Search

Your search keyword '"McCluskey, L"' showing total 230 results
Start Over Author "McCluskey, L"
230 results on '"McCluskey, L"'

3. Multiple pathologies in a patient with a progressive neurodegenerative syndrome

Author

Liang, T-W, Forman, M.S., Duda, J.E., McCluskey, L., Trojanowski, J.Q., and Siderowf, A.

Subjects
Parkinson's disease -- Diagnosis, Amyotrophic lateral sclerosis -- Diagnosis, Brain -- Abnormalities, Brain -- Research, Nervous system -- Degeneration, Nervous system -- Diagnosis, Nervous system -- Physiological aspects, Nervous system -- Research, Nervous system -- Complications and side effects, Histology, Pathological, Medical research, Medicine, Experimental, Health, Psychology and mental health
Published
2005

6. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Author

Cirulli, Et, Lasseigne, Bn, Petrovski, S, Sapp, Pc, Dion, Pa, Leblond, Cs, Couthouis, J, Yf, Lu, Wang, Q, Krueger, Bj, Ren, Z, Keebler, J, Han, Y, Levy, Se, Boone, Be, Wimbish, Jr, Waite, Ll, Jones, Al, Carulli, Jp, Day Williams, Ag, Staropoli, Jf, Xin, Ww, Chesi, A, Raphael, Ar, McKenna Yasek, D, Cady, J, Vianney de Jong, Jm, Kenna, Kp, Smith, Bn, Topp, S, Miller, J, Gkazi, A, Al Chalabi, A, van den Berg, Lh, Veldink, J, Silani, V, Ticozzi, N, Shaw, Ce, Baloh, Rh, Appel, S, Simpson, E, Lagier Tourenne, C, Pulst, Sm, Gibson, S, Trojanowski, Jq, Elman, L, Mccluskey, L, Grossman, M, Shneider, Na, Chung, Wk, Ravits, Jm, Glass, Jd, Sims, Kb, Van Deerlin, Vm, Maniatis, T, Hayes, Sd, Ordureau, A, Swarup, S, Landers, J, Baas, F, Allen, As, Bedlack, Rs, Harper, Jw, Gitler, Ad, Rouleau, Ga, Brown, R, Harms, Mb, Cooper, Gm, Harris, T, Myers, Rm, Goldstein, Db, Soraru', Gianni, Sequencing Consortium, Fals, Other departments, ANS - Amsterdam Neuroscience, Genome Analysis, and Human Genetics

Subjects
Adult, Male, Risk, Adolescent, Sequence analysis, Cell Cycle Proteins, Protein Serine-Threonine Kinases, Biology, Bioinformatics, Young Adult, TANK-binding kinase 1, Transcription Factor TFIIIA, Sequestosome-1 Protein, Autophagy, medicine, Humans, Exome, Genetic Predisposition to Disease, Amyotrophic lateral sclerosis, Gene, Genetic Association Studies, Exome sequencing, Adaptor Proteins, Signal Transducing, Aged, Optineurin, Aged, 80 and over, Genetics, Multidisciplinary, Amyotrophic Lateral Sclerosis, Membrane Transport Proteins, Sequence Analysis, DNA, Middle Aged, medicine.disease, Genes, Female, Protein Binding
Abstract

New players in Lou Gehrig's disease Amyotrophic lateral sclerosis (ALS), often referred to as “Lou Gehrig's disease,” is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Cirulli et al. sequenced the expressed genes of nearly 3000 ALS patients and compared them with those of more than 6000 controls (see the Perspective by Singleton and Traynor). They identified several proteins that were linked to disease in patients. One such protein, TBK1, is implicated in innate immunity and autophagy and may represent a therapeutic target. Science , this issue p. 1436 ; see also p. 1422

Published
2015

7. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Author

McLaughlin, RL, Schijven, D, Van Rheenen, W, Van Eijk, KR, O'Brien, M, Kahn, RS, Ophoff, RA, Goris, A, Bradley, DG, Al-Chalabi, A, Van Den Berg, LH, Luykx, JJ, Hardiman, O, Veldink, JH, Shatunov, A, Dekker, AM, Diekstra, FP, Pulit, SL, Van Der Spek, RAA, Van Doormaal, PTC, Sproviero, W, Jones, AR, Nicholson, GA, Rowe, DB, Pamphlett, R, Kiernan, MC, Bauer, D, Kahlke, T, Williams, K, Eftimov, F, Fogh, I, Ticozzi, N, Lin, K, Millecamps, S, Salachas, F, Meininger, V, Carvalho, MD, Pinto, S, Mora, JS, Rojas-Garcyá, R, Polak, M, Chandran, S, Colville, S, Swingler, R, Morrison, KE, Shaw, PJ, Hardy, J, Orrell, RW, Pittman, A, Sidle, K, Fratta, P, Malaspina, A, Petri, S, Abdulla, S, Drepper, C, Sendtner, M, Meyer, T, Wiedau-Pazos, M, Lomen-Hoerth, C, Deerlin, VMV, Trojanowski, JQ, Elman, L, McCluskey, L, Basak, N, Meitinger, T, Lichtner, P, Blagojevic-Radivojkov, M, Andres, CR, Maurel, C, Bensimon, G, Landwehrmeyer, B, Brice, A, Payan, CAM, Saker-Delye, S, Durr, A, Wood, N, Tittmann, L, Lieb, W, Franke, A, Rietschel, M, Cichon, S, Nothen, MM, Amouyel, P, Tzourio, C, Dartigues, JF, Uitterlinden, AG, Rivadeneira, F, Estrada, K, Hofman, A, Curtis, C, Derkooi, AJV, De Visser, M, Weber, M, Shaw, CE, Smith, BN, Pansarasa, O, Cereda, C, Bo, RD, Comi, GP, and D'Alfonso, S

