45 results on '"Hardev Pall"'
Search Results
2. MED27, SLC6A7, and MPPE1 variants in a complex neurodevelopmental disorder with severe dystonia
- Author
-
Kimberley M. Reid, Robert Spaull, Smrithi Salian, Katy Barwick, Esther Meyer, Juan Zhen, Hiromi Hirata, Diba Sheipouri, Hind Benkerroum, Kathleen M. Gorman, Apostolos Papandreou, Michael A. Simpson, Yoshinobu Hirano, Irene Farabella, Maya Topf, Detelina Grozeva, Keren Carss, Martin Smith, Hardev Pall, Peter Lunt, Susanna De Gressi, Erik‐Jan Kamsteeg, Tobias B. Haack, Lucinda Carr, Rita Guerreiro, Jose Bras, Eamonn R. Maher, Richard H. Scott, Robert J. Vandenberg, F. Lucy Raymond, Wui K. Chong, Sniya Sudhakar, Kshitij Mankad, Maarten E. Reith, Philippe M. Campeau, Robert J. Harvey, and Manju A. Kurian
- Subjects
MPPE1 ,Movement Disorders ,MED27 ,Proline ,SLC6A7 ,Dystonia ,Neurology ,Dystonic Disorders ,Neurodevelopmental Disorders ,Animals ,RNA ,Neurology (clinical) ,Status dystonicus ,Zebrafish - Abstract
BackgroundDespite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders.ObjectiveThe objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts.MethodsCandidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems.ResultsHomozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter–G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction.ConclusionsWe report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
- Published
- 2022
3. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis
- Author
-
Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A. Hickman, Thor D. Stein, Yevgeniya Abramzon, Sarah Ahmed, Marya S. Sabir, Makayla K. Portley, Arianna Tucci, Kristina Ibáñez, F.N.U. Shankaracharya, Pamela Keagle, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L. Waldo, Per M. Johansson, Christer F. Nilsson, James B. Rowe, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Edwin Jabbari, Coralie Viollet, Jonathan D. Glass, Andrew B. Singleton, Vincenzo Silani, Owen A. Ross, Mina Ryten, Ali Torkamani, Toshiko Tanaka, Luigi Ferrucci, Susan M. Resnick, Stuart Pickering-Brown, Christopher B. Brady, Neil Kowal, John A. Hardy, Vivianna Van Deerlin, Jean Paul Vonsattel, Matthew B. Harms, Huw R. Morris, Raffaele Ferrari, John E. Landers, Adriano Chiò, J. Raphael Gibbs, Clifton L. Dalgard, Sonja W. Scholz, Bryan J. Traynor, Adelani Adeleye, Camille Alba, Dagmar Bacikova, Daniel N. Hupalo, Elisa McGrath Martinez, Harvey B. Pollard, Gauthaman Sukumar, Anthony R. Soltis, Meila Tuck, Xijun Zhang, Matthew D. Wilkerson, Bradley N. Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon D. Topp, Jason Kost, Emma L. Scotter, Kevin P. Kenna, Jack W. Miller, Cinzia Tiloca, Caroline Vance, Eric W. Danielson, Claire Troakes, Claudia Colombrita, Safa Al-Sarraj, Elizabeth A. Lewis, Andrew King, Daniela Calini, Viviana Pensato, Barbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Russell L. McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Zorica Stevic, Sandra D’Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Wouter van Rheenen, Frank P. Diekstra, Rosa Rademakers, Marka van Blitterswijk, Kevin B. Boylan, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Claire Leblond-Manry, Guy A. Rouleau, Orla Hardiman, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Ammar Al-Chalabi, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Alberto García-Redondo, Zheyang Wu, Cinzia Gellera, Antonia Ratti, Robert H. Brown, Christopher E. Shaw, John C. Ambrose, Prabhu Arumugam, Emma L. Baple, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, H. Brittain, Mark J. Caulfield, Georgia C. Chan, Clare E.H. Craig, Louise C. Daugherty, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, Pedro Furió-Tarí, Joanne M. Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James E. Holman, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Lea Lahnstein, Kay Lawson, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Ellen M. McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Chris A. Odhams, Christine Patch, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Katherine R. Smith, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Ellen R.A. Thomas, Simon R. Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Sampath Arepalli, Pavan Auluck, Robert H. Baloh, Robert Bowser, Alexis Brice, James Broach, William Camu, John Cooper-Knock, Philippe Corcia, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, Faraz Faghri, Jennifer Farren, Eva Feldman, Mary Kay Floeter, Pietro Fratta, Glenn Gerhard, Summer B. Gibson, Stephen A. Goutman, Terry D. Heiman-Patterson, Dena G. Hernandez, Ben Hoover, Lilja Jansson, Freya Kamel, Janine Kirby, Neil W. Kowall, Hannu Laaksovirta, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel JL. MacGowan, Nicholas J. Maragakis, Gabriele Mora, Kevin Mouzat, Liisa Myllykangas, Mike A. Nalls, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Erik Pioro, Stefan M. Pulst, John M. Ravits, Alan E. Renton, Wim Robberecht, Ian Robey, Ekaterina Rogaeva, Jeffrey D. Rothstein, Michael Sendtner, Katie C. Sidle, Zachary Simmons, David J. Stone, Pentti J. Tienari, John Q. Trojanowski, Juan C. Troncoso, Miko Valori, Philip Van Damme, Ludo Van Den Bosch, Lorne Zinman, Diego Albani, Barbara Borroni, Alessandro Padovani, Amalia Bruni, Jordi Clarimon, Oriol Dols-Icardo, Ignacio Illán-Gala, Alberto Lleó, Adrian Danek, Daniela Galimberti, Elio Scarpini, Maria Serpente, Caroline Graff, Huei-Hsin Chiang, Behzad Khoshnood, Linn Öijerstedt, Christopher M. Morris, Benedetta Nacmias, Sandro Sorbi, Jorgen E. Nielsen, Lynne E. Hjermind, Valeria Novelli, Annibale A. Puca, Pau Pastor, Ignacio Alvarez, Monica Diez-Fairen, Miquel Aguilar, Robert Perneczky, Janine Diehl-Schimd, Mina Rossi, Agustin Ruiz, Mercè Boada, Isabel Hernández, Sonia Moreno-Grau, Johannes C. Schlachetzki, Dag Aarsland, Marilyn S. Albert, Johannes Attems, Matthew J. Barrett, Thomas G. Beach, Lynn M. Bekris, David A. Bennett, Lilah M. Besser, Eileen H. Bigio, Sandra E. Black, Bradley F. Boeve, Ryan C. Bohannan, Francesca Brett, Maura Brunetti, Chad A. Caraway, Jose-Alberto Palma, Andrea Calvo, Antonio Canosa, Dennis Dickson, Charles Duyckaerts, Kelley Faber, Tanis Ferman, Margaret E. Flanagan, Gianluca Floris, Tatiana M. Foroud, Juan Fortea, Ziv Gan-Or, Steve Gentleman, Bernardino Ghetti, Jesse Raphael Gibbs, Alison Goate, David Goldstein, Isabel González-Aramburu, Neill R. Graff-Radford, Angela K. Hodges, Heng-Chen Hu, Daniel Hupalo, Jon Infante, Alex Iranzo, Scott M. Kaiser, Horacio Kaufmann, Julia Keith, Ronald C. Kim, Gregory Klein, Rejko Krüger, Walter Kukull, Amanda Kuzma, Carmen Lage, Suzanne Lesage, James B. Leverenz, Giancarlo Logroscino, Grisel Lopez, Seth Love, Qinwen Mao, Maria Jose Marti, Elisa Martinez-McGrath, Mario Masellis, Eliezer Masliah, Patrick May, Ian McKeith, Marek-Marsel Mesulam, Edwin S. Monuki, Kathy L. Newell, Lucy Norcliffe-Kaufmann, Laura Palmer, Matthew Perkins, Olga Pletnikova, Laura Molina-Porcel, Regina H. Reynolds, Eloy Rodríguez-Rodríguez, Jonathan D. Rohrer, Pascual Sanchez-Juan, Clemens R. Scherzer, Geidy E. Serrano, Vikram Shakkottai, Ellen Sidransky, Nahid Tayebi, Alan J. Thomas, Bension S. Tilley, Ronald L. Walton, Randy Woltjer, Zbigniew K. Wszolek, Georgia Xiromerisiou, Chiara Zecca, Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Neil A. Shneider, Ernest Fraenkel, Noah Zaitlen, James D. Berry, Andrea Malaspina, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos.A. Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Matt Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler, Khaled Amar, Neil Archibald, Oliver Bandmann, Erica Capps, Alistair Church, Jan Coebergh, Alyssa Costantini, Peter Critchley, Boyd CP. Ghosh, Michele T.M. Hu, Christopher Kobylecki, P. Nigel Leigh, Carl Mann, Luke A. Massey, Uma Nath, Nicola Pavese, Dominic Paviour, Jagdish Sharma, Jenny Vaughan, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, Clinicum, Pentti Tienari / Principal Investigator, Parkinson's UK, Human Genetics, ARD - Amsterdam Reproduction and Development, ANS - Complex Trait Genetics, Pathology, ANS - Cellular & Molecular Mechanisms, AII - Inflammatory diseases, Universidad de Cantabria, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Huntington's Disease ,Pathology ,amyotrophic lateral sclerosis ,Huntingtin ,Neurology ,1702 Cognitive Sciences ,International ALS/FTD Genomics Consortium ,Neurodegenerative ,frontotemporal dementia ,3124 Neurology and psychiatry ,0302 clinical medicine ,Medicine ,2.1 Biological and endogenous factors ,Psychology ,Amyotrophic lateral sclerosis ,Aetiology ,Alzheimer's Disease Related Dementias (ADRD) ,NYGC ALS Consortium ,Huntingtin Protein ,DNA Repeat Expansion ,General Neuroscience ,Frontotemporal Dementia (FTD) ,International FTD Genetics Consortium ,whole-genome sequencing ,Frontotemporal Dementia ,Neurological ,Cognitive Sciences ,Lewy body dementia ,huntingtin ,repeat expansions ,Amyotrophic Lateral Sclerosis ,Humans ,Mutation ,Whole Genome Sequencing ,Frontotemporal dementia ,Huntington’s disease ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,FALS Sequencing Consortium ,Article ,03 medical and health sciences ,Atrophy ,Rare Diseases ,American Genome Center ,Clinical Research ,mental disorders ,Genetics ,Acquired Cognitive Impairment ,Dementia ,PROSPECT Consortium ,Neurology & Neurosurgery ,Lewy body ,business.industry ,International LBD Genomics Consortium ,Neurosciences ,3112 Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,nutritional and metabolic diseases ,medicine.disease ,Brain Disorders ,nervous system diseases ,030104 developmental biology ,Genomics England Research Consortium ,1701 Psychology ,ALS ,business ,1109 Neurosciences ,030217 neurology & neurosurgery - Abstract
Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
- Published
- 2020
4. Subthalamic deep brain stimulation under general anesthesia and neurophysiological guidance while on dopaminergic medication: comparative cohort study
- Author
-
Colin Shirley, Mohammed Jamil Asha, Rosalind Mitchell, Benjamin A Fisher, Hardev Pall, Hari Krovvidi, James Hodson, Jamilla Kausar, Ismail Ughratdar, Ramesh Chelvarajah, Hayley Garratt, and Anwen White
- Subjects
Male ,medicine.medical_specialty ,Deep brain stimulation ,Neurology ,Deep Brain Stimulation ,medicine.medical_treatment ,Dopamine Agents ,Microelectrode recording ,General anesthesia ,Anesthesia, General ,030218 nuclear medicine & medical imaging ,Cohort Studies ,Levodopa ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Subthalamic Nucleus ,Humans ,Medicine ,Prospective Studies ,Adverse effect ,Prospective cohort study ,Aged ,business.industry ,Dopaminergic ,Parkinson Disease ,Perioperative ,Middle Aged ,Dyskinesia ,Anesthesia ,Subthalamic nucleus deep brain stimulation ,Female ,Surgery ,Neurology (clinical) ,Original Article - Functional ,medicine.symptom ,Dopaminergic therapy ,business ,Microelectrodes ,030217 neurology & neurosurgery ,Cohort study - Abstract
Objectives The authors have previously reported on the technical feasibility of subthalamic nucleus deep brain stimulation (STN DBS) under general anesthesia (GA) with microelectrode recording (MER) guidance in Parkinsonian patients who continued dopaminergic therapy until surgery. This paper presents the results of a prospective cohort analysis to verify the outcome of the initial study, and report on wider aspects of clinical outcome and postoperative recovery. Methods All patients in the study group continued dopaminergic therapy until GA was administered. Baseline characteristics, intraoperative neurophysiological markers, and perioperative complications were recorded. Long-term outcome was assessed using selective aspects of the unified Parkinson’s disease rating scale motor score. Immediate postoperative recovery from GA was assessed using the “time needed for extubation” and “total time of recovery.” Data for the “study group” was collected prospectively. Examined variables were compared between the “study group” and “historical control group” who stopped dopaminergic therapy preoperatively. Results The study group, n = 30 (May 2014–Jan 2016), were slightly younger than the “control group,” 60 (51–64) vs. 64 (56–69) years respectively, p = 0.043. Both groups were comparable for the recorded intraoperative neurophysiological parameters; “number of MER tracks”: 60% of the “study group” had single track vs. 58% in the “control” group, p = 1.0. Length of STN MER detected was 9 vs. 7 mm (median) respectively, p = 0.037. A trend towards better recovery from GA in the study group was noted, with shorter “total recovery time”: 60 (50–84) vs. 89 (62–120) min, p = 0.09. Long-term improvement in motor scores and reduction in l-dopa daily equivalent dose were equally comparable between both groups. No cases of dopamine withdrawal or problems with immediate postop dyskinesia were recorded in the “on medications group.” The observed rate of dopamine-withdrawal side effects in the “off-medications” group was 15%. Conclusions The continuation of dopaminergic treatment for patients with PD does not affect the feasibility/outcome of the STN DBS surgery. This strategy appears to reduce the risk of dopamine-withdrawal adverse effects and may improve the recovery in the immediate postoperative period, which would help enhance patients’ perioperative experience.
