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1. 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
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2. 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
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3. 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

4. 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

5. 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
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7. Diffusion tensor imaging in amyotrophic lateral sclerosis: Volumetric analysis of the corticospinal tract

Author

Wang, S., Harish Poptani, Bilello, M., Wu, X., Woo, J. H., Elman, L. B., Mccluskey, L. F., Krejza, J., and Melhem, E. R.

Subjects
Adult, Male, Motor Neurons, Diffusion Magnetic Resonance Imaging, Amyotrophic Lateral Sclerosis, Image Processing, Computer-Assisted, Pyramidal Tracts, Brain, Humans, Female, Middle Aged, human activities, Aged
Abstract

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) allows direct visualization and volumetric analysis of the corticospinal tract (CST). The purpose of this study was to determine whether color maps and fiber tracking derived from DTI data are valuable in detecting and quantifying CST degeneration in patients with amyotrophic lateral sclerosis (ALS). METHODS: Sixteen patients with ALS with clinical signs of upper motor neuron (UMN) involvement and 17 healthy subjects were studied with the use of DTI. Disease severity was determined by means of the ALS Functional Rating Scale-Revised (ALSFRS-R) and an UMN involvement score. DTI was acquired with a 12-direction, single-shot, spin-echo echo-planar sequence. The CST from the lower pons to the corona radiata at the level of the corpus callosum on 4 contiguous coronal sections was manually segmented by using color maps generated from the DTI data. The left and right CST volumes were measured separately and normalized to the total intracranial volume. Normalized CST volumes were compared between patients with ALS and healthy subjects. RESULTS: The CST volumes of patients with ALS were significantly reduced (P < .01, unpaired t test) compared with healthy subjects, in both affected and nonaffected hemispheres. No significant correlation was found between CST volumes and any of the clinical parameters, including disease duration, ALSFRS-R, or UMN involvement score. CONCLUSION: This study shows that volumetric analysis by using DTI-based color maps is valuable in detecting and monitoring structural degeneration of the CST. This will lead to objective and quantitative assessment of axonal degeneration in ALS.

9. Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Author

Faheem, Waleed, Nandra, Taran, Richardson, Sarah, Saliu, David, Wilson, Daisy, Jackson, Thomas A., Magill, Laura, McCluskey, Lauren, Perry, Rita, Welch, Carly, Copeland, Claire, Cunningham, Emma L., Davis, Daniel, Treml, Jonathan, Pinkney, Thomas, Quinn, Terrence, Nightingale, Peter, Jelley, Benjamin, Gaunt, Victoria, Lochlainn, Mary Ni, Giridharan, Kumudhini, Alsahab, Mustafa, Makin, Stephen, Torsney, Kelli, Masoli, Jane, Ronan, Lindsay, Burton, Jenni K., Todd, Oliver, Taylor, Joanne, Willott, Ruth, Cox, Natalie, Healy, Roisin, Haddad, Nedaa, Ramakrishna, Sharan, Subhan, Zahid, Mazzoleni, Antonella, Nynaes, Olga, Crofts, Jodie, McNicholas, Emily, Baillie, Jonathan, Irwin, Sophie J., Kelly, Dominic, Leah, Eleanor, Evans, Jenny, Bowman, Mark A., Quinn, Sinead, Wilson, Joseph B., Hughes, Clare, and Moore, Emily

Subjects
Recognition, Frailty, Delirium, General Medicine, Mortality, Geriatrics and Gerontology, Gerontology
Abstract

Purpose Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes.

Published
2023
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10. Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