Subjects
Multifactorial Inheritance, Amyotrophic Lateral Sclerosis, European Continental Ancestry Group, Comorbidity, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Cohort Studies, Case-Control Studies, mental disorders, Linear Models, Odds Ratio, Schizophrenia, Humans, Genetic Predisposition to Disease, Family, Genome-Wide Association Study
Abstract

© 2017 The Author(s). We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Published
2017

10. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Author

Gendron, T.F. (Tania F.), Chew, J. (Jeannie), Stankowski, J.N. (Jeannette N.), Hayes, L.R. (Lindsey R.), Zhang, Y.-J. (Yong-Jie), Prudencio, M. (Mercedes), Carlomagno, Y. (Yari), Daughrity, L.M. (Lillian M.), Jansen-West, K. (Karen), Perkerson, E.A. (Emilie A.), O'Raw, A. (Aliesha), Cook, C. (Casey), Pregent, L. (Luc), Belzil, V. (Veronique), Van Blitterswijk, M. (Marka), Tabassian, L.J. (Lilia J.), Lee, C.W. (Chris W.), Yue, M. (Mei), Tong, J. (Jimei), Song, Y. (Yuping), Castanedes-Casey, M. (Monica), Rousseau, L. (Linda), Phillips, V. (Virginia), Dickson, D. (Dennis), Rademakers, S. (Suzanne), Fryer, J.D. (John D.), Rush, B.K. (Beth K.), Pedraza, O. (Otto), Caputo, A.M. (Ana M.), Desaro, P. (Pamela), Palmucci, C. (Carla), Robertson, A. (Amelia), Heckman, M.G. (Michael G.), Diehl, N.N. (Nancy N.), Wiggs, E. (Edythe), Tierney, M. (Michael), Braun, L. (Laura), Farren, J. (Jennifer), Lacomis, D. (David), Ladha, S. (Shafeeq), Fournier, C.N. (Christina N.), McCluskey, L. (Leo), Elman, L. (Lauren), Toledo, J.B. (Jon B.), McBride, J.D. (Jennifer D.), Tiloca, C. (Cinzia), Morelli, C. (Claudia), Poletti, B. (Barbara), Solca, F. (Federica), Prelle, A. (Alessandro), Wuu, J. (Joanne), Jockel-Balsarotti, J. (Jennifer), Rigo, F. (Frank), Ambrose, C. (Christine), Datta, A. (Abhishek), Yang, W. (Weixing), Raitcheva, D. (Denitza), Antognetti, G. (Giovanna), McCampbell, A. (Alexander), Swieten, J.C. (John) van, Miller, B.L. (Bruce Lars), Boxer, A.L. (Adam), Brown, R.H. (Robert H.), Bowser, R. (Robert), Miller, T.M. (Timothy M.), Trojanowski, J.Q. (John), Grossman, M. (Murray), Berry, J.D. (James D.), Hu, W.T. (William), Ratti, A. (Antonia), Traynor, B. (Bryan), Disney, M. (Matthew), Benatar, M. (Michael), Silani, V. (Vincenzo), Glass, J.D. (Jonathan D.), Floeter, M.K. (Mary Kay), Rothstein, J. (Jeffrey), Boylan, K.B. (Kevin B.), Petrucelli, L. (Leonard), Gendron, T.F. (Tania F.), Chew, J. (Jeannie), Stankowski, J.N. (Jeannette N.), Hayes, L.R. (Lindsey R.), Zhang, Y.-J. (Yong-Jie), Prudencio, M. (Mercedes), Carlomagno, Y. (Yari), Daughrity, L.M. (Lillian M.), Jansen-West, K. (Karen), Perkerson, E.A. (Emilie A.), O'Raw, A. (Aliesha), Cook, C. (Casey), Pregent, L. (Luc), Belzil, V. (Veronique), Van Blitterswijk, M. (Marka), Tabassian, L.J. (Lilia J.), Lee, C.W. (Chris W.), Yue, M. (Mei), Tong, J. (Jimei), Song, Y. (Yuping), Castanedes-Casey, M. (Monica), Rousseau, L. (Linda), Phillips, V. (Virginia), Dickson, D. (Dennis), Rademakers, S. (Suzanne), Fryer, J.D. (John D.), Rush, B.K. (Beth K.), Pedraza, O. (Otto), Caputo, A.M. (Ana M.), Desaro, P. (Pamela), Palmucci, C. (Carla), Robertson, A. (Amelia), Heckman, M.G. (Michael G.), Diehl, N.N. (Nancy N.), Wiggs, E. (Edythe), Tierney, M. (Michael), Braun, L. (Laura), Farren, J. (Jennifer), Lacomis, D. (David), Ladha, S. (Shafeeq), Fournier, C.N. (Christina N.), McCluskey, L. (Leo), Elman, L. (Lauren), Toledo, J.B. (Jon B.), McBride, J.D. (Jennifer D.), Tiloca, C. (Cinzia), Morelli, C. (Claudia), Poletti, B. (Barbara), Solca, F. (Federica), Prelle, A. (Alessandro), Wuu, J. (Joanne), Jockel-Balsarotti, J. (Jennifer), Rigo, F. (Frank), Ambrose, C. (Christine), Datta, A. (Abhishek), Yang, W. (Weixing), Raitcheva, D. (Denitza), Antognetti, G. (Giovanna), McCampbell, A. (Alexander), Swieten, J.C. (John) van, Miller, B.L. (Bruce Lars), Boxer, A.L. (Adam), Brown, R.H. (Robert H.), Bowser, R. (Robert), Miller, T.M. (Timothy M.), Trojanowski, J.Q. (John), Grossman, M. (Murray), Berry, J.D. (James D.), Hu, W.T. (William), Ratti, A. (Antonia), Traynor, B. (Bryan), Disney, M. (Matthew), Benatar, M. (Michael), Silani, V. (Vincenzo), Glass, J.D. (Jonathan D.), Floeter, M.K. (Mary Kay), Rothstein, J. (Jeffrey), Boylan, K.B. (Kevin B.), and Petrucelli, L. (Leonard)