- Published
- 2018
5. The effect of dopaminergic therapy on intraoperative microelectrode recordings for subthalamic deep brain stimulation under GA: can we operate on patients ‘on medications’?
- Author
-
Rosalind Mitchell, Ramesh Chelvarajah, Hari Krovvidi, James Hodson, Mohammed Jamil Asha, Anwen White, Jamilla Kausar, Colin Shirley, and Hardev Pall
- Subjects
Male ,medicine.medical_specialty ,Deep brain stimulation ,Deep Brain Stimulation ,medicine.medical_treatment ,Anesthesia, General ,Antiparkinson Agents ,Levodopa ,03 medical and health sciences ,0302 clinical medicine ,Subthalamic Nucleus ,medicine ,Clinical endpoint ,Humans ,General anaesthesia ,030212 general & internal medicine ,Prospective cohort study ,Aged ,business.industry ,Surrogate endpoint ,Contraindications ,Perioperative ,Middle Aged ,nervous system diseases ,Surgery ,Subthalamic nucleus ,Dyskinesia ,Anesthesia ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Microelectrode recording (MER) plays an important role in target refinement in deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson’s disease (PD). Traditionally, patients were operated on in the ‘off-medication’ state to allow intraoperative assessment of the patient response to direct STN stimulation. The development of intraoperative microelectrode recording (MER) has facilitated the introduction of general anaesthesia (GA). However, the routine withdrawal of dopaminergic medications has remained as standard practice. This retrospective review examines the effect of continuing these medications on intraoperative MER for subthalamic DBS insertion under GA and discusses the clinical implication of this approach. Retrospective review of PD patients who had bilateral STN DBS insertion was conducted. A cohort of seven patients (14 STN microelectrodes) between 2012 and 2013, who inadvertently underwent the procedure while ‘on medication’, was identified. This ‘on-medication’ group was compared to all other patients who underwent the same procedure between 2012 and 2013 and had their medications withdrawn preoperatively, the ‘off-medication’ group, n = 26 (52 STN DBS). The primary endpoint was defined as the number of microelectrode tracks required to obtain adequate STN recordings. A second endpoint was the length of MERs that was finally used to guide the DBS lead insertion. The Reduction of the levo-dopa equivalent daily dose (LEDD) was also examined as a surrogate marker for clinical outcome 12 months postoperatively for both groups. For the on-medication group further analysis of the clinical outcome was done relying on the change in the motor examination at 12 months following STN DBS using the following parameters (Hoehn and Yahr scale, the number of waking hours spent in the OFF state as well as the duration of dyskinesia during the ON periods). The on-medication group was statistically comparable in all baseline characteristics to the off-medication group, including age at operation 57 ± 9.9 years vs. 61.5 ± 9.2 years, p = 0.34 (mean ± SD); duration of disease (11.6 ± 5 years vs. 11.3 ± 4 years, p = 0.68); gender F:M ratio (1:6 vs. 9:17, p = 0.40). Both groups had similar PD medication regimes preoperatively expressed as levodopa equivalent daily dose (LEDD) 916 mg (558–1850) vs. 744 mg (525–3591), respectively, p = 0.77. In the on-medication group, all seven patients (14 STN electrodes) had satisfactory STN recording from a single brain track versus 15 out of 26 patients (57.7 %) in the off-medication group, p = 0.06. The length of MER was 4.5 mm (3.0–5.5) in the on-medication group compared to 3.5 mm (3.0–4.5) in the off-medication group, p = 0.16. The percentage of reduction in LEDD postoperatively for the on-medication group was comparable to that in the off-medication group, 62 % versus 58 %, respectively, p > 0.05. All patients in the on-medication group had clinically significant improvement in their PD motor symptoms as assessed by the Hoehn and Yahr scale; the number of hours (of the waking day) spent in the OFF state dropped from 6.9 (±2.3) h to 0.9 (±1.6) h; the duration of dyskinesia during the ON state dropped from 64 % (±13 %) of the ON period to only 7 % (±12 %) at 12 months following STN DBS insertion. STN DBS insertion under GA can be performed without the need to withdraw dompaminergic treatment preoperatively. In this review the inadvertent continuation of medications did not affect the physiological localisation of the STN or the clinical effectiveness of the procedure. The continuation of dopamine therapy is likely to improve the perioperative experience for PD patients, avoid dopamine-withdrawal complications and improve recovery. A prospective study is needed to verify the results of this review
- Published
- 2015
6. Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis
- Author
-
Claire Troakes, Federico Verde, Cinzia Tiloca, Simon Topp, Peter C. Sapp, Masatoshi Maki, Monkel Lek, Michael E. Weale, Kevin P. Kenna, Stephen E. Moss, Robert H. Brown, Karen E. Morrison, Jonathan D. Glass, Emma L. Scotter, Martina de Majo, Michael A. Simpson, Christopher Shaw, Jack W. Miller, Pamela J. Shaw, Alberto Garcia Redondo, Athina Soragia-Gkazi, Han-Jou Chen, Bradley N. Smith, Ammar Al-Chalabi, Hideki Shibata, Wejdan Kattuah, Vincenzo Silani, Jacqueline C. Mitchell, Anneloor L.M.A. ten Asbroek, Andrew P. King, Peter J. Nestor, Cinzia Gellera, Hardev Pall, Akane Sato, Jacqueline de Belleroche, Maryangel Jeon, Nigel Leigh, Martin R Turner, Janine Kirby, Frank Baas, Kevin Talbot, Jesús Esteban-Pérez, Safa Al-Sarraj, Orla Hardiman, Nicholas W Parkin, Claudia Fallini, Diana Marques Dias, Stefano Duga, Antonia Ratti, Christopher C.J. Miller, Caroline Vance, Chun Hao Wong, Nicola Ticozzi, John Landers, Matthew Nolan, J M Vianney de Jong, ARD - Amsterdam Reproduction and Development, Genome Analysis, Other departments, ANS - Complex Trait Genetics, Human Genetics, and Medical Research Council (MRC)
- Subjects
0301 basic medicine ,TDP-43 ,metabolism [Human Embryonic Stem Cells] ,Human Embryonic Stem Cells ,Research & Experimental Medicine ,FAMILIAL ALS ,Protein aggregation ,medicine.disease_cause ,S100 Calcium Binding Protein A6 ,Mutant protein ,Annexin ,Amyotrophic lateral sclerosis ,metabolism [S100 Calcium Binding Protein A6] ,S100A6 ,Mutation ,11 Medical And Health Sciences ,General Medicine ,Transport protein ,genetics [Amyotrophic Lateral Sclerosis] ,Protein Transport ,Medicine, Research & Experimental ,CALCIUM-BINDING ,ddc:500 ,RETICULUM EXIT SITES ,Life Sciences & Biomedicine ,Protein Binding ,Annexins ,genetics [Mutation] ,Biology ,Article ,CU/ZN SUPEROXIDE-DISMUTASE ,03 medical and health sciences ,medicine ,Humans ,metabolism [Annexins] ,GENOME-WIDE ASSOCIATION ,Gene ,Science & Technology ,Amyotrophic Lateral Sclerosis ,Haplotype ,COMMON FOUNDER ,Cell Biology ,FRONTOTEMPORAL DEMENTIA ,06 Biological Sciences ,medicine.disease ,GENE ,Molecular biology ,genetics [Annexins] ,030104 developmental biology - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (P = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing ANXA11 with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in ANXA11 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.
