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152. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, Emily, Jones, Kristi, Donkervoort, Sandra, Charlton, Amanda, Brammah, Susan, Smith, John, Ware, James, Yau, Kyle, Swanson, Lindsay, Whiffin, Nicola, Peduto, Anthony, Bournazos, Adam, Waddell, Leigh, Farrar, Michelle, Sampaio, Hugo, Teoh, Hooi Ling, Lamont, Phillipa, Mowat, David, Fitzsimons, Robin, Corbett, Alastair, Ryan, Monique, O'Grady, Gina, Sandaradura, Sarah, Ghaoui, Roula, Joshi, Himanshu, Marshall, Jamie, Nolan, Melinda, Kaur, Simranpreet, Punetha, Jaya, Töpf, Ana, Harris, Elizabeth, Bakshi, Madhura, Genetti, Casie, Marttila, Minttu, Werlauff, Ulla, Streichenberger, Nathalie, Pestronk, Alan, Mazanti, Ingrid, Pinner, Jason, Vuillerot, Carole, Grosmann, Carla, Camacho, Ana, Mohassel, Payam, Leach, Meganne, Foley, A Reghan, Bharucha-Goebel, Diana, Collins, James, Connolly, Anne, Gilbreath, Heather, Iannaccone, Susan, Castro, Diana, Cummings, Beryl, WEBSTER, Richard, Lazaro, Leila, Vissing, John, Coppens, Sandra, Deconinck, Nicolas, Luk, Ho-Ming, Thomas, Neil, Foulds, Nicola, Illingworth, Marjorie, Ellard, Sian, Mclean, Catriona, Phadke, Rahul, Ravenscroft, Gianina, Witting, Nanna, Hackman, Peter, Richard, Isabelle, Cooper, Sandra, Kamsteeg, Erik-Jan, Hoffman, Eric, Bushby, Kate, Straub, Volker, Udd, Bjarne, Ferreiro, Ana, North, Kathryn, Clarke, Nigel, Lek, Monkol, Beggs, Alan, Bönnemann, Carsten, MacArthur, Daniel, Granzier, Henk, Davis, Mark, Laing, Nigel, Foley, A. Reghan, Bharucha‐Goebel, Diana, Luk, Ho‐Ming, Kamsteeg, Erik‐Jan, The University of Sydney, Institute for Neuroscience and Muscle Research, Westmead Hospital [Sydney], Prologue, Hospices Civils de Lyon (HCL), Washington University in St Louis, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Department of Neurology, Rady Children's Hospital San Diego, National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), German Research Centre for Geosciences - Helmholtz-Centre Potsdam (GFZ), Duke University [Durham], Rothamsted Research, Département de médecine de l'enfant et de l'adolescent, University of Copenhagen = Københavns Universitet (KU), Université Libre de Bruxelles [Bruxelles] (ULB), University of Birmingham [Birmingham], Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Royal Devon and Exeter Foundation Trust, State Neuropathology Service, Department of Pathology, University of Melbourne, The University of Western Australia (UWA), Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurology Department, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neuroscience, Uppsala University, Boston Children's Hospital, Washington State University (WSU), University of East London & Glasgow Caledonian University, Centre for Medical Research, Richard, Isabelle, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Washington University in Saint Louis (WUSTL), Université de Lyon, Le CHCB, Centre Hospitalier de la Côte Basque, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université libre de Bruxelles (ULB), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre Hospitalier de la Côte Basque (CHCB), and École Pratique des Hautes Études (EPHE)

Subjects
Cardiomyopathy, Dilated, Male, MESH: Connectin, MESH: Mutation, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, education, Muscle Proteins, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Protein Isoforms, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Phenotype, Article, MESH: Muscle Proteins, Humans, Protein Isoforms, Connectin, Muscle, Skeletal, MESH: Cardiomyopathy, Dilated, health care economics and organizations, MESH: Muscle, Skeletal, MESH: Humans, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Male, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female, MESH: Female
Abstract

International audience; Objective: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.Methods: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients.Results: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder.Interpretation: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018
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153. Statistical analysis plan of a randomized controlled trial to compare a restrictive strategy to usual care for the effectiveness of cholecystectomy (SECURE trial) 11 Medical and Health Sciences 1103 Clinical Sciences

Author

Wennmacker, Sarah Z., van Dijk, Aafke H., Drenth, Joost P. H., Donkervoort, Sandra C., Boerma, Djamila, Westert, Gert P., van Laarhoven, Cornelis J. H. M., Boermeester, Marja A., Dijkgraaf, Marcel G. W., de Reuver, Philip R., APH - Methodology, Graduate School, AGEM - Digestive immunity, Surgery, Epidemiology and Data Science, and Clinical Research Unit

Abstract

Background: Cholecystectomy is the preferred treatment for symptomatic cholecystolithiasis. However, persistent pain after cholecystectomy for symptomatic cholecystolithiasis is reported in up to 40% of patients. The aim of the SECURE trial is to compare the effectiveness of usual care with a restrictive strategy using a standardized work-up with stepwise selection for cholecystectomy in patients with gallstones and abdominal complaints. The SECURE trial is designed as a multicenter, randomized, parallel-arm, non-inferiority trial in patients with abdominal symptoms and ultrasound-proven gallstones or sludge. Randomization was performed to either usual care (standard practice, according to the physician's knowledge and experience, and physician's and patient's preference) or a restrictive standardized strategy: treated with interval evaluation and stepwise selection for laparoscopic cholecystectomy based on fulfilment of pre-specified criteria. This article presents in detail the statistical analysis plan (SAP) of this trial and was submitted before outcomes were available to the investigators. Results: The primary end point of this trial is defined as the proportion of patients being pain-free at 12 months' follow-up. Pain will be assessed with the Izbicki Pain Score. Secondary endpoints will be the proportion of patients with complications due to gallstones or cholecystectomy, quality of life, the association between the patients' symptoms and treatment, work performance, and cost-effectiveness. Discussion: The data from the SECURE trial will provide evidence whether or not a restrictive strategy in patients with symptomatic cholecystolithiasis is associated with similar patient reported outcomes and a reduction in the number of cholecystectomies compared to usual care. The data from this trial will be analyzed according to this pre-specified SAP. Trial registration: The Netherlands National Trial Register NTR4022. Registered on 5 June 2013.