Abstract

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention. 2017

Published
2017
Full Text
View/download PDF

11. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Author

Majounie, E1, Renton, Ae, Mok, K, Dopper, Eg, Waite, A, Rollinson, S, Chiò, A, Restagno, G, Nicolaou, N, Simon-Sanchez, J, van Swieten JC, Abramzon, Y, Johnson, Jo, Sendtner, M, Pamphlett, R, Orrell, Rw, Mead, S, Sidle, Kc, Houlden, H, Rohrer, Jd, Morrison, Ke, Pall, H, Talbot, K, Ansorge, O, Hernandez, Dg, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Floris, Gl, Remes, Am, Laaksovirta, H, Mccluskey, L, Trojanowski, Jq, Van Deerlin VM, Schellenberg, Gd, Nalls, Ma, Drory, Ve, Lu, Cs, Yeh, Th, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, Pj, Heutink, P, Morris, Hr, Pickering-Brown, S, Traynor, Bj, Adamson, G, Bayer, Aj, Beck, J, Callister, Jb, Blake, Dj, Blumen, Sc, Collinge, J, Dunckley, T, Ealing, J, East, S, Elman, L, Gerhard, A, Guerreiro, Rj, Gwinn, K, Halliwell, N, Hamdalla, Hh, Hewitt, C, Ince, P, Jablonka, S, James, C, Kent, L, Knock, Jc, Lynch, T, Mahoney, C, Mann, D, Neal, J, Norris, D, O'Dowd, S, Richardson, A, Rossor, M, Rothstein, J, Scholz, Sw, Snowden, J, Stephan, Da, Toulson, G, Turner, Mr, Warren, Jd, Young, K, Weng, Yh, Kuo, Hc, Lai, Sc, Huang, Cl, Camuzat, A, Entraingues, L, Guillot-Noël, Verpillat, P, Blanc, F, Camu, W, Clerget-Darpoux, F, Corcia, P, Couratier, P, Didic, M, Dubois, B, Duyckaerts, C, Guedj, E, Golfier, V, Habert, Mo, Hannequin, D, Lacomblez, L, Meininger, V, Salachas, F, Levy, R, Michel, Bf, Pasquier, F, Puel, M, Thomas-Anterion, C, Sellal, F, Vercelletto, M, Moglia, C, Cammarosano, S, Canosa, A, Gallo, S, Brunetti, M, Ossola, I, Marinou, K, Papetti, L, Pisano, F, Pinter, Gl, Conte, A, Luigetti, M, Zollino, M, Lattante, S, Marangi, G, la Bella, V, Spataro, R, Colletti, T, Battistini, S, Ricci, C, Caponnetto, C, Mancardi, G, Mandich, P, Salvi, F, Bartolomei, I, Mandrioli, J, Sola, P, Lunetta, C, Penco, S, Monsurrò, Mr, Tedeschi, G, Conforti, Fl, Gambardella, A, Quattrone, A, Volanti, P, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, Mg, Murru, Mr, Pugliatti, M, Parish, Ld, Sotgiu, A, Solinas, G, Ulgheri, L, Ticca, A, Simone, I, Logroscino, G., Neurology, Erasmus MC other, The Chromosome 9-ALS/FTD Consortium, Human genetics, NCA - Neurodegeneration, Università degli studi di Torino (UNITO), Department of Clinical Genetics, Institute for Clinical Neurobiology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), MRC Prion Unit, UCL Institute of neurology, UCL Institute of Neurology, UCL Institute of Neurology, Queen Square, London, Department of Neuroscience, Catholic University, Roma, Fondazione Maugeri, Department of Neuroscience, University of Siena, Siena, Department of Neurology, Chang Gung Memorial Hospital [Taipei] (CGMH), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Università degli studi di Torino = University of Turin (UNITO), Julius-Maximilians-Universität Würzburg (JMU), UCL Institute of Neurology, Queen Square [London], Università degli Studi di Siena = University of Siena (UNISI), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
MESH: Signal Transduction, Male, MESH: Vesicular Transport Proteins, MESH: Membrane Glycoproteins, MESH: DNA Repeat Expansion, MESH: Genotype, Cohort Studies, MESH: Protein Structure, Tertiary, MESH: Aged, 80 and over, MESH: Interferon Regulatory Factor-3, 0302 clinical medicine, C9orf72, MESH: Child, MESH: RNA, Small Interfering, 80 and over, genetics, Age of Onset, Child, MESH: Cohort Studies, MESH: Amyotrophic Lateral Sclerosis, MESH: Aged, Genetics, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, DNA Repeat Expansion, MESH: Toll-Like Receptor 4, Middle Aged, Penetrance, 3. Good health, Settore MED/26 - NEUROLOGIA, Neurology, MESH: Young Adult, MESH: HEK293 Cells, Child, Preschool, Frontotemporal Dementia, Female, Sample collection, Chromosomes, Human, Pair 9, MESH: Myeloid Differentiation Factor 88, Frontotemporal dementia, Human, Pair 9, Adult, MESH: Protein Transport, medicine.medical_specialty, Adolescent, Genotype, MESH: Age of Onset, MESH: RNA Interference, Clinical Neurology, MESH: Frontotemporal Dementia, MESH: Genetic Loci, TARDBP, Chromosomes, 03 medical and health sciences, Open Reading Frames, Young Adult, MESH: Cross-Sectional Studies, Internal medicine, medicine, MESH: Chemokine CCL5, Humans, ddc:610, Preschool, MESH: Adaptor Proteins, Signal Transducing, 030304 developmental biology, Aged, MESH: Adolescent, MESH: Humans, business.industry, MESH: Transfection, MESH: Child, Preschool, Haplotype, Amyotrophic Lateral Sclerosis, MESH: Adult, MESH: Adaptor Proteins, Vesicular Transport, MESH: Open Reading Frames, medicine.disease, MESH: Male, MESH: Cell Line, C9orf72 Protein, Cross-Sectional Studies, MESH: Endosomes, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), MESH: Lipopolysaccharides, MESH: Chromosomes, Human, Pair 9, business, Trinucleotide repeat expansion, MESH: Female, Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, genetics, Child, Child, Preschool, Chromosomes, genetics, Cohort Studies, Cross-Sectional Studies, DNA Repeat Expansion, genetics, Female, Frontotemporal Dementia, genetics, Genetic Loci, Genotype, Humans, Male, Middle Aged, Open Reading Frames, genetics, Young Adult, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7*0%) of 3377 white individuals from the USA, Europe, and Australia, two (4*1%) of 49 black individuals from the USA, and six (8*3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39*3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6*0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24*8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. INTERPRETATION: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Published
2012
Full Text
View/download PDF