- Published
- 2017
7. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia
- Author
-
Brian T. Wilson, Vasiliki Nakou, Henry Houlden, Angela Barnicoat, Joost Nicolai, Miriam S. Reuter, Patrick Rump, F Lucy Raymond, Nicholas W. Wood, Serena Barral, Sanjay Bhate, Jonathan R. Chubb, Manju A. Kurian, Michèl A.A.P. Willemsen, Esther Meyer, André Reis, Nicola Foulds, Shekeeb S Mohammed, Kathryn J. Peall, Patricia Limousin, Apostolos Papandreou, Margaret Kaminska, Magnus Nilsson, Russell C. Dale, Susan M. White, Paul Gissen, Hilla Ben-Pazi, Gregory Peters, Christopher Wragg, Zvi Israel, Jean-Pierre Lin, Sarah Wiethoff, Simon Pope, Deciphering Developmental Disorders Study, William A. Gahl, Alan Pittman, Niccolo E. Mencacci, Wui K. Chong, Margje Sinnema, Dagmar Wieczorek, Erik-Jan Kamsteeg, Martin Smith, A. Hills, John M.E. Nichols, Shane McKee, Keren J. Carss, Maya Topf, S Heales, Gidon Winter, Amber Boys, Hardev Pall, Peter D. Turnpenny, Camilo Toro, Julia Rankin, Jane A. Hurst, Reeval Segel, Nicholas Gutowski, Hagai Bergman, Niklas Darin, Shibalik Misra, Lucinda Carr, Agnel Praveen Joseph, Joanne Ng, Deborah Morrogh, David Arkadir, Detelina Grozeva, Adeline Ngoh, Daniel E. Lumsden, Belén Pérez-Dueñas, Prab Prabhakar, Kailash P. Bhatia, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
- Subjects
0301 basic medicine ,Male ,Methyltransferase ,Deep brain stimulation ,Adolescent ,Histone lysine methylation ,DISORDERS ,medicine.medical_treatment ,VARIANTS ,Bioinformatics ,bcs ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,MECHANISMS ,Histones ,03 medical and health sciences ,BRAIN IRON ACCUMULATION ,Genetics ,medicine ,KABUKI SYNDROME ,Humans ,Laryngeal dystonia ,Dystonia ,Regulation of gene expression ,biology ,Lysine ,METHYLATION ,NEURODEGENERATION ,Nuclear Proteins ,Histone-Lysine N-Methyltransferase ,medicine.disease ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,DNA-Binding Proteins ,030104 developmental biology ,Histone ,Histone methyltransferase ,Mathematik ,Mutation ,biology.protein ,Histone Methyltransferases ,UPDATE ,Female ,PROTEIN STABILITY ,LEUKEMIA - Abstract
Item does not contain fulltext Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.
- Published
- 2017
8. Theory of mind deficits in Parkinson's disease: A product of executive dysfunction?
- Author
-
Hardev Pall, Clare M. Eddy, Peter Praamstra, Sarah R. Beck, and Ian J. Mitchell
- Subjects
Male ,Memory errors ,Working memory ,Mental Disorders ,Statistics as Topic ,Theory of Mind ,Short-term memory ,Parkinson Disease ,Cognition ,Middle Aged ,Neuropsychological Tests ,Executive Function ,Memory, Short-Term ,Neuropsychology and Physiological Psychology ,Humans ,Verbal fluency test ,Female ,Cognition Disorders ,Psychology ,DCN NN - Brain networks and neuronal communication ,Aged ,Comic strip ,Cognitive psychology ,Executive dysfunction ,Stroop effect - Abstract
Item does not contain fulltext OBJECTIVE: Patients with Parkinson's disease (PD) can perform poorly on tasks involving theory of mind (ToM): the ability to reason about mental states. We investigated whether patients' ToM deficits were independent of executive dysfunction. METHOD: Experiment 1 aimed to establish that ToM deficits were present, and 2 following experiments manipulated the working memory (WM) demands of the ToM task. RESULTS: In Experiment 1, 15 patients with PD performed significantly more poorly than controls on a false belief vignette task but not on a faux pas task. Errors were related to poor verbal fluency. In Experiment 2, 24 patients with PD made fewer errors on shorter false belief vignettes than the original FBT, and errors on the latter were related to WM impairment. In Experiment 3, the FBT was presented as a comic strip visible throughout questioning, reducing WM demands. Patients (n = 24) made memory errors but no false belief errors on the comic strip. They exhibited no verbal fluency or WM impairments, but did exhibit deficits on a black-and-white Stroop task. False belief errors were not correlated with executive performance. CONCLUSIONS: PD patients made very few ToM errors that were independent of errors on memory questions, so in this sample, ToM deficits per se appear unlikely. However, patients still made errors on ToM tasks when associated incidental WM demands were considerably reduced, highlighting the need for future investigations of ToM in PD to account for the role of more general cognitive restrictions exhibited by even some medicated, early stage patients.
- Published
- 2013
9. SGCE mutations cause psychiatric disorders: clinical and genetic characterization
- Author
-
Manju A. Kurian, Sean O'Riordan, Jean-Pierre Lin, George Kirov, Alan L Whone, Huw R. Morris, Kathryn J. Peall, Mark Wardle, Adrian James Waite, Derek J. Blake, Daniel J. Smith, Mary D. King, Tammy Hedderly, Hardev Pall, Philip Jardine, Martin Smith, Narinder Bajaj, Thomas T. Warner, Michael John Owen, Cathy White, Bryan Lynch, T. Lynch, Patrick F. Chinnery, Andrew L Lux, and Michael Samuel
- Subjects
Adult ,Male ,Myoclonus ,Proband ,Obsessive-Compulsive Disorder ,medicine.medical_specialty ,Movement disorders ,Generalized anxiety disorder ,Adolescent ,Article ,SGCE ,Sarcoglycans ,medicine ,Humans ,Genetic Predisposition to Disease ,Child ,Psychiatry ,Aged ,Dystonia ,Middle Aged ,Focal dystonia ,medicine.disease ,Anxiety Disorders ,nervous system diseases ,Alcoholism ,Phenotype ,Dystonic Disorders ,Child, Preschool ,Mutation ,Quality of Life ,Female ,Neurology (clinical) ,medicine.symptom ,Psychology ,Dystonic disorder - Abstract
Myoclonus dystonia syndrome is a childhood onset hyperkinetic movement disorder characterized by predominant alcohol responsive upper body myoclonus and dystonia. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. Previous studies have suggested that patients with SGCE mutations may have an increased rate of psychiatric disorders. We established a cohort of patients with myoclonus dystonia syndrome and SGCE mutations to determine the extent to which psychiatric disorders form part of the disease phenotype. In all, 89 patients with clinically suspected myoclonus dystonia syndrome were recruited from the UK and Ireland. SGCE was analysed using direct sequencing and for copy number variants. In those patients where no mutation was found TOR1A (GAG deletion), GCH1, THAP1 and NKX2-1 were also sequenced. SGCE mutation positive cases were systematically assessed using standardized psychiatric interviews and questionnaires and compared with a disability-matched control group of patients with alcohol responsive tremor. Nineteen (21%) probands had a SGCE mutation, five of which were novel. Recruitment of family members increased the affected SGCE mutation positive group to 27 of whom 21 (77%) had psychiatric symptoms. Obsessive–compulsive disorder was eight times more likely (P < 0.001) in mutation positive cases, compulsivity being the predominant feature (P < 0.001). Generalized anxiety disorder (P = 0.003) and alcohol dependence (P = 0.02) were five times more likely in mutation positive cases than tremor controls. SGCE mutations are associated with a specific psychiatric phenotype consisting of compulsivity, anxiety and alcoholism in addition to the characteristic motor phenotype. SGCE mutations are likely to have a pleiotropic effect in causing both motor and specific psychiatric symptoms.
- Published
- 2013
10. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder
- Author
-
Karen E. Morrison, Franco Taroni, Simon Topp, Janine Kirby, Jacqueline de Belleroche, Robert H. Brown, J. M. B. Vianney de Jong, Wim Robberecht, Markus Weber, Simon Lovestone, Bradley N. Smith, Vincenzo Silani, Michael E. Weale, Michelle K. Lupton, Anneloor ten Asbroek, Claire Troakes, Nicola Ticozzi, John Powell, Peter C. Sapp, Youn-Bok Lee, Kirsten M. Scott, Helenius J. Schelhaas, Jamie Wright, Leonard H. van den Berg, John Landers, Hardev Pall, Safa Al-Sarraj, Christopher Shaw, Alex G. Morris, Pamela J. Shaw, Ammar Al-Chalabi, Jack W. Miller, Ashley R. Jones, Phillip Van Damme, Peter J. Nestor, Cinzia Gellera, Aleksey Shatunov, Jan H. Veldink, Ian Gray, Tibor Hortobágyi, Peter M. Andersen, Lauren Johnson, Caroline Vance, Stephen Newhouse, Boris Rogelj, Frank Baas, ANS - Amsterdam Neuroscience, Human Genetics, Genome Analysis, and Neurology
- Subjects
Biology ,TARDBP ,Polymorphism, Single Nucleotide ,Genomic Instability ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,C9orf72 ,Genetics ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Age of Onset ,Allele frequency ,Genetics (clinical) ,030304 developmental biology ,Repetitive Sequences, Nucleic Acid ,0303 health sciences ,C9orf72 Protein ,Haplotype ,Amyotrophic Lateral Sclerosis ,Proteins ,medicine.disease ,Founder Effect ,3. Good health ,Europe ,Haplotypes ,Frontotemporal Dementia ,Mutation ,Age of onset ,Trinucleotide repeat expansion ,030217 neurology & neurosurgery ,Founder effect - Abstract
A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P
- Published
- 2013
- Full Text
- View/download PDF
11. Management of sialorrhoea in motor neuron disease: a survey of current UK practice
- Author
-
Andrea Malaspina, Richard W. Orrell, Christopher J McDermott, Siddharthan Chandran, David Dick, Karen E. Morrison, Kevin Talbot, Ashwin Pinto, Esther V. Hobson, Tim Williams, Alexander J McGeachan, Martin R Turner, Timothy Harrower, Colette Donaghy, Hardev Pall, John Ealing, Pamela J. Shaw, Ammar Al-Chalabi, George Gorrie, Tahir Majeed, Carolyn A Young, Clemens Oliver Hanemann, Agam Jung, C M Ellis, and Francesca Crawley
- Subjects
medicine.medical_specialty ,Botulinum Toxins ,Evidence-based practice ,Attitude of Health Personnel ,Population ,MEDLINE ,Disease ,Physicians ,medicine ,Humans ,Motor Neuron Disease ,Disease management (health) ,education ,education.field_of_study ,business.industry ,Data Collection ,Disease Management ,Sialorrhea ,Botulinum toxin ,Dysphagia ,United Kingdom ,Neurology ,Family medicine ,Physical therapy ,Observational study ,Neurology (clinical) ,medicine.symptom ,business ,medicine.drug - Abstract
Our objective was to better understand UK-wide practice in managing sialorrhoea in motor neuron disease among specialist clinicians. We used a survey of neurologists in the UK with a special interest in motor neuron disease designed to establish clinicians' attitudes towards treatment options and resources for sialorrhoea management. Twenty-three clinicians replied, representing 21 centres. Sixteen centres were specialist MND Care Centres. Clinicians estimated seeing a total of 1391 newly diagnosed patients with MND in 2011. One hundred and ninety-three patients were described. Forty-two percent of patients reviewed in clinicians' last clinic had sialorrhoea and 46% of those with sialorrhoea had uncontrolled symptoms. Clinicians' preferred drugs were hyoscine patches, amitriptyline, carbocisteine and botulinum toxin. Botulinum toxin was used in 14 centres. Risk of dysphagia and staff skills were identified as the main barriers to botulinum toxin use. This survey suggests that there may be as many as 1700 patients with MND in the UK who have symptoms of sialorrhoea and that symptoms may be poorly controlled in nearly half. Treatment strategies varied, reflecting the lack of evidence based guidelines. The use of specialist treatments was influenced by local infrastructure. This study highlights the need for further work to develop evidence based guidance.