Published
2018

155. Recurrent TTN metatranscript‐only c.39974–11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy

Author

Bryen, Samantha J., primary, Ewans, Lisa J., additional, Pinner, Jason, additional, MacLennan, Suzanna C., additional, Donkervoort, Sandra, additional, Castro, Diana, additional, Töpf, Ana, additional, O'Grady, Gina, additional, Cummings, Beryl, additional, Chao, Katherine R., additional, Weisburd, Ben, additional, Francioli, Laurent, additional, Faiz, Fathimath, additional, Bournazos, Adam M., additional, Hu, Ying, additional, Grosmann, Carla, additional, Malicki, Denise M., additional, Doyle, Helen, additional, Witting, Nanna, additional, Vissing, John, additional, Claeys, Kristl G., additional, Urankar, Kathryn, additional, Beleza‐Meireles, Ana, additional, Baptista, Julia, additional, Ellard, Sian, additional, Savarese, Marco, additional, Johari, Mridul, additional, Vihola, Anna, additional, Udd, Bjarne, additional, Majumdar, Anirban, additional, Straub, Volker, additional, Bönnemann, Carsten G., additional, MacArthur, Daniel G., additional, Davis, Mark R., additional, and Cooper, Sandra T., additional

Published
2019
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156. Identification of a Novel Deep Intronic Mutation in CAPN3 Presenting a Promising Target for Therapeutic Splice Modulation

Author

Hu, Ying, primary, Mohassel, Payam, additional, Donkervoort, Sandra, additional, Yun, Pomi, additional, Bolduc, Véronique, additional, Ezzo, Daniel, additional, Dastgir, Jahannaz, additional, Marshall, Jamie L., additional, Lek, Monkol, additional, MacArthur, Daniel G., additional, Foley, A. Reghan, additional, and Bönnemann, Carsten G., additional

Published
2019
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157. Genetic regulatory variation in populations informs transcriptome analysis in rare disease

Author

Mohammadi, Pejman, primary, Castel, Stephane E., additional, Cummings, Beryl B., additional, Einson, Jonah, additional, Sousa, Christina, additional, Hoffman, Paul, additional, Donkervoort, Sandra, additional, Jiang, Zhuoxun, additional, Mohassel, Payam, additional, Foley, A. Reghan, additional, Wheeler, Heather E., additional, Im, Hae Kyung, additional, Bonnemann, Carsten G., additional, MacArthur, Daniel G., additional, and Lappalainen, Tuuli, additional

Published
2019
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158. Dominant collagen XII mutations cause a distal myopathy

Author

Mohassel, Payam, primary, Liewluck, Teerin, additional, Hu, Ying, additional, Ezzo, Daniel, additional, Ogata, Tracy, additional, Saade, Dimah, additional, Neuhaus, Sarah, additional, Bolduc, Véronique, additional, Zou, Yaqun, additional, Donkervoort, Sandra, additional, Medne, Livija, additional, Sumner, Charlotte J., additional, Dyck, P. James B., additional, Wierenga, Klaas J., additional, Tennekoon, Gihan, additional, Finkel, Richard S., additional, Chen, Jiani, additional, Winder, Thomas L., additional, Staff, Nathan P., additional, Foley, A. Reghan, additional, Koch, Manuel, additional, and Bönnemann, Carsten G., additional

Published
2019
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159. An ultrafast system for signaling mechanical pain in human skin

Author

Nagi, Saad S., primary, Marshall, Andrew G., additional, Makdani, Adarsh, additional, Jarocka, Ewa, additional, Liljencrantz, Jaquette, additional, Ridderström, Mikael, additional, Shaikh, Sumaiya, additional, O’Neill, Francis, additional, Saade, Dimah, additional, Donkervoort, Sandra, additional, Foley, A. Reghan, additional, Minde, Jan, additional, Trulsson, Mats, additional, Cole, Jonathan, additional, Bönnemann, Carsten G., additional, Chesler, Alexander T., additional, Bushnell, M. Catherine, additional, McGlone, Francis, additional, and Olausson, Håkan, additional

Published
2019
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160. Restrictive strategy versus usual care for cholecystectomy in patients with gallstones and abdominal pain (SECURE): a multicentre, randomised, parallel-arm, non-inferiority trial

Author

van Dijk, Aafke H, primary, Wennmacker, Sarah Z, additional, de Reuver, Philip R, additional, Latenstein, Carmen S S, additional, Buyne, Otmar, additional, Donkervoort, Sandra C, additional, Eijsbouts, Quirijn A J, additional, Heisterkamp, Joos, additional, Hof, Klaas in 't, additional, Janssen, Jan, additional, Nieuwenhuijs, Vincent B, additional, Schaap, Henk M, additional, Steenvoorde, Pascal, additional, Stockmann, Hein B A C, additional, Boerma, Djamila, additional, Westert, Gert P, additional, Drenth, Joost P H, additional, Dijkgraaf, Marcel G W, additional, Boermeester, Marja A, additional, and van Laarhoven, Cornelius J H M, additional

Published
2019
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161. Quantifying genetic regulatory variation in human populations improves transcriptome analysis in rare disease patients

Author

Mohammadi, Pejman, primary, Castel, Stephane E., additional, Cummings, Beryl B., additional, Einson, Jonah, additional, Sousa, Christina, additional, Hoffman, Paul, additional, Donkervoort, Sandra, additional, Mohassel, Payam, additional, Foley, Reghan, additional, Wheeler, Heather E., additional, Im, Hae Kyung, additional, Bonnemann, Carsten G., additional, MacArthur, Daniel G., additional, and Lappalainen, Tuuli, additional

Published
2019
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163. A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity

Author

Beck, David B., primary, Subramanian, T., additional, Vijayalingam, S., additional, Ezekiel, Uthayashankar R., additional, Donkervoort, Sandra, additional, Yang, Michele L., additional, Dubbs, Holly A., additional, Ortiz-Gonzalez, Xilma R., additional, Lakhani, Shenela, additional, Segal, Devorah, additional, Au, Margaret, additional, Graham, John M., additional, Verma, Sumit, additional, Waggoner, Darrel, additional, Shinawi, Marwan, additional, Bönnemann, Carsten G., additional, Chung, Wendy K., additional, and Chinnadurai, G., additional

Published
2019
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164. A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies

Author

Bolduc, Véronique, primary, Foley, A. Reghan, additional, Solomon-Degefa, Herimela, additional, Sarathy, Apurva, additional, Donkervoort, Sandra, additional, Hu, Ying, additional, Chen, Grace S., additional, Sizov, Katherine, additional, Nalls, Matthew, additional, Zhou, Haiyan, additional, Aguti, Sara, additional, Cummings, Beryl B., additional, Lek, Monkol, additional, Tukiainen, Taru, additional, Marshall, Jamie L., additional, Regev, Oded, additional, Marek-Yagel, Dina, additional, Sarkozy, Anna, additional, Butterfield, Russell J., additional, Jou, Cristina, additional, Jimenez-Mallebrera, Cecilia, additional, Li, Yan, additional, Gartioux, Corine, additional, Mamchaoui, Kamel, additional, Allamand, Valérie, additional, Gualandi, Francesca, additional, Ferlini, Alessandra, additional, Hanssen, Eric, additional, Wilton, Steve D., additional, Lamandé, Shireen R., additional, MacArthur, Daniel G., additional, Wagener, Raimund, additional, Muntoni, Francesco, additional, and Bönnemann, Carsten G., additional