Author

Johnson, Janel O., Mandrioli, Jessica, Benatar, Michael, Abramzon, Yevgeniya, Van Deerlin, Vivianna M., Trojanowski, John Q., Gibbs, J. Raphael, Brunetti, Maura, Gronka, Susan, Wuu, Joanne, Ding, Jinhui, Mccluskey, Leo, Martinez Lage, Maria, Falcone, Dana, Hernandez, Dena G., Arepalli, Sampath, Chong, Sean, Schymick, Jennifer C., Rothstein, Jeffrey, Landi, Francesco, Wang, Yong Dong, Calvo, Andrea, Mora, Gabriele, Sabatelli, Mario, Battistini, Stefania, Salvi, Fabrizio, Spataro, Rossella, Sola, Patrizia, Borghero, Giuseppe, Giannini, Fabio, Ricci, Claudia, Moglia, Cristina, Ossola, Irene, Canosa, Antonio, Gallo, Sara, Bartolomei, Ilaria, Marinou, Kalliopi, Papetti, Laura, Conte, Amelia, Luigetti, Marco, La Bella, Vincenzo, Paladino, Piera, Caponnetto, Claudia, Volanti, Paolo, Marrosu, Maria Teresa, Murru, Maria Rita, Galassi, Giuliana, Scholz, Sonja W., Taylor, J. Paul, Restagno, Gabriella, Chiò, Adriano, Traynor, Bryan J., MONSURRO', Maria Rosaria, TEDESCHI, Gioacchino, 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, F, Wang, Y-D, Calvo, A, Mora, G, Sabatelli, M, Monsurrò, MR, Battistini, S, Salvi, F, Spataro, R, Sola, P, Borghero, G, Galassi, G, Scholz, SW, Taylor, JP, Restagno, G, Chiò, A, Traynor, BJ, Johnson, Janel O., Mandrioli, Jessica, Benatar, Michael, Abramzon, Yevgeniya, Van Deerlin, Vivianna M., Trojanowski, John Q., Gibbs, J. Raphael, Brunetti, Maura, Gronka, Susan, Wuu, Joanne, Ding, Jinhui, Mccluskey, Leo, Martinez Lage, Maria, Falcone, Dana, Hernandez, Dena G., Arepalli, Sampath, Chong, Sean, Schymick, Jennifer C., Rothstein, Jeffrey, Landi, Francesco, Wang, Yong Dong, Calvo, Andrea, Mora, Gabriele, Sabatelli, Mario, Monsurro', Maria Rosaria, Battistini, Stefania, Salvi, Fabrizio, Spataro, Rossella, Sola, Patrizia, Borghero, Giuseppe, Giannini, Fabio, Ricci, Claudia, Moglia, Cristina, Ossola, Irene, Canosa, Antonio, Gallo, Sara, Tedeschi, Gioacchino, Bartolomei, Ilaria, Marinou, Kalliopi, Papetti, Laura, Conte, Amelia, Luigetti, Marco, La Bella, Vincenzo, Paladino, Piera, Caponnetto, Claudia, Volanti, Paolo, Marrosu, Maria Teresa, Murru, Maria Rita, Galassi, Giuliana, Scholz, Sonja W., Taylor, J. Paul, Restagno, Gabriella, Chiò, Adriano, and Traynor, Bryan J.

Subjects
Adenosine Triphosphatase, Male, Cell Cycle Proteins, UBQLN2, Cohort Studies, 0302 clinical medicine, Reference Values, Valosin Containing Protein, Cell Cycle Protein, Reference Value, Amyotrophic lateral sclerosis, Exome sequencing, Adenosine Triphosphatases, Genetics, 0303 health sciences, General Neuroscience, Exons, Middle Aged, Pedigree, 3. Good health, Multisystem proteinopathy, Female, Settore MED/26 - Neurologia, Case-Control Studie, Chromosomes, Human, Pair 9, Human, Frontotemporal dementia, Neuroscience(all), Valosin-containing protein, Exon, Biology, Protein degradation, TARDBP, Article, 03 medical and health sciences, medicine, Humans, Aged, 030304 developmental biology, Amyotrophic lateral sclerosis, familial ALS, exome sequencing, Neuroscience (all), business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Amino Acid Substitution, Case-Control Studies, Mutation, biology.protein, Cohort Studie, business, 030217 neurology & neurosurgery, Amyotrophic Lateral Sclerosi
Abstract