- Published
- 2016
12. Apathy in patients with Parkinson's disease following deep brain stimulation of the subthalamic nucleus
- Author
-
Andrea E. Cavanna, Rosalind Mitchell, Isabel Hindle Fisher, Jamilla Kausar, Hardev Pall, Hindle Fisher, I, Pall, H, Mitchell, R, Kausar, J, and Cavanna, A
- Subjects
Male ,medicine.medical_specialty ,Deep brain stimulation ,Parkinson's disease ,medicine.medical_treatment ,Deep Brain Stimulation ,Population ,Apathy ,Severity of Illness Index ,050105 experimental psychology ,Antiparkinson Agents ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Quality of life ,Risk Factors ,Subthalamic Nucleus ,Internal medicine ,Severity of illness ,medicine ,Prevalence ,Humans ,0501 psychology and cognitive sciences ,education ,Aged ,education.field_of_study ,behavior ,05 social sciences ,Parkinson Disease ,Middle Aged ,medicine.disease ,Psychiatry and Mental health ,Subthalamic nucleus ,Case-Control Studies ,Physical therapy ,Quality of Life ,Female ,Neurology (clinical) ,medicine.symptom ,Psychology ,030217 neurology & neurosurgery - Abstract
ObjectiveApathy has been reported as a possible adverse effect of deep brain stimulation of the subthalamic nucleus (STN-DBS). We investigated the prevalence and severity of apathy in 22 patients with Parkinson’s disease (PD) who underwent STN-DBS, as well as the effects of apathy on quality of life (QOL).MethodsAll patients were assessed with the Lille Apathy Rating Scale (LARS), the Apathy Scale (AS), and the Parkinson’s Disease Questionnaire and were compared to a control group of 38 patients on pharmacotherapy alone.ResultsThere were no significant differences in the prevalence or severity of apathy between patients who had undergone STN-DBS and those on pharmacotherapy alone. Significant correlations were observed between poorer QOL and degree of apathy, as measured by the LARS (pConclusionOur findings suggest that STN-DBS is not necessarily associated with apathy in the PD population; however, more severe apathy appears to be associated with a higher level of disability due to PD and worse QOL, but no other clinico-demographic characteristics.
- Published
- 2016
13. Subthalamic nucleus microelectrode recordings (MER) can be reliably detected despite general anaesthesia and dopaminergic treatment
- Author
-
Jamilla Kausar, Colin Shirely, Hardev Pall, Mohammed Jamil Asha, Rosalind Mitchell, Ramesh Chelvarajah, Hari Krovvidi, and Anwen White
- Subjects
medicine.medical_specialty ,Neurology ,Deep Brain Stimulation ,Anesthesia, General ,03 medical and health sciences ,0302 clinical medicine ,Subthalamic Nucleus ,Medicine ,Humans ,General anaesthesia ,030212 general & internal medicine ,Neuroradiology ,medicine.diagnostic_test ,business.industry ,Dopaminergic ,Interventional radiology ,Parkinson Disease ,Subthalamic nucleus ,Microelectrode ,Anesthesia ,Surgery ,Neurology (clinical) ,Neurosurgery ,business ,Microelectrodes ,030217 neurology & neurosurgery - Published
- 2016
14. Health-related quality of life and supportive care in patients with rare long-term neurological conditions
- Author
-
Catherine Sackley, Benjamin Eaton, Melanie Calvert, Hardev Pall, Edward Savill, and Thomas J Hoppitt
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Health Status ,Population ,Disease ,Anxiety ,Severity of Illness Index ,Health Services Accessibility ,Social support ,Rare Diseases ,Quality of life (healthcare) ,EQ-5D ,Sickness Impact Profile ,Severity of illness ,medicine ,Humans ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,business.industry ,Public Health, Environmental and Occupational Health ,Social Support ,Middle Aged ,medicine.disease ,Health Surveys ,Long-Term Care ,humanities ,Long-term care ,Cross-Sectional Studies ,Quality of Life ,Female ,Nervous System Diseases ,business ,Motor neurone disease ,Social Welfare - Abstract
Rare long-term neurological conditions (rLTNCs) may have significant impact on patients’ health-related quality of life (HRQL); however, evidence is sparse. We assessed HRQL and access to supportive care in patients with rLTNCs. Survey of patients with rare rLTNCs (motor neurone disease, Huntington’s disease, cerebellar ataxia, progressive supranuclear palsy, multiple system atrophy, Charcot–Marie–Tooth disease and postpolio syndrome) to assess current access to health and social care, and HRQL using the Euroqol EQ-5D. A total of 266 participants with rLTNCs completed the survey. The HRQL of patients is substantially reduced compared to the general population. Many patients reported pain, were anxious or depressed and experienced problems with mobility, self-care and usual activities (mean EQ-5D index scores ranged from 0.2 to 0.44). Although some patients have accessed rehabilitative services, results suggest care coordination could be improved. Rare long-term neurological conditions have a significant impact on HRQL. Many patients with rLTNCs do not seem to be accessing the level of health and social care services that could improve their HRQL.
- Published
- 2012
15. Analysis of European case-control studies suggests that common inherited variation in mitochondrial DNA is not involved in susceptibility to amyotrophic lateral sclerosis
- Author
-
Michael Sendtner, Christopher A Plaster, Michael E. Weale, Elizabeth M. C. Fisher, Karen E. Morrison, Marcus Beck, Neil Bradman, Hardev Pall, Catherine J. E. Ingram, Emily F. Goodall, Dalia Kasperavičiūtė, and Sibylle Jablonka
- Subjects
Adult ,Male ,Mitochondrial DNA ,Genotype ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,DNA, Mitochondrial ,Polymorphism, Single Nucleotide ,Genome ,White People ,Haplogroup ,Cohort Studies ,Humans ,Genetic Predisposition to Disease ,Genetic Association Studies ,Aged ,Aged, 80 and over ,Genetics ,Amyotrophic Lateral Sclerosis ,Haplotype ,General Medicine ,Middle Aged ,Hypervariable region ,Haplotypes ,Neurology ,Case-Control Studies ,Genome, Mitochondrial ,Female ,Neurology (clinical) - Abstract
While some cases of familial ALS can be entirely attributed to known inherited variation, the majority (∼ 90%) are sporadic, where the cause(s) are not entirely understood. Both genetic and environmental factors may contribute to susceptibility. Mitochondrial damage, a common feature of neurodegenerative disease, is observed in most patients and inherited polymorphism in the mitochondrial genome has been suggested as a contributing factor. We used an economic and efficient method to test whether such involvement is probable. We genotyped 22 mtDNA coding region SNPs and sequenced the mtDNA hypervariable region 1 to determine the position of each mitochondrial genome within the genealogy of mitochondrial haplotypes in samples of ALS patients (n = 700) and controls (n = 462) from two European populations. We compared haplotype and haplogroup distribution in cases and controls drawn from the same populations. No statistical difference was observed between cases and controls at either the haplogroup or haplotype level (p = ≥ 0.2). In conclusion, it is unlikely that common, shared genetic variants in the mitochondrial genome contribute substantially to ALS. Combining the data with other studies will allow meta-analysis to look for variants with modest effect sizes. The sequencing of complete mitochondrial genomes will be required to assess the role of rare mutations.
- Published
- 2012
16. Deep brain stimulation of the subthalamic nucleus for advanced Parkinson disease using general anesthesia: long-term results
- Author
-
Rosalind Mitchell, James Hodson, Jamilla Kausar, Anwen M. Harries, Hardev Pall, Stuart A. G. Roberts, and A. Paul Mocroft
- Subjects
medicine.medical_specialty ,Deep brain stimulation ,business.industry ,medicine.medical_treatment ,General Medicine ,Long term results ,Disease ,Functional neurosurgery ,Surgery ,Subthalamic nucleus ,Microelectrode recording ,Rating scale ,Anesthesia ,medicine ,business ,BMI - Body mass index - Abstract
Object The authors analyze long-term outcome in a substantial number of patients who underwent subthalamic nucleus (STN) deep brain stimulation (DBS) surgery under general anesthesia. Methods Eighty-two patients underwent bilateral placement of DBS electrodes under general anesthesia for advanced Parkinson disease; the STN was the target in all cases. All patients underwent intraoperative microelectrode recording of the STN. No intraoperative macrostimulation was performed. Unified Parkinson's Disease Rating Scale (UPDRS) data were recorded in 28 patients. Assessment of outcome was performed using the UPDRS (in 28 cases), the electrophysiological recordings (in all 82 cases), medication reduction (in 78 cases), and complications (in 82 cases). Results There was improvement in UPDRS scores across all measures following surgery. The total UPDRS score, off medication, improved from 68.78 (geometrical mean, 95% CI 61.76–76.60) preoperatively to 45.89 (geometrical mean, 95% CI 34.86–60.41) at 1 year postoperatively (p = 0.003, data available in 26 patients). Improvements were obtained in UPDRS Part II (Activities of Daily Living) off medication (p = 0.001) and also UPDRS Part III (Motor Examination) off medication (p < 0.001). Results for the on-medication and on-stimulation states also showed a statistically significant improvement for UPDRS Part III (p = 0.047). Good microelectrode recording of the STN was obtained under general anesthesia; the median first-track length was 4.0 mm, and the median number of tracks passed per patient was 3.0. The median reduction in levodopa medication was 58.1% (interquartile range 42.9%–73.3%). One patient had an intracerebral hemorrhage in the track of 1 electrode but did not require surgical evacuation. One patient had generalized convulsive seizures 24 hours postoperatively and was intubated for seizure control. Unified Parkinson's Disease Rating Scale scores were obtained in 26 patients at 1 year, 28 patients at 3 years, 17 at 5 years, and 7 at 7 years postoperatively. Up to 7 years postoperatively, there was sustained improvement in the total UPDRS score. The results in these patients showed minimal deterioration in the motor section of the UPDRS over time, up to 7 years following the operation. The authors found no evidence that the UPDRS Part II scores changed significantly over the period of 1–7 years after surgery (p = 0.671, comparison of mean scores at 1 and 7 years using generalized estimating equations). Conclusions Long-term outcomes confirm that it is both safe and effective to perform STN DBS under general anesthesia. As part of patient choice, this option should be offered to all DBS candidates with advanced Parkinson disease to enable more of these patients to undergo this beneficial surgery.
- Published
- 2012
17. Patient's expression of hope and illness narratives in three neurological conditions: a meta-ethnography
- Author
-
Hardev Pall, Katrina Gimbrere, Jill Ramsay, Helen Dawes, Brett Smith, and Andrew Soundy
- Subjects
medicine.medical_specialty ,Transcendence (philosophy) ,Psychotherapist ,Neurology ,business.industry ,Patient narratives ,Illness narratives ,Context (language use) ,Psychiatry and Mental health ,Clinical Psychology ,Meta ethnography ,Neurological rehabilitation ,Medicine ,Narrative ,business - Abstract
Hope has been identified as a key attribute required for neurological rehabilitation. Expressions of hope form the basis for patient narratives within this context. The purpose of this study was to use patient's experience of hope as a way of understanding narrative types. This study looks at three different neurological conditions: spinal cord injury, stroke and multiple sclerosis. Using a meta-ethnographical method, eight narrative macrostructures were identified by three groups of hope: (1) hope as a dichotomy, (2) hope as a paradox and (3) transcendence. The discussion provides further details of these groups and establishes how therapeutic emplotment may influence and guide narratives within neurological rehabilitation.