Published
2019
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165. ACTN2 mutations cause “Multiple structured Core Disease” (MsCD)

Author

Lornage, Xavière, primary, Romero, Norma B., additional, Grosgogeat, Claire A., additional, Malfatti, Edoardo, additional, Donkervoort, Sandra, additional, Marchetti, Michael M., additional, Neuhaus, Sarah B., additional, Foley, A. Reghan, additional, Labasse, Clémence, additional, Schneider, Raphaël, additional, Carlier, Robert Y., additional, Chao, Katherine R., additional, Medne, Livija, additional, Deleuze, Jean-François, additional, Orlikowski, David, additional, Bönnemann, Carsten G., additional, Gupta, Vandana A., additional, Fardeau, Michel, additional, Böhm, Johann, additional, and Laporte, Jocelyn, additional

Published
2019
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166. Congenital Titinopathy:Comprehensive characterization and pathogenic insights

Author

Oates, Emily C., Jones, Kristi J., Donkervoort, Sandra, Charlton, Amanda, Brammah, Susan, Smith, John E., Ware, James S., Yau, Kyle S., Swanson, Lindsay C., Whiffin, Nicola, Peduto, Anthony J., Bournazos, Adam, Waddell, Leigh B., Farrar, Michelle A., Sampaio, Hugo A., Teoh, Hooi Ling, Lamont, Phillipa J., Mowat, David, Fitzsimons, Robin B., Corbett, Alastair J., Ryan, Monique M., O'Grady, Gina L., Sandaradura, Sarah A., Ghaoui, Roula, Joshi, Himanshu, Marshall, Jamie L., Nolan, Melinda A., Kaur, Simranpreet, Punetha, Jaya, Töpf, Ana, Harris, Elizabeth, Bakshi, Madhura, Genetti, Casie A., Marttila, Minttu, Werlauff, Ulla, Streichenberger, Nathalie, Pestronk, Alan, Mazanti, Ingrid, Pinner, Jason R., Vuillerot, Carole, Grosmann, Carla, Camacho, Ana, Mohassel, Payam, Leach, Meganne E., Foley, A. Reghan, Bharucha-Goebel, Diana, Collins, James, Connolly, Anne M., Gilbreath, Heather R., Iannaccone, Susan T., Castro, Diana, Cummings, Beryl B., Webster, Richard I., Lazaro, Leïla, Vissing, John, Coppens, Sandra, Deconinck, Nicolas, Luk, Ho Ming, Thomas, Neil H., Foulds, Nicola C., Illingworth, Marjorie A., Ellard, Sian, McLean, Catriona A., Phadke, Rahul, Ravenscroft, Gianina, Witting, Nanna, Hackman, Peter, Richard, Isabelle, Cooper, Sandra T., Kamsteeg, Erik Jan, Hoffman, Eric P., Bushby, Kate, Straub, Volker, Udd, Bjarne, Ferreiro, Ana, North, Kathryn N., Clarke, Nigel F., Lek, Monkol, Beggs, Alan H., Bönnemann, Carsten G., MacArthur, Daniel G., Granzier, Henk, Davis, Mark R., Laing, Nigel G., Oates, Emily C., Jones, Kristi J., Donkervoort, Sandra, Charlton, Amanda, Brammah, Susan, Smith, John E., Ware, James S., Yau, Kyle S., Swanson, Lindsay C., Whiffin, Nicola, Peduto, Anthony J., Bournazos, Adam, Waddell, Leigh B., Farrar, Michelle A., Sampaio, Hugo A., Teoh, Hooi Ling, Lamont, Phillipa J., Mowat, David, Fitzsimons, Robin B., Corbett, Alastair J., Ryan, Monique M., O'Grady, Gina L., Sandaradura, Sarah A., Ghaoui, Roula, Joshi, Himanshu, Marshall, Jamie L., Nolan, Melinda A., Kaur, Simranpreet, Punetha, Jaya, Töpf, Ana, Harris, Elizabeth, Bakshi, Madhura, Genetti, Casie A., Marttila, Minttu, Werlauff, Ulla, Streichenberger, Nathalie, Pestronk, Alan, Mazanti, Ingrid, Pinner, Jason R., Vuillerot, Carole, Grosmann, Carla, Camacho, Ana, Mohassel, Payam, Leach, Meganne E., Foley, A. Reghan, Bharucha-Goebel, Diana, Collins, James, Connolly, Anne M., Gilbreath, Heather R., Iannaccone, Susan T., Castro, Diana, Cummings, Beryl B., Webster, Richard I., Lazaro, Leïla, Vissing, John, Coppens, Sandra, Deconinck, Nicolas, Luk, Ho Ming, Thomas, Neil H., Foulds, Nicola C., Illingworth, Marjorie A., Ellard, Sian, McLean, Catriona A., Phadke, Rahul, Ravenscroft, Gianina, Witting, Nanna, Hackman, Peter, Richard, Isabelle, Cooper, Sandra T., Kamsteeg, Erik Jan, Hoffman, Eric P., Bushby, Kate, Straub, Volker, Udd, Bjarne, Ferreiro, Ana, North, Kathryn N., Clarke, Nigel F., Lek, Monkol, Beggs, Alan H., Bönnemann, Carsten G., MacArthur, Daniel G., Granzier, Henk, Davis, Mark R., and Laing, Nigel G.

Abstract

Objective: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. Methods: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. Results: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. Interpretation: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105–1124.

