Phillips, Anna Kostera-Pruszczyk, Nanna Witting, Miren Zulaica Ijurco, Maja von der Hagen, Ana Töpf, Kristl G. Claeys, Jaume Colomer, Monkol Lek, Shahriar Nafissi, L. Xu, Daniel G. MacArthur, Elise Valkanas, Jonathan Baets, Anna Potulska-Chromik, Volker Straub, Anna Łusakowska, Peter Van den Bergh, Sonja Strang-Karlsson, Thomas E. Mullen, John Vissing, Marta Bertoli, Juan Bautista Espinal Valencia, Carina Wallgren-Pettersson, Willem De Ridder, Hacer Durmus, Tracey Willis, Katherine Johnson, Andreas Hahn, Roberto Fernández-Torrón, Nicolas Deconinck

المساهمون: UCL - (SLuc) Service de neurologie, UCL - SSS/IONS/NEUR - Clinical Neuroscience, Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Clinicum, Children's Hospital, HUS Children and Adolescents

المصدر: Skeletal Muscle, Vol. 8, no. 1, p. 23 [1-12] (2018)
Skeletal muscle 8(1), 23 (2018). doi:10.1186/s13395-018-0170-1
Skeletal Muscle
Johnson, K, Bertoli, M, Phillips, L, Töpf, A, Van den Bergh, P, Vissing, J, Witting, N, Nafissi, S, Jamal-Omidi, S, Łusakowska, A, Kostera-Pruszczyk, A, Potulska-Chromik, A, Deconinck, N, Wallgren-Pettersson, C, Strang-Karlsson, S, Colomer, J, Claeys, K G, De Ridder, W, Baets, J, von der Hagen, M, Fernández-Torrón, R, Zulaica Ijurco, M, Espinal Valencia, J B, Hahn, A, Durmus, H, Willis, T, Xu, L, Valkanas, E, Mullen, T E, Lek, M, MacArthur, D G & Straub, V 2018, ' Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness ', Skeletal Muscle, vol. 8, 23 . https://doi.org/10.1186/s13395-018-0170-1Test
SKELET MUSCLE
r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname
Skeletal Muscle, 8 (1
r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
Fundació Sant Joan de Déu
Skeletal Muscle, Vol 8, Iss 1, Pp 1-12 (2018)
Skeletal muscle

مصطلحات موضوعية: 0301 basic medicine, Male, lcsh:Diseases of the musculoskeletal system, Glycosylation, Whole Exome Sequencing/methods, Muscle Proteins, Hygiène et médecine sportives, Bioinformatics, WALKER-WARBURG-SYNDROME, 0302 clinical medicine, Orthopedics and Sports Medicine, Limb-girdle muscle weakness, Child, Dystroglycans, Exome sequencing, Muscle Proteins/genetics, Aged, 80 and over, Homozygote, Middle Aged, Dystroglycanopathies, 3. Good health, Whole-exome sequencing, medicine.anatomical_structure, Phenotype, Dystroglycans/metabolism, Child, Preschool, Orthopédie, Congenital muscular dystrophy, SKELETAL-MUSCLE, Female, medicine.symptom, GLYCOPROTEIN COMPLEX, Life Sciences & Biomedicine, ALPHA-DYSTROGLYCAN, Adult, Heterozygote, Proximal muscle weakness, Adolescent, EYE-BRAIN DISEASE, 03 medical and health sciences, Young Adult, Glycoprotein complex, Exome Sequencing, medicine, Humans, ABNORMAL GLYCOSYLATION, Genetic Predisposition to Disease, Walker–Warburg syndrome, Biology, Molecular Biology, POMT2 MUTATIONS, Aged, Science & Technology, Genetic heterogeneity, business.industry, Research, Muscular Dystrophies, Limb-Girdle/genetics, Muscle weakness, Skeletal muscle, Genetic Variation, Cell Biology, medicine.disease, Cancérologie, 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, Mutation, CONGENITAL MUSCULAR-DYSTROPHY, 1182 Biochemistry, cell and molecular biology, Biologie cellulaire, Human medicine, DEFECTIVE GLYCOSYLATION, 3111 Biomedicine, lcsh:RC925-935, business, 030217 neurology & neurosurgery, MENTAL-RETARDATION

الوصف: Background: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. Methods: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250ng DNA was completed using an Illumina exome capture and a 38Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. Results: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. Conclusions: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.
SCOPUS: ar.j
info:eu-repo/semantics/published