- Published
- 2011
18. Huntington’s Disease: Current Epidemiology and Pharmacological Management in UK Primary Care
- Author
-
Paramjit Gill, Guiqing Yao, Melanie Calvert, Catherine Sackley, Thomas J Hoppitt, Benjamin Eaton, and Hardev Pall
- Subjects
Male ,medicine.medical_specialty ,Pediatrics ,Epidemiology ,Population ,Read codes ,Prevalence ,medicine ,Humans ,Neuroepidemiology ,Age of Onset ,Practice Patterns, Physicians' ,Medical prescription ,Family history ,Formulary ,Psychiatry ,education ,Analgesics ,education.field_of_study ,Primary Health Care ,Nutritional Support ,business.industry ,Incidence ,Pharmacoepidemiology ,Antidepressive Agents ,United Kingdom ,Huntington Disease ,Female ,Neurology (clinical) ,business ,Central Nervous System Agents - Abstract
Background: Recent debate suggests Huntington’s disease (HD) may be more prevalent than previously reported. In addition, relatively little is known about current disease management. This study aims to provide epidemiological data and describe the pharmacological management of HD in the United Kingdom. Methods: A primary care research database was accessed to identify incident and prevalent HD cases between January 1, 2004, and December 31, 2008. Patients with Read codes denoting a definite diagnosis or possible diagnosis, and undiagnosed patients with a positive family history were identified. A subset of patients with a definite diagnosis and prescribed medication indicating symptom onset was also identified. Epidemiological data were estimated. Pharmacological prescriptions to HD patients from 2004 to 2008 were identified, and prescription frequencies were grouped according to the British National Formulary categories. Results: HD incidence estimates ranged from 0.44 to 0.78 per 100,000 person-years, and HD prevalence ranged from 5.96 to 6.54 per 100,000 of the population. Forty-four percent of pharmacological prescriptions targeted the central nervous system. Nearly half of the HD patients were prescribed antidepressants, and over 40% were prescribed analgesics. Conclusions: Although prevalence estimates fell short of figures suggested in recent debate, it is feasible that the true prevalence may be much higher than previously reported. Pharmacological management appears to rely heavily on central nervous system drugs and nutrition support. Many of these drugs are prescribed to HD patients for reasons other than the medication’s primary use. Further work is required to evaluate the impact of alternative management strategies, such as therapist intervention, counselling, and organisation support, on the patients’ quality of life.
- Published
- 2011
19. Contents Vol. 37, 2011
- Author
-
Pornpet Panjapiyakul, Monika Balzer-Geldsetzer, Hans-Ulrich Wittchen, Neşe Güler, Ülkü Türk Börü, Marcelo Schultz, Satz Mengensatzproduktion, Bernadette Boden-Albala, L. Fernando Gonzalez, Ana Sofia Costa, Julián Benito-León, Carlos Romero, Claudia Trenkwalder, Alexander Storch, Mustafa Taşdemir, Ahmed Jusabani, Susanne Gräber-Sultan, Maurice Giroud, Cédric Annweiler, Günther Deuschl, John F. Kurtzke, Rashmi Kumar, Mark Swai, Juha E. Jääskeläinen, Haydar Sur, William K. Gray, Stavropoula Tjoumakaris, Mikael von und zu Fraunberg, Martin Kronenbürger, J. Hernesniemi, Stéphane Haïk, Jaakko Rinne, Antti Ronkainen, Adam E. Handel, Roongroj Bhidayasiri, Terhi Huttunen, Arlette Welaratne, Sabine Nunnemann, Kiyan Heshmat-Ghahdarijani, William K. Wohlgemuth, Christine Schneider, Elif Dilaver Ayık, Christián Begué, Myunghee Cho Paik, Annamaija Riihinen, Sreeram V. Ramagopalan, Thanin Asawavichienjinda, Antti E. Lindgren, Julio R. Vieira, Albertine Aouaba, Alireza Minagar, Thomas Klockgether, Carlos D'Giano, Maren Bodden, Hervé Aube, Thomas Gasser, Kanittha Chimabutra, Jörg B. Schulz, Wolfgang H. Oertel, Eric Benzenine, Renu Srismith, Estefania Rojas, Véronique Vaillant, Isabelle Capek, Vahab Moradi, Yves Cottin, Luca Mascitelli, M.S.V. Elkind, Alexander Kurz, Hans Förstl, Arda Duman, Richard Dodel, Safieh Nonahal, Alberto R. Ramos, Chuanhui Dong, Sandra Röske, Timo Koivisto, Tatjana Rundek, Samart Tananyakul, Kammant Phanthumchinda, Nele Schmidt, Mitja I. Kurki, Chanvit Tharathep, Ana Lia Taratuto, Hannah Gardener, Oliver Riedel, Catherine Quantin, Guiqing Yao, Tibor Schuster, Jean-Philippe Brandel, Catherine Sackley, Marianne Zeller, Olivier Beauchet, Gustavo Sevlever, Chiadi U. Onyike, Anwar Rizvi, Ayşegül Kumaş, Luc Lorgis, Brit Mollenhauer, Daniela Berg, Horacio Martinetto, Yannick Béjot, Pascal Jabbour, Annick Alpérovitch, Elke Kalbe, Serhan Yıldırım, Siegfried Muhlack, Supaporn Choeytim, Melanie Calvert, Anupama Bhave, Janine Diehl-Schmid, Yolsilp Suchonwanich, Abbas Ghorbani, Carola Seifried, Talat Rizvi, Annika Spottke, Inga Liepelt-Scarfone, Ralph L. Sacco, Paramjit Gill, Hardev Pall, Mitchell S.V. Elkind, Karsten Witt, Thomas Müller, Benjamin Eaton, Masoud Etemadifar, Amir-Hadi Maghzi, Natnipa Wannachai, Aaron S. Dumont, Taavi Saavalainen, Richard Walker, Roli Bhargava, Ullrich Wüllner, Mark R. Goldstein, Sudaratana Limpabandhu, Rüdiger Hilker, Clinton B. Wright, Yeseon P. Moon, Thomas J Hoppitt, Dominique Salomon, Manuel J. Somoza, Druck Reinhardt Druck Basel, and Dirk Woitalla
- Subjects
Traditional medicine ,Epidemiology ,business.industry ,Medicine ,Neurology (clinical) ,business - Published
- 2011
20. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study
- Author
-
Bradley N. Smith, Cathryn M. Lewis, John Hardy, Wim Robberecht, Christopher Shaw, Stephen Newhouse, Adriano Chiò, Isabella Fogh, Aleksey Shatunov, Richard W. Orrell, Olubunmi Abel, Vincenzo Silani, Peter M. Andersen, Michael A van Es, Peter McGuffin, P. Nigel Leigh, John Powell, Karen E. Morrison, Leonard H. van den Berg, Jonathan D. Glass, Caroline Vance, Kin Y. Mok, Robert H. Brown, Pamela J. Shaw, John Landers, Jan H. Veldink, Ammar Al-Chalabi, Bryan J. Traynor, Anne Farmer, Lauren Johnson, Hardev Pall, Vincent Meininger, Orla Hardiman, Michael E. Weale, Philip Van Damme, Amy W. Butler, and Judith Melki
- Subjects
medicine.medical_specialty ,Internationality ,Population ,Clinical Neurology ,Locus (genetics) ,Single-nucleotide polymorphism ,Genome-wide association study ,Polymorphism, Single Nucleotide ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Fast track — Articles ,medicine ,Humans ,Amyotrophic lateral sclerosis ,education ,Aged ,030304 developmental biology ,Genetic association ,Aged, 80 and over ,Genetics ,0303 health sciences ,education.field_of_study ,business.industry ,Amyotrophic Lateral Sclerosis ,Odds ratio ,Middle Aged ,medicine.disease ,United Kingdom ,United States ,3. Good health ,Europe ,Case-Control Studies ,Frontotemporal Dementia ,Neurology (clinical) ,Chromosomes, Human, Pair 9 ,business ,Motor neurone disease ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Summary Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS–frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries. Methods We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10 −7 Findings After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10 −6 ; odds ratio [OR] 1·39, 95% CI 1·21–1·59) and rs2814707 (p=3·32×10 −6 ; 1·38, 1·20–1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10 −10 ; OR 1·22, 95% CI 1·15–1·30) and rs2814707 (p=4·72×10 −10 ; 1·22, 1·15–1·30) were associated with ALS. Interpretation We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS–frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS–frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene. Funding ALS Therapy Alliance, the Angel Fund, the Medical Research Council, the Motor Neurone Disease Association of Great Britain and Northern Ireland, the Wellcome Trust, and the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network (DeNDRoN).
- Published
- 2010
21. Hypoxic challenge testing in motor neurone disease
- Author
-
Emma Crawford, Ian Cliff, Karen E. Morrison, Helen Stone, Naveed Mustfa, and Hardev Pall
- Subjects
Spirometry ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Blood gas measurements ,Respiratory disease ,Disease ,medicine.disease ,Breathing ,Physical therapy ,Medicine ,In patient ,business ,Intensive care medicine ,Challenge testing ,Motor neurone disease - Abstract
British Thoracic Society guidance on air travel in patients with respiratory disease advises that a hypoxic challenge test (HCT) can be used to determine the need for in-flight oxygen in patients at high risk of medical complications. Evidence to inform the clinician as to which patients are high-risk, particularly disease-specific evidence, is lacking. We present a case series of 40 patients with motor neurone disease (MND) referred for hypoxic challenge testing. We aimed to identify parameters that might predict the outcome of an HCT in patients with MND to aid clinicians undertaking pre-flight assessments. An HCT was performed and capillary blood gas measurements, spirometric data and sinus nasal inspiratory pressure measurements were obtained. Data from those patients requiring in-flight oxygen according to the HCT was compared to data obtained from patients who did not and results are summarised below. According to our data, baseline paCO2 was the only independent predictor of hypoxaemia following an HCT. Our data also suggests that inability to perform spirometry and need for home non-invasive ventilation reflect disease severe enough to warrant an HCT as part of a pre-flight assessment.