Published
2018

167. A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history

Author

Giunta, Cecilia, Baumann, Matthias, Fauth, Christine, Lindert, Uschi, Abdalla, Ebtesam M, Brady, Angela F, Collins, James, Dastgir, Jahannaz, Donkervoort, Sandra, Ghali, Neeti, Johnson, Diana S, Kariminejad, Ariana, Koch, Johannes, Kraenzlin, Marius, Lahiri, Nayana, Lozic, Bernarda, Manzur, Adnan Y, Morton, Jenny E V, Pilch, Jacek, Pollitt, Rebecca C, Schreiber, Gudrun, Shannon, Nora L, Sobey, Glenda, Vandersteen, Anthony, van Dijk, Fleur S, Witsch-Baumgartner, Martina, Zschocke, Johannes, Pope, F Michael, Bönnemann, Carsten G, Rohrbach, Marianne, Giunta, Cecilia, Baumann, Matthias, Fauth, Christine, Lindert, Uschi, Abdalla, Ebtesam M, Brady, Angela F, Collins, James, Dastgir, Jahannaz, Donkervoort, Sandra, Ghali, Neeti, Johnson, Diana S, Kariminejad, Ariana, Koch, Johannes, Kraenzlin, Marius, Lahiri, Nayana, Lozic, Bernarda, Manzur, Adnan Y, Morton, Jenny E V, Pilch, Jacek, Pollitt, Rebecca C, Schreiber, Gudrun, Shannon, Nora L, Sobey, Glenda, Vandersteen, Anthony, van Dijk, Fleur S, Witsch-Baumgartner, Martina, Zschocke, Johannes, Pope, F Michael, Bönnemann, Carsten G, and Rohrbach, Marianne

Abstract

PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS.

Published
2018

168. An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.

Author

Pagnamenta, Alistair T, Kaiyrzhanov, Rauan, Zou, Yaqun, Da'as, Sahar I, Maroofian, Reza, Donkervoort, Sandra, Dominik, Natalia, Lauffer, Marlen, Ferla, Matteo P, Orioli, Andrea, Giess, Adam, Tucci, Arianna, Beetz, Christian, Sedghi, Maryam, Ansari, Behnaz, Barresi, Rita, Basiri, Keivan, Cortese, Andrea, Elgar, Greg, and Fernandez-Garcia, Miguel A

Subjects
MOTOR neuron diseases, REVERSE transcriptase polymerase chain reaction, SYMPTOMS, PHENOTYPES, SPINOCEREBELLAR ataxia, VON Willebrand factor, CEREBELLUM degeneration, PROTEINS, ANIMAL behavior, RESEARCH, GENETIC mutation, SKELETAL muscle, ANIMAL experimentation, RESEARCH methodology, MEDICAL cooperation, EVALUATION research, COMPARATIVE studies, CHARCOT-Marie-Tooth disease, FISHES, RESEARCH funding, GENETIC techniques, GENEALOGY
Abstract

The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses. [ABSTRACT FROM AUTHOR]

Published
2021
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169. FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability.

Author

Schneider, Amy L., Myers, Candace T., Muir, Alison M., Calvert, Sophie, Basinger, Alice, Perry, M. Scott, Rodan, Lance, Helbig, Katherine L., Chambers, Chelsea, Gorman, Kathleen M., King, Mary D., Donkervoort, Sandra, Soldatos, Ariane, Bönnemann, Carsten G., Spataro, Nino, Gabau, Elisabeth, Arellano, Montserrat, Cappuccio, Gerarda, Brunetti‐Pierri, Nicola, and Rossignol, Elsa

Subjects
INTELLECTUAL disabilities, CHILDREN with epilepsy, MOVEMENT disorders, LENNOX-Gastaut syndrome, INFANTILE spasms, 22Q11 deletion syndrome, AGE of onset, PEOPLE with epilepsy
Abstract

Chromosome 1q41‐q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41‐q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41‐q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41‐q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41‐q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug‐resistant epilepsy, and hyperkinetic movement disorders. [ABSTRACT FROM AUTHOR]

Published
2021
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170. Clinical and Molecular Spectrum Associated with COL6A3c.7447A>G p.(Lys2483Glu) Variant: Elucidating its Role in Collagen VI-related Myopathies

Author

Villar-Quiles, Rocío N., Donkervoort, Sandra, de Becdelièvre, Alix, Gartioux, Corine, Jobic, Valérie, Foley, A. Reghan, McCarty, Riley M., Hu, Ying, Menassa, Rita, Michel, Laurence, Gousse, Gaelle, Lacour, Arnaud, Petiot, Philippe, Streichenberger, Nathalie, Choumert, Ariane, Declerck, Léa, Urtizberea, J.A., Sole, Guilhem, Furby, Alain, Cérino, Matthieu, Krahn, Martin, Campana- Salort, Emmanuelle, Ferreiro, Ana, Eymard, Bruno, Bönnemann, Carsten G., Bharucha-Goebel, Diana, Sumner, Charlotte J., Connolly, Anne M., Richard, Pascale, Allamand, Valérie, Métay, Corinne, and Stojkovic, Tanya

Abstract

Background: Dominant and recessive autosomal pathogenic variants in the three major genes (COL6A1-A2-A3) encoding the extracellular matrix protein collagen VI underlie a group of myopathies ranging from early-onset severe conditions (Ullrich congenital muscular dystrophy) to milder forms maintaining independent ambulation (Bethlem myopathy). Diagnosis is based on the combination of clinical presentation, muscle MRI, muscle biopsy, analysis of collagen VI secretion, and COL6A1-A2-A3genetic analysis, the interpretation of which can be challenging.Objective: To refine the phenotypical spectrum associated with the frequent COL6A3missense variant c.7447A>G (p.Lys2483Glu).Methods: We report the clinical and molecular findings in 16 patients: 12 patients carrying this variant in compound heterozygosity with another COL6A3variant, and four homozygous patients.Results: Patients carrying this variant in compound heterozygosity with a truncating COL6A3variant exhibit a phenotype consistent with COL6-related myopathies (COL6-RM), with joint contractures, proximal weakness and skin abnormalities. All remain ambulant in adulthood and only three have mild respiratory involvement. Most show typical muscle MRI findings. In five patients, reduced collagen VI secretion was observed in skin fibroblasts cultures. All tested parents were unaffected heterozygous carriers. Conversely, two out of four homozygous patients did not present with the classical COL6-RM clinical and imaging findings. Collagen VI immunolabelling on cultured fibroblasts revealed rather normal secretion in one and reduced secretion in another. Muscle biopsy from one homozygous patient showed myofibrillar disorganization and rimmed vacuoles.Conclusions: In light of our results, we postulate that the COL6A3variant c.7447A>G may act as a modulator of the clinical phenotype. Thus, in patients with a typical COL6-RM phenotype, a second variant must be thoroughly searched for, while for patients with atypical phenotypes further investigations should be conducted to exclude alternative causes. This works expands the clinical and molecular spectrum of COLVI-related myopathies.

