Author: "Marina Frontali" - Searchworks@Jio Institute Digital Library Search Results

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1. Does arterial hypertension influence the onset of Huntington's disease?

Author: Leire Valcárcel-Ocete, Asier Fullaondo, Gorka Alkorta-Aranburu, María García-Barcina, Raymund A C Roos, Lena E Hjermind, Carsten Saft, Marina Frontali, Ralf Reilmann, Hugh Rickards, REGISTRY investigators of the European Huntington’s Disease Network (EHDN), Ana M Zubiaga, and Ana Aguirre
Subjects: Medicine, Science
Abstract: Huntington's disease (HD) age of onset (AO) is mainly determined by the length of the CAG repeat expansion in the huntingtin gene. The remaining AO variability has been attributed to other little-known factors. A factor that has been associated with other neurodegenerative diseases is arterial hypertension (AHT). The aim of this study is to evaluate the contribution of AHT to the AO of HD. We used data from a cohort of 630 European HD patients with adult onset collected by the REGISTRY project of the European Huntington's Disease Network. Multiple linear regression and ANOVA, controlling for the CAG repeat number of the expanded allele (CAGexp) of each patient, were performed to assess the association between the AHT condition and the AO of the motor symptoms (mAO). The results showed a significant association between AHT and mAO, especially when we only considered the patients diagnosed with AHT prior to manifesting any HD signs (pre-HD AHT). Remarkably, despite the low number of cases, those patients developed motor symptoms 5-8 years later than normotensive patients in the most frequent CAGexp range (40-44). AHT is an age-related condition and consequently, the age of the patient at the time of data collection could be a confounder variable. However, given that most pre-HD AHT patients included in our study had started treatment with antihypertensive drugs prior to the onset of HD, and that antihypertensive drugs have been suggested to confer a neuroprotective effect in other neurodegenerative diseases, raises the interest in elucidating the impact of AHT and/or AHT treatment in HD age of onset in further studies. A confirmation of our results in a larger sample set would open the possibility to significantly improve HD management.
Published: 2018
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2. Is the oxidant/antioxidant status altered in CADASIL patients?

Author: Jonica Campolo, Renata De Maria, Caterina Mariotti, Chiara Tomasello, Marina Parolini, Marina Frontali, Domenico Inzitari, Raffaella Valenti, Antonio Federico, Franco Taroni, and Oberdan Parodi
Subjects: Medicine, Science
Abstract: The altered aggregation of proteins in non-native conformation is associated with endoplasmic reticulum derangements, mitochondrial dysfunction and excessive production of reactive oxygen species. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary systemic vasculopathy, caused by NOTCH3 mutations within the receptor extracellular domain, that lead to abnormal accumulation of the mutated protein in the vascular wall. NOTCH3 misfolding could cause free radicals increase also in CADASIL. Aim of the study was to verify whether CADASIL patients have increased oxidative stress compared to unrelated healthy controls. We enrolled 15 CADASIL patients and 16 gender- and age-matched healthy controls with comparable cardiovascular risk factor. Blood and plasma reduced and total aminothiols (homocysteine, cysteine, glutathione, cysteinylglycine) were measured by HPLC and plasma 3-nitrotyrosine by ELISA. Only plasma reduced cysteine (Pr-Cys) and blood reduced glutathione (Br-GSH) concentrations differed between groups: in CADASIL patients Br-GSH levels were higher (p = 0.019) and Pr-Cys lower (p = 0.010) than in controls. No correlation was found between Br-GSH and Pr-Cys either in CADASIL patients (rho 0.25, P = 0.36) or in controls (rho -0.15, P = 0.44). Conversely, 3-nitrotyrosine values were similar in CADASIL and healthy subjects (p = 0.82). The high levels of antioxidant molecules and low levels of oxidant mediators found in our CADASIL population might either be expression of an effective protective action against free radical formation at an early stage of clinical symptoms or they could suggest that oxidative stress is not directly involved in the pathogenesis of CADASIL.
Published: 2013
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3. Fractal analysis reveals reduced complexity of retinal vessels in CADASIL.

Author: Michele Cavallari, Teresa Falco, Marina Frontali, Silvia Romano, Francesca Bagnato, and Francesco Orzi
Subjects: Medicine, Science
Abstract: The Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) affects mainly small cerebral arteries and leads to disability and dementia. The relationship between clinical expression of the disease and progression of the microvessel pathology is, however, uncertain as we lack tools for imaging brain vessels in vivo. Ophthalmoscopy is regarded as a window into the cerebral microcirculation. In this study we carried out an ophthalmoscopic examination in subjects with CADASIL. Specifically, we performed fractal analysis of digital retinal photographs. Data are expressed as mean fractal dimension (mean-D), a parameter that reflects complexity of the retinal vessel branching. Ten subjects with genetically confirmed diagnosis of CADASIL and 10 sex and age-matched control subjects were enrolled. Fractal analysis of retinal digital images was performed by means of a computer-based program, and the data expressed as mean-D. Brain MRI lesion volume in FLAIR and T1-weighted images was assessed using MIPAV software. Paired t-test was used to disclose differences in mean-D between CADASIL and control groups. Spearman rank analysis was performed to evaluate potential associations between mean-D values and both disease duration and disease severity, the latter expressed as brain MRI lesion volumes, in the subjects with CADASIL. The results showed that mean-D value of patients (1.42±0.05; mean±SD) was lower than control (1.50±0.04; p = 0.002). Mean-D did not correlate with disease duration nor with MRI lesion volumes of the subjects with CADASIL. The findings suggest that fractal analysis is a sensitive tool to assess changes of retinal vessel branching, likely reflecting early brain microvessel alterations, in CADASIL patients.
Published: 2011
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4. Leukocyte Telomere Length as Potential Biomarker of HD Progression: A Follow-Up Study

Author: Daniela Scarabino, Liana Veneziano, Elide Mantuano, Ivan Arisi, Alessia Fiore, Marina Frontali, and Rosa Maria Corbo
Subjects: fluid biomarkers, Organic Chemistry, Huntington’s disease, leukocyte telomere length, neurodegenerative diseases, General Medicine, Telomere, Catalysis, Computer Science Applications, Inorganic Chemistry, Huntington Disease, Leukocytes, Mononuclear, Leukocytes, Humans, Physical and Theoretical Chemistry, Molecular Biology, Biomarkers, Spectroscopy, Follow-Up Studies
Abstract: The identification of biomarkers for neurodegenerative disorders such as Huntington’s disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39–51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects.
Published: 2022
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5. Episodic Ataxias: Faux or Real?

Author: Elide Mantuano, Paola Giunti, and Marina Frontali
Subjects: 0301 basic medicine, CACNA1A, FGF14, KCNA1, PRRT2, SCN2A, SLC1A3, SLCA1, channelopathies, episodic ataxia, Pediatrics, Review, Ion Channels, lcsh:Chemistry, 0302 clinical medicine, lcsh:QH301-705.5, Spectroscopy, NAV1.2 Voltage-Gated Sodium Channel, General Medicine, Computer Science Applications, Excitatory Amino Acid Transporter 1, medicine.symptom, medicine.medical_specialty, Ataxia, Cerebellar Ataxia, Context (language use), Catalysis, Inorganic Chemistry, 03 medical and health sciences, medicine, Humans, Ictal, Physical and Theoretical Chemistry, Molecular Biology, Episodic ataxia, business.industry, Organic Chemistry, Cerebellar dysfunction, medicine.disease, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Calcium Channels, business, Kv1.1 Potassium Channel, 030217 neurology & neurosurgery
Abstract: The term Episodic Ataxias (EA) was originally used for a few autosomal dominant diseases, characterized by attacks of cerebellar dysfunction of variable duration and frequency, often accompanied by other ictal and interictal signs. The original group subsequently grew to include other very rare EAs, frequently reported in single families, for some of which no responsible gene was found. The clinical spectrum of these diseases has been enormously amplified over time. In addition, episodes of ataxia have been described as phenotypic variants in the context of several different disorders. The whole group is somewhat confused, since a strong evidence linking the mutation to a given phenotype has not always been established. In this review we will collect and examine all instances of ataxia episodes reported so far, emphasizing those for which the pathophysiology and the clinical spectrum is best defined.
Published: 2020
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6. Frataxin deficiency in Friedreich’s ataxia is associated with reduced levels of HAX-1, a regulator of cardiomyocyte death and survival

Author: Alessandra Rufini, Silvia Gioiosa, Caterina Mariotti, Francesca Tiano, Francesca Amati, Carlo Casali, Ivano Condò, Giuseppe Novelli, Sara Maletta, Monica Benini, Luca Panarello, M. Fichera, Elena Morini, Marina Frontali, Chiara Vancheri, Silvia Romano, Roberto Testi, Florence Malisan, Fabio Cherubini, Giulia Alfedi, Christian Marcotulli, Andrea Quatrana, Dario Serio, Riccardo Luffarelli, Nicola Toschi, Silvia Fortuni, Alessia Mongelli, Tiano, F, Amati, F, Cherubini, F, Morini, E, Vancheri, C, Maletta, S, Fortuni, S, Serio, D, Quatrana, A, Luffarelli, R, Benini, M, Alfedi, G, Panarello, L, Rufini, A, Toschi, N, Frontali, M, Romano, S, Marcotulli, C, Casali, C, Gioiosa, S, Mariotti, C, Mongelli, A, Fichera, M, Condo, I, Novelli, G, Testi, R, and Malisan, F
Subjects: 0301 basic medicine, Adult, Male, Ataxia, cardiomyocyte, Ataxia, Cardiac, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Downregulation and upregulation, Iron-Binding Proteins, Genetics, medicine, Gene silencing, Humans, Myocytes, Cardiac, Molecular Biology, Genetics (clinical), Adaptor Proteins, Signal Transducing, Aged, Heart Failure, Settore MED/04 - Patologia Generale, frataxin, biology, Microarray analysis techniques, Lymphoblast, HEK 293 cells, Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio, General Medicine, Transfection, Cardiomyopathy, Hypertrophic, Middle Aged, 030104 developmental biology, Gene Expression Regulation, Settore MED/03 - Genetica Medica, Friedreich Ataxia, Frataxin, biology.protein, Cancer research, Friedreich ataxia, HAX-1, Leukocytes, Mononuclear, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract: Frataxin deficiency, responsible for Friedreich’s ataxia (FRDA), is crucial for cell survival since it critically affects viability of neurons, pancreatic beta cells and cardiomyocytes. In FRDA, the heart is frequently affected with typical manifestation of hypertrophic cardiomyopathy, which can progress to heart failure and cause premature death. A microarray analysis performed on FRDA patient’s lymphoblastoid cells stably reconstituted with frataxin, indicated HS-1-associated protein X-1 (HAX-1) as the most significantly upregulated transcript (FC = +2, P
Published: 2020