- Published
- 2015
22. Cost-utility analysis of deep brain stimulation surgery plus best medical therapy versus best medical therapy in patients with Parkinson's: Economic evaluation alongside the PD SURG trial
- Author
-
A.C. Williams, Emma McIntosh, Natalie Ives, Smitaa Patel, Alastair Gray, Crispin Jenkinson, Niall Quinn, Rosalind Mitchell, Steven S. Gill, Caroline Rick, Jane P Daniels, Keith Wheatley, and Hardev Pall
- Subjects
medicine.medical_specialty ,Randomization ,Deep brain stimulation ,medicine.medical_treatment ,Cost-Benefit Analysis ,Deep Brain Stimulation ,Disease ,Antiparkinson Agents ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,EQ-5D ,Outcome Assessment, Health Care ,medicine ,Humans ,030212 general & internal medicine ,Cost–utility analysis ,business.industry ,Parkinson Disease ,Confidence interval ,Neurology ,Economic evaluation ,Physical therapy ,Drug Therapy, Combination ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Introduction Williams and colleagues reported that DBS surgery for patients with advanced PD improves motor function and quality of life compared to best medical therapy alone at 1 year, but with surgery-related side effects in a minority. This article reports on the economic evaluation alongside this trial. Methods Detailed resource use and quality of life over 12 months after randomization was obtained from the trial reported by Williams and colleagues. Outcomes were measured using the EQ-5D and quality-adjusted life years calculated. Results Year 1 costs for surgery were significantly higher than in best medical therapy, at £19,069 compared to £9,813, a difference of £9,256 (95% confidence interval [CI]: £7,625, £10,887). There was a small, significant gain in utility at 1 year but a statistically insignificant gain of 0.02 quality-adjusted life years (95% CI: −0.015, 0.05) in the surgical arm. The incremental cost per quality-adjusted life year of surgery at 1 year was £468,528. Extrapolation reveals that after 5 years, this ratio is likely to reduce to £45,180, but subsequently rise to £70,537 at 10 years owing to the increased probability of battery replacements (and re-replacements) beyond 5 years. Conclusion In this patient group, DBS is not cost-effective at 1 year. Extrapolation, however, reveals an increasing likelihood of cost-effectiveness up to 5 years and reducing cost-effectiveness between 5 and 10 years. These models are sensitive to assumptions about future costs and quality-adjusted life years gained. © 2016 International Parkinson and Movement Disorder Society
- Published
- 2015
23. SUBTHALAMIC NUCLEUS DEEP BRAIN STIMULATION AND APATHY IN PATIENTS WITH PARKINSON'S DISEASE
- Author
-
Andrea E. Cavanna, Jamilla Kausar, Hardev Pall, Rosalind Mitchell, Isabel Hindle Fisher, Hindle Fisher, I, Pall, H, Mitchell, R, Kausar, J, and Cavanna, A
- Subjects
education.field_of_study ,medicine.medical_specialty ,Deep brain stimulation ,Parkinson's disease ,medicine.medical_treatment ,Population ,Neurosciences ,medicine.disease ,nervous system diseases ,Psychiatry and Mental health ,Subthalamic nucleus ,surgical procedures, operative ,Pharmacotherapy ,nervous system ,Quality of life ,Rating scale ,medicine ,Physical therapy ,Surgery ,Apathy ,Neurology (clinical) ,medicine.symptom ,education ,Psychology ,therapeutics - Abstract
Objective Apathy has been reported as a possible adverse effect of deep brain stimulation of the subthalamic nucleus (STN-DBS). We investigated the prevalence and severity of apathy in 22 patients with Parkinson's disease (PD) who underwent STN-DBS and the effects on quality of life (QOL). Method All patients were assessed with the Lille Apathy Rating Scale (LARS), the Apathy Scale (AS) and the Parkinson's Disease Questionnaire and were compared to a control group of 38 patients on pharmacotherapy alone. The relationship between apathy and clinico-demographic variables was explored through correlation analysis. Results Apathy was reported by a similar proportion of patients in the two groups: 18.4% in the DBS group and 22.7% in the control group according to LARS ratings; 45.5% in the DBS group and 42.1% in the control group according to AS ratings. There was no significant difference in apathy or QOL ratings between the two groups. Significant correlations were observed between poorer QOL and degree of apathy, as measured by the LARS (p
- Published
- 2015
24. Implicit Motor Learning in Parkinson's Disease
- Author
-
Rich S. W. Masters, Kenneth Macmahon, and Hardev Pall
- Subjects
medicine.medical_specialty ,Rehabilitation ,Parkinson's disease ,medicine.medical_treatment ,Physical Therapy, Sports Therapy and Rehabilitation ,Muscle memory ,medicine.disease ,Incidental learning ,Psychiatry and Mental health ,Clinical Psychology ,Motor imagery ,Physical medicine and rehabilitation ,medicine ,Intentional learning ,Motor learning ,Psychology - Published
- 2004
25. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death
- Author
-
Jörgen Andersson, Karen E. Morrison, Loïc Lang-Lazdunski, Takuya Awata, Shigehiro Katayama, Rhiannon Musson, Nigel Leigh, Lieve Moons, Masafumi Morimoto, Robert Vlietinck, Desire Collen, Jurgen Del-Favero, Ingrid van Marion, Vincent Thijs, Stéphanie Bornes, Erik Storkebaum, Stefan L. Marklund, Frederik Desmet, Peter Carmeliet, Peter M. Andersen, Christopher Shaw, Rolf Adolfsson, Wim Robberecht, Valerie K. Hansen, Lars Beckman, Diether Lambrechts, Paul Rutgeerts, Christine Van Broeckhoven, Ammar Al-Chalabi, Sabine Wyns, Hervé Prats, Hardev Pall, Severine Vermeire, Mieke Dewerchin, Populatie Genetica, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, and RS: CARIM School for Cardiovascular Diseases
- Subjects
Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Programmed cell death ,endocrine system ,Ratón ,Transgene ,SOD1 ,Ischemia ,Variation (Genetics) ,Mice, Transgenic ,Endothelial Growth Factors ,Biology ,Mice ,Degenerative disease ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Paralysis ,Amyotrophic lateral sclerosis ,Child ,Alleles ,Aged ,Mice, Knockout ,Motor Neurons ,Sweden ,Lymphokines ,Cell Death ,Spinal Cord Ischemia ,Vascular Endothelial Growth Factors ,Research Support, Non-U.S. Gov't ,Amyotrophic Lateral Sclerosis ,Genetic Variation ,Anatomy ,Middle Aged ,medicine.disease ,Vascular endothelial growth factor A ,Endocrinology ,nervous system ,Haplotypes ,Child, Preschool ,Nerve Degeneration ,Intercellular Signaling Peptides and Proteins ,Female - Abstract
VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death.Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P.The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology and Department of Neurology, University Hospital Gasthuisberg, KU Leuven, Leuven, B-3000, Belgium.Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.
- Published
- 2003
26. Erratum: Corrigendum: Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia
- Author
-
Esther Meyer, Manju A. Kurian, Sanjay Bhate, Jean-Pierre Lin, Agnel Praveen Joseph, Angela Barnicoat, F. Lucy Raymond, Jonathan R. Chubb, Niklas Darin, Shibalik Misra, Lucinda Carr, Joanne Ng, Deborah Morrogh, Julia Rankin, Henry Houlden, Erik-Jan Kamsteeg, Martin Smith, Patricia Limousin, Shane McKee, David Arkadir, Sarah Wiethoff, Hilla Ben-Pazi, Patrick Rump, Wui K. Chong, John M.E. Nichols, Michèl A.A.P. Willemsen, William A. Gahl, Gregory Peters, Detelina Grozeva, S Heales, Camilo Toro, André Reis, Shekeeb S Mohammed, Simon Pope, Deciphering Developmental Disorders Study, Adeline Ngoh, Joost Nicolai, Zvi Israel, Russell C. Dale, Nicholas W. Wood, Serena Barral, Niccolo E. Mencacci, Dagmar Wieczorek, Hardev Pall, Gidon Winter, Vasiliki Nakou, Peter D. Turnpenny, Prab Prabhakar, Kailash P. Bhatia, Alan Pittman, Margje Sinnema, Christopher Wragg, Keren J. Carss, Maya Topf, Amber Boys, Apostolos Papandreou, Hagai Bergman, Reeval Segel, Jane A. Hurst, Susan M. White, Nicholas Gutowski, A. Hills, Margaret Kaminska, Daniel E. Lumsden, Belén Pérez-Dueñas, Nicola Foulds, Kathryn J. Peall, Paul Gissen, Miriam S. Reuter, Magnus Nilsson, and Brian T. Wilson
- Subjects
0301 basic medicine ,Dystonia ,Biology ,medicine.disease ,Bioinformatics ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Histone methyltransferase ,Genetics ,medicine ,Gene ,030217 neurology & neurosurgery ,Early onset - Abstract
Nat. Genet. 49, 223–237 (2017); published online 19 December 2016; corrected after print 20 April 2017 Following publication of this article, the authors were asked to remove a clinical image and some video footage of one of the affected individuals. Although consent was obtained, in keeping with their ethical consent framework, the authors allow for withdrawal of consent and are carrying out the wishes of the research subjects under their consent process.
- Published
- 2017
27. SGCE and myoclonus dystonia: motor characteristics, diagnostic criteria and clinical predictors of genotype
- Author
-
Manju A. Kurian, Mary D. King, Tammy Hedderly, Andrew L Lux, Bryan Lynch, George Kirov, Philip Jardine, Martin Smith, Jean-Pierre Lin, Timothy Lynch, Alan L Whone, Derek J. Blake, Michael Samuel, Huw R. Morris, Kathryn J. Peall, Adrian James Waite, Mark Wardle, Michael John Owen, Cathy White, Patrick F. Chinnery, Thomas T. Warner, Sean O'Riordan, and Hardev Pall
- Subjects
Proband ,Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Microcephaly ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Genotype ,Short stature ,Article ,Cohort Studies ,Young Adult ,SGCE ,Sarcoglycans ,medicine ,Humans ,Age of Onset ,Child ,Aged ,Dystonia ,Genetics ,business.industry ,Middle Aged ,medicine.disease ,United Kingdom ,nervous system diseases ,Phenotype ,Neurology ,Dystonic Disorders ,Child, Preschool ,Female ,Neurology (clinical) ,medicine.symptom ,Age of onset ,business ,Myoclonus ,Ireland ,Dystonic disorder ,Gene Deletion - Abstract
Myoclonus dystonia syndrome (MDS) is a young-onset movement disorder. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. We assembled the largest cohort of MDS patients to date, and determined the frequency and type of SGCE mutations. The aim was to establish the motor phenotype in mutation carriers and utility of current diagnostic criteria. Eighty-nine probands with clinical features compatible with MDS were recruited from the UK and Ireland. Patients were phenotypically classified as “definite”, “probable” or “possible” MDS according to previous guidelines. SGCE was analyzed using direct sequencing and copy number variant analysis. In those where no mutation was found, DYT1 (GAG deletion), GCH1, THAP1 and NKX2.1 genes were also sequenced. Nineteen (21.3 %) probands had an SGCE mutation. Three patterns of motor symptoms emerged: (1) early childhood onset upper body myoclonus and dystonia, (2) early childhood onset lower limb dystonia, progressing later to more pronounced myoclonus and upper body involvement, and (3) later childhood onset upper body myoclonus and dystonia with evident cervical involvement. Five probands had large contiguous gene deletions ranging from 0.7 to 2.3 Mb in size with distinctive clinical features, including short stature, joint laxity and microcephaly. Our data confirms that SGCE mutations are most commonly identified in MDS patients with (1) age at onset ≤10 years and (2) predominant upper body involvement of a pure myoclonus-dystonia. Cases with whole SGCE gene deletions had additional clinical characteristics, which are not always predicted by deletion size or gene involvement.