12. Survival profiles of patients with frontotemporal dementia and motor neuron disease

Author

Hu, W.T., Seelaar, H., Josephs, K.A., Knopman, D.S., Boeve, B.F., Sorenson, E.J., McCluskey, L., Elman, L., Schelhaas, H.J., Parisi, J.E., Kuesters, B., Lee, V.M., Trojanowski, J.Q., Petersen, R.C., Swieten, J.C. van, and Grossman, M.

Subjects
Perception and Action [DCN 1], Alzheimer Centre [NCEBP 11], Functional Neurogenomics [DCN 2]
Abstract

Contains fulltext : 81426.pdf (Publisher’s version ) (Closed access) BACKGROUND: Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases associated with TAR DNA-binding protein 43- and ubiquitin-immunoreactive pathologic lesions. OBJECTIVE: To determine whether survival is influenced by symptom of onset in patients with frontotemporal dementia and amyotrophic lateral sclerosis. DESIGN, SETTING, AND PATIENTS: Retrospective review of patients with both cognitive impairment and motor neuron disease consecutively evaluated at 4 academic medical centers in 2 countries. MAIN OUTCOME MEASURES: Clinical phenotypes and survival patterns of patients. RESULTS: A total of 87 patients were identified, including 60 who developed cognitive symptoms first, 19 who developed motor symptoms first, and 8 who had simultaneous onset of cognitive and motor symptoms. Among the 59 deceased patients, we identified 2 distinct subgroups of patients according to survival. Long-term survivors had cognitive onset and delayed emergence of motor symptoms after a long monosymptomatic phase and had significantly longer survival than the typical survivors (mean, 67.5 months vs 28.2 months, respectively; P < .001). Typical survivors can have simultaneous or discrete onset of cognitive and motor symptoms, and the simultaneous-onset patients had shorter survival (mean, 19.2 months) than those with distinct cognitive or motor onset (mean, 28.6 months) (P = .005). CONCLUSIONS: Distinct patterns of survival profiles exist in patients with frontotemporal dementia and motor neuron disease, and overall survival may depend on the relative timing of the emergence of secondary symptoms.