7. Identification of genetic variants associated with Huntington's disease progression

Author: Davina J Hensman Moss, Antonio F Pardiñas, Douglas Langbehn, Kitty Lo, Blair R Leavitt, Raymund Roos, Alexandra Durr, Simon Mead, Peter Holmans, Lesley Jones, Sarah J Tabrizi, A Coleman, R Dar Santos, J Decolongon, A Sturrock, E Bardinet, C Jauff Ret, D Justo, S Lehericy, C Marelli, K Nigaud, R Valabrègue, SJA van den Bogaard, E M Dumas, J van der Grond, EP t'Hart, C Jurgens, M-N Witjes-Ane, N Arran, J Callaghan, C Stopford, C Frost, R Jones, N Hobbs, N Lahiri, R Ordidge, G Owen, T Pepple, J Read, M Say, E Wild, A Patel, N C Fox, C Gibbard, I Malone, H Crawford, D Whitehead, S Keenan, D M Cash, C Berna, N Bechtel, S Bohlen, A Hoff Man, P Kraus, E Axelson, C Wang, T Acharya, S Lee, W Monaco, C Campbell, S Queller, K Whitlock, M Campbell, E Frajman, C Milchman, A O'Regan, I Labuschagne, J Stout, B Landwehrmeyer, D Craufurd, R Scahill, S Hicks, C Kennard, H Johnson, A Tobin, HD Rosas, R Reilmann, B Borowsky, C Pourchot, S C Andrews, Anne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael Bonelli, Jean-Marc Burgunder, Stephen Dunnett, Joaquim Ferreira, Olivia Handley, Arvid Heiberg, Torsten Illmann, G. Bernhard Landwehrmeyer, Jamie Levey, Maria A. Ramos-Arroyo, Jørgen Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A.C. Roos, A Rojo Sebastián, Sarah Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Monica Bascuñana Garde, Sabrina Betz, Reineke Bos, Jenny Callaghan, Adrien Come, Leonor Correia Guedes, Daniel Ecker, Ana Maria Finisterra, Ruth Fullam, Mette Gilling, Lena Gustafsson, Olivia J Handley, Carina Hvalstedt, Christine Held, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saül Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Michael Orth, Hélène Padieu, Laurent Paterski, Nadia Peppa, Martina Di Renzo, Amandine Rialland, Niini Røren, Pavla Šašinková, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Wildson Vieira da Silva, Marleen R van Walsem, Carina Whalstedt, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Raphael M. Bonelli, Sabine Lilek, Karen Hecht, Brigitte Herranhof, Anna Holl, Hans-Peter Kapfhammer, Michael Koppitz, Markus Magnet, Nicole Müller, Daniela Otti, Annamaria Painold, Karin Reisinger, Monika Scheibl, Helmut Schöggl, Jasmin Ullah, Eva-Maria Braunwarth, Florian Brugger, Lisa Buratti, Eva-Maria Hametner, Caroline Hepperger, Christiane Holas, Anna Hotter, Anna Hussl, Christoph Müller, Werner Poewe, Klaus Seppi, Fabienne Sprenger, Gregor Wenning, Andrea Boogaerts, Godelinde Calmeyn, Isabelle Delvaux, Dirk Liessens, Nele Somers, Michel Dupuit, Cécile Minet, Dominique van Paemel, Pascale Ribaï, Dimphna van Reijen, Jirí Klempír, Veronika Majerová, Jan Roth, Irena Stárková, Lena E. Hjermind, Oda Jacobsen, Jørgen E. Nielsen, Ida Unmack Larsen, Tua Vinther-Jensen, Heli Hiivola, Hannele Hyppönen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau, Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Rekha Barthélémy, Christelle De Bruycker, Maryline Cabaret Anne-Sophie Carette, Eric Decorte Luc Defebvre, Marie Delliaux, Arnaud Delval, Alain Destee, Kathy Dujardin, Marie-Hélène Lemaire, Sylvie Manouvrier, Mireille Peter, Lucie Plomhouse, Bernard Sablonnière, Clémence Simonin, Stéphanie Thibault-Tanchou, Isabelle Vuillaume, Marcellin Bellonet, Hassan Berrissoul, Stéphanie Blin, Françoise Courtin, Cécile Duru, Véronique Fasquel, Olivier Godefroy, Pierre Krystkowiak, Béatrice Mantaux, Martine Roussel, Sandrine Wannepain, Jean-Philippe Azulay, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Laura Mundler, Mathieu Anheim, Celine Julié, Ouhaid Lagha Boukbiza, Nadine Longato, Gabrielle Rudolf, Christine Tranchant, Marie-Agathe Zimmermann, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J. Werner, Harald Gelderblom, Josef Priller, Harald Prüß, Eike Jakob Spruth, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Peter Kotz, Christian Prehn, Carsten Saft, Herwig Lange, Robert Maiwald, Matthias Löhle, Antonia Maass, Simone Schmidt, Cecile Bosredon, Alexander Storch, Annett Wolz, Martin Wolz, Philipp Capetian, Johann Lambeck, Birgit Zucker, Kai Boelmans, Christos Ganos, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Heike Gorzolla, Christoph Schrader, Pawel Tacik, Michael Ribbat, Bernhard Longinus, Katrin Bürk, Jens Carsten Möller, Ida Rissling, Mark Mühlau, Alexander Peinemann, Michael Städtler, Adolf Weindl, Juliane Winkelmann, Cornelia Ziegler, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Eva Hölzner, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Natalia Weber, Matthias Dose, Gabriele Leythäuser, Ralf Marquard, Tina Raab, Alexandra Wiedemann, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Christina Lang, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süßmuth, Sonja Trautmann, Patrick Weydt, Claudia Cormio, Vittorio Sciruicchio, Claudia Serpino, Marina de Tommaso, Sabina Capellari, Pietro Cortelli, Roberto Galassi, Giovanni Rizzo, Roberto Poda, Cesa Scaglione, Elisabetta Bertini, Elena Ghelli, Andrea Ginestroni, Francesca Massaro, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giovanni Abbruzzese, Monica Bandettini di Poggio, Giovanna Ferrandes, Paola Mandich, Roberta Marchese, Alberto Albanese, Daniela Di Bella, Anna Castaldo, Stefano Di Donato, Cinzia Gellera, Silvia Genitrini, Caterina Mariotti, Lorenzo Nanetti, Dominga Paridi, Paola Soliveri, Chiara Tomasello, Giuseppe De Michele, Luigi Di Maio, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Elena Salvatore, Pierpaolo Sorrentino, Enrico Amico, Mariagrazia Favellato, Annamaria Griguoli, Irene Mazzante, Martina Petrollini, Ferdinando Squitieri, Barbara D'Alessio, Chiara Esposito, Rita Bentivoglio, Marina Frontali, Arianna Guidubaldi, Tamara Ialongo, Gioia Jacopini, Carla Piano, Silvia Romano, Francesco Soleti, Maria Spadaro, Monique S.E. van Hout, Marloes E. Verhoeven, Jeroen P.P. van Vugt, A. Marit de Weert, J.J.W. Bolwijn, M. Dekker, B. Kremer, K.L. Leenders, J.C.H. van Oostrom, Simon J.A. van den Bogaard, Eve M. Dumas, Ellen P. 't Hart, Berry Kremer, C.C.P. Verstappen, Olaf Aaserud, Jan Frich C, Ragnhild Wehus, Kathrine Bjørgo, Madeleine Fannemel, Per F. Gørvell, Eirin Lorentzen, Lars Retterstøl, Bodil Stokke, Inga Bjørnevoll, Sigrid Botne Sando, Artur Dziadkiewicz, Malgorzata Nowak, Piotr Robowski, Emilia Sitek, Jaroslaw Slawek, Witold Soltan, Michal Szinwelski, Magdalena Blaszcyk, Magdalena Boczarska-Jedynak, Ewelina Ciach-Wysocka, Agnieszka Gorzkowska, Barbara Jasinska-Myga, Gabriela Klodowska-Duda, Gregorz Opala, Daniel Stompel, Krzysztof Banaszkiewicz, Dorota Bocwinska, Kamila Bojakowska-Jaremek, Malgorzata Dec, Malgorzata Krawczyk, Monika Rudzinska, Elzbieta Szczygiel, Andrzej Szczudlik, Anna Wasielewska, Magdalena Wójcik, Anna Bryl, Anna Ciesielska, Aneta Klimberg, Jerzy Marcinkowski, Husam Samara, Justyna Sempolowicz, Anna Gogol, Piotr Janik, Hubert Kwiecinski, Zygmunt Jamrozik, Jakub Antczak, Katarzyna Jachinska, Wioletta Krysa, Maryla Rakowicz, Przemyslaw Richter, Rafal Rola, Danuta Ryglewicz, Halina Sienkiewicz-Jarosz, Iwona Stepniak, Anna Sulek, Elzbieta Zdzienicka, Karolina Zieora-Jakutowicz, Joaquim J Ferreira, Miguel Coelho, Tiago Mendes, Anabela Valadas, Carlos Andrade, Miguel Gago, Carolina Garrett, Maria Rosália Guerra, Carmen Durán Herrera, Patrocinio Moreno Garcia, Miquel Aguilar Barbera, Dolors Badenes Guia, Laura Casas Hernanz, Judit López Catena, Pilar Quiléz Ferrer, Ana Rojo Sebastián, Gemma Tome Carruesco, Jordi Bas, Núria Busquets, Matilde Calopa, Misericordia Floriach Robert, Celia Mareca Viladrich, Jesús Miguel Ruiz Idiago, Antonio Villa Riballo, Esther Cubo, Cecilia Gil Polo, Natividad Mariscal, Perez Jessica Rivadeneyra, Francisco Barrero, Blas Morales, María Fenollar, Rocío García-Ramos García, Paloma Ortega, Clara Villanueva, Javier Alegre, Mónica Bascuñana, Juan Garcia Caldentey, Marta Fatás Ventura, Guillermo García Ribas, Justo García de Yébenes, José Luis López-Sendón Moreno, Fernando Alonso Frech, Pedro J García Ruíz, Asunción Martínez-Descals, Rosa Guerrero, María José Saiz Artiga, Vicenta Sánchez, María Fuensanta Noguera Perea, Lorenza Fortuna, Salvadora Manzanares, Gema Reinante, María Martirio Antequera Torres, Laura Vivancos Moreau, Sonia González González, Luis Menéndez Guisasola, Carlos Salvador, Esther Suaréz San Martín, Inés Legarda Ramirez, Aranzazú Gorospe, Mónica Rodriguez Lopera, Penelope Navas Arques, María José Torres Rodríguez, Barbara Vives Pastor, Itziar Gaston, Maria Dolores Martinez-Jaurrieta, Jose Manuel Garcia Moreno, Carolina Mendez Lucena, Fatima Damas, Hermoso Eva Pacheco Cortegana, José Chacón Peña, Luis Redondo, Fátima Carrillo, María Teresa Cáceres, Pablo Mir, María José Lama Suarez, Laura Vargas-González, Maria E. Bosca, Francisco Castera Brugada, Juan Andres Burguera, Anabel Campos, Garcia Carmen Peiró Vilaplana, Peter Berglund, Radu Constantinescu, Gunnel Fredlund, Ulrika Høsterey-Ugander, Petra Linnsand, Liselotte Neleborn-Lingefjärd, Magnus Wentzel, Ghada Loutfi, Carina Olofsson, Eva-Lena Stattin, Laila Westman, Birgitta Wikström, Yanik Stebler, Alain Kaelin, Irene Romero, Michael Schüpbach, Sabine Weber Zaugg, Maria Hauer, Roman Gonzenbach, Hans H. Jung, Violeta Mihaylova, Jens Petersen, Roisin Jack, Kirsty Matheson, Zosia Miedzybrodzka, Daniela Rae, Sheila A Simpson, Fiona Summers, Alexandra Ure, Vivien Vaughan, Shahbana Akhtar, Jenny Crooks, Adrienne Curtis, Jenny de Souza, John Piedad, Hugh Rickards, Jan Wright, Elizabeth Coulthard, Louise Gethin, Beverley Hayward, Kasia Sieradzan, Matthew Armstrong, Roger A. Barker, Deidre O'Keefe, Anna Di Pietro, Kate Fisher, Anna Goodman, Susan Hill, Ann Kershaw, Sarah Mason, Nicole Paterson, Lucy Raymond, Rachel Swain, Natalie Valle Guzman, Monica Busse, Cynthia Butcher, Catherine Clenaghan, Sarah Hunt, Una Jones, Hanan Khalil, Michael Owen, Kathleen Price, Anne Rosser, Maureen Edwards, Carrie Ho, Teresa Hughes, Marie McGill, Pauline Pearson, Mary Porteous, Paul Smith, Peter Brockie, Jillian Foster, Nicola Johns, Sue McKenzie, Jean Rothery, Gareth Thomas, Shona Yates, Liz Burrows, Carol Chu, Amy Fletcher, Deena Gallantrae, Stephanie Hamer, Alison Harding, Stefan Klöppel, Alison Kraus, Fiona Laver, Monica Lewis, Mandy Longthorpe, Ivana Markova, Ashok Raman, Nicola Robertson, Mark Silva, Aileen Thomson, Sue Wild, Pam Yardumian, Carole Evans, Deena Gallentrae, Emma Hobson, Stuart Jamieson, Hannah Musgrave, Liz Rowett, Jean Toscano, Colin Bourne, Jackie Clapton, Carole Clayton, Heather Dipple, Dawn Freire-Patino, Janet Grant, Diana Gross, Caroline Hallam, Julia Middleton, Ann Murch, Catherine Thompson, Sundus Alusi, Rhys Davies, Kevin Foy, Emily Gerrans, Louise Pate, Thomasin Andrews, Andrew Dougherty, Charlotte Golding, Fred Kavalier, Hana Laing, Alison Lashwood, Dene Robertson, Deborah Ruddy, Alastair Santhouse, Anna Whaite, Stefania Bruno, Karen Doherty, Salman Haider, Davina Hensman, Nayana Lahiri, Marianne Novak, Aakta Patel, Elisabeth Rosser, Rachel Taylor, Thomas Warner, Edward Wild, Natalie Arran, Judith Bek, David Craufurd, Marianne Hare, Liz Howard, Susan Huson, Liz Johnson, Mary Jones, Helen Murphy, Emma Oughton, Lucy Partington-Jones, Dawn Rogers, Andrea Sollom, Julie Snowden, Cheryl Stopford, Jennifer Thompson, Iris Trender-Gerhard, Nichola Verstraelen, Leann Westmoreland, Richard Armstrong, Kathryn Dixon, Andrea H Nemeth, Gill Siuda, Ruth Valentine, David Harrison, Max Hughes, Andrew Parkinson, Beverley Soltysiak, Oliver Bandmann, Alyson Bradbury, Paul Gill, Helen Fairtlough, Kay Fillingham, Isabella Foustanos, Mbombe Kazoka, Kirsty O'Donovan, Cat Taylor, Katherine Tidswell, Oliver Quarrell, Puay Ngoh Lau, Emmanul Pica, Louis Tan, Univ Angers, Okina, Moss, Davina J. Hensman, Tabrizi, Sarah J, Mead, Simon, Kitty, Lo, Pardiã±as, Antonio F, Holmans, Peter, Jones, Lesley, Langbehn, Dougla, Coleman, A., Santos, R. Dar, Decolongon, J., Sturrock, A., Bardinet, E., Ret, C. Jauff, Justo, D., Lehericy, S., Marelli, C., Nigaud, K., Valabrãgue, R., van den Bogaard, S. J. A., Dumas, E. M., van der Grond, J., T'Hart, E. P., Jurgens, C., Witjes-Ane, M. -. N., Arran, N., Callaghan, J., Stopford, C., Frost, C., Jones, R., Hobbs, N., Lahiri, N., Ordidge, R., Owen, G., Pepple, T., Read, J., Say, M., Wild, E., Patel, A., Fox, N. C., Gibbard, C., Malone, I., Crawford, H., Whitehead, D., Keenan, S., Cash, D. M., Berna, C., Bechtel, N., Bohlen, S., Man, A. Hoff, Kraus, P., Axelson, E., Wang, C., Acharya, T., Lee, S., Monaco, W., Campbell, C., Queller, S., Whitlock, K., Campbell, M., Frajman, E., Milchman, C., O'Regan, A., Labuschagne, I., Stout, J., Landwehrmeyer, B., Craufurd, D., Scahill, R., Hicks, S., Kennard, C., Johnson, H., Tobin, A., Rosas, H. D., Reilmann, R., Borowsky, B., Pourchot, C., Andrews, S. C., Bachoud-LÃ©vi, Anne-Catherine, Bentivoglio, Anna Rita, Biunno, Ida, Bonelli, Raphael, Burgunder, Jean-Marc, Dunnett, Stephen, Ferreira, Joaquim, Handley, Olivia, Heiberg, Arvid, Illmann, Torsten, Landwehrmeyer, G. Bernhard, Levey, Jamie, Ramos-Arroyo, Maria A., Nielsen, Jã¸rgen, Koivisto, Susana Pro, Pã¤ivã¤rinta, Markku, Roos, Raymund A. C., Sebastiã¡n, A. Rojo, Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlstrã¶m, Jan, Zaremba, Jacek, Baake, Verena, Barth, Katrin, Garde, Monica BascuÃ±ana, Betz, Sabrina, Bos, Reineke, Callaghan, Jenny, Come, Adrien, Guedes, Leonor Correia, Ecker, Daniel, Finisterra, Ana Maria, Fullam, Ruth, Gilling, Mette, Gustafsson, Lena, Handley, Olivia J, Hvalstedt, Carina, Held, Christine, Koppers, Kerstin, Lamanna, Claudia, Laurã , Matilde, Descals, AsunciÃ³n MartÃnez, Martinez-Horta, Saã¼l, Mestre, Tiago, Minster, Sara, Monza, Daniela, Mã¼tze, Lisanne, Oehmen, Martin, Orth, Michael, Padieu, Hã©lãne, Paterski, Laurent, Peppa, Nadia, Di Renzo, Martina, Rialland, Amandine, Rã¸ren, Niini, Å aå¡inkovã¡, Pavla, Timewell, Erika, Townhill, Jenny, Cubillo, Patricia Trigo, da Silva, Wildson Vieira, van Walsem, Marleen R, Whalstedt, Carina, Witjes-AnÃ©, Marie-Noelle, Witkowski, Grzegorz, Wright, Abigail, Zielonka, Daniel, Zielonka, Eugeniusz, Zinzi, Paola, Bonelli, Raphael M., Lilek, Sabine, Hecht, Karen, Herranhof, Brigitte, Holl, Anna, Kapfhammer, Hans-Peter, Koppitz, Michael, Magnet, Marku, Mã¼ller, Nicole, Otti, Daniela, Painold, Annamaria, Reisinger, Karin, Scheibl, Monika, Schã¶ggl, Helmut, Ullah, Jasmin, Braunwarth, Eva-Maria, Brugger, Florian, Buratti, Lisa, Hametner, Eva-Maria, Hepperger, Caroline, Holas, Christiane, Hotter, Anna, Hussl, Anna, Mã¼ller, Christoph, Poewe, Werner, Seppi, Klau, Sprenger, Fabienne, Wenning, Gregor, Boogaerts, Andrea, Calmeyn, Godelinde, Delvaux, Isabelle, Liessens, Dirk, Somers, Nele, Dupuit, Michel, Minet, Cã©cile, van Paemel, Dominique, Ribaã¯, Pascale, van Reijen, Dimphna, Klempãr, Jirã, Majerovã¡, Veronika, Roth, Jan, Stã¡rkovã¡, Irena, Hjermind, Lena E., Jacobsen, Oda, Nielsen, JÃ¸rgen E., Larsen, Ida Unmack, Vinther-Jensen, Tua, Hiivola, Heli, Hyppã¶nen, Hannele, Martikainen, Kirsti, Tuuha, Katri, Allain, Philippe, Bonneau, Dominique, Bost, Marie, Gohier, Bã©nã©dicte, Guã©rid, Marie-Anne, Olivier, Audrey, Prundean, 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Natalie, Beckmann, Heike, Bohlen, Stefan, Hã¶lzner, Eva, Reilmann, Ralf, Rohm, Stefanie, Rumpf, Silke, Schepers, Sigrun, Weber, Natalia, Dose, Matthia, Leythã¤user, Gabriele, Marquard, Ralf, Raab, Tina, Wiedemann, Alexandra, Buck, Andrea, Connemann, Julia, Geitner, Carolin, Kesse, Andrea, Landwehrmeyer, Bernhard, Lang, Christina, Lezius, Franziska, Nepper, Solveig, Niess, Anke, Schneider, Ariane, Schwenk, Daniela, Sã¼ã muth, Sigurd, Trautmann, Sonja, Weydt, Patrick, Cormio, Claudia, Sciruicchio, Vittorio, Serpino, Claudia, de Tommaso, Marina, Capellari, Sabina, Cortelli, Pietro, Galassi, Roberto, Rizzo, Giovanni, Poda, Roberto, Scaglione, Cesa, Bertini, Elisabetta, Ghelli, Elena, Ginestroni, Andrea, Massaro, Francesca, Mechi, Claudia, Paganini, Marco, Piacentini, Silvia, Pradella, Silvia, Romoli, Anna Maria, Sorbi, Sandro, Abbruzzese, Giovanni, di Poggio, Monica Bandettini, Ferrandes, Giovanna, Mandich, Paola, Roberta, Marchese, Albanese, Alberto, Di Bella, Daniela, Castaldo, Anna, Di Donato, Stefano, Gellera, Cinzia, Genitrini, Silvia, Mariotti, Caterina, Nanetti, Lorenzo, Paridi, Dominga, Soliveri, Paola, Tomasello, Chiara, De Michele, Giuseppe, Di Maio, Luigi, Massarelli, Marco, Peluso, Silvio, Roca, Alessandro, Russo, Cinzia Valeria, Salvatore, Elena, Sorrentino, Pierpaolo, Amico, Enrico, Favellato, Mariagrazia, Griguoli, Annamaria, Mazzante, Irene, Petrollini, Martina, Squitieri, Ferdinando, D'Alessio, Barbara, Esposito, Chiara, Bentivoglio, Rita, Frontali, Marina, Guidubaldi, Arianna, Ialongo, Tamara, Jacopini, Gioia, Piano, Carla, Romano, Silvia, Soleti, Francesco, Spadaro, Maria, van Hout, Monique S. E., Verhoeven, Marloes E., van Vugt, Jeroen P. P., de Weert, A. Marit, Bolwijn, J. J. W., Dekker, M., Kremer, B., Leenders, K. L., van Oostrom, J. C. H., van den Bogaard, Simon J. A., Dumas, Eve M., â t Hart, Ellen P., Kremer, Berry, Verstappen, C. C. P., Aaserud, Olaf, Jan Frich, C., Wehus, Ragnhild, Bjã¸rgo, Kathrine, Fannemel, Madeleine, Gã¸rvell, Per F., Lorentzen, Eirin, Retterstã¸l, Lar, Stokke, Bodil, Bjã¸rnevoll, Inga, Sando, Sigrid Botne, Dziadkiewicz, Artur, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Blaszcyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasinska-Myga, Barbara, Klodowska-Duda, Gabriela, Opala, Gregorz, Stompel, Daniel, Banaszkiewicz, Krzysztof, Bocwinska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Malgorzata, Krawczyk, Malgorzata, Rudzinska, Monika, Szczygiel, Elzbieta, Szczudlik, Andrzej, Wasielewska, Anna, Wã³jcik, Magdalena, Bryl, Anna, Ciesielska, Anna, Klimberg, Aneta, Marcinkowski, Jerzy, Samara, Husam, Sempolowicz, Justyna, Gogol, Anna, Janik, Piotr, Kwiecinski, Hubert, Jamrozik, Zygmunt, Antczak, Jakub, Jachinska, Katarzyna, Krysa, Wioletta, Rakowicz, Maryla, Richter, Przemyslaw, Rola, Rafal, Ryglewicz, Danuta, Sienkiewicz-Jarosz, Halina, Stepniak, Iwona, Sulek, Anna, Zdzienicka, Elzbieta, Zieora-Jakutowicz, Karolina, Ferreira, Joaquim J, Coelho, Miguel, Mendes, Tiago, Valadas, Anabela, Andrade, Carlo, Gago, Miguel, Garrett, Carolina, Guerra, Maria RosÃ¡lia, Herrera, Carmen DurÃ¡n, Garcia, Patrocinio Moreno, Barbera, Miquel Aguilar, Guia, Dolors Badene, Hernanz, Laura Casa, Catena, Judit LÃ³pez, Ferrer, Pilar QuilÃ©z, Sebastiã¡n, Ana Rojo, Carruesco, Gemma Tome, Bas, Jordi, Busquets, Nãºria, Calopa, Matilde, Robert, Misericordia Floriach, Viladrich, Celia Mareca, Idiago, JesÃºs Miguel Ruiz, Riballo, Antonio Villa, Cubo, Esther, Polo, Cecilia Gil, Mariscal, Natividad, Rivadeneyra, Perez Jessica, Barrero, Francisco, Morales, Bla, Fenollar, Marãa, Garcãa, RocÃo GarcÃa-Ramo, Ortega, Paloma, Villanueva, Clara, Alegre, Javier, Bascuã±ana, Mã³nica, Caldentey, Juan Garcia, Ventura, Marta FatÃ¡, Ribas, Guillermo GarcÃa, de YÃ©benes, Justo GarcÃa, Moreno, JosÃ© Luis LÃ³pez-SendÃ³n, Frech, Fernando Alonso, Ruãz, Pedro J. GarcÃa, MartÃnez-Descals, Asunciã³n, Guerrero, Rosa, Artiga, MarÃa JosÃ© Saiz, Sã¡nchez, Vicenta, Perea, MarÃa Fuensanta Noguera, Fortuna, Lorenza, Manzanares, Salvadora, Reinante, Gema, Torres, MarÃa Martirio Antequera, Moreau, Laura Vivanco, GonzÃ¡lez GonzÃ¡lez, Sonia, Guisasola, Luis MenÃ©ndez, Salvador, Carlo, Martãn, Esther SuarÃ©z San, Ramirez, InÃ©s Legarda, Gorospe, Aranzazãº, Lopera, MÃ³nica Rodriguez, Arques, Penelope Nava, Rodrãguez, MarÃa JosÃ© Torre, Pastor, Barbara Vive, Gaston, Itziar, Martinez-Jaurrieta, Maria Dolore, Moreno, Jose Manuel Garcia, Lucena, Carolina Mendez, Damas, Fatima, Cortegana, Hermoso Eva Pacheco, Peã±a, JosÃ© ChacÃ³n, Redondo, Lui, Carrillo, Fã¡tima, Teresa CÃ¡ceres, Marãa, Mir, Pablo, Suarez, MarÃa JosÃ© Lama, Vargas-GonzÃ¡lez, Laura, Bosca, Maria E., Brugada, Francisco Castera, Burguera, Juan Andre, Campos, Anabel, Vilaplana, Garcia Carmen PeirÃ³, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, HÃ¸sterey-Ugander, Ulrika, Linnsand, Petra, Neleborn-LingefjÃ¤rd, Liselotte, Wentzel, Magnu, Loutfi, Ghada, Olofsson, Carina, Stattin, Eva-Lena, Westman, Laila, Wikstrã¶m, Birgitta, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schã¼pbach, Michael, Weber Zaugg, Sabine, Hauer, Maria, Gonzenbach, Roman, Jung, Hans H., Mihaylova, Violeta, Petersen, Jen, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, Simpson, Sheila A, Summers, Fiona, Ure, Alexandra, Vaughan, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Armstrong, Matthew, Barker, Roger A., O'Keefe, Deidre, Di Pietro, Anna, Fisher, Kate, Goodman, Anna, Hill, Susan, Kershaw, Ann, Mason, Sarah, Paterson, Nicole, Raymond, Lucy, Swain, Rachel, Guzman, Natalie Valle, Busse, Monica, Butcher, Cynthia, Clenaghan, Catherine, Hunt, Sarah, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Edwards, Maureen, Carrie, Ho, Hughes, Teresa, Mcgill, Marie, Pearson, Pauline, Porteous, Mary, Smith, Paul, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Burrows, Liz, Chu, Carol, Fletcher, Amy, Gallantrae, Deena, Hamer, Stephanie, Harding, Alison, Klã¶ppel, Stefan, Kraus, Alison, Laver, Fiona, Lewis, Monica, Longthorpe, Mandy, Markova, Ivana, Raman, Ashok, Robertson, Nicola, Silva, Mark, Thomson, Aileen, Wild, Sue, Yardumian, Pam, Evans, Carole, Gallentrae, Deena, Hobson, Emma, Jamieson, Stuart, Musgrave, Hannah, Rowett, Liz, Toscano, Jean, Bourne, Colin, Clapton, Jackie, Clayton, Carole, Dipple, Heather, Freire-Patino, Dawn, Grant, Janet, Gross, Diana, Hallam, Caroline, Middleton, Julia, Murch, Ann, Thompson, Catherine, Alusi, Sundu, Davies, Rhy, Foy, Kevin, Gerrans, Emily, Pate, Louise, Andrews, Thomasin, Dougherty, Andrew, Golding, Charlotte, Kavalier, Fred, Laing, Hana, Lashwood, Alison, Robertson, Dene, Ruddy, Deborah, Santhouse, Alastair, Whaite, Anna, Bruno, Stefania, Doherty, Karen, Haider, Salman, Hensman, Davina, Lahiri, Nayana, Novak, Marianne, Patel, Aakta, Rosser, Elisabeth, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Rogers, Dawn, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Armstrong, Richard, Dixon, Kathryn, Nemeth, Andrea H, Siuda, Gill, Valentine, Ruth, David, Harrison, Hughes, Max, Parkinson, Andrew, Soltysiak, Beverley, Bandmann, Oliver, Bradbury, Alyson, Gill, Paul, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Kazoka, Mbombe, O'Donovan, Kirsty, Taylor, Cat, Tidswell, Katherine, Quarrell, Oliver, Lau, Puay Ngoh, Pica, Emmanul, Tan, Louis, Amsterdam Neuroscience - Neurodegeneration, Neurology, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Moss, Davina J Hensman, Lo, Kitty, Pardiñas, Antonio F, Santos, R Dar, Ret, C Jauff, Valabrègue, R., Witjes-Ane, M. -N., Man, A Hoff, Bachoud-Lévi, Anne-Catherine, Nielsen, Jørgen, Päivärinta, Markku, Sebastián, A Rojo, Wahlström, Jan, Garde, Monica Bascuñana, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mütze, Lisanne, Padieu, Hélène, Røren, Niini, Šašinková, Pavla, Witjes-Ané, Marie-Noelle, Müller, Nicole, Schöggl, Helmut, Müller, Christoph, Minet, Cécile, Ribaï, Pascale, Klempír, Jirí, Majerová, Veronika, Stárková, Irena, Nielsen, Jørgen E., Hyppönen, Hannele, Gohier, Bénédicte, Guérid, Marie-Anne, Duché, Charlotte, Lafoucrière, Danielle, Barthélémy, Rekha, Lemaire, Marie-Hélène, Sablonnière, Bernard, Simonin, Clémence, Thibault-Tanchou, Stéphanie, Blin, Stéphanie, Courtin, Françoise, Duru, Cécile, Fasquel, Véronique, Mantaux, Béatrice, Fluchere, Frédérique, Julié, Celine, Prüß, Harald, Löhle, Matthia, Münchau, Alexander, Bürk, Katrin, Möller, Jens Carsten, Mühlau, Mark, Städtler, Michael, Hölzner, Eva, Leythäuser, Gabriele, Süßmuth, Sigurd, Marchese, Roberta, DI MAIO, Luigi, ’t Hart, Ellen P., Bjørgo, Kathrine, Gørvell, Per F., Retterstøl, Lar, Bjørnevoll, Inga, Wójcik, Magdalena, Guerra, Maria Rosália, Herrera, Carmen Durán, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastián, Ana Rojo, Busquets, Núria, Idiago, Jesús Miguel Ruiz, Fenollar, María, García, Rocío García-Ramo, Bascuñana, Mónica, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Ruíz, Pedro J García, Martínez-Descals, Asunción, Artiga, María José Saiz, Sánchez, Vicenta, Perea, María Fuensanta Noguera, Torres, María Martirio Antequera, González González, Sonia, Guisasola, Luis Menéndez, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Rodríguez, María José Torre, Peña, José Chacón, Carrillo, Fátima, Teresa Cáceres, María, Suarez, María José Lama, Vargas-González, Laura, Vilaplana, Garcia Carmen Peiró, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Wikström, Birgitta, Schüpbach, Michael, Ho, Carrie, Klöppel, Stefan, Harrison, David, Cardiff University, University of Iowa [Iowa City], University of British Columbia (UBC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UCL, Institute of Neurology [London], National Oceanography Centre [Southampton] (NOC), University of Southampton, Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), TRACK-HD investigators, Pardinas, Antonio F, Langbehn, Douglas, Lee, S Hong, TRACK-HD Investigators, and REGISTRY Investigators
Subjects: 0301 basic medicine, Oncology, Registrie, Genome-wide association study, Longitudinal Studie, Disease, Bioinformatics, Severity of Illness Index, Principal Component Analysi, Longitudinal Studies, Registries, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Huntington disease, DNA-Binding Proteins, Settore MED/26 - NEUROLOGIA, Adult, Genome-Wide Association Study, Humans, Huntington Disease, MutS Homolog 3 Protein, Principal Component Analysis, Disease Progression, Neurology (clinical), huntingtin gene, age of onest, Huntington’s disease, Human, medicine.medical_specialty, cag repeat, instability, DNA-Binding Protein, Clinical Neurology, Principal component analysis, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, Huntington's disease, Internal medicine, medicine, SNP, genome-wide association study, medicine.disease, R1, meta-analysis, Minor allele frequency, 030104 developmental biology, Age of onset, Trinucleotide repeat expansion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.
Published: 2017
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8. Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders

Author: Chiara Perria, Italia Loddo, Marco Seri, Milena Crippa, Stefano Sotgiu, Maria Piccione, Marina Frontali, Lidia Larizza, Elisa Biamino, Palma Finelli, Pamela Magini, Maria Chiara Gandini, Elisa Colombo, Gloria Negri, Antonella Boni, Donatella Milani, Tommaso Pippucci, Michael J. Bamshad, Deborah A. Nickerson, Joshua D. Smith, Elisabetta Di Fede, Cristina Gervasini, Giuseppina Vitiello, Negri G., Magini P., Milani D., Crippa M., Biamino E., Piccione M., Sotgiu S., Perria C., Vitiello G., Frontali M., Boni A., Di Fede E., Gandini M.C., Colombo E.A., Bamshad M.J., Nickerson D.A., Smith J.D., Loddo I., Finelli P., Seri M., Pippucci T., Larizza L., Gervasini C., Negri, Gloria, Magini, Pamela, Milani, Donatella, Crippa, Milena, Biamino, Elisa, Piccione, Maria, Sotgiu, Stefano, Perrìa, Chiara, Vitiello, Giuseppina, Frontali, Marina, Boni, Antonella, Di Fede, Elisabetta, Gandini, Maria Chiara, Colombo, Elisa Adele, Bamshad, Michael J., Nickerson, Deborah A., Smith, Joshua D., Loddo, Italia, Finelli, Palma, Seri, Marco, Pippucci, Tommaso, Larizza, Lidia, and Gervasini, Cristina
Subjects: Male, Genetic Association Studie, Compound heterozygosity, Whole Exome Sequencing, Article, Epigenesis, Genetic, 03 medical and health sciences, whole exome sequencing, Rubinstein–Taybi syndrome, epigenetic mutations, Exome Sequencing, Genetics, medicine, Humans, Epigenetics, EP300, Child, Genetics (clinical), Exome sequencing, Genetic Association Studies, 030304 developmental biology, Rubinstein-Taybi Syndrome, 0303 health sciences, Comparative Genomic Hybridization, biology, Rubinstein–Taybi syndrome, 030305 genetics & heredity, Infant, Newborn, Facies, Infant, medicine.disease, Facie, CREB-Binding Protein, Human genetics, RSTS, KMT2A, Phenotype, Child, Preschool, Mutation, biology.protein, Neurodegenerative disorders, Female, Haploinsufficiency, E1A-Associated p300 Protein, Human
Abstract: Rubinstein–Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60%) or its homologous EP300 (~ 10%). No causative mutation is identified in up to 30% of patients. We performed whole-exome sequencing (WES) on eight RSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative, to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring–Opitz, Kabuki and Wiedemann–Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.
Published: 2018
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9. Leukocyte telomere shortening in Huntington's disease

Author: Martina Peconi, Daniela Scarabino, Rosa Maria Corbo, Marina Frontali, Liana Veneziano, and Elide Mantuano
Subjects: Adult, Male, medicine.medical_specialty, Huntigton Disease, Disease, Neurodegenerative disease, Gastroenterology, CAG expansion, 03 medical and health sciences, Young Adult, 0302 clinical medicine, age of onset, Huntington's disease, Internal medicine, Huntingtin Protein, medicine, Leukocytes, Humans, 030212 general & internal medicine, RNA, Messenger, Young adult, Huntington's disease development, Telomere Shortening, Aged, Analysis of Variance, business.industry, Case-control study, Age Factors, Biomarker, Middle Aged, Telomere, medicine.disease, Leukocyte telomere length, Huntington Disease, Neurology, Case-Control Studies, Disease Progression, Biomarker (medicine), Regression Analysis, Female, Neurology (clinical), Analysis of variance, Trinucleotide repeat expansion, business, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery, Leukocyte Telomere Lenght
Abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. Though symptom onset commonly occurs at midlife and inversely correlates with the CAG repeat expansion, age at clinical onset and progression rate are variable. In the present study we investigated the relationship between leukocyte telomere length (LTL) and HD development. LTL was measured by real-time PCR in manifest HD patients (HD, n = 62), pre-manifest HD patients (pre-HD, n = 38), and age-matched controls (n = 76). Significant LTL differences were observed between the three groups (p < .0001), with LTL values in the order: HD < pre-HD < controls. The relationship between LTL and age was different in the three groups. An inverse relationship between mean LTL and CAG repeat number was found in the pre-HD (p = .03). The overall data seem to indicate that after age 30 years, LT begins to shorten markedly in pre-HD patients according to CAG number and increasing age, up to the values observed in HD. This very suggestive picture allowed us to hypothesize that in pre-manifest HD, LTL could be a measure of time to clinical HD onset. The possible use of LTL as a reliable biomarker to track HD development and progression was evaluated and discussed.
Published: 2018
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10. Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia

Author: Francesco Nicita, Enrico Bertini, Marina Frontali, Giovanni Ristori, Arianna Fornasiero, Silvia Romano, Lorena Travaglini, Giulia Coarelli, Maria Spadaro, Michela Ferraldeschi, and Marco Salvetti
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Pes cavus, Cerebellar ataxia, hereditary spastic paraplegias (HSP), thin corpus callosum (TCC), b-glucosidase 2 gene (GBA2), Corpus Callosum, 03 medical and health sciences, 0302 clinical medicine, medicine, Spastic, Humans, Cognitive decline, Spastic Paraplegia, Hereditary, Genetic heterogeneity, business.industry, beta-Glucosidase, Peripheral Nervous System Diseases, General Medicine, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Pedigree, 030104 developmental biology, Peripheral neuropathy, Mutation, Glucosylceramidase, Surgery, Cerebellar atrophy, Neurology (clinical), medicine.symptom, Paraplegia, business, 030217 neurology & neurosurgery
Abstract: Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurological disorders characterized primarily by a pyramidal syndrome with lower limb spasticity, which can manifest as pure HSP or associated with a number of neurological or non-neurological signs (i.e., complicated HSPs). The clinical variability of HSPs is associated with a wide genetic heterogeneity, with more than eighty causative genes known. Recently, next generation sequencing (NGS) has allowed increasing genetic definition in such a heterogeneous group of disorders. We report on a 56- year-old man affected by sporadic complicated HSP consisting of a pyramidal syndrome, cerebellar ataxia, congenital cataract, pes cavus, axonal sensory-motor peripheral neuropathy and cognitive decline. Brain MRI showed cerebellar atrophy and thin corpus callosum. By NGS we found a novel homozygous biallelic c.452-1G > C mutation in the b-glucosidase 2 gene (GBA2), known to be causative for autosomal recessive hereditary spastic paraplegia type 46 (SPG46). The rarity of this inherited form besides reporting on a novel mutation, expands the genetic and clinical spectrum of SPG46 related HSP.
Published: 2018

11. Affrontare il rischio genetico e preservare la speranza. Storia e risultati di un modello di collaborazione tra ricercatori, medici e famiglie con Malattia di Huntington

Author: Gioia, Jacopini, Marina, Frontali, Maria, Spadaro, Anna Rita, Bentivoglio, Silvia Romano, Carolina, Casciani, Laura, Torrelli, and Francesca, Rosati
Subjects: fattori genetici, corea di huntington, malattia di huntington
Published: 2017

12. Genes that affect synaptic excitability and transmission identified by rare variant analyses in episodic ataxias

Author: Stephanie Efthymiou (1), Vincenzo Salpietro (1), Marisol Sampedro-Castañeda (1), Andreea Manole (1), Thomas Bourinaris (1, Emer O'Connor (1), Liana Veneziano (3), Elide Mantuano (3), Marina Frontali (3), Paola Giunti (1), Richard Boles (4, 5, Elena Dominguez Garrido (7), Conceicao Bettencourt (1), Juan A. Botia (1), Mina Ryten (1), Jana Vandrovcova (1), Samuel McCall (8), Robyn W. Labrum (8), Sameer Zuberi (9), Alfons Macaya (10), Dimitri M. Kullmann (11), Roope Manniko (1), Henry Houlden (1), Michael G. Hanna (1, 12), and SYNAPS Study Group
Subjects: Episodic ataxia, Synaptopathies, Transportopathies, Channelopathies, Paroxysmal neurological disorders
Abstract: The episodic ataxias are a heterogeneous group of paroxysmal neurological disorders characterized by intermittent attacks of unsteadiness and incoordination, often associated with additional neurological features including migraine or hemiplegic migraine, epilepsy, fluctuating weakness, or progressive ataxia. There are at least ten causative genes reported, with some of these only identified in isolated cases or families. Although separate screening studies have been carried out on each of the episodic ataxia genes, so far there has been no report of large study using a next generation sequencing approach in the analysis of these disorders, thus little is known about their molecular heterogeneity. The identification in the present study of rare variants in genes implicated in synaptic excitability and transmission highlight overlapping molecular pathways and pleiotropic clinical presentations in paroxysmal neurological disorders.
Published: 2017

13. Movement disorders and brain iron overload in a new subtype of aceruloplasminemia

Author: Cristina Arosio, Gaetano Salomone, Alberto Piperno, Mariacristina Siotto, Lazzaro di Biase, Massimo Marano, Rosanna Squitti, Federica Scrascia, Carlo Cosimo Quattrocchi, Fabrizio Vernieri, Sara Nuovo, Jean Marc Melgari, Marina Frontali, Riccardo Altavilla, Melgari, J, Marano, M, Quattrocchi, C, Piperno, A, Arosio, C, Frontali, M, Nuovo, S, Siotto, M, Salomone, G, Altavilla, R, di Biase, L, Scrascia, F, Squitti, R, and Vernieri, F
Subjects: medicine.medical_specialty, Neurology, Movement disorders, Tetrabenazine, Chorea, medicine, Ceruloplasmin, Dystonia, NBIA, Adrenergic Uptake Inhibitors, Brain, Diagnosis, Differential, Female, Humans, Iron Metabolism Disorders, Iron Overload, Middle Aged, Movement Disorders, Neurodegenerative Diseases, Treatment Outcome, iron deposit, Aceruloplasminemia, biology, business.industry, aceruloplasminemia, medicine.disease, biology.protein, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, business, Neuroscience, medicine.drug
Abstract: A female patient is reported affected by aceruloplasminemia with absence of iron deposits in liver and other splancnic organs
Published: 2015
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14. Another patient with 12q13 microduplication

Author: C. Palmieri, Anna Maria Nardone, Stefania Zampatti, Francesca Gullotta, M.R. Abate, Marina Frontali, Antonio Novelli, Viola Alesi, and Marta Bertoli
Subjects: Pediatrics, medicine.medical_specialty, Hyperkeratosis, Intellectual disability, Gene duplication, Genetics, medicine, Humans, Child, In Situ Hybridization, Fluorescence, Genetics (clinical), Chromosome 12, Phenocopy, Comparative Genomic Hybridization, Chromosomes, Human, Pair 12, Wolf-Hirschhorn Syndrome, business.industry, medicine.disease, Phenotype, Associated phenotype, Wolf-Hirschhorn syndrome phenocopy, Review Literature as Topic, Homogeneous, Female, 12q13 duplication, Chromosome Deletion, business
Abstract: Interstitial duplication of the long arm of chromosome 12 is a rare cytogenetic condition. While several reports describe distal 12q duplication, only one case report of homogeneous, non-mosaic interstitial 12q13 duplication has been documented to date. The authors of that observation proposed that the associated phenotype represented a phenocopy of Wolf–Hirschhorn syndrome [Dallapiccola et al., 2009]. Only a few other recorded patients with deletion 12q13 → 12q21 involved mosaicism. We describe a new patient with homogeneous 12q13 duplication in a 6-year-old girl who, in early infancy, presented with dysmorphic features suggesting Wolf–Hirschhorn syndrome. What is potentially significant about this patient is that her facial phenotype evolved with age, suggesting a different gestalt in older patients. © 2013 Wiley Periodicals, Inc.
Published: 2013
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15. Clinical manifestations of intermediate allele carriers in Huntington disease