Published
2021
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171. Pathogenic TNNI1variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease

Author

Donkervoort, Sandra, van de Locht, Martijn, Ronchi, Dario, Reunert, Janine, McLean, Catriona A., Zaki, Maha, Orbach, Rotem, de Winter, Josine M., Conijn, Stefan, Hoomoedt, Daan, Neto, Osorio Lopes Abath, Magri, Francesca, Viaene, Angela N., Foley, A. Reghan, Gorokhova, Svetlana, Bolduc, Véronique, Hu, Ying, Acquaye, Nicole, Napoli, Laura, Park, Julien H., Immadisetty, Kalyan, Miles, Lee B., Essawi, Mona, McModie, Salar, Ferreira, Leonardo F., Zanotti, Simona, Neuhaus, Sarah B., Medne, Livija, ElBagoury, Nagham, Johnson, Kory R., Zhang, Yong, Laing, Nigel G., Davis, Mark R., Bryson-Richardson, Robert J., Hwee, Darren T., Hartman, James J., Malik, Fady I., Kekenes-Huskey, Peter M., Comi, Giacomo Pietro, Sharaf-Eldin, Wessam, Marquardt, Thorsten, Ravenscroft, Gianina, Bönnemann, Carsten G., and Ottenheijm, Coen A. C.

Abstract

Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast (TNNI2) and TnI-slow (TNNI1), are predominantly expressed in fast- and slow-twitch myofibers, respectively. TNNI2variants are a rare cause of arthrogryposis, whereas TNNI1variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function TNNI1variants as well as dominant gain-of-function TNNI1variants as a cause of muscle disease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelic TNNI1variants (F1: p.R14H/c.190-9G>A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifesting with early-onset progressive muscle weakness and rod formation on histology. We also identified two families with a dominantly acting heterozygous TNNI1variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifesting with muscle cramping, myalgias, and rod formation in F5. In zebrafish, TnI proteins with either of the missense variants (p.R14H; p.R174Q) incorporated into thin filaments. Molecular dynamics simulations suggested that the loss-of-function p.R14H variant decouples TnI from TnC, which was supported by functional studies showing a reduced force response of sarcomeres to submaximal [Ca2+] in patient myofibers. This contractile deficit could be reversed by a slow skeletal muscle troponin activator. In contrast, patient myofibers with the gain-of-function p.R174Q variant showed an increased force to submaximal [Ca2+], which was reversed by the small-molecule drug mavacamten. Our findings demonstrated that TNNI1variants can cause muscle disease with variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype, suggesting rational therapeutic strategies for each mechanism.

Published
2024
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172. Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.

Author

Donkervoort, Sandra, Mohassel, Payam, Laugwitz, Lucia, Zaki, Maha S., Kamsteeg, Erik‐Jan, Maroofian, Reza, Chao, Katherine R., Verschuuren‐Bemelmans, Corien C., Horber, Veronka, Fock, Annemarie J. M., McCarty, Riley M., Jain, Minal S., Biancavilla, Victoria, McMacken, Grace, Nalls, Matthew, Voermans, Nicol C., Elbendary, Hasnaa M., Snyder, Molly, Cai, Chunyu, and Lehky, Tanya J.

Abstract

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin‐2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant‐negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS‐disease gene and expands its clinical and genetic spectrum to include recessive loss‐of‐function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications. [ABSTRACT FROM AUTHOR]

Published
2020
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173. The clinical, histologic, and genotypic spectrum of -related myopathy: A case series.

Author

Villar-Quiles, Rocio N., von der Hagen, Maja, Métay, Corinne, Gonzalez, Victoria, Donkervoort, Sandra, Bertini, Enrico, Castiglioni, Claudia, Chaigne, Denys, Colomer, Jaume, Cuadrado, Maria Luz, de Visser, Marianne, Desguerre, Isabelle, Eymard, Bruno, Goemans, Nathalie, Kaindl, Angela, Lagrue, Emmanuelle, Lütschg, Jürg, Malfatti, Edoardo, Mayer, Michèle, and Merlini, Luciano

Published
2020
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174. Hypoglycemia in patients with congenital muscle disease.

Author

Hayes, Leslie H., Yun, Pomi, Mohassel, Payam, Norato, Gina, Donkervoort, Sandra, Leach, Meganne E., Alvarez, Rachel, Rutkowski, Anne, Shaw, Natalie D., Foley, A. Reghan, and Bönnemann, Carsten G.

Subjects
CONGENITAL disorders, MUSCLE diseases, HYPOGLYCEMIA, NEUROMUSCULAR diseases, JUVENILE diseases
Abstract

Background: Only a few small studies have previously reported episodes of hypoglycemia in children with neuromuscular diseases; however, there has been no broader investigation into the occurrence of hypoglycemia in children with congenital muscle disease (CMD).Methods: Pediatric patients enrolled in the CMD International Registry (CMDIR) with a history of hypoglycemia were included in this retrospective review. Hypoglycemic episodes and associated clinical and biochemical characteristics were characterized.Results: Ten patients with CMD (5 with LAMA2-related muscular dystrophy) reported at least one episode of hypoglycemia beginning at an average age of 3.5 years. Predominant symptoms included altered mental status and nausea/vomiting, and laboratory studies demonstrated metabolic acidosis and ketonuria, consistent with ketotic hypoglycemia.Conclusion: Patients with CMD may have an increased risk of hypoglycemia during fasting, illness, or stress due to their relatively low muscle mass and hence, paucity of gluconeogenic substrate. Clinicians should therefore maintain a high index of suspicion for hypoglycemia in this high-risk patient population and caregivers should routinely be trained to recognize and treat hypoglycemia. [ABSTRACT FROM AUTHOR]

Published
2020
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175. Recurrent TTN metatranscript‐only c.39974–11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy.

Author

Bryen, Samantha J., Ewans, Lisa J., Pinner, Jason, MacLennan, Suzanna C., Donkervoort, Sandra, Castro, Diana, Töpf, Ana, O'Grady, Gina, Cummings, Beryl, Chao, Katherine R., Weisburd, Ben, Francioli, Laurent, Faiz, Fathimath, Bournazos, Adam M., Hu, Ying, Grosmann, Carla, Malicki, Denise M., Doyle, Helen, Witting, Nanna, and Vissing, John

Abstract

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice‐site variant (NM_001267550.1:c.39974‐11T>G), inherited in trans with a second pathogenic TTN variant. Muscle‐derived RNA studies of three individuals confirmed mis‐splicing induced by the c.39974‐11T>G variant; in‐frame exon 214 skipping or use of a cryptic 3′ splice‐site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213‐217 within the described skeletal muscle TTN N2A isoform. However, RNA‐sequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213‐217 in TTN transcripts (inclusion rate ≥66%). Further, RNA‐sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213‐217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript‐only exons. [ABSTRACT FROM AUTHOR]

Published
2020
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176. Anti-HMGCR myopathy may resemble limb-girdle muscular dystrophy