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

Author

Johnathan Cooper-Knock, Jill R. Murrell, Ann C. McKee, Päivi Hartikainen, Randall L. Woltjer, Peter Paul De Deyn, Lisa C. Silbert, Virginia M.-Y. Lee, Alice Chen-Plotkin, Leo McCluskey, Carol Dobson-Stone, Albert Lladó, David G. Munoz, Paul G. Ince, Nenad Bogdanovic, Carl W. Cotman, Douglas Galasko, Julie van der Zee, Patrick Cras, Christopher J McDermott, Pamela J. Shaw, Murray Grossman, Nick C. Fox, Jillian J. Kril, Stephen B. Wharton, Jonathan D. Rohrer, Eliezer Masliah, Salvatore Spina, Andrew P. Lieberman, Bernardino Ghetti, Olivier Piguet, Kimmo J. Hatanpaa, John B.J. Kwok, Glenda M. Halliday, Vivianna M. Van Deerlin, Janine Kirby, Mary Sano, Julia Kofler, Lauren Elman, Christine M. Hulette, Christine Van Broeckhoven, Irina Alafuzoff, Jordan Grafman, John Q. Trojanowski, Simon Mead, Ilse Gijselinck, Nigel J. Cairns, Sebastiaan Engelborghs, Danielle Seilhean, Lee-Way Jin, Catriona McLean, Allan I. Levey, William S. Brooks, Josh Miller, Julie A. Schneider, Charles L. White, Anna Antonell, Raquel Sánchez-Valle, Safa Al-Sarraj, Ellen Gelpi, John C. van Swieten, Manuela Neumann, Matthew P. Frosch, Henry L. Paulson, Tim Van Langenhove, EunRan Suh, Jason D. Warren, J. Robin Highley, Marc Cruts, John R. Hodges, Martin N. Rossor, Jean Jacques Martin, Charles DeCarli, Michael D. Gallagher, Marla Gearing, Carol A. Miller, Neurology, Obstetrics & Gynecology, Surgery, Human genetics, and NCA - neurodegeneration

Subjects
Male, mortality [Amyotrophic Lateral Sclerosis], Aging, Neurodegenerative, Genetic modifier, Cohort Studies, 0302 clinical medicine, Progranulins, C9orf72, Genotype, 80 and over, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, Age of Onset, Alzheimer's Disease Related Dementias (ADRD), genetics [Nerve Tissue Proteins], Genetics, Aged, 80 and over, 0303 health sciences, DNA Repeat Expansion, blood [Intercellular Signaling Peptides and Proteins], Age Factors, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, 3. Good health, genetics [Amyotrophic Lateral Sclerosis], genetics [Membrane Proteins], Frontotemporal Dementia (FTD), Neurological, mortality [Frontotemporal Lobar Degeneration], Intercellular Signaling Peptides and Proteins, Female, genetics [Frontotemporal Lobar Degeneration], Frontotemporal dementia, Adult, Heterozygote, Clinical Sciences, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, TMEM106B protein, human, Rare Diseases, SDG 3 - Good Health and Well-being, mental disorders, medicine, Acquired Cognitive Impairment, Humans, Genetic Predisposition to Disease, ddc:610, blood [Frontotemporal Lobar Degeneration], Allele, Polymorphism, Alleles, 030304 developmental biology, Aged, Neurology & Neurosurgery, C9orf72 Protein, Prevention, Amyotrophic Lateral Sclerosis, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), nutritional and metabolic diseases, Membrane Proteins, Proteins, medicine.disease, genetics [Proteins], Brain Disorders, nervous system diseases, TMEM106B, GRN protein, human, Dementia, Neurology (clinical), Human medicine, Age of onset, C9orf72 protein, human, Frontotemporal Lobar Degeneration, 030217 neurology & neurosurgery
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.

Published
2014
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14. Palliative Medicine : A Case-based Manual

Author

Doreen Oneschuk, Neil Hagen, Neil MacDonald, Doreen Oneschuk, Neil Hagen, and Neil MacDonald

Subjects
Living wills, Advance directives (Medical care), Palliative treatment
Abstract

Palliative care is now an integral part of the undergraduate medical curriculum. Medical education across the board is adopting a case-based approach. This book uses a series of cases to illustrate critical points in palliative medicine. The case-studies have been carefully chosen to reflect real life clinical practice. The contributors illustrate, through the case studies, the desired skills, attitudes, and knowledge required in this field of medicine. Since publication of the second edition, many approaches to palliative care have been further refined and developed. Ongoing research has led to the improved use of existing medications, and the development of several new treatments. More is known about the psychosocial existential distress experienced by patients and their families resulting in an improved understanding by health care providers of how best to approach and assist those affected by advanced illness, and more is known about methadone and other medications with emerging uses. The third edition of this highly popular book continues to offer a panoramic view of palliative care. It introduces a number of new topics including Neurological Disorders, The Last Days, and Palliative Sedation.

Published
2012

15. The Endothelium in Clinical Practice : Source and Target of Novel Therapies

Author

Rubanyi, Gabor M., Dzau, Victor J., Rubanyi, Gabor M., and Dzau, Victor J.

Subjects
Vascular endothelium--Pathophysiology, Vascular endothelium--Physiology, Endothelium, Endothelins, Thromboxanes, Prostacyclin, Heart Diseases--therapy, Heart Diseases--physiopathology, Endothelium--physiology
Published
1997

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