وصف الملف: application/pdf; Electronic; 1 full-text file(s): application/pdf; pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ed866fead030563b4d9ea59130e00061Test
https://hdl.handle.net/2078.1/220057Test

المؤلفون: Matt Parton, Wei Wei Liu, Maryam Sedghi, Andrew M. Schaefer, Maria Elena Farrugia, Katsiaryna Belaya, Susan Maxwell, Jacqueline Palace, Hanns Lochmüller, Simon J. McGowan, Keivan Basiri, Anna Sarkozy, Wyatt W. Yue, Kate Bushby, Matthew Pitt, David Beeson, Richard E. Petty, Timothy J. Walls, Pedro M. Rodríguez Cruz, Marta Bertoli, Robin Kennett, Francesco Muntoni

المصدر: Brain

مصطلحات موضوعية: Adult, Male, Pathology, medicine.medical_specialty, Weakness, glycosylation, Adolescent, DNA Mutational Analysis, Neuromuscular transmission, Neuromuscular Junction, GMPPB, Transfection, Neuromuscular junction, dystroglycan, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Medicine, Humans, Repetitive nerve stimulation, Muscular dystrophy, Myopathy, Dystroglycans, Muscle, Skeletal, 030304 developmental biology, Family Health, Myasthenic Syndromes, Congenital, 0303 health sciences, business.industry, neurotransmission defect, DPAGT1, Original Articles, Congenital myasthenic syndrome, medicine.disease, Magnetic Resonance Imaging, Nucleotidyltransferases, 3. Good health, medicine.anatomical_structure, HEK293 Cells, congenital myasthenic syndrome, Immunology, Mutation, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery

الوصف: Congenital myasthenic syndromes are associated with impairments in neuromuscular transmission. Belaya et al. show that mutations of the glycosylation pathway enzyme GMPPB, which has previously been implicated in muscular dystrophy dystroglycanopathy, also cause a congenital myasthenic syndrome. This differential diagnosis is important to ensure that affected individuals receive appropriate medication.
Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4caad57ca8c6d0ca5b81ac994de9e2ceTest
http://europepmc.org/articles/PMC4547052Test

المؤلفون: Miloš Brkušanin, L. Phillips, Straub, Ana Töpf, Vidosava Rakocevic Stojanovic, Daniel G. MacArthur, M. Cassop-Thompson, Dusanka Savic-Pavicevic, Hanns Lochmüller, JN Glumac, Katherine Johnson, L. Xu, Vedrana Milic Rasic, Stojan Peric, S Milenkovic, Marta Bertoli, Ruzica Maksimovic, Monkol Lek, Bojan Banko

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, Adolescent, Population, Mutation, Missense, Genes, Recessive, Biology, Compound heterozygosity, Article, Muscular Dystrophies, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Genetics, medicine, Missense mutation, Humans, Connectin, Myopathy, education, Child, Creatine Kinase, Genetics (clinical), education.field_of_study, Haplotype, Syndrome, Middle Aged, Founder Effect, 3. Good health, Distal Myopathies, 030104 developmental biology, Phenotype, Haplotypes, Case-Control Studies, biology.protein, Titin, Female, medicine.symptom, Serbia, 030217 neurology & neurosurgery

الوصف: Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2aabd18a1f68ec347c33ec0784e2c02eTest
https://europepmc.org/articles/PMC5437897Test/