Author

Mohassel, Payam, primary, Landon-Cardinal, Océane, additional, Foley, A. Reghan, additional, Donkervoort, Sandra, additional, Pak, Katherine S., additional, Wahl, Colleen, additional, Shebert, Robert T., additional, Harper, Amy, additional, Fequiere, Pierre, additional, Meriggioli, Matthew, additional, Toro, Camilo, additional, Drachman, Daniel, additional, Allenbach, Yves, additional, Benveniste, Olivier, additional, Béhin, Anthony, additional, Eymard, Bruno, additional, Lafôret, Pascal, additional, Stojkovic, Tanya, additional, Mammen, Andrew L., additional, and Bönnemann, Carsten G., additional

Published
2018
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177. Novel SPEG mutations in congenital myopathies: Genotype–phenotype correlations

Author

Qualls, Anita E., primary, Donkervoort, Sandra, additional, Herkert, Johanna C., additional, D'gama, Alissa M., additional, Bharucha‐Goebel, Diana, additional, Collins, James, additional, Chao, Katherine R., additional, Foley, A. Reghan, additional, Schoots, Mirthe H., additional, Jongbloed, Jan D.H., additional, Bönnemann, Carsten G., additional, and Agrawal, Pankaj B., additional

Published
2018
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179. STAC3variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility

Author

Zaharieva, Irina T., primary, Sarkozy, Anna, additional, Munot, Pinki, additional, Manzur, Adnan, additional, O'Grady, Gina, additional, Rendu, John, additional, Malfatti, Eduardo, additional, Amthor, Helge, additional, Servais, Laurent, additional, Urtizberea, J. Andoni, additional, Neto, Osorio Abath, additional, Zanoteli, Edmar, additional, Donkervoort, Sandra, additional, Taylor, Juliet, additional, Dixon, Joanne, additional, Poke, Gemma, additional, Foley, A. Reghan, additional, Holmes, Chris, additional, Williams, Glyn, additional, Holder, Muriel, additional, Yum, Sabrina, additional, Medne, Livija, additional, Quijano-Roy, Susana, additional, Romero, Norma B., additional, Fauré, Julien, additional, Feng, Lucy, additional, Bastaki, Laila, additional, Davis, Mark R., additional, Phadke, Rahul, additional, Sewry, Caroline A., additional, Bönnemann, Carsten G., additional, Jungbluth, Heinz, additional, Bachmann, Christoph, additional, Treves, Susan, additional, and Muntoni, Francesco, additional

Published
2018
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180. PIEZO2 mediates injury-induced tactile pain in mice and humans

Author

Szczot, Marcin, primary, Liljencrantz, Jaquette, additional, Ghitani, Nima, additional, Barik, Arnab, additional, Lam, Ruby, additional, Thompson, James H., additional, Bharucha-Goebel, Diana, additional, Saade, Dimah, additional, Necaise, Aaron, additional, Donkervoort, Sandra, additional, Foley, A. Reghan, additional, Gordon, Taylor, additional, Case, Laura, additional, Bushnell, M. Catherine, additional, Bönnemann, Carsten G., additional, and Chesler, Alexander T., additional

Published
2018
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181. Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high risk patients (CHOCOLATE): multicentre randomised clinical trial

Author

Loozen, Charlotte S, primary, van Santvoort, Hjalmar C, additional, van Duijvendijk, Peter, additional, Besselink, Marc GH, additional, Gouma, Dirk J, additional, Nieuwenhuijzen, Grard AP, additional, Kelder, Johannes C, additional, Donkervoort, Sandra C, additional, van Geloven, Anna AW, additional, Kruyt, Philip M, additional, Roos, Daphne, additional, Kortram, Kirsten, additional, Kornmann, Verena NN, additional, Pronk, Apollo, additional, van der Peet, Donald L, additional, Crolla, Rogier MPH, additional, van Ramshorst, Bert, additional, Bollen, Thomas L, additional, and Boerma, Djamila, additional

Published
2018
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184. Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot

Author

Sapp, Julie C., primary, Johnston, Jennifer J., additional, Driscoll, Kate, additional, Heidlebaugh, Alexis R., additional, Miren Sagardia, Ane, additional, Dogbe, D. Nadine, additional, Umstead, Kendall L., additional, Turbitt, Erin, additional, Alevizos, Ilias, additional, Baron, Jeffrey, additional, Bönnemann, Carsten, additional, Brooks, Brian, additional, Donkervoort, Sandra, additional, Jee, Youn Hee, additional, Linehan, W. Marston, additional, McMahon, Francis J., additional, Moss, Joel, additional, Mullikin, James C., additional, Nielsen, Deborah, additional, Pelayo, Eileen, additional, Remaley, Alan T., additional, Siegel, Richard, additional, Su, Helen, additional, Zarate, Carlos, additional, Manolio, Teri A., additional, Biesecker, Barbara B., additional, Biesecker, Leslie G., additional, Barnabas, Beatrice B., additional, Bouffard, Gerard G., additional, Brooks, Shelise Y., additional, Coleman, Holly, additional, Dekhtyar, Lyudmila, additional, Guan, Xiaobin, additional, Han, Joel, additional, Ho, Shi-ling, additional, Legaspi, Richelle, additional, Maduro, Quino L., additional, Masiello, Catherine A., additional, McDowell, Jennifer C., additional, Montemayor, Casandra, additional, Park, Morgan, additional, Riebow, Nancy L., additional, Schandler, Karen, additional, Scharer, Chanthra, additional, Schmidt, Brian, additional, Sison, Christina, additional, Stantripop, Sirintorn, additional, Thomas, James W., additional, Thomas, Pamela J., additional, Vemulapalli, Meghana, additional, and Young, Alice C., additional

Published
2018
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185. Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy

Author

Burns, David T., primary, Donkervoort, Sandra, additional, Müller, Juliane S., additional, Knierim, Ellen, additional, Bharucha-Goebel, Diana, additional, Faqeih, Eissa Ali, additional, Bell, Stephanie K., additional, AlFaifi, Abdullah Y., additional, Monies, Dorota, additional, Millan, Francisca, additional, Retterer, Kyle, additional, Dyack, Sarah, additional, MacKay, Sara, additional, Morales-Gonzalez, Susanne, additional, Giunta, Michele, additional, Munro, Benjamin, additional, Hudson, Gavin, additional, Scavina, Mena, additional, Baker, Laura, additional, Massini, Tara C., additional, Lek, Monkol, additional, Hu, Ying, additional, Ezzo, Daniel, additional, AlKuraya, Fowzan S., additional, Kang, Peter B., additional, Griffin, Helen, additional, Foley, A. Reghan, additional, Schuelke, Markus, additional, Horvath, Rita, additional, and Bönnemann, Carsten G., additional