- Published
- 2014
28. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS
- Author
-
Bradley N. Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon Topp, Kevin P. Kenna, Emma L. Scotter, Jason Kost, Pamela Keagle, Jack W. Miller, Daniela Calini, Caroline Vance, Eric W. Danielson, Claire Troakes, Cinzia Tiloca, Safa Al-Sarraj, Elizabeth A. Lewis, Andrew King, Claudia Colombrita, Viviana Pensato, Barbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor LMA ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Russell L. McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Michael Simpson, Wouter van Rheenen, Frank P. Diekstra, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Karen E. Morrison, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Patrick A. Dion, Claire S. Leblond, Guy A. Rouleau, Orla Hardiman, Jan H. Veldink, Leonard H. van den Berg, Ammar Al-Chalabi, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Alberto García-Redondo, Zheyang Wu, Jonathan D. Glass, Cinzia Gellera, Antonia Ratti, Robert H. Brown, Vincenzo Silani, Christopher E. Shaw, John E. Landers, Sandra D’Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, ANS - Amsterdam Neuroscience, Genome Analysis, and Human Genetics
- Subjects
Neurons ,Genetics ,Mutation ,Sequence analysis ,General Neuroscience ,Neuroscience(all) ,Amyotrophic Lateral Sclerosis ,Brain ,Sequence Analysis, DNA ,Disease ,Biology ,medicine.disease ,medicine.disease_cause ,Article ,Tubulin ,medicine ,Missense mutation ,Humans ,Exome ,Genetic Predisposition to Disease ,Amyotrophic lateral sclerosis ,Gene ,Exome sequencing - Abstract
SummaryExome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.Video Abstract
- Published
- 2014
29. Motor neurone disease
- Author
-
Hardev Pall
- Subjects
medicine.medical_specialty ,Palliative care ,business.industry ,medicine.medical_treatment ,medicine.disease ,Surgery ,Riluzole ,Physical medicine and rehabilitation ,Gait impairment ,Anterior Horn Cell ,Percutaneous endoscopic gastrostomy ,Medicine ,Motor neurone ,Geriatrics and Gerontology ,Amyotrophic lateral sclerosis ,business ,Gerontology ,Motor neurone disease ,medicine.drug - Published
- 1995
30. Motor Neurone Disease
- Author
-
Hardev Pall
- Subjects
business.industry ,Medicine ,business ,medicine.disease ,Neuroscience ,Motor neurone disease - Published
- 2012
31. Reaching the ‘hard to reach’: strategies to recruit black and minority ethnic service users with rare long-term neurological conditions
- Author
-
Hardev Pall, Peter Bradburn, Melanie Calvert, Qulsom Fazil, Paramjit Gill, Sonal Shah, Catherine Sackley, Mel Stewart, and Thomas J Hoppitt
- Subjects
medicine.medical_specialty ,Family medicine ,Health services research ,medicine ,Ethnic group ,General Social Sciences ,Social care ,Service user ,Recruitment methods ,Psychology ,Social psychology - Abstract
Little is known about health and social care experiences of patients with rare long-term neurological conditions. Furthermore, black and minority ethnic (BME) service users are often perceived to be under-represented in health services research. BME service users have been described as ‘hard to reach’ in the past. However, evidence suggests that a variety of recruitment methods need to be used in order to increase recruitment. We employed a range of recruitment strategies shown to be effective in recruiting BME patients, to recruit patients to participate in one-to-one interviews to establish experiences of health and social care. Strategies included community and clinically based strategies. In total we recruited 15 participants through these recruitment methods, with all recruits ultimately coming from neurology clinics and disease-specific charities. Despite community-based strategies generating interest and a willingness to be involved, the rare nature of these conditions resulted in a lack of recruit...
- Published
- 2011
32. Duration of Parkinson disease is associated with an increased propensity for 'reinvestment'
- Author
-
Richard S. W. Masters, Kenneth Macmahon, Frank F. Eves, and Hardev Pall
- Subjects
Adult ,Male ,Volition ,medicine.medical_specialty ,Psychometrics ,medicine.medical_treatment ,050109 social psychology ,Sample (statistics) ,Disease ,050105 experimental psychology ,Developmental psychology ,Physical medicine and rehabilitation ,medicine ,Humans ,0501 psychology and cognitive sciences ,Duration (project management) ,Motor skill ,Aged ,Aged, 80 and over ,Rehabilitation ,Mini–Mental State Examination ,medicine.diagnostic_test ,05 social sciences ,Parkinson Disease ,General Medicine ,Middle Aged ,Motor Skills ,Scale (social sciences) ,Female ,Age of onset ,Psychology - Abstract
Background. As a consequence of difficulties in movement initiation and execution, people with Parkinson’s disease (PD) are typically encouraged to consciously monitor and control the mechanics of their actions. This is described as ‘reinvestment’ and has been shown to help mediate effective motor output. Paradoxically, in situations where people with PD are particularly motivated to move effectively, reinvestment may exacerbate existing movement deficits. Objective. To examine the propensity for reinvestment in a sample of people with PD. Methods. A volunteer sample of 55 people with PD was asked to complete a previously validated measure, the Reinvestment Scale. A sub-sample (and age matched controls) was asked to complete a recently developed, movement specific, version of the Scale. Data was collected on Mini Mental State Examination and the Hoehn & Yahr Scale. Participant demographics, including age of onset and duration of disease, were also collated. Results. Multiple regression analyses showed that duration of disease was associated with reinvestment score on both the Reinvestment Scale and the Movement Specific Reinvestment Scale. Conclusions. Participants appeared to become more aware of the mechanics of their actions over time. Possible explanations for this finding are discussed with reference to rehabilitation.
- Published
- 2007
33. ARE PSYCHIATRIC SYMPTOMS A CORE PHENOTYPE OF MYOCLONUS DYSTONIA SYNDROME CAUSED BY SGCE MUTATIONS?
- Author
-
J-P Lin, Manju A. Kurian, Kathryn J. Peall, T. Lynch, Patrick F. Chinnery, Andrew L Lux, Cathy White, Bryan Lynch, N. Bajaj, Thomas T. Warner, Michael Samuel, Michael John Owen, Mike L. Smith, Sean O'Riordan, Mark Wardle, Adrian James Waite, Alan L Whone, M King, Huw R. Morris, Hardev Pall, Deborah L. Smith, Derek J. Blake, George Kirov, Tammy Hedderly, and Philip Jardine
- Subjects
Dystonia ,medicine.medical_specialty ,business.industry ,medicine.disease ,Personality disorders ,Phenotype ,Psychiatry and Mental health ,SGCE ,Cohort ,medicine ,Child and adolescent psychiatry ,Surgery ,Neurology (clinical) ,medicine.symptom ,Psychiatry ,business ,Myoclonus ,Mini-international neuropsychiatric interview - Abstract
Objective Myoclonus Dystonia Syndrome (MDS) is a childhood onset, alcohol responsive movement disorder caused by mutations in the SGCE gene in a proportion of cases. Single family and case series have suggested co-morbid psychiatric disease but have not compared cases to a control group. Aims To establish a cohort of MDS patients with SGCE mutations and a control group of alcohol-responsive tremor patients, and to systematically assess for psychiatric symptoms using standardised questionnaires. Method We collected 27 patients with SGCE mutations and 45 tremor control cases. The MINI International Neuropsychiatric Interview, PHQ-9, MADRS, YBOCS and AUDIT were used to assess psychiatric disease according to DSM-IV criteria. Results There was a higher rate of psychiatric disease in MDS patients compared to controls (p Conclusion Overall psychiatric disease is elevated amongst the MDS cohort compared to a control group with a chronic, socially stigmatizing disorder. OCD appears to be the greatest contributor to this effect and may reflect a pleiotropic function for the SGCE gene.
- Published
- 2013
34. The Use Of Non-invasive Ventilation During Percutaneous Endoscopic Gastrostomy Insertion In Patients With Impaired Respiratory Ventilation
- Author
-
Fitton, Frances, primary, Wood, Gordon J., additional, Weeraman, Sachini, additional, Evans, Ellen, additional, Edwards, Gill, additional, Edwards, louise, additional, mountford, marie, additional, Allen, Martin, additional, Leslie, Fiona, additional, Hardev, Pall, additional, Morrison, Karen, additional, and Mustfa, Naveed, additional
- Published
- 2010
- Full Text
- View/download PDF
35. P.08 Low dose L-dopa induced dystonic dyskinesia in Parkinson's disease patients with deep brain stimulation
- Author
-
B Wright, Rosalind Mitchell, Jamilla Kausar, Hardev Pall, and A Tanaris
- Subjects
Parkinson's disease ,Deep brain stimulation ,business.industry ,medicine.medical_treatment ,Low dose ,medicine.disease ,Dopamine agonist ,nervous system diseases ,Psychiatry and Mental health ,Dyskinesia ,Anesthesia ,High doses ,Medicine ,Surgery ,In patient ,Neurology (clinical) ,medicine.symptom ,business ,Complication ,medicine.drug - Abstract
L-dopa given to Parkinson9s disease (PD) patients for prolonged periods or at sustained high doses is known to produce disabling choreiform and dystonic dyskinesias. The production of dystonic dyskinesias at small doses in patients with deep brain stimulation surgery (DBS) has been poorly reported. We present a case series of 13 patients who tolerated high doses of l-dopa prior to DBS, who subsequently developed severe disabling dystonic dyskinesias on minimal doses of l-dopa after surgery. Of the 13 patients (7 male, 6 female), mean age was 54 (range 46–63), and mean disease duration was 10 years (range 6–17). 11 patients had presented with tremor as their first motor symptom of PD, and 10 had developed dyskinesias prior to surgery. At time of DBS the mean calculated L-dopa equivalent dose was 1073 mg (range 480–1566.7 mg) of which the mean l-dopa dose was 581 mg (range 300–1350 mg). The mean time from DBS to develop dystonic dyskinesias was 3 years (range 0.3–5 years), at which time the mean l-dopa equivalent dose was 366 mg (range 50–660 mg) and the mean l-dopa dose was 196 mg (range 50–600). Replacing l-dopa with a dopamine agonist either removed or largely relieved this motor complication. This case series highlights an important motor complication in the DBS PD patient and suggests one method to ameliorate it. It also raises important questions about the mechanism for reduction of dyskinesia threshold following DBS.
- Published
- 2011
36. P.07 The role of amantadine in motor complications after deep brain stimulation for Parkinson's disease
- Author
-
R A Bosnell, D Siddique, Rosalind Mitchell, A P Mocroft, Hardev Pall, and Jamilla Kausar
- Subjects
Deep brain stimulation ,Parkinson's disease ,business.industry ,medicine.medical_treatment ,Dopaminergic ,Amantadine ,Disease ,medicine.disease ,nervous system diseases ,Psychiatry and Mental health ,Glutamatergic ,surgical procedures, operative ,Dyskinesia ,Anesthesia ,Total dose ,medicine ,Surgery ,Neurology (clinical) ,medicine.symptom ,business ,medicine.drug - Abstract
Subthalamic deep brain stimulation (STN DBS) for Parkinson9s disease typically enables a 50% reduction in dopaminergic medication postoperatively. This reduction in medication is accompanied by a 60% reduction in dyskinesia and a reduction in off periods. However, there remains a subgroup of patients who have disabling dyskinesias despite optimisation of drug and stimulator setting. Amantadine is sometimes used for the medical management of drug-induced dyskinesias in Parkinson9s disease. Its use in dyskinesias after DBS has not been formally assessed. We report a series of 8 cases who had bilateral STN DBS. These patients had similar characteristics to our local database of patients who have had DBS. However, these patients had disabling bradykinesia and/or dyskinesias despite attempts at optimisation of stimulator settings and dopaminergic medication. The addition of amantadine led to clear improvements in dsykinesias and/or mobility, without the need to increase the total dose of dopaminergic medication. Stopping amantadine caused worsening of symptoms. This case series suggests amantadine is an important additional medication in the small group of patients whose disease has not been stabilised after DBS. The outflow of the STN includes a glutamatergic pathway. The glutamate receptor blocking properties of amantadine provide a possible mechanism for the observed benefit. We plan to extend the results of this case series to include objective scoring in subsequent patients.