Author: Cubo E., Ramos-Arroyo M. A., Martinez-Horta S., Martinez-Descalls A., Calvo S., Gil-Polo CAnne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael M Bonelli, Jean-Marc Burgunder, Stephen B Dunnett, Joaquim J Ferreira, Olivia J Handley, Arvid Heiberg, Torsten Illmann, G Bernhard Landwehrmeyer, Jamie Levey, Maria Ramos-Arroyo, Jørgen E Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A C Roos, Ana Rojo Sebastián, Sarah J Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Adrien Come, Leonor Correia Guedes, Ana Maria Finisterra, Monica Bascuñana Garde, Reineke Bos, Sabrina Betz, Jenny Callaghan, Selene Capodarca, Sébastien Charpentier, Wildson Vieira da Silva, Martina Di Renzo, Daniel Ecker, Ruth Fullam, Camille Genoves, Mette Gilling, Carina Hvalstedt, Christine Held, Andrea Horta-Barba, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saul Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Helene Padieu, Laurent Paterski, Nadia Peppa, Beate Rindal, Dawn Rogers, Niini Røren, Pavla Šašinková, Yuri Seliverstov, Catherine Taylor, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Marleen R van Walsem, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Elizaveta Yudina, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Cécile Minet, Pascale Ribaï, Dominique Van Paemel, Lena Hjermind, Oda Jacobsen, Suzanne Lindquist, Jørgen Nielsen, Lisbeth Regeur, Jette Stockholm, Ida Unmack Larsen, Christina Vangsted-Hansen, Tua Vinther-Jensen, Pia Eklund, Heli Hiivola, Hannele Hypponen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Julie Prouzet, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Anne-Catherine Bachoud-Lévi, Farideh Badei, Lotfi Boudali, Catherine Bourdet, Laurent Cléret, Maryline Couette, Cécile Focseneanu, Laurie Lemoine, Graça Morgado, Mehdi Sebaiti, Claire Thiriez, Laetitia Vervoitte, Katia Youssov, Jean-Philippe Azulay, Christelle Chabot, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Christine Garreau, Aicha Ghenam, Hélène Grosjean, Laura Mundler, Marielle Nowak, Roland Raseta, Maïté Bertrand, Fabienne Calvas, Samia Cheriet, Laurent Marquine, Michèle Pierre, Jérémie Pariente, Sandrine Rolland, Alice Seris, Valérie Vaquie, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J Werner, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Carsten Saft, Kai Boelmans, Christos Ganos, Ines Goerendt, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Michael Orth, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Flverly Francis, Sabine Gayde-Stephan, Heike Gorzolla, Bianca Kramer, Rebecca Minschke, Christoph Schrader, Pawel Tacik, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Nicole Göpfert, Eva Hölzner, Herwig Lange, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Nathalia Weber, Michael Bachmeier, Matthias Dose, Nina Hofstetter, Ralf Marquard, Alzbeta Mühlbäck, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süssmuth, Sonja Trautmann, Patrick Weydt, Stephan Klebe, Thomas Musacchio, Christine Leypold, Kerstin Nöth, Claudia Cormio, Marina de Tommaso, Anna Rita Dellomonaco, Olimpia Difruscolo, Giovanni Franco, Vittorio Sciruicchio, Claudia Serpino, Michela Figorilli, Francesco Marrosu, Antonella Muroni, Valeria Piras, Melisa Vacca, Caterina Bartoli, Elisabetta Bertini, Fernanda Fortunato, Elena Ghelli, Andrea Ginestroni, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giuseppe De Michele, Luigi Di Maio, Carlo Rinaldi, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Pierpaolo Sorrentino, Elena Salvatore, Tecla Tucci, Milena Cannella, Valentina Codella, Francesca De Gregorio, Annunziata De Nicola, Francesca Elifani, Tiziana Martino, Francesca Lovo, Irene Mazzante, Martina Petrollini, Maria Simonelli, Ferdinando Squitieri, Maurizio Vezza, Barbara D'Alessio, Chiara Esposito, Giulia Coarelli, Michela Ferraldeschi, Marina Frontali, Gioia Jacopini, Giovanni Ristori, Silvia Romano, Monique S E van Hout, Jeroen P P van Vugt, A Marit de Weert, Marloes Verhoeven, Simon J A van den Bogaard, Eve M Dumas, Ellen P 't Hart, Milou Jacobs, Anne Kampstra, Anne Schoonderbeek, Nils Olav Aanonsen, Olaf Aaserud, Liv Barnett, Kathrine Bjørgo, Nancy Borgerød, Elisabeth Dramstad, Madeleine Fannemel, Jan Frich, Helen Gundersen, Per Gørvell, Kathrine Haggag, Cecilie Haggag Johannessen, Lars Retterstøl, Oddveig Rosby, Jutta Rummel, Alma Sikiric, Olga Solberg, Marleen van Walsem, Ragnhild Wehus, Artur Dziadkiewicz, Agnieszka Konkel, Ewa Narożańska, Malgorzata Nowak, Piotr Robowski, Emilia Sitek, Jaroslaw Slawek, Witold Soltan, Michal Szinwelski, Michał Arkuszewski, Magdalena Błaszczyk, Magdalena Boczarska-Jedynak, Ewelina Ciach-Wysocka, Agnieszka Gorzkowska, Barbara Jasińska-Myga, Aleksandra Kaczmarczyk, Gabriela Kłodowska-Duda, Grzegorz Opala, Monika Rudzińska, Daniel Stompel, Krzysztof Banaszkiewicz, Dorota Boćwińska, Kamila Bojakowska-Jaremek, Małgorzata Dec, Natalia Grabska, Malgorzata Krawczyk, Ewelina Kubowicz, Michalina Malec-Litwinowicz, Agata Stenwak, Andrzej Szczudlik, Elżbieta Szczygieł, Magdalena Wójcik, Anna Wasielewska, Jacek Anioła Anna Bryl, Anna Ciesielska, Aneta Klimberg, Jerzy Marcinkowski, Husam Samara, Justyna Sempołowicz, Bartłomiej Wiśniewski, Anna Gogol, Piotr Janik, Zygmunt Jamrozik, Anna Kaminska, Hubert Kwiecinski, Jakub Antczak, Katarzyna Jachinska, Wioletta Krysa, Maryla Rakowicz, Przemyslaw Richter, Rafal Rola, Danuta Ryglewicz, Halina Sienkiewicz-Jarosz, Iwona Stępniak, Anna Sułek, Elzbieta Zdzienicka, Karolina Ziora-Jakutowicz, Cristina Januário, Filipa Júlio, Ana Salgueiro, Miguel Coelho, Tiago Mendes, Mário Miguel Rosa, Anabela Valadas, Cristina Semedo, Ana Calado, Joana Morgado, Margarida Dias, Manuel Almeida, Carmen Durán Herrera, Patrocinio Garcia Moreno, Jordi Bas, Núria Busquets, Matilde Calopa, Serge Jaumà Classen, Nadia Rodríguez Dedichá, Miquel Aguilar Barbera, Sonia Arribas Pardo, Dolors Badenes Guia, Noemi Calzado, Laura Casas Hernanz, Juan Pablo Tartari Díaz-Zorita, Judit López Catena, Pilar Quiléz Ferrer, Gemma Tome Carruesco, Misericordia Floriach Robert, Cèlia Mareca Viladrich, Elvira Roca, Jesús Miguel Ruiz Idiago, Antonio Villa Riballo, Antonia Campolongo, Ramon Fernandez de Bobadilla, Jaime Kulisevsky Bojarsky, Javier Pagonabarraga, Jesus Perez Perez, Carolina Villa, Maria Angeles Acera Gil, Koldo Berganzo Corrales, Juan Carlos Gomez Esteban, Amaia González, Beatriz Tijero Merino, Esther Cubo, Natividad Mariscal, Sandra Gutierrez Romero, José Matías Arbelo, Rocío Malo de Molina, Idaira Martín, Juan Manuel Periañez, Beatriz Udaeta, Fernando Alonso-Frech, Belén Frades, Marina Ávila Villanueva, Maria Ascension Zea Sevilla, Fernando Alonso Frech, María Del Mar Fenollar, Rocío García-Ramos García, Clara Villanueva, Mónica Bascuñana, Marta Fatás Ventura, Juan García Caldentey, Guillermo García Ribas, Justo García de Yébenes, José Luis López-Sendón Moreno, Verónica Mañanes Barral, Cici Feliz Feliz, Pedro José García Ruíz, Ana García, Rosa Guerrero López, Antonio Herranz Bárcenas, Asunción Martínez-Descals, Angel Martínez Pueyo, Veronica Puertas Martin, Noelia Rodríguez Martínez, María José Sainz Artiga, Vicenta Sánchez, Javier Del Val Fernandez, Carmen Antúnez Almagro, Salvadora Manzanares, Juan Marín Muñoz, María Martirio Antequera Torres, Fuensanta Noguera Perea, Laura Vivancos Moreau, Sonia González, Luis Menéndez Guisasola, Carlos Salvador, René Ribacoba, Pablo Sánchez Lozano, Marta Para Prieto, Aránzazu Gorospe, Inés Legarda Ramirez, Penelope Navas Arques, Monica Rodriguez Lopera, Barbara Vives Pastor, Itziar Gaston, Maria Antonia Ramos-Arroyo, Maria Dolores Martinez-Jaurrieta, José Manuel García Moreno, Carolina Mendez Lucena, José Chacón Peña, Fátima Damas Hermoso, Eva Pacheco Cortegana, Luis Redondo, Cristina Melgar Fernandez, Maite Paredes Mata, Maria Dolores Romero Lemos, Maria Bosca, Juan Andres Burguera, Francisco Castera Brugada Carmen Peiró Vilaplana, Elena Bellosta Diago, Javier López Del Val, Laura Martinez Martinez, Elena López, Peter Berglund, Radu Constantinescu, Gunnel Fredlund, Ulrika Høsterey-Ugander, Liselotte Neleborn-Lingefjärd, Yanik Stebler, Alain Kaelin, Irene Romero, Michael Schüpbach, Sabine Weber Zaugg, Lorna Downie, Roisin Jack, Kirsty Matheson, Zosia Miedzybrodzka, Daniela Rae, Sheila A Simpson, Fiona Summers, Alexandra Ure, Vivien Vaughn, Shahbana Akhtar, Jenny Crooks, Adrienne Curtis, Jenny de Souza, John Piedad, Hugh Rickards, Jan Wright, Elizabeth Coulthard, Louise Gethin, Beverley Hayward, Kasia Sieradzan, Monica Busse, Cynthia Butcher, Stephen Dunnett, Catherine Clenaghan, Sarah Hunt, Lesley Jones, Una Jones, Hanan Khalil, Michael Owen, Kathleen Price, Anne Rosser, Peter Brockie, Jillian Foster, Nicola Johns, Sue McKenzie, Jean Rothery, Gareth Thomas, Shona Yates, Alyson Andrew, Julie Frost, Rupert Noad, Jeremy Cosgrove, Deena Gallantree, Stephanie Hamer, Emma Hobson, Stuart Jamieson, Alison Kraus, Mandy Longthorpe, Ivana Markova, Hannah Musgrave, Caroline Peacy, Ashok Raman, Liz Rowett, Jean Toscano, Sue Wild, Carole Clayton, Pam Yardumian, Heather Dipple, Dawn Freire- Patino, Caroline Hallam, Julia Middleton, Uruj Anjum, Jan Coebergh, Charlotte Eddy, Nayana Lahiri, Meriel McEntagart, Michael Patton, Maria Peterson, Sarah Rose, Thomasin Andrews, Stefanie Brown, Stefania Bruno, Elvina Chu, Karen Doherty, Charlotte Golding, Salman Haider, Davina Hensman, Monica Lewis, Marianne Novak, Aakta Patel, Joy Read, Nicola Robertson, Elisabeth Rosser, Sarah Tabrizi, Rachel Taylor, Thomas Warner, Edward Wild, Natalie Arran, Judith Bek, David Craufurd, Marianne Hare, Liz Howard, Susan Huson, Liz Johnson, Mary Jones, Ashok Krishnamoorthy, Helen Murphy, Emma Oughton, Lucy Partington-Jones, Andrea Sollom, Julie Snowden, Cheryl Stopford, Jennifer Thompson, Iris Trender-Gerhard, Nichola Verstraelen, Leann Westmoreland, Ginette Cass, Lynn Davidson, Jill Davison, Neil Fullerton, Katrina Holmes, Suresh Komati, Sharon McDonnell, Zeid Mohammed, Karen Morgan, Lois Savage, Baldev Singh, Josh Wood, Andrea H Nemeth, Gill Siuda, Ruth Valentine, Kathryn Dixon, Richard Armstrong, David Harrison, Max Hughes, Sandra Large, John O Donovan, Amy Palmer, Andrew Parkinson, Beverley Soltysiak, Leanne Timings, Josh Williams, Oliver Bandmann, Alyson Bradbury, Helen Fairtlough, Kay Fillingham, Isabella Foustanos, Paul Gill, Mbombe Kazoka, Kirsty O'Donovan, Louise Nevitt, Oliver Quarrell, Cat Taylor, Katherine Tidswell, Lesley Gowers, Kingsley Powell, Pamela Bethwaite, Rachel Edwards, Kathleen Fuller, Michelle Phillips, Univ Angers, Okina, E., Cubo, M. A., Ramos-Arroyo, S., Martinez-Horta, A., Martinez-Descall, S., Calvo, CAnne-Catherine Bachoud-Lévi, Gil-Polo, Rita Bentivoglio, Anna, Biunno, Ida, M Bonelli, Raphael, Burgunder, Jean-Marc, B Dunnett, Stephen, J Ferreira, Joaquim, J Handley, Olivia, Heiberg, Arvid, Illmann, Torsten, Bernhard Landwehrmeyer, G, Levey, Jamie, Ramos-Arroyo, Maria, E Nielsen, Jørgen, Pro Koivisto, Susana, Päivärinta, Markku, C Roos, Raymund A, Rojo Sebastián, Ana, J Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlström, Jan, Zaremba, Jacek, Baake, Verena, Barth, Katrin, Come, Adrien, Correia Guedes, Leonor, Maria Finisterra, Ana, Bascuñana Garde, Monica, Bos, Reineke, Betz, Sabrina, Callaghan, Jenny, Capodarca, Selene, Charpentier, Sébastien, Vieira da Silva, Wildson, Di Renzo, Martina, Ecker, Daniel, Fullam, Ruth, Genoves, Camille, Gilling, Mette, Hvalstedt, Carina, Held, Christine, Horta-Barba, Andrea, Koppers, Kerstin, Lamanna, Claudia, Laurà, Matilde, Martínez Descals, Asunción, Martinez-Horta, Saul, Mestre, Tiago, Minster, Sara, Monza, Daniela, Mütze, Lisanne, Oehmen, Martin, Padieu, Helene, Paterski, Laurent, Peppa, Nadia, Rindal, Beate, Rogers, Dawn, Røren, Niini, Šašinková, Pavla, Seliverstov, Yuri, Taylor, Catherine, Timewell, Erika, Townhill, Jenny, Trigo Cubillo, Patricia, R van Walsem, Marleen, Witjes-Ané, Marie-Noelle, Witkowski, Grzegorz, Wright, Abigail, Yudina, Elizaveta, Zielonka, Daniel, Zielonka, Eugeniusz, Zinzi, Paola, Minet, Cécile, Ribaï, Pascale, Van Paemel, Dominique, Hjermind, Lena, Jacobsen, Oda, Lindquist, Suzanne, Nielsen, Jørgen, Regeur, Lisbeth, Stockholm, Jette, Unmack Larsen, Ida, Vangsted-Hansen, Christina, Vinther-Jensen, Tua, Eklund, Pia, Hiivola, Heli, Hypponen, Hannele, Martikainen, Kirsti, Tuuha, Katri, Allain, Philippe, Bonneau Marie Bost, Dominique, Gohier, Bénédicte, Guérid, Marie-Anne, Olivier, Audrey, Prouzet, Julie, Prundean, Adriana, Scherer-Gagou, Clarisse, Verny, Christophe, Babiloni, Blandine, Debruxelles, Sabrina, Duché, Charlotte, Goizet, Cyril, Jameau, Laetitia, Lafoucrière, Danielle, Spampinato, Umberto, Bachoud-Lévi, Anne-Catherine, Badei, Farideh, Boudali, Lotfi, Bourdet, Catherine, Cléret, Laurent, Couette, Maryline, Focseneanu, Cécile, Lemoine, Laurie, Morgado, Graça, Sebaiti, Mehdi, Thiriez, Claire, Vervoitte, Laetitia, Youssov, Katia, Azulay, Jean-Philippe, Chabot, Christelle, Delfini, Marie, Eusebio, Alexandre, Fluchere, Frédérique, Garreau, Christine, Ghenam, Aicha, Grosjean, Hélène, Mundler, Laura, Nowak, Marielle, Raseta, Roland, Bertrand, Maïté, Calvas, Fabienne, Cheriet, Samia, Marquine, Laurent, Pierre, Michèle, Pariente, Jérémie, Rolland, Sandrine, Seris, Alice, Vaquie, Valérie, Michael Kosinski, Christoph, Milkereit, Eva, Probst, Daniela, Reetz, Kathrin, Sass, Christian, Schiefer, Johanne, Schlangen, Christiane, J Werner, Corneliu, Ellrichmann, Gisa, Herrmann, Lennard, Hoffmann, Rainer, Kaminski, Barbara, Saft, Carsten, Boelmans, Kai, Ganos, Christo, Goerendt, Ine, Heinicke, Walburgi, Hidding, Ute, Lewerenz, Jan, Münchau, Alexander, Orth, Michael, Schmalfeld, Jenny, Stubbe, Lar, Zittel, Simone, Diercks, Gabriele, Dressler, Dirk, Francis, Flverly, Gayde-Stephan, Sabine, Gorzolla, Heike, Kramer, Bianca, Minschke, Rebecca, Schrader, Christoph, Tacik, Pawel, Bechtel, Natalie, Beckmann, Heike, Bohlen, Stefan, Göpfert, Nicole, Hölzner, Eva, Lange, Herwig, Reilmann, Ralf, Rohm, Stefanie, Rumpf, Silke, Schepers, Sigrun, Weber, Nathalia, Bachmeier, Michael, Dose, Matthia, Hofstetter, Nina, Marquard, Ralf, Mühlbäck, Alzbeta, Buck, Andrea, Connemann, Julia, Geitner, Carolin, Kesse, Andrea, Landwehrmeyer, Bernhard, Lezius, Franziska, Nepper, Solveig, Niess, Anke, Schneider, Ariane, Schwenk, Daniela, Süssmuth, Sigurd, Trautmann, Sonja, Weydt, Patrick, Klebe, Stephan, Musacchio, Thoma, Leypold, Christine, Nöth, Kerstin, Cormio, Claudia, de Tommaso, Marina, Rita Dellomonaco, Anna, Difruscolo, Olimpia, Franco, Giovanni, Sciruicchio, Vittorio, Serpino, Claudia, Figorilli, Michela, Marrosu, Francesco, Muroni, Antonella, Piras, Valeria, Vacca, Melisa, Bartoli, Caterina, Bertini, Elisabetta, Fortunato, Fernanda, Ghelli, Elena, Ginestroni, Andrea, Mechi, Claudia, Paganini, Marco, Piacentini, Silvia, Pradella, Silvia, Maria Romoli, Anna, Sorbi, Sandro, DE MICHELE, Giuseppe, Di Maio, Luigi, Rinaldi, Carlo, Massarelli, Marco, Peluso, Silvio, Roca, Alessandro, Russo, CINZIA VALERIA, Sorrentino, Pierpaolo, Salvatore, Elena, Tucci, Tecla, Cannella, Milena, Codella, Valentina, De Gregorio, Francesca, De Nicola, Annunziata, Elifani, Francesca, Martino, Tiziana, Lovo, Francesca, Mazzante, Irene, Petrollini, Martina, Simonelli, Maria, Squitieri, Ferdinando, Vezza, Maurizio, D'Alessio, Barbara, Esposito, Chiara, Coarelli, Giulia, Ferraldeschi, Michela, Frontali, Marina, Jacopini, Gioia, Ristori, Giovanni, Romano, Silvia, E van Hout, Monique S, P van Vugt, Jeroen P, Marit de Weert, A, Verhoeven, Marloe, A van den Bogaard, Simon J, M Dumas, Eve, P 't Hart, Ellen, Jacobs, Milou, Kampstra, Anne, Schoonderbeek, Anne, Olav Aanonsen, Nil, Aaserud, Olaf, Barnett, Liv, Bjørgo, Kathrine, Borgerød, Nancy, Dramstad, Elisabeth, Fannemel, Madeleine, Frich, Jan, Gundersen, Helen, Gørvell, Per, Haggag, Kathrine, Haggag Johannessen, Cecilie, Retterstøl, Lar, Rosby, Oddveig, Rummel, Jutta, Sikiric, Alma, Solberg, Olga, van Walsem, Marleen, Wehus, Ragnhild, Dziadkiewicz, Artur, Konkel, Agnieszka, Narożańska, Ewa, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Arkuszewski, Michał, Błaszczyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasińska-Myga, Barbara, Kaczmarczyk, Aleksandra, Kłodowska-Duda, Gabriela, Opala, Grzegorz, Rudzińska, Monika, Stompel, Daniel, Banaszkiewicz, Krzysztof, Boćwińska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Małgorzata, Grabska, Natalia, Krawczyk, Malgorzata, Kubowicz, Ewelina, Malec-Litwinowicz, Michalina, Stenwak, Agata, Szczudlik, Andrzej, Szczygieł, Elżbieta, Wójcik, Magdalena, Wasielewska, Anna, Anioła Anna Bryl, Jacek, Ciesielska, Anna, Klimberg, Aneta, Marcinkowski, Jerzy, Samara, Husam, Sempołowicz, Justyna, Wiśniewski, Bartłomiej, Gogol, Anna, Janik, Piotr, Jamrozik, Zygmunt, Kaminska, Anna, Kwiecinski, Hubert, Antczak, Jakub, Jachinska, Katarzyna, Krysa, Wioletta, Rakowicz, Maryla, Richter, Przemyslaw, Rola, Rafal, Ryglewicz, Danuta, Sienkiewicz-Jarosz, Halina, Stępniak, Iwona, Sułek, Anna, Zdzienicka, Elzbieta, Ziora-Jakutowicz, Karolina, Januário, Cristina, Júlio, Filipa, Salgueiro, Ana, Coelho, Miguel, Mendes, Tiago, Miguel Rosa, Mário, Valadas, Anabela, Semedo, Cristina, Calado, Ana, Morgado, Joana, Dias, Margarida, Almeida, Manuel, Durán Herrera, Carmen, Garcia Moreno, Patrocinio, Bas, Jordi, Busquets, Núria, Calopa, Matilde, Jaumà Classen, Serge, Rodríguez Dedichá, Nadia, Aguilar Barbera, Miquel, Arribas Pardo, Sonia, Badenes Guia, Dolor, Calzado, Noemi, Casas Hernanz, Laura, Pablo Tartari Díaz-Zorita, Juan, López Catena, Judit, Quiléz Ferrer, Pilar, Tome Carruesco, Gemma, Floriach Robert, Misericordia, Mareca Viladrich, Cèlia, Roca, Elvira, Miguel Ruiz Idiago, Jesú, Villa Riballo, Antonio, Campolongo, Antonia, Fernandez de Bobadilla, Ramon, Kulisevsky Bojarsky, Jaime, Pagonabarraga, Javier, Perez Perez, Jesu, Villa, Carolina, Angeles Acera Gil, Maria, Berganzo Corrales, Koldo, Carlos Gomez Esteban, Juan, González, Amaia, Tijero Merino, Beatriz, Cubo, Esther, Mariscal, Natividad, Gutierrez Romero, Sandra, Matías Arbelo, José, Malo de Molina, Rocío, Martín, Idaira, Manuel Periañez, Juan, Udaeta, Beatriz, Alonso-Frech, Fernando, Frades, Belén, Ávila Villanueva, Marina, Ascension Zea Sevilla, Maria, Alonso Frech, Fernando, Del Mar Fenollar, María, García-Ramos García, Rocío, Villanueva, Clara, Bascuñana, Mónica, Fatás Ventura, Marta, García Caldentey, Juan, García Ribas, Guillermo, García de Yébenes, Justo, Luis López-Sendón Moreno, José, Mañanes Barral, Verónica, Feliz Feliz, Cici, José García Ruíz, Pedro, García, Ana, Guerrero López, Rosa, Herranz Bárcenas, Antonio, Martínez-Descals, Asunción, Martínez Pueyo, Angel, Puertas Martin, Veronica, Rodríguez Martínez, Noelia, José Sainz Artiga, María, Sánchez, Vicenta, Del Val Fernandez, Javier, Antúnez Almagro, Carmen, Manzanares, Salvadora, Marín Muñoz, Juan, Martirio Antequera Torres, María, Noguera Perea, Fuensanta, Vivancos Moreau, Laura, González, Sonia, Menéndez Guisasola, Lui, Salvador, Carlo, Ribacoba, René, Sánchez Lozano, Pablo, Para Prieto, Marta, Gorospe, Aránzazu, Legarda Ramirez, Iné, Navas Arques, Penelope, Rodriguez Lopera, Monica, Vives Pastor, Barbara, Gaston, Itziar, Antonia Ramos-Arroyo, Maria, Dolores Martinez-Jaurrieta, Maria, Manuel García Moreno, José, Mendez Lucena, Carolina, Chacón Peña, José, Damas Hermoso, Fátima, Pacheco Cortegana, Eva, Redondo, Lui, Melgar Fernandez, Cristina, Paredes Mata, Maite, Dolores Romero Lemos, Maria, Bosca, Maria, Andres Burguera, Juan, Castera Brugada Carmen Peiró Vilaplana, Francisco, Bellosta Diago, Elena, López Del Val, Javier, Martinez Martinez, Laura, López, Elena, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schüpbach, Michael, Weber Zaugg, Sabine, Downie, Lorna, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, A Simpson, Sheila, Summers, Fiona, Ure, Alexandra, Vaughn, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Busse, Monica, Butcher, Cynthia, Dunnett, Stephen, Clenaghan, Catherine, Hunt, Sarah, Jones, Lesley, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Andrew, Alyson, Frost, Julie, Noad, Rupert, Cosgrove, Jeremy, Gallantree, Deena, Hamer, Stephanie, Hobson, Emma, Jamieson, Stuart, Kraus, Alison, Longthorpe, Mandy, Markova, Ivana, Musgrave, Hannah, Peacy, Caroline, Raman, Ashok, Rowett, Liz, Toscano, Jean, Wild, Sue, Clayton, Carole, Yardumian, Pam, Dipple, Heather, Freire- Patino, Dawn, Hallam, Caroline, Middleton, Julia, Anjum, Uruj, Coebergh, Jan, Eddy, Charlotte, Lahiri, Nayana, Mcentagart, Meriel, Patton, Michael, Peterson, Maria, Rose, Sarah, Andrews, Thomasin, Brown, Stefanie, Bruno, Stefania, Chu, Elvina, Doherty, Karen, Golding, Charlotte, Haider, Salman, Hensman, Davina, Lewis, Monica, Novak, Marianne, Patel, Aakta, Read, Joy, Robertson, Nicola, Rosser, Elisabeth, Tabrizi, Sarah, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Krishnamoorthy, Ashok, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Cass, Ginette, Davidson, Lynn, Davison, Jill, Fullerton, Neil, Holmes, Katrina, Komati, Suresh, Mcdonnell, Sharon, Mohammed, Zeid, Morgan, Karen, Savage, Loi, Singh, Baldev, Wood, Josh, H Nemeth, Andrea, Siuda, Gill, Valentine, Ruth, Dixon, Kathryn, Armstrong, Richard, Harrison, David, Hughes, Max, Large, Sandra, O Donovan, John, Palmer, Amy, Parkinson, Andrew, Soltysiak, Beverley, Timings, Leanne, Williams, Josh, Bandmann, Oliver, Bradbury, Alyson, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Gill, Paul, Kazoka, Mbombe, O'Donovan, Kirsty, Nevitt, Louise, Quarrell, Oliver, Taylor, Cat, Tidswell, Katherine, Gowers, Lesley, Powell, Kingsley, Bethwaite, Pamela, Edwards, Rachel, Fuller, Kathleen, Phillips, Michelle, Cubo, E., Ramos-Arroyo, M. A., Martinez-Horta, S., Martinez-Descalls, A., Russo, C. V., Calvo, S., Gil-Polo, C., Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Ramos-Arroyo, María A., Martínez-Descalls, Asunción, Calvo, Sara, and Gil-Polo, Cecilia
Subjects: 0301 basic medicine, Registrie, Adult, Male, medicine.medical_specialty, Aging, Heterozygote, Genetic counseling, Motor Disorders, Disease, Severity of Illness Index, 03 medical and health sciences, Cognition Disorder, 0302 clinical medicine, Trinucleotide Repeats, Internal medicine, medicine, Humans, Registries, Allele, Motor Disorder, Alleles, Huntingtin Protein, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Medicine (all), Trinucleotide Repeat, Cognition, Genetic Status, Middle Aged, Phenotype, Europe, Settore MED/26 - NEUROLOGIA, 030104 developmental biology, Huntington Disease, Case-Control Studies, Cohort, medicine (all), neurology (clinical), controlled clinical trial (topic), Quality of Life, Female, Neurology (clinical), business, Case-Control Studie, Cognition Disorders, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Human
Abstract: International audience; OBJECTIVE: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry.METHODS: We assessed a cohort of participants at risk with RESULTS: Of 12,190 participants, 657 (5.38%) with CONCLUSIONS: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling.CLINICALTRIALSGOV IDENTIFIER: NCT01590589.
Published: 2016