Published
2018
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186. A cohort of 17 patients with kyphoscoliotic Ehlers–Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history

Author

Giunta, Cecilia, primary, Baumann, Matthias, additional, Fauth, Christine, additional, Lindert, Uschi, additional, Abdalla, Ebtesam M., additional, Brady, Angela F., additional, Collins, James, additional, Dastgir, Jahannaz, additional, Donkervoort, Sandra, additional, Ghali, Neeti, additional, Johnson, Diana S., additional, Kariminejad, Ariana, additional, Koch, Johannes, additional, Kraenzlin, Marius, additional, Lahiri, Nayana, additional, Lozic, Bernarda, additional, Manzur, Adnan Y., additional, Morton, Jenny E.V., additional, Pilch, Jacek, additional, Pollitt, Rebecca C., additional, Schreiber, Gudrun, additional, Shannon, Nora L., additional, Sobey, Glenda, additional, Vandersteen, Anthony, additional, van Dijk, Fleur S., additional, Witsch-Baumgartner, Martina, additional, Zschocke, Johannes, additional, Pope, F. Michael, additional, Bönnemann, Carsten G., additional, and Rohrbach, Marianne, additional

Published
2018
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187. De novo variants in SNAP25cause an early-onset developmental and epileptic encephalopathy

Author

Klöckner, Chiara, Sticht, Heinrich, Zacher, Pia, Popp, Bernt, Babcock, Holly E., Bakker, Dewi P., Barwick, Katy, Bonfert, Michaela V., Bönnemann, Carsten G., Brilstra, Eva H., Chung, Wendy K., Clarke, Angus J., Devine, Patrick, Donkervoort, Sandra, Fraser, Jamie L., Friedman, Jennifer, Gates, Alyssa, Ghoumid, Jamal, Hobson, Emma, Horvath, Gabriella, Keller-Ramey, Jennifer, Keren, Boris, Kurian, Manju A., Lee, Virgina, Leppig, Kathleen A., Lundgren, Johan, McDonald, Marie T., McLaughlin, Heather M., McTague, Amy, Mefford, Heather C., Mignot, Cyril, Mikati, Mohamad A., Nava, Caroline, Raymond, F. Lucy, Sampson, Julian R., Sanchis-Juan, Alba, Shashi, Vandana, Shieh, Joseph T.C., Shinawi, Marwan, Slavotinek, Anne, Stödberg, Tommy, Stong, Nicholas, Sullivan, Jennifer A., Taylor, Ashley C., Toler, Tomi L., van den Boogaard, Marie-José, van der Crabben, Saskia N., van Gassen, Koen L.I., van Jaarsveld, Richard H., Van Ziffle, Jessica, Wadley, Alexandrea F., Wagner, Matias, Wigby, Kristen, Wortmann, Saskia B., Zarate, Yuri A., Møller, Rikke S., Lemke, Johannes R., and Platzer, Konrad

Abstract

This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

Published
2021
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188. Frequency of Births Due to Assisted Reproductive Technology (ART) in Prader-Willi Syndrome

Author

Gold, June-Anne, Ruth, Chelsey, Osann, Kathryn, Flodman, Pamela, McManus, Barbara, Lee, Hye-Seung, Donkervoort, Sandra, Khare, Manaswitha, Roof, Elizabeth, Dykens, Elizabeth, Driscoll, Daniel J., Butler, Merlin G., Heinemann, Janalee, Cassidy, Suzanne, and Kimonis, Virginia

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Chromosomes, Human, Pair 15, Reproductive Techniques, Assisted, Twins, nutritional and metabolic diseases, twinning, Uniparental Disomy, Health Surveys, Article, Genomic Imprinting, RDCRN, Humans, Prader-Willi syndrome, assisted reproductive techniques, imprinting
Abstract

Prader-Willi syndrome is an imprinting disorder characterized by typical facial, physical, and cognitive/behavioral features, resulting from lack of paternally expressed genes on chromosome 15q11.2-q13. Studies have suggested an increased risk of other imprinting disorders in children conceived by assisted reproductive techniques. This study was designed to determine the association between assisted reproductive technology and Prader-Willi syndrome.Data on individuals with Prader-Willi syndrome were collected from three distinct sources and the proportion of assisted reproductive technology births analyzed.The proportions of assisted reproductive technology births in the Prader-Willi Syndrome Association (USA), Rare Diseases Clinical Research Network, and University of California, Irvine Medical Center populations were 1.0% (18/1,736), 1.0% (1/98), and 2.0% (1/50), respectively (overall 1.1%; population frequency for the United States was 1.0%). Of note, 2.4% (45/1,898) of participants were co-twins (11 born after assisted reproductive technology procedures); US twin frequency is 1.6% (P = 0.007). The proportion of individuals with maternal disomy 15/imprinting defects born after assisted reproductive technology was higher than that in the total sample, 55.6% (10/18) and 34.5% (431/1,250), respectively.This study found no association between assisted reproductive technology and Prader-Willi syndrome. There was an increased frequency of twinning. The number of individuals with maternal disomy 15/imprinting defect was nearly double in the assisted reproductive technology group as compared with the total Prader-Willi syndrome participants.

Published
2013

189. A Dominant-Negative COL6A1 Pseudoexon Insertion Is Skippable Using Splice-Modulating Oligonucleotides

Author

Bolduc, Veronique, Foley, A. Reghan, Donkervoort, Sandra, Hu, Ying, Cummings, Beryl B., Lek, Monkol, Sarathy, Apurva, Sizov, Katherine, Degefa, Herimela Solomon, Wagener, Raimund, Hennig, Grant W., Hanssen, Eric, Lamande, Shireen R., Muntoni, Francesco, Wilton, Steve D., MacArthur, Daniel G., Bonnemann, Carsten G., Bolduc, Veronique, Foley, A. Reghan, Donkervoort, Sandra, Hu, Ying, Cummings, Beryl B., Lek, Monkol, Sarathy, Apurva, Sizov, Katherine, Degefa, Herimela Solomon, Wagener, Raimund, Hennig, Grant W., Hanssen, Eric, Lamande, Shireen R., Muntoni, Francesco, Wilton, Steve D., MacArthur, Daniel G., and Bonnemann, Carsten G.