المؤلفون: S. Richardson, E. Kimber, H. Kim, Diana Castro, H. Johnson, A. C. Tesi Rocha, Matthias Eckenweiler, C. Manzitti, John W. Day, R. De Sanctis, M. Gormley, Mar Tulinius, Mirac Yildirim, C. M. Temucin, M. Gratacos Vinola, S. Matsumaru, F. Weber-Guzman, J. Kitsuwa-Lowe, Lavinia Fanelli, T. Sato, W. C. Virginia, J. H. Hsu, S. Nagata, A. Michoulas, Sally Dunaway, Mariacristina Scoto, R. Shell, R. Laine, D. DiBella, C. King, Jacqueline Montes, Haluk Topaloglu, Maryam Oskoui, Didem Ardicli, K. Rupprich, C. Stella, F. Dorban, Alan C Farrow-Gillespie, S. A. Choi, T. Ikai, W. C. Liang, N. Matsushima, PH Lister, Arnaud Vanlander, N. Rausch, T. T. Duong, Marika Pane, Melissa Gibbons, M. M. Homi, A. K. Kroksmark, B. Andres, Kristin J. Krosschell, S. Patnaik, L. Welsh, Eduardo F. Tizzano, M. Gallardo, Michèle Mayer, Sarada Sakamuri, W. Liew, T. Spain, M. Yang, Kayoko Saito, Edward C. Smith, L. Sanabria, Astrid Pechmann, H. Kaneko, Leslie Nelson, Basil T. Darras, C. Milleson, Janbernd Kirschner, R. Arakawa, Margot Morrison, Y. Kaburagi, P. Dinunzio, C. K.W. Joseph, M. Chadehumbe, Craig M. Zaidman, S. Nicolarsen, Hyung Ik Shin, Alberto Garaventa, James J. Dowling, J. S. Lee, K. Booker, A. Takeshita, D. McElroy, K. Carroll, D. Vens, Y. Chiba, L. Wand, C. Kelly, Luke Smith, H. Shimomura, M. Srour, J. B. Bodensteriner, B. Rippberger, A. Herbert, Eugenio Mercuri, H. Jo, J. Turner, A. Camuto, N. Parziale, J. O'Brien, N. Nelson, E. Serdaroglu, Jong-Hee Chae, V. Tahon, E. Toro Tamargo, L. Weimer, T. Voit, L. W.M. Wendy, J. Rambaud, G. Gilbert, C. Zimmerman, S. Kramer, D. McFall, Jennifer Perez, N. Berthon-Jones, Jessica Taytard, Marco Luigetti, J. Pisco Domingos, R. Van Der Looven, Genevieve D'Souza, C. Berde, E. Roland, M. de Los Angeles Tormos Munoz, J. Zigmont, S. Baily, S. Gilabert, H. Nakatsukasa, S. Trest, Bahadır Konuşkan, H. A. Ferreira Sampaio, Z. John Zhong, G. VanderVeen, V. Allen, C. Aguilar, N. Taniguchi, G. Ordonez, Elizabeth Kichula, F. Shu, M. N. Chui-San, M. Zinn, Anne M. Connolly, Ian R. Woodcock, Ayşe Karaduman, R. Haldenby, K. Hirasawa, F. Munell Casadesus, L.D.M. Peña, Vamshi K. Rao, Allan M. Glanzman, Claudia A. Chiriboga, A. Martinez Bermejo, John F. Brandsema, S. Epinosa Garcia, M. K. Schroth, T. Shibano, Richard Gee, Valeria Ricotti, Y. Ito, Y. Tanaka, S. Arpin, C. S. Yan, L. Schottlaender, Marco Piastra, M. Kauk, Francesco Muntoni, K. Sugimoto, Öznur Yilmaz, K. DeCock, Kathryn Selby, T. Yanagishita, Concetta Palermo, H. W. Chung, B. Taicher, Jiri Vajsar, K. Zilke, R. Gadeken, A. Yamauchi, Marta Bertoli, Nancy L. Kuntz, T. Tachikawa, C. Johnson, A. Mayhew, Jahannaz Dastgir, Y. J. Jong, P. C. Chou, G. Rivera, T. N. Shun, Y. H. Ju, N. Holuba La Marca, M. Toms, Matthew Civitello, Eugene Schneider, C. Lilien, S. Ito, C. Skura, Y. Yvonne, K. O'Reardon, Barry S. Russman, Janet Quigley, J. W. Said, B. Planas Pascual, R. J. Ramamurthi, Wildon Farwell, V. Selby, W. Y. Connie, M. Souris, Nicholas E. Johnson, M. Miki, N. Sponemann, Andrei Constantinescu, K. Mayne, H. H. Shih, B. Sanjanwala, Teresa Gidaro, D. Berry, Gihan Tennekoon, A. G. Le Moing, Danielle Ramsey, C. Poulin, S. Goldman, K. Watson, H. L. Teoh, N. J. Palacios, Tai-Heng Chen, A. C. Chung, Terri Carry, J. Coates, D. Zielinski, R. Vialle, F. G. Yildiz Sarikaya, Marcus Krüger, M. del Mar Garcia Romero, E. Michael, E. D. Austin, J. Janas, K. Engelstad, S. Y. Kim, M. Alavarez Molinero, Leon G. Epstein, Monique M. Ryan, Jean Flickinger, D. Benjamin, S. Wider, C. S. Davis, Jena M. Krueger, I. J.K. Janice, Darryl C. De Vivo, M. del Mar Melendez Plumed, Y. Takeshima, C. Gunbey, Serena Sivo, A. Christiaens, Q. Ollievier, Elizabeth Mirek, D. Stanford, Susan T. Iannaccone, Jonathan E. Kurz, D. Cook, C. S. Ng, A. Koka, V. Chau, M. del Pilar Tirado Requero, M. B. Gomez Garcia de la Banda, E. M. Yiu, Amy Pasternak, Rosangel Cruz, S. So, S. I. Pascual Pascual, V. G. Haliloglu, E. S. Schroers, P. Jachertz, C. Ortiz-Miller, Sandra Coppens, J. Lee, M. Popolizio, Michael Doumit, Rachel Salazar, Michelle A. Farrar, Peter G. Fuhr, M. Pedermonte, L. S. Lord-Halvorson, W. Leon, Y. S. Zeng, L. D'Argenzio, Russell J. Butterfield, C. Blomgren, Erika Finanger, S. Shea, Paola Tacchetti, N. Y. Ki, H. W. Choi, K. Oriyama, S. Wittevrongel, Catherine Siener, K. Mizuochi, M. Cowie, R. Van Coster, E. Gargaun, S. M. Scuplak, Sibylle Vogt, S. Stein, Tim Harrington, P. M. Ingelmo, J. Wootton, M. Tanyildiz, A. F. Rucian, Jonathan Marra, C. Frank Bennett, Claire L Wood, Nicolas Deconinck, Adnan Y. Manzur, Helene Verhelst, B. Purse, P. L. Léger, J. Cappell, S. Aziz-Zaman, H. Y. Wang, Claudio Bruno, S. Garcia Guixot, Robert Muni Lofra, Federica Trucco, S. M. Chun, Catherine E. Roberts, Ulrike Schara, Walter G. Bradley, K. L. De Valle, E. De Vos voor, S. Borell, A. Lim, Sophelia H. S. Chan, L. Rao, M. Shichiji, S. Rooze, T. M. Newcomb, Fouad Al-Ghamdi, Chiara Fiorillo, J. D. Endsley, L. Y. Sigurdardottir, Pallavi Anand, A. Zuffi, Julie A. Parsons, M. Kasper, A. Nishikawa, Sarah Gheuens, S. Turgeon-Desilet, T. Fujino, L. Staudt, Y. C. Wu, Jacinda B. Sampson, Paola Lanteri, Stephanie DeArmey, Partha S. Ghosh, Alexandra C. Ross, L. Adang, Laurent Servais, V. Tran, Alan Bielsky, Y. Otani, Navil F. Sethna, J. Hen, Perry B. Shieh, N. Fukuda, N. Miller, K. Eto, S. Paulose, Niklas Darin, C. Sabapathy, Robert J. Graham, Christopher Proud, Richard S. Finkel, Alexander G. Khandji, A. Della Marina, Adrian Murphy, Kathie M. Bishop, Tejaswi Kandula, Valentina Lanzillotta, Heather Szelag, Kalliopi Sofou, Y. H. Chou, Heike Koelbel, J. Eldblom, T. Lee, M. M. Martinez Moreno, Volker Straub, Laura E. Case, A. Lindstedt, G. Gili, A. Frank, H. C.C. Alvin, A. Ganfuss, Karen Herbert, Paul T. Golumbek, D. Villano, B. Wenderickx, B. C. Lim, W. S. Son