16. DRPLA.Synonym: Dentatorubral-Pallidoluysian Atrophy

Author: Liana Veneziano and PhD and Marina Frontali
Subjects: DRPLA Clinical characteristics. Diagnosis/testing. Management. Genetic counseling, education
Abstract: GeneReviews, an international point-of-care resource for busy clinicians, provides clinically relevant and medically actionable information for inherited conditions in a standardized journal-style format, covering diagnosis, management, and genetic counseling for patients and their families. Each chapter in GeneReviews is written by one or more experts on the specific condition or disease and goes through a rigorous editing and peer review process before being published online. In this chapter Dr VENEZIANO and Dr FRONTALI revises the Clinical characteristics, Diagnosis, testing, Management and Genetic counseling of Dentatorubral-pallidoluysian atrophy, commonly known as DRPLA, a progressive brain disorder that causes involuntary movements, mental and emotional problems.
Published: 2016

17. Rhabdoid tumor predisposition syndrome caused by SMARCB1 constitutional deletion: prenatal detection of new case of recurrence in siblings due to gonadal mosaicism

Author: Irene Paganini, Laura Gigante, Laura Papi, Marina Frontali, Federica Sangiuolo, and Serena Ciabattoni
Subjects: Male, 0301 basic medicine, Proband, Cancer Research, Pathology, medicine.medical_specialty, Chromosomal Proteins, Non-Histone, Prenatal diagnosis, Loss of Heterozygosity, SMARCB1, Germline mosaicism, 030105 genetics & heredity, Biology, medicine.disease_cause, Rhabdoid Tumor Predisposition Syndrome, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Pregnancy, Gonadal mosaicism, Genetics, medicine, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Genetics (clinical), Mutation, 22q deletion, Brain Neoplasms, Mosaicism, Siblings, Infant, SMARCB1 Protein, Kidney Neoplasms, Human genetics, Pedigree, DNA-Binding Proteins, Oncology, Settore MED/03 - Genetica Medica, 030220 oncology & carcinogenesis, Cancer research, Female, Rhabdoid tumor, Multiplex Polymerase Chain Reaction, Transcription Factors
Abstract: Rhabdoid tumors are aggressive malignancies that show loss-of-function mutations of SMARCB1 gene, a member of the SWI/SNF chromatin-remodeling complex controlling gene transcription. One-third of patients affected by rhabdoid tumor harbor a germ-line mutation of SMARCB1 defining a rhabdoid tumor predisposition syndrome. The occurrence of a second somatic mutation determines the development of neoplasia in a two-hit model. Most germ-line mutations occur de novo, and few cases of recurrence in a sibship have been described. Here we report on a new Italian family with recurrence of SMARCB1 germ-line deletion in two siblings due to gonadal mosaicism. The deletion was identified in the 9-month-old proband with malignant rhabdoid tumor of the right kidney and disseminated metastases. Testing of both parents confirmed the de novo origin of the mutation, but recurrence was then detected prenatally in a new pregnancy. This is the sixth family with malignant rhabdoid tumor predisposition syndrome with the recurrence of the same germ-line SMARCB1 mutation in the sibship but not in healthy parents, suggesting that gonadal mosaicism is a less rare event than supposed. The clinical outcome in our patient confirms previous data of poorer outcome in patients with rhabdoid tumor predisposition syndrome.
Published: 2016
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18. TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington’s disease

Author: Tammy Gillis, Tiffany C. Hadzi, Ruth K. Abramson, Andrea Novelletto, Eliana Marisa Ramos, Ira Shoulson, Marcy E. MacDonald, Ronald J. Trent, Ferdinando Squitieri, Madaline B. Harrison, Russell L. Margolis, James F. Gusella, Estrella Gómez-Tortosa, Ji Hyun Lee, Steven M. Hersch, Patrick J. Morrison, Karen Marder, Carmen Ayuso, Shotaro Kishikawa, H. D. Rosas, Oksana Suchowersky, Elizabeth McCusker, Randi Jones, Audrey E. Hendricks, Andrea Zanko, Diane Lucente, Jayalakshmi S. Mysore, G. Bernhard Landwehrmeyer, Christopher A. Ross, Samuel Frank, Cinzia Gellera, Martha Nance, Jong-Min Lee, Marina Frontali, Tetsuo Ashizawa, Marie Saint-Hilaire, Richard H. Myers, Michael R. Hayden, and Jorge Sequeiros
Subjects: Adult, Male, Adolescent, Biophysics, Disease, Biology, Biochemistry, Article, Young Adult, Receptors, Kainic Acid, Genetic, Trinucleotide Repeats, Huntington's disease, Polymorphism (computer science), GRIK2, Codon, Terminator, Age of Onset, Polymorphism, Genetic, Humans, Aged, Child, Child, Preschool, Alleles, Aged, 80 and over, Middle Aged, 3' Untranslated Regions, Female, Huntington Disease, Receptors, 80 and over, medicine, Terminator, Polymorphism, Allele, Young adult, Codon, Preschool, Molecular Biology, Genetics, Kainic Acid, Cell Biology, medicine.disease, Settore BIO/18 - Genetica, biology.protein, Age of onset, Trinucleotide repeat expansion
Abstract: Huntington's disease is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat whose length is the major determinant of age at onset but remaining variation appears to be due in part to the effect of genetic modifiers. GRIK2, which encodes GluR6, a mediator of excitatory neurotransmission in the brain, has been suggested in several studies to be a modifier gene based upon a 3′ untranslated region TAA trinucleotide repeat polymorphism. Prior to investing in detailed studies of the functional impact of this polymorphism, we sought to confirm its effect on age at onset in a much larger dataset than in previous investigations. We genotyped the HD CAG repeat and the GRIK2 TAA repeat in DNA samples from 2,911 Huntington's disease subjects with known age at onset, and tested for a potential modifier effect of GRIK2 using a variety of statistical approaches. Unlike previous reports, we detected no evidence of an influence of the GRIK2 TAA repeat polymorphism on age at motor onset. Similarly, the GRIK2 polymorphism did not show significant modifier effect on psychiatric and cognitive age at onset in HD. Comprehensive analytical methods applied to a much larger sample than in previous studies do not support a role for GRIK2 as a genetic modifier of age at onset of clinical symptoms in Huntington's disease.
Published: 2012
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19. Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset

Author: Estrella Gómez-Tortosa, Ferdinando Squitieri, Marie-Helene Saint-Hilaire, Isabel Alonso, Marcy E. MacDonald, James F. Gusella, Samuel Frank, Marina Frontali, H. D. Rosas, Andrea Novelletto, Richard H. Myers, Ji Hyun Lee, Martha Nance, Madaline B. Harrison, Russell L. Margolis, Stefano Di Donato, Jong-Min Lee, Elizabeth McCusker, Karen Marder, Steven M. Hersch, Oksana Suchowersky, Randi Jones, Jeanne C. Latourelle, Diane Lucente, Jayalakshmi S. Mysore, Ronald J. Trent, Eliana Marisa Ramos, Tetsuo Ashizawa, Patrick J. Morrison, Tammy Gillis, Carmen Ayuso, Andrea Zanko, Christopher A. Ross, Michael R. Hayden, Jorge Sequeiros, and Alba Di Pardo
Subjects: Adult, Male, Population, Nerve Tissue Proteins, Biology, Population stratification, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Genotype, Genetics, Humans, Genetics(clinical), Allele, Age of Onset, education, Genetics (clinical), Heat-Shock Proteins, 030304 developmental biology, Genetic association, Original Investigation, 0303 health sciences, education.field_of_study, Huntingtin Protein, Middle Aged, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Minor allele frequency, Europe, Settore BIO/18 - Genetica, Genetics, Population, Huntington Disease, Female, Age of onset, Trinucleotide repeat expansion, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p
Published: 2012

20. Common SNP-Based Haplotype Analysis of the 4p16.3 Huntington Disease Gene Region

Author: H. D. Rosas, Marie Saint-Hilaire, Richard H. Myers, Carmen Ayuso, James F. Gusella, Madaline B. Harrison, Stefano Di Donato, Diane Lucente, Samuel Frank, Marina Frontali, Andrea Zanko, Karen Marder, Oksana Suchowersky, Ruth K. Abramson, Ronald J. Trent, Ferdinando Squitieri, Martha Nance, Eliana Marisa Ramos, Estrella Gómez-Tortosa, Jong-Min Lee, Jayalakshmi S. Mysore, Marcy E. MacDonald, Tetsuo Ashizawa, Steven M. Hersch, Andrea Novelletto, Elizabeth McCusker, Christopher A. Ross, Randi Jones, Annamaria Griguoli, Russell L. Margolis, Michael R. Hayden, Jorge Sequeiros, Tammy Gillis, and Patrick J. Morrison
Subjects: Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Trinucleotide Repeats, Genetic variation, Genetics, Humans, Genetics(clinical), Age of Onset, Allele, education, Alleles, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, Haplotype, Founder Effect, Settore BIO/18 - Genetica, Huntington Disease, Haplotypes, Case-Control Studies, Mutation, Chromosomes, Human, Pair 4, Trinucleotide repeat expansion, 030217 neurology & neurosurgery, Genome-Wide Association Study, Founder effect
Abstract: Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of “synthetic association” with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.
Published: 2012
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21. Corrigendum to 'Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia' [Clin. Neurol. Neurosurg. 168 (May) (2018) 60–63]

Author: Arianna Fornasiero, Michela Ferraldeschi, Giulia Coarelli, Marco Salvetti, Enrico Bertini, Giovanni Ristori, Lorena Travaglini, Maria Spadaro, Francesco Nicita, Silvia Romano, and Marina Frontali
Subjects: business.industry, Mutation (genetic algorithm), Spastic, Medicine, Surgery, Neurology (clinical), General Medicine, Bioinformatics, business, Paraplegia, medicine.disease
Published: 2018
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22. Riluzole in cerebellar ataxia: A randomized, double-blind, placebo-controlled pilot trial

Author: Nicola Vanacore, Marina Frontali, Maria Spadaro, Giovanni Ristori, Silvia Romano, Stefania Cannoni, Francesco E. Pontieri, Andrea Visconti, and Marco Salvetti
Subjects: Adult, Male, medicine.medical_specialty, Cerebellar Ataxia, Pilot Projects, Placebo, Severity of Illness Index, law.invention, Young Adult, Double-Blind Method, Randomized controlled trial, law, Internal medicine, Outcome Assessment, Health Care, Severity of illness, Confidence Intervals, Odds Ratio, Humans, Medicine, Aged, Riluzole, Cerebellar ataxia, business.industry, Odds ratio, Middle Aged, Surgery, Clinical trial, Neuroprotective Agents, Female, International Cooperative Ataxia Rating Scale, Neurology (clinical), medicine.symptom, business, Follow-Up Studies, medicine.drug
Abstract: BACKGROUND: The pleiotropic effects of riluzole may antagonize common mechanisms underlying chronic cerebellar ataxia, a debilitating and untreatable consequence of various diseases. METHODS: In a randomized, double-blind, placebo-controlled pilot trial, 40 patients presenting with cerebellar ataxias of different etiologies were randomly assigned to riluzole (100 mg/day) or placebo for 8 weeks. The following outcome measures were compared: proportion of patients with a decrease of at least 5 points in the International Cooperative Ataxia Rating Scale (ICARS) total score after 4 and 8 weeks compared with the baseline score; mean changes from the baseline to posttreatment ICARS (total score and subscores at 8 weeks); and occurrence of adverse events. RESULTS: Riluzole and placebo groups did not differ in baseline characteristics. The number of patients with a 5-point ICARS drop was significantly higher in the riluzole group than in the placebo group after 4 weeks (9/19 vs 1/19; odds ratio [OR] = 16.2; 95% confidence interval [CI ] 1.8-147.1) and 8 weeks (13/19 vs 1/19; OR = 39.0; 95% CI 4.2-364.2). The mean change in the riluzole group ICARS after treatment revealed a decrease (p < 0.001) in the total score (-7.05 [4.96] vs 0.16 [2.65]) and major subscores (-2.11 [2.75] vs 0.68 [1.94] for static function, -4.11 [2.96] vs 0.37 [2.0] for kinetic function, and -0.74 [0.81] vs 0.05 [0.40] for dysarthria). Sporadic, mild adverse events occurred. CONCLUSIONS: These findings indicate the potential effectiveness of riluzole as symptomatic therapy in diverse forms of cerebellar ataxia. Classification of evidence: This study provides Class I evidence that riluzole reduces, by at least 5 points, the ICARS score in patients with a wide range of disorders that cause cerebellar ataxia (risk difference 63.2%, 95% CI 33.5%-79.9%).
Published: 2010
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23. EMQN Best Practice Guidelines for molecular genetic testing of SCAs