- Published
- 2011
37. PO.08 Colorectal cancer risk in Parkinson's disease: insights from a surgically treated cohort
- Author
-
G Pall, Rosalind Mitchell, Jamilla Kausar, P Mocroft, and Hardev Pall
- Subjects
Oncology ,medicine.medical_specialty ,education.field_of_study ,Lung ,Parkinson's disease ,Colorectal cancer ,business.industry ,Population ,Cancer ,Disease ,medicine.disease ,Psychiatry and Mental health ,medicine.anatomical_structure ,Internal medicine ,Histological diagnosis ,Cohort ,medicine ,Surgery ,Neurology (clinical) ,business ,education - Abstract
Background A number of epidemiologic studies show a decreased risk of non-melanoma cancer in Parkinson9s disease (PD). Cigarette smoking is less prevalent in PD and hence the risk of smoking related neoplasia such as lung and colon would be expected to be decreased in PD. A link is shown between decreased physical activity and colorectal cancer. Increased dietary intake of iron increases colorectal cancer risk and iron deposition in the basal ganglia is a feature of PD. Thus common mechanisms may be involved in both disorders. Our study looks at a cohort of surgically treated PD patients to see if there is an altered risk of colorectal cancer among them. Method In our population of patients fitted with a deep brain stimulator between 2002 and 2010, we searched for causes of death confirmed against death certificates and a histological diagnosis of colorectal cancer in the patient records. Results Of 22 patients who had died, 3 had a diagnosis colorectal cancer. 1 more died of a carcinoembryonic antigen positive cancer of unknown origin. Discussion From UK national statistics, colorectal cancer accounts for between 2.7 and 3.2% of all deaths. Although the small number of deaths in our cohort requires careful interpretation of the results, 14% of our cohort having a diagnosis of colorectal cancer suggests that the lifetime risk of colorectal cancer is not reduced in PD patients. This observation merits further investigation in a larger cohort of PD patients.
- Published
- 2011
38. Huntington's disease
- Author
-
H Rickards, Hardev Pall, Melanie Calvert, Catherine Sackley, Thomas J Hoppitt, and Clinical Neuropsychology
- Subjects
medicine.medical_specialty ,Microglia ,business.industry ,Incidence ,Neurodegeneration ,Excitotoxicity ,General Medicine ,Disease ,medicine.disease ,medicine.disease_cause ,United Kingdom ,Pathogenesis ,Huntington Disease ,medicine.anatomical_structure ,Huntington's disease ,Internal medicine ,Prevalence ,Huntingtin Protein ,medicine ,Humans ,NFKB Activation Pathway ,business ,Neuroscience ,Neuroinflammation - Abstract
Multiple lines of evidence have implicated neuroinflammation as both a cause and an effect of neurodegeneration in Huntington’s disease (HD). Studies of post mortem human HD brains and HD mouse models have demonstrated that the huntingtin protein (mHTT) has neurotoxic effects due to cell-autonomous defects in neurons and through cell-cell interactions with dysfunctional astrocytes and microglia in the brain. Neurodegeneration has been linked to excitotoxicity caused by ion and neurotransmitter concentrations in the brain, supported by evidence that extracellular levels of these molecules are modulated by astrocyte-specific mechanisms which are impaired in HD. mHTT causes monocytes and microglia to be hyper-reactive in HD patients and mouse models, contributing to neurodegeneration. Key pro-inflammatory players NFkB, IL-6, and TNF-α are implicated with disease progression, and several lines of evidence suggest that these molecules are associated with more severe neurodegeneration. Dysregulation of the NFkB activation pathway in particular is seen in HD neurons, astrocytes, microglia, and monocytes and thus may be a major component of the cellular response to mHTT with therapeutic potential. Collectively, the immune response and neuroinflammation are seen as key aspects of pathogenesis in HD, and multiple lines of evidence suggest that the neuroimmune response is both a cause and effect of neurodegeneration.
- Published
- 2010
39. N-methylation of pyridines in Parkinson's disease
- Author
-
S. Sturman, Rosemary H. Waring, Hardev Pall, Steve Buttrum, Glyn B. Steventon, Helen Molloy, Adrian Williams, and Sandra Green
- Subjects
Niacinamide ,Parkinson's disease ,business.industry ,Parkinson Disease ,General Medicine ,N methylation ,Middle Aged ,Bioinformatics ,medicine.disease ,Methylation ,Text mining ,medicine ,Humans ,business - Published
- 1991
40. Subacute polyradiculopathy with optic and auditory nerve involvement
- Author
-
Adrian Williams and Hardev Pall
- Subjects
Adult ,Male ,medicine.medical_specialty ,Hearing loss ,Eye disease ,Central nervous system ,Audiology ,Arts and Humanities (miscellaneous) ,Influenza, Human ,Optic Nerve Diseases ,medicine ,Vestibulocochlear Nerve Diseases ,Humans ,Blindness ,Guillain-Barre syndrome ,business.industry ,Peripheral Nervous System Diseases ,Polyradiculopathy ,medicine.disease ,Optic Atrophy ,medicine.anatomical_structure ,Optic nerve ,Neurology (clinical) ,medicine.symptom ,business ,Spinal Nerve Roots ,Neuroscience - Abstract
• Two patients are described, who, after an otherwise trivial viral upset, presented with an acute syndrome consisting of polyradioculopathy affecting all four limbs, with additional severe optic and auditory nerve involvement and other central nervous system signs. A combination of some of the features of the Guillain-Barre syndrome and a simultaneous acute episode of demyelination in the central nervous system were seen in these patients.
- Published
- 1987
41. Raised cerebrospinal-fluid copper concentration in Parkinson's disease
- Author
-
John M.C. Gutteridge, A.C. Williams, Andrew J. Taylor, Michael B. Hall, D R Blake, Hardev Pall, and Joseph Lunec
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Manganese ,Parkinson's disease ,business.industry ,Iron ,Spectrophotometry, Atomic ,chemistry.chemical_element ,Parkinson Disease ,General Medicine ,Middle Aged ,medicine.disease ,Copper ,Severity of Illness Index ,Cerebrospinal fluid ,Degenerative disease ,chemistry ,Medicine ,Humans ,Female ,business ,Phenanthrolines - Abstract
The cerebrospinal-fluid copper concentration, measured by electrothermal atomisation/atomic absorption spectrophotometry, was significantly higher in 24 patients with untreated, idiopathic Parkinson's disease than in a control population of 34 patients (p less than 0.001). The difference in the in-vitro capacity of copper to damage DNA, measured by the phenanthroline assay was even greater. The high phenanthroline-copper concentration correlated with disease severity (p = 0.02) and with the rate of progression of disease (p less than 0.05). A possible role is suggested for copper-catalysed oxidative mechanisms in the pathogenesis of Parkinson's disease.
- Published
- 1987
42. Deterioration of Wilson's Disease Following the Start of Penicillamine Therapy
- Author
-
A. C. Williams, Hardev Pall, and D. R. Blake
- Subjects
medicine.medical_specialty ,Chemistry ,Penicillamine ,chemistry.chemical_element ,Pharmacology ,medicine.disease ,Nervous System ,Copper ,Surgery ,Wilson's disease ,Zinc ,Cerebrospinal fluid ,Hepatolenticular Degeneration ,Arts and Humanities (miscellaneous) ,Toxicity ,medicine ,Humans ,Neurologic deterioration ,Chelation ,Neurology (clinical) ,Chelation therapy ,medicine.drug - Abstract
To the Editor. —Brewer and coworkers 1 suggest that the phenomenon of neurologic deterioration seen in some patients with Wilson's disease after starting penicillamine therapy may result from the redistribution of copper. Curzon 2 has previously suggested this mechanism, and Blake and coworkers 3 and Pall and coworkers 4 have shown that increases in copper in the cerebrospinal fluid occur during chelation therapy with desferrioxamine, relating this to the neurologic and the ophthalmic toxicity of the drug. The copper chelating agent, diethyl dithiocarbamate, has been shown to increase the copper content of neural tissue (spinal cord) in experimental animals. 5 Other compounds that are capable of ligating with metal ions, such as the phenothiazines, 6 can cause alterations of neural copper content, 7 and can result in permanent neurologic deficit. 8 The postulate of abnormalities of metal distribution being caused by metal chelating agents is not restricted to copper. British
- Published
- 1989
43. ALLOPURINOL/N-ACETYLCYSTEINE FOR CARBON MONOXIDE POISONING
- Author
-
D R Blake, IanD. Green, RobertJ.M.W. Howard, A.C. Williams, and Hardev Pall
- Subjects
Acetylcysteine ,business.industry ,Carbon monoxide poisoning ,medicine ,Allopurinol ,General Medicine ,Pharmacology ,business ,medicine.disease ,medicine.drug - Published
- 1987
44. Restless legs syndrome
- Author
-
A. C. Williams, A. Fonseca, D. R. Blake, and Hardev Pall
- Subjects
03 medical and health sciences ,medicine.medical_specialty ,0302 clinical medicine ,Physical medicine and rehabilitation ,business.industry ,medicine ,030212 general & internal medicine ,Neurology (clinical) ,Restless legs syndrome ,medicine.disease ,business ,030217 neurology & neurosurgery - Published
- 1987
45. Does stimulus predict the best candidates for deep brain stimulation for PD?
- Author
-
Keith Wheatley, Hardev Pall, Smitaa Patel, Francis Dowling, Jane P Daniels, Steven S. Gill, Crispin Jenkinson, Natalie Ives, A.C. Williams, Rosalind Mitchell, Caroline Rick, Niall Quinn, Carl E Clarke, and Trk Varma
- Subjects
medicine.medical_specialty ,Deep brain stimulation ,business.industry ,medicine.medical_treatment ,Medicine (miscellaneous) ,Stimulus (physiology) ,Bioinformatics ,nervous system diseases ,Physical medicine and rehabilitation ,Poster Presentation ,Medicine ,Pharmacology (medical) ,business ,Medical therapy - Abstract
Background Deep Brain Stimulation (DBS) is used for people with Parkinson’s disease (PwPD) who are experiencing motor complications that are not controlled by medication. To date, PD SURG is the largest trial to compare DBS to best medical therapy in PwPD. Outcomes to DBS for PwPD are varied and there is an ongoing question as whether patient selection can be improved. To date, subgroup analyses have not been powered to provide an answer. An algorithm (STIMULUS) was designed to try to identify suitable candidates for DBS for PD symptoms based on the clinical opinion of an expert panel. The PD SURG data set provides an opportunity to test the ability of STIMULUS to predict suitable candidates.
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.