Published
2009

13. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Author

Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, Chiò A, Restagno G, Nicolaou N, Simon Sanchez J, van Swieten JC, Abramzon Y, Johnson JO, Sendtner M, Pamphlett R, Orrell RW, Mead S, Sidle KC, Houlden H, Rohrer JD, Morrison KE, Pall H, Talbot K, Ansorge O, Chromosome 9 ALS/FTD Consortium, French research network on FTLD/FTLD/ALS, ITALSGEN Consortium, Adamson G, Bayer AJ, Beck J, Callister JB, Blake DJ, Blumen SC, Collinge J, Dunckley T, Ealing J, East S, Elman L, Gerhard A, Guerreiro RJ, Gwinn K, Halliwell N, Hamdalla HH, Hewitt C, Ince P, Jablonka S, James C, Kent L, Knock JC, Lynch T, Mahoney C, Mann D, Neal J, Norris D, O'Dowd S, Richardson A, Rossor M, Rothstein J, Scholz SW, Snowden J, Stephan DA, Toulson G, Turner MR, Warren JD, Young K, Weng YH, Kuo HC, Lai SC, Huang CL, Camuzat A, Entraingues L, Guillot Noël, Verpillat P, Blanc F, Camu W, Clerget Darpoux F, Corcia P, Couratier P, Didic M, Dubois B, Duyckaerts C, Guedj E, Golfier V, Habert MO, Hannequin D, Lacomblez L, Meininger V, Salachas F, Levy R, Michel BF, Pasquier F, Puel M, Thomas Anterion C, Sellal F, Vercelletto M, Moglia C, Cammarosano S, Canosa A, Gallo S, Brunetti M, Ossola I, Marinou K, Papetti L, Pisano F, Pinter GL, Conte A, Luigetti M, Zollino M, Lattante S, Marangi G, la Bella V, Spataro R, Colletti T, Battistini S, Ricci C, Caponnetto C, Mancardi G, Mandich P, Salvi F, Bartolomei I, Mandrioli J, Sola P, Lunetta C, Penco S, Conforti FL, Gambardella A, Quattrone A, Volanti P, Floris G, Cannas A, Piras V, Marrosu F, Marrosu MG, Murru MR, Pugliatti M, Parish LD, Sotgiu A, Solinas G, Ulgheri L, Ticca A, Simone I, Logroscino G, Hernandez DG, Arepalli S, Sabatelli M, Mora G, Corbo M, Giannini F, Calvo A, Englund E, Borghero G, Floris GL, Remes AM, Laaksovirta H, McCluskey L, Trojanowski JQ, Van Deerlin VM, Schellenberg GD, Nalls MA, Drory VE, Lu CS, Yeh TH, Ishiura H, Takahashi Y, Tsuji S, Le Ber I, Brice A, Drepper C, Williams N, Kirby J, Shaw P, Hardy J, Tienari PJ, Heutink P, Morris HR, Pickering Brown S, Traynor BJ, MONSURRO', Maria Rosaria, TEDESCHI, Gioacchino, Majounie, E, Renton, Ae, Mok, K, Dopper, Eg, Waite, A, Rollinson, S, Chiò, A, Restagno, G, Nicolaou, N, Simon Sanchez, J, van Swieten, Jc, Abramzon, Y, Johnson, Jo, Sendtner, M, Pamphlett, R, Orrell, Rw, Mead, S, Sidle, Kc, Houlden, H, Rohrer, Jd, Morrison, Ke, Pall, H, Talbot, K, Ansorge, O, Chromosome, 9 ALS/FTD Consortium, French research network on, Ftld/ftld/al, Italsgen, Consortium, Adamson, G, Bayer, Aj, Beck, J, Callister, Jb, Blake, Dj, Blumen, Sc, Collinge, J, Dunckley, T, Ealing, J, East, S, Elman, L, Gerhard, A, Guerreiro, Rj, Gwinn, K, Halliwell, N, Hamdalla, Hh, Hewitt, C, Ince, P, Jablonka, S, James, C, Kent, L, Knock, Jc, Lynch, T, Mahoney, C, Mann, D, Neal, J, Norris, D, O'Dowd, S, Richardson, A, Rossor, M, Rothstein, J, Scholz, Sw, Snowden, J, Stephan, Da, Toulson, G, Turner, Mr, Warren, Jd, Young, K, Weng, Yh, Kuo, Hc, Lai, Sc, Huang, Cl, Camuzat, A, Entraingues, L, Guillot, Noël, Verpillat, P, Blanc, F, Camu, W, Clerget Darpoux, F, Corcia, P, Couratier, P, Didic, M, Dubois, B, Duyckaerts, C, Guedj, E, Golfier, V, Habert, Mo, Hannequin, D, Lacomblez, L, Meininger, V, Salachas, F, Levy, R, Michel, Bf, Pasquier, F, Puel, M, Thomas Anterion, C, Sellal, F, Vercelletto, M, Moglia, C, Cammarosano, S, Canosa, A, Gallo, S, Brunetti, M, Ossola, I, Marinou, K, Papetti, L, Pisano, F, Pinter, Gl, Conte, A, Luigetti, M, Zollino, M, Lattante, S, Marangi, G, la Bella, V, Spataro, R, Colletti, T, Battistini, S, Ricci, C, Caponnetto, C, Mancardi, G, Mandich, P, Salvi, F, Bartolomei, I, Mandrioli, J, Sola, P, Lunetta, C, Penco, S, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Conforti, Fl, Gambardella, A, Quattrone, A, Volanti, P, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, Mg, Murru, Mr, Pugliatti, M, Parish, Ld, Sotgiu, A, Solinas, G, Ulgheri, L, Ticca, A, Simone, I, Logroscino, G, Hernandez, Dg, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Floris, Gl, Remes, Am, Laaksovirta, H, Mccluskey, L, Trojanowski, Jq, Van Deerlin, Vm, Schellenberg, Gd, Nalls, Ma, Drory, Ve, Lu, C, Yeh, Th, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, Pj, Heutink, P, Morris, Hr, Pickering Brown, S, and Traynor, Bj

Published
2012

14. Erratum exome sequencing reveals VCP mutations as a cause of familial ALS

Author

Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., Mccluskey, L., Martinez-Lage, M., Falcone, D., Hernandez, D. G., Arepalli, S., Chong, S., Schymick, J. C., Rothstein, J., Landi, F., Wang, Y. -D., Calvo, A., Mora, G., Sabatelli, M., Monsurro, M. R., Battistini, S., Salvi, F., Spataro, R., Sola, P., Borghero, G., Galassi, G., Scholz, S. W., Taylor, J. P., Restagno, G., Chio, A., and Traynor, B. J.

Published
2011

16. The Third Competition on Knowledge Engineering for Planning and Scheduling

Author

Roman Barták, Fratini, S., and Mccluskey, L.

Subjects
Artificial Intelligence, Computer Science
Abstract

We report on the staging of the third competition on knowledge engineering for AI planning and scheduling systems, held during ICAPS-09 at Thessaloniki, Greece in September 2009. We give an overview of how the competition has developed since its first run in 2005, and its relationship with the AI planning field. This run of the competition focused on translators that when input with some formal description in an application-area-specific language, output solver-ready domain models. Despite a fairly narrow focus within knowledge engineering, seven teams took part in what turned out to be a very interesting and successful competition.