المساهمون: Schara, Ulrike (Beitragende*r), Ganfuss, Andrea (Beitragende*r), Koelbel, Heike (Beitragende*r), Rupprich, Katrin (Beitragende*r), Schroers, Ester Sarah (Beitragende*r), Sponemann, Nina (Beitragende*r), Çocuk Sağlığı ve Hastalıkları

مصطلحات موضوعية: Male, 0301 basic medicine, Pathology, Movement disorders, animal diseases, Messenger, Oligonucleotides, Medizin, Spinal Muscular Atrophies of Childhood, 0302 clinical medicine, Age of Onset, Disease-Free Survival, Double-Blind Method, Female, Humans, Infant, Injections, Spinal, Motor Skills, Oligonucleotides, Antisense, RNA, Messenger, Respiration, Artificial, Survival Analysis, Survival of Motor Neuron 2 Protein, Medicine (all), Respiration, General Medicine, Settore MED/26 - NEUROLOGIA, medicine.anatomical_structure, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Artificial, Nusinersen, medicine.symptom, medicine.medical_specialty, Spinal, Injections, 03 medical and health sciences, Atrophy, General & Internal Medicine, Settore MED/41 - ANESTESIOLOGIA, medicine, Antisense, Survival analysis, business.industry, Spinal muscular atrophy, Motor neuron, medicine.disease, nervous system diseases, 030104 developmental biology, nervous system, RNA, Infantile onset, Age of onset, business, 030217 neurology & neurosurgery

الوصف: Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre–messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. Methods: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. Results: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P Conclusions: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug.