Published
2017

190. Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis

Author

Mohassel, Payam, Donkervoort, Sandra, Lone, Museer A., Nalls, Matthew, Gable, Kenneth, Gupta, Sita D., Foley, A. Reghan, Hu, Ying, Saute, Jonas Alex Morales, Moreira, Ana Lucila, Kok, Fernando, Introna, Alessandro, Logroscino, Giancarlo, Grunseich, Christopher, Nickolls, Alec R., Pourshafie, Naemeh, Neuhaus, Sarah B., Saade, Dimah, Gangfuß, Andrea, Kölbel, Heike, Piccus, Zoe, Le Pichon, Claire E., Fiorillo, Chiara, Ly, Cindy V., Töpf, Ana, Brady, Lauren, Specht, Sabine, Zidell, Aliza, Pedro, Helio, Mittelmann, Eric, Thomas, Florian P., Chao, Katherine R., Konersman, Chamindra G., Cho, Megan T., Brandt, Tracy, Straub, Volker, Connolly, Anne M., Schara, Ulrike, Roos, Andreas, Tarnopolsky, Mark, Höke, Ahmet, Brown, Robert H., Lee, Chia-Hsueh, Hornemann, Thorsten, Dunn, Teresa M., and Bönnemann, Carsten G.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease.

Published
2021
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191. Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients

Author

Abath Neto, Osorio, primary, Moreno, Cristiane de Araújo Martins, additional, Malfatti, Edoardo, additional, Donkervoort, Sandra, additional, Böhm, Johann, additional, Guimarães, Júlio Brandão, additional, Foley, A. Reghan, additional, Mohassel, Payam, additional, Dastgir, Jahannaz, additional, Bharucha-Goebel, Diana Xerxes, additional, Monges, Soledad, additional, Lubieniecki, Fabiana, additional, Collins, James, additional, Medne, Līvija, additional, Santi, Mariarita, additional, Yum, Sabrina, additional, Banwell, Brenda, additional, Salort-Campana, Emmanuelle, additional, Rendu, John, additional, Fauré, Julien, additional, Yis, Uluc, additional, Eymard, Bruno, additional, Cheraud, Chrystel, additional, Schneider, Raphaël, additional, Thompson, Julie, additional, Lornage, Xaviere, additional, Mesrob, Lilia, additional, Lechner, Doris, additional, Boland, Anne, additional, Deleuze, Jean-François, additional, Reed, Umbertina Conti, additional, Oliveira, Acary Souza Bulle, additional, Biancalana, Valérie, additional, Romero, Norma B., additional, Bönnemann, Carsten G., additional, Laporte, Jocelyn, additional, and Zanoteli, Edmar, additional

Published
2017
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194. Cytoplasmic body pathology in severe ACTA1 -related myopathy in the absence of typical nemaline rods

Author

Donkervoort, Sandra, primary, Chan, Sophelia H.S., additional, Hayes, Leslie H., additional, Bradley, Nathaniel, additional, Nguyen, David, additional, Leach, Meganne E., additional, Mohassel, Payam, additional, Hu, Ying, additional, Thangarajh, Mathula, additional, Bharucha-Goebel, Diana, additional, Kan, Amanda, additional, Ho, Ronnie S.L., additional, Reyes, Christine A., additional, Nance, Jessica, additional, Moore, Steven A., additional, Foley, A. Reghan, additional, and Bönnemann, Carsten G., additional

Published
2017
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195. HSP and deafness

Author

Donkervoort, Sandra, primary, Bharucha-Goebel, Diana, additional, Yun, Pomi, additional, Hu, Ying, additional, Mohassel, Payam, additional, Hoke, Ahmet, additional, Zein, Wadih M., additional, Ezzo, Daniel, additional, Atherton, Andrea M., additional, Modrcin, Ann C., additional, Dasouki, Majed, additional, Foley, A. Reghan, additional, and Bönnemann, Carsten G., additional

Published
2017
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196. Electrical impedance myography in individuals with collagen 6 and laminin α‐2 congenital muscular dystrophy: a cross‐sectional and 2‐year analysis

Author

Nichols, Carmel, primary, Jain, Minal S., additional, Meilleur, Katherine G., additional, Wu, Tianxia, additional, Collins, James, additional, Waite, Melissa R., additional, Dastgir, Jahannaz, additional, Salman, Anam, additional, Donkervoort, Sandra, additional, Duong, Tina, additional, Keller, Katherine, additional, Leach, Meganne E., additional, Lott, Donovan J., additional, McGuire, Michelle N., additional, Nelson, Leslie, additional, Rutkowski, Anne, additional, Vuillerot, Carole, additional, Bönnemann, Carsten G., additional, and Lehky, Tanya J., additional

Published
2017
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197. P4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye

Author

Zou, Yaqun, primary, Donkervoort, Sandra, additional, Salo, Antti M., additional, Foley, A. Reghan, additional, Barnes, Aileen M., additional, Hu, Ying, additional, Makareeva, Elena, additional, Leach, Meganne E., additional, Mohassel, Payam, additional, Dastgir, Jahannaz, additional, Deardorff, Matthew A., additional, Cohn, Ronald D., additional, DiNonno, Wendy O., additional, Malfait, Fransiska, additional, Lek, Monkol, additional, Leikin, Sergey, additional, Marini, Joan C., additional, Myllyharju, Johanna, additional, and Bönnemann, Carsten G., additional

Published
2017
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198. Upper extremity outcome measures for collagen VI-related myopathy and LAMA2-related muscular dystrophy

Author

Bendixen, Roxanna M., primary, Butrum, Jocelyn, additional, Jain, Mina S., additional, Parks, Rebecca, additional, Hodsdon, Bonnie, additional, Nichols, Carmel, additional, Hsia, Michelle, additional, Nelson, Leslie, additional, Keller, Katherine C., additional, McGuire, Michelle, additional, Elliott, Jeffrey S., additional, Linton, Melody M., additional, Arveson, Irene C., additional, Tounkara, Fatou, additional, Vasavada, Ruhi, additional, Harnett, Elizabeth, additional, Punjabi, Monal, additional, Donkervoort, Sandra, additional, Dastgir, Jahannaz, additional, Leach, Meganne E., additional, Rutkowski, Anne, additional, Waite, Melissa, additional, Collins, James, additional, Bönnemann, Carsten G., additional, and Meilleur, Katherine G., additional

Published
2017
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199. Comparison of sitting and supine forced vital capacity in collagen VI‐related dystrophy and laminin α2‐related dystrophy

Author

Meilleur, Katherine G., primary, Linton, Melody M., additional, Fontana, Joseph, additional, Rutkowski, Anne, additional, Elliott, Jeffrey, additional, Barton, Mark, additional, McGraw, Peter, additional, Kokkinis, Angela, additional, Donkervoort, Sandra, additional, Leach, Meganne, additional, Jain, Minal, additional, Dastgir, Jahannaz, additional, Collins, James, additional, Szczesniak, Rhonda, additional, Yang, Kelly, additional, Sawnani, Hemant, additional, and Bönnemann, Carsten G., additional

Published
2017
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