Published
2010

17. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Author

Gallagher, MD, Suh, E, Grossman, M, Elman, L, McCluskey, L, Van Swieten, JC, Al-Sarraj, S, Neumann, M, Gelpi, E, Ghetti, B, Rohrer, JD, Halliday, G, Van Broeckhoven, C, Seilhean, D, Shaw, PJ, Frosch, MP, Alafuzoff, I, Antonell, A, Bogdanovic, N, Brooks, W, Cairns, NJ, Cooper-Knock, J, Cotman, C, Cras, P, Cruts, M, De Deyn, PP, Decarli, C, Dobson-Stone, C, Engelborghs, S, Fox, N, Galasko, D, Gearing, M, Gijselinck, I, Grafman, J, Hartikainen, P, Hatanpaa, KJ, Highley, JR, Hodges, J, Hulette, C, Ince, PG, Jin, LW, Kirby, J, Kofler, J, Kril, J, Kwok, JBJ, Levey, A, Lieberman, A, Llado, A, Martin, JJ, Masliah, E, McDermott, CJ, McKee, A, McLean, C, Mead, S, Miller, CA, Miller, J, Munoz, DG, Murrell, J, Paulson, H, Piguet, O, Rossor, M, Sanchez-Valle, R, Sano, M, Schneider, J, Silbert, LC, Spina, S, Van Der Zee, J, Van Langenhove, T, Warren, J, Wharton, SB, White, CL, Woltjer, RL, Trojanowski, JQ, Lee, VMY, Van Deerlin, V, Chen-Plotkin, AS, Gallagher, MD, Suh, E, Grossman, M, Elman, L, McCluskey, L, Van Swieten, JC, Al-Sarraj, S, Neumann, M, Gelpi, E, Ghetti, B, Rohrer, JD, Halliday, G, Van Broeckhoven, C, Seilhean, D, Shaw, PJ, Frosch, MP, Alafuzoff, I, Antonell, A, Bogdanovic, N, Brooks, W, Cairns, NJ, Cooper-Knock, J, Cotman, C, Cras, P, Cruts, M, De Deyn, PP, Decarli, C, Dobson-Stone, C, Engelborghs, S, Fox, N, Galasko, D, Gearing, M, Gijselinck, I, Grafman, J, Hartikainen, P, Hatanpaa, KJ, Highley, JR, Hodges, J, Hulette, C, Ince, PG, Jin, LW, Kirby, J, Kofler, J, Kril, J, Kwok, JBJ, Levey, A, Lieberman, A, Llado, A, Martin, JJ, Masliah, E, McDermott, CJ, McKee, A, McLean, C, Mead, S, Miller, CA, Miller, J, Munoz, DG, Murrell, J, Paulson, H, Piguet, O, Rossor, M, Sanchez-Valle, R, Sano, M, Schneider, J, Silbert, LC, Spina, S, Van Der Zee, J, Van Langenhove, T, Warren, J, Wharton, SB, White, CL, Woltjer, RL, Trojanowski, JQ, Lee, VMY, Van Deerlin, V, and Chen-Plotkin, AS

Abstract

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease. © 2014 Springer-Verlag Berlin Heidelberg.

Published
2014

18. Clinical and pathological continuum of multisystem TDP-43 proteinopathies

Author

Geser, F, Martinez-Lage, M, Robinson, J, Uryu, K, Neumann, M, Brandmeir, N J, Xie, S X, Kwong, L K, Elman, L, McCluskey, L, Clark, C M, Malunda, J, Miller, B L, Zimmerman, E A, Qian, J, Van Deerlin, V, Grossman, M, Lee, V M Y, Trojanowski, J Q, and University of Zurich

Subjects
2728 Neurology (clinical), 1201 Arts and Humanities (miscellaneous), 10208 Institute of Neuropathology, 570 Life sciences, biology, 610 Medicine & health
Published
2009
Full Text
View/download PDF

20. Amyotrophic lateral sclerosis: An emerging era of collaboratie gene discovery

Author

Gwinn, K, Corriveau, RA, Mitsumoto, H, Bednarz, K, Brown, RH, Cudkowicz, M, Gordon, PH, Hardy, J, Kasarskis, EJ, Kaufmann, P, Miller, R, Sorenson, E, Tandan, R, Traynor, BJ, Nash, J, Sherman, A, Mailman, MD, Ostell, J, Bruijn, L, Cwik, V, Rich, SS, Singleton, A, Refolo, L, Andrews, J, Zhang, R, Conwit, R, Keller, MA, Lomen-Hoerth, C, Simmons, Z, Newman, DS, Barohn, RJ, Crum, B, Stevens, JC, Simpson, EP, Boylan, KB, McCluskey, L, Bedlack, RS, Bosch, EP, Barkhaus, PE, Dibernardo, A, Caress, JB, Lacomis, D, Pestronk, A, Shefner, JM, Maragakis, NJ, Heitzman, D, Goslin, KL, Jackson, CE, Glass, JD, Mozaffar, T, Bertorini, TE, Chad, DA, Trivedi, JR, Rezania, K, Heiman-Patterson, TD, Gutmann, L, Rosenfeld, J, Brooks, BR, Hayat, G, Chapin, JE, Rudnicki, SA, Harati, Y, Rana, SS, Verma, A, Russell, JA, Pioro, EP, Thornton, CA, Sams, L, Kelly, J, Bayat, E, Kelkar, PM, Shivapour, ET, Scelsa, SN, Walk, D, Peltier, AC, Sachs, G, Belsh, JM, Graves, MC, Thakore, NJ, Brent, HT, Cho, C, Wymer, JP, Lou, JS, Weiss, MD, Carter, GS, Armon, C, Vidic, TR, Bromberg, MB, and Lange, DJ

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.