وصف الملف: text/plain

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1902aea91371408a707bf0d8e637462Test
https://www.ncbi.nlm.nih.gov/pubmed/29091570Test

المؤلفون: C. Scotton, Mark Roberts, Judith N Hudson, E. Harris, Hanns Lochmüller, Bas Vroling, Teresinha Evangelista, Chiara Marini-Bettolo, Umar Burki, Tuomo Polvikoski, Rita Barresi, Marcella Neri, Marta Bertoli, Ana Töpf, Kate Bushby, Volker Straub, Daniel McArthur, Alessandra Ferlini

مصطلحات موضوعية: 0301 basic medicine, Male, Models, Molecular, Exome sequencing, DNA Mutational Analysis, Cell Culture Techniques, medicine.disease_cause, Pediatrics, Dyslexia, 0302 clinical medicine, Hypocalcaemia, Genetics (clinical), Blood Platelet Disorders, Mutation, Ichthyosis, Middle Aged, Miosis, Perinatology and Child Health, Store-operated calcium entry, Magnetic Resonance Imaging, Neoplasm Proteins, Neurology, STIM1, Stormorken syndrome, Tubular aggregate myopathy, York platelet syndrome, Pediatrics, Perinatology and Child Health, Neurology (clinical), Muscle Fatigue, Female, medicine.symptom, Myopathies, Structural, Congenital, inorganic chemicals, Adult, Asplenia, Migraine Disorders, Erythrocytes, Abnormal, Socio-culturale, 03 medical and health sciences, medicine, Humans, Stromal Interaction Molecule 1, Myopathy, Muscle, Skeletal, Genetic Association Studies, Family Health, business.industry, Fibroblasts, medicine.disease, NAD, Bleeding diathesis, Microscopy, Electron, 030104 developmental biology, Immunology, Calcium, business, 030217 neurology & neurosurgery, Spleen

الوصف: Dominant mutations in STIM1 are a cause of three allelic conditions: tubular aggregate myopathy, Stormorken syndrome (a complex phenotype including myopathy, hyposplenism, hypocalcaemia and bleeding diathesis), and a platelet dysfunction disorder, York platelet syndrome. Previous reports have suggested a genotype-phenotype correlation with mutations in the N-terminal EF-hand domain associated with tubular aggregate myopathy, and a common mutation at p.R304W in a coiled coil domain associated with Stormorken syndrome. In this study individuals with STIM1 variants were identified by exome sequencing or STIM1 direct sequencing, and assessed for neuromuscular, haematological and biochemical evidence of the allelic disorders of STIM1. STIM1 mutations were investigated by fibroblast calcium imaging and 3D modelling. Six individuals with STIM1 mutations, including two novel mutations (c.262A>G (p.S88G) and c.911G>A (p.R304Q)), were identified. Extra-neuromuscular symptoms including thrombocytopenia, platelet dysfunction, hypocalcaemia or hyposplenism were present in 5/6 patients with mutations in both the EF-hand and CC domains. 3/6 patients had psychiatric disorders, not previously reported in STIM1 disease. Review of published STIM1 patients (n = 49) confirmed that neuromuscular symptoms are present in most patients. We conclude that the phenotype associated with activating STIM1 mutations frequently includes extra-neuromuscular features such as hypocalcaemia, hypo-/asplenia and platelet dysfunction regardless of mutation domain.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::08f602728c67ab79a24d787c8492fde8Test
http://hdl.handle.net/11392/2384546Test

المؤلفون: E. Harris, Volker Straub, Hanns Lochmüller, Marta Bertoli, Anna Sarkozy, Steve Laval, Stephen G. Lynch, Ana Töpf

المصدر: Neuromuscular Disorders. 25:S276-S277

مصطلحات موضوعية: Distal symphalangism, business.industry, External ophthalmoplegia, Anatomy, Neurology, Ptosis, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), medicine.symptom, business, Myopathy, Novel mutation, Genetics (clinical)

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1b38cc894901cccaca6331e3430f6990Test
https://doi.org/10.1016/j.nmd.2015.06.327Test