Author: Jorge, Sequeiros, Joanne, Martindale, Sara, Seneca, Paola, Giunti, Outi, Kämäräinen, Victor, Volpini, Helga, Weirich, Kyproula, Christodoulou, Nazli, Bazak, Richard, Sinke, Anna, Sulek-Piatkowska, Javier, Garcia-Planells, Mark, Davis, Marina, Frontali, Petra, Hämäläinen, Stefan, Wieczorek, Christine, Zühlke, Maria-Luiza, Saraiva-Pereira, Jon, Warner, Eric, Leguern, Francine, Thonney, Beatriz, Quintáns Castro, Jenni, Jonasson, Katrien, Storm, Anna, Andersson, Anna, Ravani, Luís, Correia, Isabel, Silveira, Isabel, Alonso, Carla, Martins, Jorge, Pinto Basto, Paula, Coutinho, Andreia, Perdigão, David, Barton, and Mary, Davis
Subjects: Policy, Molecular genetic testing, Best practice, media_common.quotation_subject, Genetics, Humans, Spinocerebellar Ataxias, Art history, Professional practice, Genetic Testing, Art, Genetics (clinical), media_common
Abstract: Other participants at the EMQN Best Practice Meeting and/or at the electronic discussions thereafter were Isabel Alonso, Anna Andersson, David Barton, Nazli Bazac, Kyproula Christodoulou, Luís Correia, Mark Davis, Mary Davis, Rob Elles, Marina Frontali, Javier Garcia-Planells, Paola Giunti, Petra Hämäläinen, Jenni Jonasson, Outi Kamarainen, Nina Larsson, Eric Leguern, Monique Losekoot, Carla Martins, Michael Morris, Clemens Müller-Reible, Simon Patton, M Luiza Saraiva-Pereira, Jorge Pinto-Basto, Beatriz Quintáns, Simon C Ramsden, Anna Ravani, Laura Rooke, Isabel Silveira, Richard Sinke, Su Stenhouse, Laura Stewart, Katrien Storm, Anna Sulek-Piatkowska, Francine Thonney, Victor Volpini, Jon Warner, Helga Weirich, Stefan Wieczorek and Christine Zühlke.
Published: 2010
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24. Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea

Author: Liana Veneziano, Donato Civitareale, Marina Frontali, Claudia Provenzano, and Richard Appleton
Subjects: Genetic Markers, Cytoplasm, Heterozygote, endocrine system, Thyroid Nuclear Factor 1, Genotype, Choreiform movement, DNA Mutational Analysis, Gene mutation, Biology, Benign hereditary chorea, Chorea, medicine, Animals, Humans, Point Mutation, Genetic Predisposition to Disease, Respiratory function, Brain Chemistry, Cell Nucleus, Genetics, Wild type, Brain, Infant, Nuclear Proteins, Rats, Phenotype, England, Haplotypes, Neurology, Codon, Nonsense, Mutation, Female, Neurology (clinical), medicine.symptom, Haploinsufficiency, Transcription Factors
Abstract: Benign hereditary chorea (BHC) is an autosomal dominant disorder of early onset characterised by non progressive choreic movements with normal cognitive function occasionally associated with hypothyroidism and respiratory problems. Numerous pieces of evidence link BHC with TITF-1/NKX2.1 gene mutations. We studied a patient with a familial benign hereditary chorea and normal thyroid and respiratory function. Sequence analysis of TITF-1 revealed the presence of a heterozygous C>T substitution at nucleotide 532, predicted to change an arginine (CGA) with a stop codon (TGA) at position 178 (R178X). A functional analysis shows that the mutated TTF-1 is not binding DNA, nor activating the canonical thyroid target gene promoter or interfering with the ability of wild type TTF-1 to activate transcription. In addition, the mutated protein is predominantly cytoplasmic, rather than nuclear as in the case of the wild type TTF-1. Thus, we have identified a new mutation in the TTF-1 coding gene in a patient with benign hereditary chorea. The results show that the mutation leads to a haploinsufficiency of TITF-1 and opens the question of genotype/phenotype correlation.
Published: 2008
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25. Analyzing the Effects of a G137V Mutation in the FXN Gene

Author: Annalisa Pastore, Tommaso Vannocci, Roberto Testi, Silvia Fortuni, Nathalie Faggianelli, Rita Puglisi, Silvia Romano, Marina Frontali, Liana Veneziano, Faggianelli, Nathalie, Puglisi, Rita, Veneziano, Liana, Romano, Silvia, Frontali, Marina, Vannocci, Tommaso, Fortuni, Silvia, Testi, Roberto, and Pastore, Annalisa
Subjects: functional mutants, Ataxia, functional mutant, medicine.disease_cause, Cellular and Molecular Neuroscience, Disease mechanisms, Frataxin, Friedreich’s ataxia, Functional mutants, Protein folding, disease mechanisms, protein folding, medicine, Gene silencing, disease mechanism, friedreich's ataxia, Molecular Biology, Gene, frataxin, friedreich’s ataxia, cellular and molecular neuroscience, molecular biology, Original Research, Genetics, Settore MED/04 - Patologia Generale, Mutation, biology, Point mutation, Heterozygote advantage, Phenotype, biology.protein, medicine.symptom, Neuroscience
Abstract: Reduced levels of frataxin, an essential mitochondrial protein involved in the regulation of iron-sulfur cluster biogenesis, are responsible for the recessive neurodegenerative Friedreich Ataxia (FRDA). Expansion of a GAA triplet in the first intron of the FRDA is essential for disease development which causes partial silencing of frataxin. In the vast majority of cases, patients are homozygotes for the expansion, but a small number of FRDA patients are heterozygotes for expansion and point mutations in the frataxin coding frame. In this study, we analyze the effects of a point mutation G137V. The patient P94–2, with a history of alcohol and drug abuse, showed a FRDA onset at the border between the classic and late onset phenotype. We applied a combination of biophysical and biochemical methods to characterize its effects on the structure, folding and activity of frataxin. Our study reveals no impairment of the structure or activity of the protein but a reduced folding stability. We suggest that the mutation causes misfolding of the native chain with consequent reduction of the protein concentration in the patient and discuss the possible mechanism of disease.
Published: 2015
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26. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial

Author: Giulia Coarelli, Carlo Casali, Marina Frontali, Luca Leonardi, Maria Chiara Vulpiani, Silvia Romano, Nicola Vanacore, Antonio Petrucci, Maria Spadaro, Federica Ponzelli, Giovanni Ristori, Francesca Piccolo, Christian Marcotulli, Michela Ferraldeschi, Francesco Orzi, and Marco Salvetti
Subjects: Adult, Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Ataxia, Neurology, liver enzyme, placebo, riluzole, Placebo-controlled study, Placebo, Severity of Illness Index, law.invention, Double-Blind Method, Randomized controlled trial, law, Internal medicine, atassia di Friedreich, Clinical endpoint, Humans, Spinocerebellar Ataxias, Medicine, riluzolo, Riluzole, Cerebellar ataxia, business.industry, atassia spinocerebellare, Middle Aged, medicine.disease, nervous system diseases, Treatment Outcome, nervous system, Friedreich Ataxia, Spinocerebellar ataxia, Physical therapy, Female, Neurology (clinical), medicine.symptom, business, Excitatory Amino Acid Antagonists, medicine.drug
Abstract: Summary Background Our previous study in patients with cerebellar ataxias of different causes showed significant benefit of riluzole after 8 weeks. We aimed to confirm these results in patients with spinocerebellar ataxia or Friedreich's ataxia in a 1-year trial. Methods Patients with spinocerebellar ataxia or Friedreich's ataxia (2:1 ratio) from three Italian neurogenetic units were enrolled in this multicentre, double-blind, placebo-controlled trial, and randomly assigned to riluzole (50 mg orally, twice daily) or placebo for 12 months. The randomisation list was computer-generated and a centralised randomisation system was implemented. Participants and assessing neurologists were masked to treatment allocation. The primary endpoint was the proportion of patients with improved Scale for the Assessment and Rating of Ataxia (SARA) score (a drop of at least one point) at 12 months. An intention-to-treat analysis was done. This trial is registered at ClinicalTrials.gov, number NCT01104649. Findings Between May 22, 2010, and Feb 25, 2013, 60 patients were enrolled. Two patients in the riluzole group and three in the placebo group withdrew their consent before receiving treatment, so the intention-to-treat analysis was done on 55 patients (19 with spinocerebellar ataxia and nine with Friedreich's ataxia in the riluzole group, and 19 with spinocerebellar ataxia and eight with Friedreich's ataxia in the placebo group). The proportion with decreased SARA score was 14 (50%) of 28 patients in the riluzole group versus three (11%) of 27 in the placebo group (OR 8·00, 95% CI 1·95–32·83; p=0·002). No severe adverse events were recorded. In the riluzole group, two patients had an increase in liver enzymes (less than two times above normal limits). In two participants in the riluzole group and two participants in the placebo group, sporadic mild adverse events were reported. Interpretation Our findings lend support to the idea that riluzole could be a treatment for cerebellar ataxia. Longer studies and disease-specific trials are needed to confirm whether these findings can be applied in clinical practice. Funding Agenzia Italiana del Farmaco.
Published: 2015
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27. Diagnostic genetic testing for Huntington's disease

Author: Asunción Martinez, Oliver Quarrell, Raymund A.C. Roos, David Craufurd, Lena E. Hjermind, Mary B. Davis, Paola Mandich, Emilia K. Bijlsma, Nayana Lahiri, Rhona MacLeod, Aad Tibben, and Marina Frontali
Subjects: medicine.medical_specialty, Pediatrics, medicine.diagnostic_test, Autosomal dominant trait, Neurogenetics, General Medicine, Gene mutation, medicine.disease, Huntington's Disease Diagnostic genetic test, Huntington Disease, Huntington's disease, Mutation (genetic algorithm), medicine, Huntingtin Protein, Humans, Genetic Testing, Neurology (clinical), Psychiatry, Psychology, Predictive testing, Genetic testing
Abstract: Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by a combination of motor abnormalities (chorea, dystonia, hypokinesia), cognitive impairment and neuropsychiatric symptoms, including depression, irritability and apathy. The age at onset is typically 35–45 years but it can present in juveniles and the elderly.1 The disease slowly progresses over 15–20 years.1 It is inherited as an autosomal dominant trait, with each child of an affected parent having a 50% risk of carrying the gene mutation and therefore of developing HD themselves. The cause is a CAG trinucleotide expansion mutation in the HTT gene that encodes the ubiquitously expressed huntingtin protein. Genetic testing by direct mutation analysis has been available clinically since the mutation was identified in 1993.2 Measurement of the CAG repeat length acts as a trait marker rather than a state marker; that is, the genetic test can be used either to confirm a clinical diagnosis of HD in symptomatic people or to predict whether or not an at-risk person will go on to develop HD. An abnormal result indicates that the person will one day develop HD, but gives no indication of his or her clinical state at the time of testing. The pretest counselling requirements differ for diagnostic and presymptomatic (predictive) testing. The variety and complexity of clinical situations where diagnostic genetic testing for HD may be indicated make it impractical to construct guidelines such as those governing predictive testing.3 ,4 The purpose of this article is to draw the attention of neurologists and psychiatrists to the challenges and pitfalls encountered in diagnostic testing for HD. We make the following recommendations to guide practice and help ensure the best possible outcome for individuals and their family. A diagnostic genetic test is carried out where an individual is already symptomatic. According to current convention, …
Published: 2015
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28. Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease

Author: Colin J. D. Ross, Estrella Gómez-Tortosa, L. A. Cupples, Qiong Yang, Catherine Dodé, Martha Nance, Ronald J. Trent, Ruth K. Abramson, Elizabeth McCusker, Luc Djoussé, D. Mayo, Marina Frontali, Patrick J. Morrison, Jane S. Paulsen, Randi Jones, Russell L. Margolis, Ryan R. Brinkman, Madeline Harrison, J. F. Gusella, Andrea Zanko, Oksana Suchowersky, Adam Rosenblatt, Alexandra Durr, Richard H. Myers, Andrea Novelletto, E. Almqvist, Beth Knowlton, Marcy E. MacDonald, and Michael R. Hayden
Subjects: Genetics, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Biology, Heritability, medicine.disease, Central nervous system disease, Degenerative disease, Endocrinology, Internal medicine, Cohort, medicine, Allele, Age of onset, Trinucleotide repeat expansion, Genetics (clinical), Cohort study
Abstract: Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.
Published: 2003
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29. Spinocerebellar ataxia type 6 and episodic ataxia type 2: differences and similarities between two allelic disorders

Author: Liana Veneziano, Marina Frontali, C. Jodice, and Elide Mantuano
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Ataxia, Biology, Genetics, medicine, Point Mutation, Spinocerebellar Ataxias, Humans, Spinocerebellar ataxia type 6, Allele, Molecular Biology, Gene, Alleles, Genetics (clinical), Familial hemiplegic migraine, Point mutation, Calcium Channels, Trinucleotide Repeat Expansion, medicine.disease, Settore BIO/18 - Genetica, Spinocerebellar ataxia, medicine.symptom, Trinucleotide repeat expansion
Abstract: Spinocerebellar ataxia type 6 (SCA6) is one of three allelic disorders caused by mutations of CACNA1A gene, coding for the pore-forming subunit of calcium channel type P/Q. SCA6 is associated with small expansions of a CAG repeat at the 3′ end of the gene, while point mutations are responsible for its two allelic disorders (Episodic Ataxia type 2 and Familial Hemiplegic Migraine). Genetic, clinical, pathological and pathophysiological data of SCA6 patients are reviewed and compared to those of other SCAs with expanded CAG repeats as well as to those of its allelic channelopathies, with particular reference to Episodic Ataxia type 2. Overall SCA6 appears to share features with both types of disorders, and the question as to whether it belongs to polyglutamine disorders or to channelopathies remains unanswered at present.
Published: 2003
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30. A shared haplotype for dentatorubropallidoluysian atrophy (DRPLA) in Italian families testifies of the recent introduction of the mutation

Author: Elide Mantuano, Liana Veneziano, Marina Frontali, Claudio Catalli, Alexandra Durr, Maria Spadaro, Cinzia Gellera, Silvia Romano, and Andrea Novelletto
Subjects: Male, Cag expansion, haplotype/polyglutamine expansion diseases, atn1, genetic dating, haplotype, gene flow, polyglutamine expansion diseases, dentatorubropallidoluysian atrophy, drpla, Extended haplotype, Population, Biology, Gene flow, Genetics, Humans, education, Base Pairing, Genetics (clinical), Recombination, Genetic, education.field_of_study, Settore BIO/18, Haplotype, Neurodegenerative Diseases, Dentatorubropallidoluysian atrophy, Pedigree, Haplotypes, Italy, Genetic marker, Mutation, Mutation (genetic algorithm), Female, Atrophy
Abstract: To clarify the population history of dentatorubropallidoluysian atrophy ( DRPLA) in Italy and to date back the introduction of the mutation, we reconstructed extended haplotypes flanking the CAG repeat in 10 patients of Italian ancestry, analyzing their similarity/dissimilarity as a function of distance from the CAG repeat. Our aim was to compare the hypothesis of a single, recent genealogy connecting all the observed haplotypes with the alternative hypothesis of multiple introductions by more distantly related haplotypes from outer sources. Polymorphic DNA markers were chosen to cover a region of 153 kb flanking the CAG repeat, that is, informative for dating the age of the DNA segment unaffected by recombination. In all patients, an expansion of the ATN1 CAG segment was confirmed residing onto the same narrow haplotype described to be associated with the CAG expansion in the Japanese and Portuguese populations. We also observed the disruption of the DRPLA haplotype at longer distances, on both sides of the CAG. Our results are compatible with a single founder in the last 600 years, most likely before the last 270 years. These estimates for the Sicilian population largely overlap a period in which the Japanese haplotype with the DRPLA mutation could have been introduced by the Portuguese maritime travelers.
Published: 2014
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31. Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL: A Randomized Controlled Trial

Author: Leonardo Pantoni, Francesco Orzi, Valentina Sedda, Raffaella Valenti, Alessandra Tavani, Marina Frontali, Elisabetta Spagnolo, Marina Parolini, Domenico Inzitari, Nicola De Stefano, Maria Teresa Dotti, Jonica Campolo, Oberdan Parodi, Caterina Mariotti, Chiara Tomasello, Silvia Romano, Claudio Pelucchi, Antonio Federico, Renata De Maria, Francesca Pescini, Franco Taroni, Ada Francia, Emanuele Puca, and Maria Laura Stromillo
Subjects: Adult, Male, medicine.medical_specialty, Vascular smooth muscle, Endothelium, endothelium, Vasodilation, Hyperemia, CADASIL, Nitric oxide, Leukoencephalopathy, chemistry.chemical_compound, Double-Blind Method, vascular, nitric oxide, Internal medicine, randomized controlled trial, tetrahydrobiopterin, Medicine, Humans, Reactive hyperemia, Aged, Advanced and Specialized Nursing, business.industry, Tetrahydrobiopterin, Middle Aged, medicine.disease, Biopterin, medicine.anatomical_structure, chemistry, Anesthesia, Cardiology, Female, Neurology (clinical), Endothelium, Vascular, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract: Background and Purpose— Cerebral autosomal–dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. Methods— In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. Results— The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, −0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. Conclusions— Sapropterin was safe and well-tolerated at the average dose of 5 mg/kg/day, but did not affect endothelium-dependent vasodilation in CADASIL patients. Clinical Trial Registration— URL: https://www.clinicaltrialsregister.eu . Unique identifier: 2007-004370-55.
Published: 2014
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32. Localization of a Novel Locus for Autosomal Recessive Early-Onset Parkinsonism, PARK6, on Human Chromosome 1p35-p36