Published
2007

22. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study

Author

Majounie, E. (Elisa), Renton, A. (Alan), Mok, K. (Kin), Dopper, E.G.P. (Elise), Waite, A. (Adrian), Rollinson, S. (Sara), Chiò, A. (Adriano), Restagno, G. (Gabriella), Nicolaou, N. (Nayia), Simón-Sánchez, J. (Javier), Swieten, J.C. (John) van, Abramzon, Y. (Yevgeniya), Johnson, J. (Janel), Sendtner, M. (Michael), Pamphlett, R. (Roger), Orrell, R. (Richard), Mead, S. (Simon), Sidle, K.C. (Katie), Houlden, H. (Henry), Rohrer, J.D. (Jonathan), Morrison, K.E. (Karen), Pall, H. (Hardev), Talbot, D., Ansorge, O. (Olaf), Hernandez, D.G. (Dena), Arepalli, S. (Sampath), Sabatelli, M. (Mario), Mora, G. (Gabriele), Corbo, J.C. (Joseph), Giannini, F. (Fabio), Calvo, A. (Andrea), Englund, E. (Elisabet), Borghero, G. (Giuseppe), Floris, O.A.M., Remes, A. (Anne), Laaksovirta, H. (Hannu), McCluskey, L. (Leo), Trojanowski, J.Q. (John), Deerlin, V.M. (Vivianna), Schellenberg, G.D. (Gerard), Nalls, M.A. (Michael), Drory, V.E. (Vivian E), Lu, C.S. (Chin-Song), Yeh, T.-H. (Tu-Hsueh), Ishiura, H. (Hiroyuki), Takahashi, Y. (Yukari), Tsuji, S. (Shoji), Le Ber, I. (Isabelle), Brice, A., Drepper, C. (Carsten), Williams, N. (Nigel), Kirby, J. (Janine), Shaw, P.J. (Pamela), Hardy, J. (John), Tienari, P.J. (Pentti), Heutink, P. (Peter), Morris, H. (Huw), Pickering-Brown, S. (Stuart), Traynor, B.J. (Bryan), Majounie, E. (Elisa), Renton, A. (Alan), Mok, K. (Kin), Dopper, E.G.P. (Elise), Waite, A. (Adrian), Rollinson, S. (Sara), Chiò, A. (Adriano), Restagno, G. (Gabriella), Nicolaou, N. (Nayia), Simón-Sánchez, J. (Javier), Swieten, J.C. (John) van, Abramzon, Y. (Yevgeniya), Johnson, J. (Janel), Sendtner, M. (Michael), Pamphlett, R. (Roger), Orrell, R. (Richard), Mead, S. (Simon), Sidle, K.C. (Katie), Houlden, H. (Henry), Rohrer, J.D. (Jonathan), Morrison, K.E. (Karen), Pall, H. (Hardev), Talbot, D., Ansorge, O. (Olaf), Hernandez, D.G. (Dena), Arepalli, S. (Sampath), Sabatelli, M. (Mario), Mora, G. (Gabriele), Corbo, J.C. (Joseph), Giannini, F. (Fabio), Calvo, A. (Andrea), Englund, E. (Elisabet), Borghero, G. (Giuseppe), Floris, O.A.M., Remes, A. (Anne), Laaksovirta, H. (Hannu), McCluskey, L. (Leo), Trojanowski, J.Q. (John), Deerlin, V.M. (Vivianna), Schellenberg, G.D. (Gerard), Nalls, M.A. (Michael), Drory, V.E. (Vivian E), Lu, C.S. (Chin-Song), Yeh, T.-H. (Tu-Hsueh), Ishiura, H. (Hiroyuki), Takahashi, Y. (Yukari), Tsuji, S. (Shoji), Le Ber, I. (Isabelle), Brice, A., Drepper, C. (Carsten), Williams, N. (Nigel), Kirby, J. (Janine), Shaw, P.J. (Pamela), Hardy, J. (John), Tienari, P.J. (Pentti), Heutink, P. (Peter), Morris, H. (Huw), Pickering-Brown, S. (Stuart), and Traynor, B.J. (Bryan)

Abstract

Background: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings: In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black i

Published
2012
Full Text
View/download PDF

23. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Author

Majounie, E, Renton, AE, Mok, K, Dopper, Elise, Waite, A, Rollinson, S, Chio, A, Restagno, G, Nicolaou, N, Simon-Sanchez, J, van Swieten, J.C., Abramzon, Y, Johnson, JO, Sendtner, M, Pamphlett, R, Orrell, RW, Mead, S, Sidle, KC, Houlden, H, Rohrer, JD, Morrison, KE, Pall, H, Talbot, K, Ansorge, O, Hernandez, DG, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Foris, GL, Remes, AM, Laaksovirta, H, McCluskey, L, Trojanowski, JQ, Van Deerlin, VM, Schellenberg, GD, Nalls, MA, Drory, VE, Lu, CS, Yeh, TH, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, PJ, Heutink, P, Morris, HR, Pickering-Brown, S, Traynor, BJ, Majounie, E, Renton, AE, Mok, K, Dopper, Elise, Waite, A, Rollinson, S, Chio, A, Restagno, G, Nicolaou, N, Simon-Sanchez, J, van Swieten, J.C., Abramzon, Y, Johnson, JO, Sendtner, M, Pamphlett, R, Orrell, RW, Mead, S, Sidle, KC, Houlden, H, Rohrer, JD, Morrison, KE, Pall, H, Talbot, K, Ansorge, O, Hernandez, DG, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Foris, GL, Remes, AM, Laaksovirta, H, McCluskey, L, Trojanowski, JQ, Van Deerlin, VM, Schellenberg, GD, Nalls, MA, Drory, VE, Lu, CS, Yeh, TH, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, PJ, Heutink, P, Morris, HR, Pickering-Brown, S, and Traynor, BJ

Abstract

Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7.0%) of 3377 white individuals from the USA, Europe, and Australia, two (4.1%) of 49 black individuals from the USA, and six (8.3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39.3%) of 552 white individuals with familial MS from Europe and the USA. 59 (6.0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24.8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic MS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years

Published
2012

24. Exome sequencing reveals VCP mutations as a cause of familial ALS

Author

Johnson, Jo, Mandrioli, J, Benatar, M, Abramzon, Y, Van Deerlin, Vm, Trojanowski, Jq, Gibbs, Jr, Brunetti, M, Gronka, S, Wuu, J, Ding, J, Mccluskey, L, Martinez Lage, M, Falcone, D, Hernandez, Dg, Arepalli, S, Chong, S, Schymick, Jc, Rothstein, J, Landi, Francesco Luigi, Wang, Y, Calvo, A, Mora, G, Sabatelli, Mario, Monsurrò, Mr, Battistini, S, Salvi, F, Spataro, R, Sola, P, Borghero, G, Galassi, G, Scholz, Sw, Taylor, Jp, Restagno, G, Chiò, A, Traynor, Bj, Sabatelli, Mario (ORCID:0000-0001-6635-4985), Johnson, Jo, Mandrioli, J, Benatar, M, Abramzon, Y, Van Deerlin, Vm, Trojanowski, Jq, Gibbs, Jr, Brunetti, M, Gronka, S, Wuu, J, Ding, J, Mccluskey, L, Martinez Lage, M, Falcone, D, Hernandez, Dg, Arepalli, S, Chong, S, Schymick, Jc, Rothstein, J, Landi, Francesco Luigi, Wang, Y, Calvo, A, Mora, G, Sabatelli, Mario, Monsurrò, Mr, Battistini, S, Salvi, F, Spataro, R, Sola, P, Borghero, G, Galassi, G, Scholz, Sw, Taylor, Jp, Restagno, G, Chiò, A, Traynor, Bj, and Sabatelli, Mario (ORCID:0000-0001-6635-4985)

Abstract

Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.

Published
2010

26. The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration

Author

Yu, C E, Bird, T D, Bekris, L M, Montine, T J, Leverenz, J B, Steinbart, E, Galloway, N M, Feldman, H, Woltjer, R, Miller, C A, Wood, E, Grossman, M, McCluskey, L, Clark, C M, Neumann, M, Danek, A, Galasko, D R, Arnold, S E, Chen-Plotkin, A, Karydas, A, Miller, B L, Trojanowski, J Q, Lee, V M Y, Schellenberg, G D, Van Deerlin, V M, Yu, C E, Bird, T D, Bekris, L M, Montine, T J, Leverenz, J B, Steinbart, E, Galloway, N M, Feldman, H, Woltjer, R, Miller, C A, Wood, E, Grossman, M, McCluskey, L, Clark, C M, Neumann, M, Danek, A, Galasko, D R, Arnold, S E, Chen-Plotkin, A, Karydas, A, Miller, B L, Trojanowski, J Q, Lee, V M Y, Schellenberg, G D, and Van Deerlin, V M

Subjects
Frontotemporal dementia Genetic aspects., Brain Diseases Genetic aspects., Démence frontotemporale Aspect génétique., Cerveau Maladies Aspect génétique.
Abstract

BACKGROUND: Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations. OBJECTIVES: To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants. DESIGN: Case-control study. SETTING: Clinical and neuropathology dementia research studies at 8 academic centers. PARTICIPANTS: Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/motor neuron disease, corticobasal syndrome/corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease. MAIN OUTCOME MEASURES: Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays. RESULTS: We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history. CONCLUSIONS: Pathogenic mutations were found only in FTD-spectrum cases and not in

Published
2010

36. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial

Author

Sorenson, E. J., primary, Windbank, A. J., additional, Mandrekar, J. N., additional, Bamlet, W. R., additional, Appel, S. H., additional, Armon, C., additional, Barkhaus, P. E., additional, Bosch, P., additional, Boylan, K., additional, David, W. S., additional, Feldman, E., additional, Glass, J., additional, Gutmann, L., additional, Katz, J., additional, King, W., additional, Luciano, C. A., additional, McCluskey, L. F., additional, Nash, S., additional, Newman, D. S., additional, Pascuzzi, R. M., additional, Pioro, E., additional, Sams, L. J., additional, Scelsa, S., additional, Simpson, E. P., additional, Subramony, S. H., additional, Tiryaki, E., additional, and Thornton, C. A., additional

Published
2008
Full Text
View/download PDF

42. Amyotrophic Lateral Sclerosis-Specific Quality of Life

Author

Simmons, Zachary, primary, Felgoise, S. H., additional, Bremer, B. A., additional, Walsh, S. M., additional, Hufford, D. J., additional, Bromberg, M. B., additional, David, W., additional, Forshew, D. A., additional, Heiman-Patterson, T. D., additional, Lai, E. C., additional, and McCluskey, L., additional

Published
2006
Full Text
View/download PDF

50. Clinical Retrospective Evaluation of 2 Orthodontic Band Cements.

Author

Millett, D. T., Hallgren, A., McCluskey, L.-A., McAuley, F., Fornell, A.-C., Love, J., and Christie, H.

Subjects
DENTAL bonding, DENTAL adhesives, RETROSPECTIVE studies, DENTISTRY, ORTHODONTICS
Abstract

This study aimed to compare the time to first failure of stainless steel orthodontic first permanent molar bands cemented with either a modified composite (Band-Lok, Reliance Orthodontic Products) or a conventional glass ionomer cement (AquaCem, De Trey Dentsply). The effect of patient sex, patient age at the start of treatment, the presenting malocclusion, treatment mechanics, and the operator proficiency on band survival was also assessed. Data for 219 bands cemented with Band-Lok in 108 patients and for 395 bands cemented with AquaCem in 183 patients were analyzed. For each case, a single molar band, either the band that was first to fail or the band that had the shortest follow-up time, was chosen for analysis. For each cement, whether headgear was used or not, there was no significant difference in time to first band failure (P = .398). Twenty-six percent of patients had at least one band failure with Band-Lok, and 30% of patients had at least one band failure with AquaCem, representing an 18% band failure rate for each cement. There was no significant difference in time to first band failure for either cement with respect to sex of the patient (P = .842), patient age at the start of treatment (P = .257), presenting malocclusion (P = .319), or operator proficiency (P = .062). The use of headgear, however, reduced significantly the time to first band failure irrespective of cement type (P = .0069). Headgear use was identified as a predictor of first permanent molar band survival. Clinical performance of bands cemented with either cement appears to be similar and was influenced significantly by the use of headgear. [ABSTRACT FROM AUTHOR]

Published
2001

Catalog

Books, media, physical & digital resources
See catalog results