Author: Anna Rita Bentivoglio, Enza Maria Valente, Marina Frontali, Alberto Albanese, Alessandro Ferraris, Tamara Ialongo, Peter H. Dixon, and Nicholas W. Wood
Subjects: Adult, Genetic Markers, Male, Genetic Linkage, Ubiquitin-Protein Ligases, Genes, Recessive, Locus (genetics), Biology, Parkin, Ligases, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Parkinsonian Disorders, Genetic linkage, Genetics, medicine, Humans, Genetics(clinical), Age of Onset, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Genetic heterogeneity, Parkinsonism, Homozygote, Haplotype, Chromosome Mapping, Proteins, Articles, Middle Aged, medicine.disease, Pedigree, nervous system diseases, 3. Good health, Phenotype, Haplotypes, Italy, Chromosomes, Human, Pair 1, Genetic marker, Female, Lod Score, Age of onset, 030217 neurology & neurosurgery
Abstract: The cause of Parkinson disease (PD) is still unknown, but genetic factors have recently been implicated in the etiology of the disease. So far, four loci responsible for autosomal dominant PD have been identified. Autosomal recessive juvenile parkinsonism (ARJP) is a clinically and genetically distinct entity; typical PD features are associated with early onset, sustained response to levodopa, and early occurrence of levodopa-induced dyskinesias, which are often severe. To date, only one ARJP gene, Parkin, has been identified, and multiple mutations have been detected both in families with autosomal recessive parkinsonism and in sporadic cases. The Parkin-associated phenotype is broad, and some cases are indistinguishable from idiopathic PD. In > or = 50% of families with ARJP that have been analyzed, no mutations could be detected in the Parkin gene. We identified a large Sicilian family with four definitely affected members (the Marsala kindred). The phenotype was characterized by early-onset (range 32-48 years) parkinsonism, with slow progression and sustained response to levodopa. Linkage of the disease to the Parkin gene was excluded. A genomewide homozygosity screen was performed in the family. Linkage analysis and haplotype construction allowed identification of a single region of homozygosity shared by all the affected members, spanning 12.5 cM on the short arm of chromosome 1. This region contains a novel locus for autosomal recessive early-onset parkinsonism, PARK6. A maximum LOD score 4.01 at recombination fraction .00 was obtained for marker D1S199.
Published: 2001
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33. Italian family with cranial cervical dystonia: Clinical and genetic study

Author: Enza Maria Valente, Emanuele Cassetta, Alberto Albanese, Anna Rita Bentivoglio, Marina Frontali, and Nicoletta Del Grosso
Subjects: Proband, Dystonia, medicine.medical_specialty, Pediatrics, business.industry, Neurological disorder, Disease, medicine.disease, Dyt1 gene, Surgery, Family member, Neurology, Genetic linkage, medicine, Neurology (clinical), Cervical dystonia, business
Abstract: A white Italian family affected by primary torsion dystonia (PTD) is described. The family phenotype most commonly presented with adult onset, cranial cervical involvement, and focal or segmental distribution without progression to generalization. Thirty-nine family members and nine spouses were studied. Five subjects received a diagnosis of definite PTD, three of probable PTD. Age at onset was in adulthood for all. In four definitely affected subjects, dystonia started in the cranial or cervical districts; in one it presented as writer's cramp. Familial writer's cramp also occurred in the family of the unrelated parent of the latter patient. The mean age at time of examination was 61.8 years in the individuals with a definite diagnosis; 60 in those with a probable diagnosis. At the time of examination, in most of the affected subjects, dystonia was focal; in three cases (two definitely and one probably affected), it was segmental. DNA linkage analysis, although limited by the size of the family, suggested exclusion of linkage between the disease and known PTD loci (DYT6 and DYT7). The GAG deletion in the DYT1 gene was excluded in the proband and in the family member affected by writer's cramp.
Published: 1999
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34. Localization and genomic structure of human deoxyhypusine synthase gene on chromosome 19p13.2-distal 19p13.1

Author: Anne S. Olsen, Elide Mantuano, Carla Jodice, Flavia Trettel, Greg Lennon, and Marina Frontali
Subjects: DNA, Complementary, cell proliferation, dhps gene isoforms, hypusine biosynthesis, Molecular Sequence Data, DHPS, Chromosomes, Exon, chemistry.chemical_compound, Complementary, Genetics, Humans, Deoxyhypusine synthase, Coding region, Oxidoreductases Acting on CH-NH Group Donors, Chromosome Mapping, Isoenzymes, Genes, Chromosomes, Human, Pair 19, Exons, Introns, Alternative Splicing, Hypusine, Pair 19, biology, Alternative splicing, Intron, DNA, General Medicine, Deoxyhypusine Hydroxylase, Molecular biology, Settore BIO/18 - Genetica, chemistry, biology.protein, Human
Abstract: The amino acid hypusine is formed post-translationally in a single cellular protein, the eukaryotic translation initiation factor 5A, by two enzymes, namely deoxyhypusine synthase and deoxyhypusine hydroxylase. Hypusine is found in all eukaryotes and in some archaebacteria, but not in eubacteria. The deoxyhypusine synthase cDNA was cloned and mapped by fluorescence in situ hybridization on chromosome 19p13.11-p13.12. Rare cDNAs containing internal deletions were also found. We localized the deoxyhypusine synthase gene on a high resolution cosmid/BAC contig map of chromosome 19 to a region in 19p13.2-distal 19p13.1 between MANB and JUNB. Analysis of the genomic exon/intron structure of the gene coding region showed that it consists of nine exons and spans a length of 6.6 kb. From observation of the genomic structure, it seems likely that the internally deleted forms of mature RNA are the result of alternative splicing, rather than of artifacts.
Published: 1998
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35. The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates

Author: Nw Wood, Marina Frontali, Elide Mantuano, Paola Giunti, Mb Davis, Liana Veneziano, G. Sabbadini, R Plasmati, MG Sweeney, and Antonio Federico
Subjects: Adult, Male, Aging, Spinocerebellar Ataxia Type 1, Adolescent, Cerebellar Ataxia, Biology, Gene Frequency, Trinucleotide Repeats, Autosomal dominant cerebellar ataxia, medicine, Humans, Allele, Genes, Dominant, Spinocerebellar Degenerations, Genetics, Sex Characteristics, Cerebellar ataxia, Haplotype, Middle Aged, medicine.disease, Haplotypes, Mutation, Spinocerebellar ataxia, Female, Neurology (clinical), medicine.symptom, Trinucleotide repeat expansion, Machado–Joseph disease
Abstract: The spinocerebellar ataxia type 2 (SCA2) is caused by a trinucleotide (CAG) expansion in the coding region of the ataxin 2 gene on chromosome 12q.89 families with autosomal dominant cerebellar ataxia (ADCA) types I, II and III, and 47 isolated cases with idiopathic late onset cerebellar ataxia (ILOCA), were analysed for this mutation. The identification of the SCA2 mutation in 31 out of 38 families with the ADCA I phenotype, but in none of those with ADCA II, ADCA III or ILOCA confirms the specificity of this mutation. A clinical comparison of the ADCA I patients with the three known mutations (SCA1, -2 or -3) highlights significant differences between the groups; SCA2 patients tended to have a longer disease duration, a higher frequency of slow saccades and depressed tendon reflexes. However, these neurological signs were also seen in an ADCA I family in which the SCA2 mutation was not identified, illustrating the importance of a direct genetic test. The SCA2 families were from different geographical and ethnic backgrounds. However, haplotype analysis failed to show evidence of a founder mutation, even in families from the same geographical origin. The range of normal alleles varied from 17 to 30 CAG repeats and from 35 to 51 repeats for the pathological alleles. Similar to the other diseases caused by unstable trinucleotide repeats, a significant inverse correlation has been found between the number of repeats and age of onset, and there is a significantly higher paternal instability of repeat length on transmission to offspring. The SCA2 mutation is the most frequent amongst ADCA I patients, accounting for 40%, compared with SCA1 and SCA3 which account for 35% and 15%, respectively.
Published: 1998
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36. Proton magnetic resonance spectroscopy in an italian family with spinocerebellar ataxia type 1

Author: F. Valzania, Maria Cristina Bianchi, Carlo Alberto Tassinari, Mario Mascalchi, Rosaria Plasmati, Carlo Tessa, Michela Tosetti, Fabrizio Salvi, Carlo Bartolozzi, and Marina Frontali
Subjects: Adult, Male, In vivo magnetic resonance spectroscopy, Heterozygote, medicine.medical_specialty, Cerebellum, Spinocerebellar Ataxia Type 1, Pathology, Magnetic Resonance Spectroscopy, Genetic Linkage, Creatine, Statistics, Nonparametric, Choline, chemistry.chemical_compound, Pons, Cerebellar hemisphere, Internal medicine, Humans, Medicine, Spinocerebellar Degenerations, Brain Chemistry, Neurologic Examination, Aspartic Acid, business.industry, Pons Varolii, Chromosome Mapping, DNA, Middle Aged, Magnetic Resonance Imaging, Pedigree, medicine.anatomical_structure, Endocrinology, Italy, nervous system, Neurology, chemistry, Female, Neurology (clinical), Brainstem, business, Inositol
Abstract: Linkage and DNA analysis, magnetic resonance (MR) imaging, and single-voxel proton MR spectroscopy were obtained in 10 members of an Italian kindred with spinocerebellar ataxia type 1 (SCA1). The size of the basis pontis, cerebellar hemispheres, middle cerebellar peduncles, and medulla oblongata were decreased in 4 members carrying the SCA1 gene, compared with 6 unaffected subjects. Diffuse signal changes in the pons and cerebellum were observed only in the carrier with the longest disease duration and greatest disability. The N-acetylaspartate/creatine ratio and the choline/creatine ratio in the basis pontis were markedly decreased in 2 symptomatic SCA1 carriers and moderately decreased in 2 asymptomatic SCA1 carriers, compared with the unaffected family members and a control group of 10 healthy volunteers. Minor decreases in the N-acetylaspartate/creatine ratio and the normal choline/creatine ratio were observed in the cerebellar hemisphere of the SCA1 carriers. Reduction of the N-acetylaspartate/creatine ratio, demonstrated by MR spectroscopy in the pons, is likely to reflect a loss of neuronal viability and might represent a biochemical marker of SCA1 more sensitive than brainstem and cerebellum atrophy and signal changes shown by MR imaging.
Published: 1998
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37. Acetazolamide-responsive episodic ataxia in an Italian family refines gene mapping on chromosome 19p13

Author: M. Manfredi, Flavia Trettel, P Viviani, L. Calandriello, Elide Mantuano, Claudio Colonnese, G. Sabbadini, Carla Jodice, Marina Frontali, Ada Francia, and Liana Veneziano
Subjects: Adult, Male, Cerebellum, Ataxia, Biology, Central nervous system disease, Gene mapping, Chromosome 19, medicine, Humans, Aged, Episodic ataxia, Genetics, autosomal dominant cerebellar ataxias, cerebellar vermis atrophy, chromosome 19p, episodic ataxia type 2, vestibulocerebellar paroxysmal ataxia, Brain, Chromosome Mapping, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Pedigree, Acetazolamide, Settore BIO/18 - Genetica, medicine.anatomical_structure, Settore MED/03 - Genetica Medica, Italy, Cerebellar vermis atrophy, Cerebellar vermis, Female, Neurology (clinical), medicine.symptom, Chromosomes, Human, Pair 19, Microsatellite Repeats
Abstract: Episodic ataxia type 2 is an autosomal dominant disorder with attacks of vertigo and ataxia which respond to acetazolamide treatment. The gene, distinct from the KCNA1 responsible for episodic ataxia type 1, has been mapped on chromosome 19p13 in a 11-12 cM region. A large Italian kindred affected with acetazolamide-responsive episodic ataxia is reported, with onset in adulthood, a strong vestibular component during attacks and a high frequency of cerebellar vermis degeneration. The genetic analysis (i) showed strong linkage between the disease and the 19p13 microsatellite markers in a region which widely overlaps that previously reported and (ii) set a new distal boundary of the gene-containing region. Combining present and previous mapping data, the gene of episodic etaxia type 2 is most probably located in an interval approximately 1.5 Mb between markers D19S221 and D19S226.
Published: 1997
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38. Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington's disease motor onset

Author: Marie Saint-Hilaire, Patrick J. Morrison, Richard H. Myers, James F. Gusella, Diane Lucente, Ronald J. Trent, H. D. Rosas, Andrea Novelletto, Cinzia Gellera, Tammy Gillis, Isabel Alonso, Elizabeth McCusker, Oksana Suchowersky, Jayalakshmi S. Mysore, Marcy E. MacDonald, Michael R. Hayden, Carmen Ayuso, Jeanne C. Latourelle, Estrella Gómez-Tortosa, Tetsuo Ashizawa, Jorge Sequeiros, Steven M. Hersch, Randi Jones, Alba Di Pardo, Russell L. Margolis, Madaline B. Harrison, Stefano Di Donato, Martha Nance, Karen Marder, Andrea Zanko, Christopher A. Ross, Jong-Min Lee, Marina Frontali, Samuel Frank, F Squitieri, Ruth K. Abramson, and Eliana Marisa Ramos
Subjects: Genetic modifiers, Catechol O-Methyltransferase, Receptors, N-Methyl-D-Aspartate, Receptors, Dopamine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Huntington's disease, Dopamine, mental disorders, Neural Pathways, medicine, Genetics, Humans, Genetics(clinical), Age of Onset, Dopamine pathway, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, 0303 health sciences, Dopamine Plasma Membrane Transport Proteins, Catechol-O-methyl transferase, Polymorphism, Genetic, biology, Settore BIO/18, Receptors, Dopamine D2, Dopaminergic, Receptors, Dopamine D4, Glutamate receptors, medicine.disease, Variable number tandem repeat, Huntington Disease, biology.protein, GRIN2A, GRIN2B, Original Article, Age of onset, 030217 neurology & neurosurgery, medicine.drug, Huntington’s disease
Abstract: Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations.
Published: 2013
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39. D6 Dna damage in lymphocytes as a predictor of illness evolution in pre-manifest and overt huntington’s disease

Author: Silvia Romano, Giovanni Ristori, Marina Frontali, A Delmondo, Antonio Porcellini, Michela Ferraldeschi, A Monaco, and Maria Spadaro
Subjects: medicine.medical_specialty, Huntingtin, Ficoll, Biology, medicine.disease, medicine.disease_cause, Peripheral blood mononuclear cell, Pathogenesis, Psychiatry and Mental health, Endocrinology, Huntington's disease, Internal medicine, Immunology, medicine, Biomarker (medicine), Surgery, Neurology (clinical), Trinucleotide repeat expansion, Oxidative stress
Abstract: Background Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the HTT gene that encodes huntingtin (HTT). Mutant HTT leads to abnormalities in cellular function and transcriptional dysregulation that have long been recognised as central to the pathogenesis of HD. Our previous work showed that expression for 3 h of a polyQ-expanded protein (GPF-polyQ, Ataxin-2 and Huntingtin) stimulated cellular reactive oxygen species (ROS) levels and significantly reduced the mitochondrial electrochemical gradient. This result suggest that mutant HTT-induced oxidative stress may lead to persistent activation of DNA damage response (DMR) that may represent an early, main cause of neuronal dysfunction. Methods To quantify DMR, we used cytofluorimetric analysis to detect phosphorylated H2AX (PH2AH). Blood samples were obtained by venous punctures in EDTA-tubes. Freshly isolated peripheral blood mononuclear cells (PBMC) by differential centrifugation through Ficoll were fixed 10 minutes in 4% paraformaldehyde, made permeable with ice-cold 70% ethanol for 30 min, incubated with anti-Fc to block non-specific binding of Fc receptor expressing cells and incubated with anti-PH2AX. We enrolled pre-manifest HD, stratified according to the risk of motor onset into low, medium and high groups, as previously described; symptomatic HD patients, whose disease severity was quantified according to UHDRS, and healthy subjects as controls. Exclusion criteria were: drugs HDAC inhibitors, or NADP inhibitors and other factors known to interfere with the oxidative status of the subject; concomitant serious illnesses; pregnancy and breast-feeding. Results We included 14 (female/male ratio 8/6; age F 30.0 ± 6.7; M 41.8 ± 11.68) pre-manifest HD (pre-HD; Mean Repeat: 42.8 ± 2.7); 29 (female/male ratio 11/18; age F 46.7 ± 9.4; M 55.0 ± 10.1) symptomatic HD patients (Mean Repeat: 42.66 ± 1.9) and 18 healthy subjects as controls (C) (female/male ratio 13/5; age F 49.5 ± 9.6; M 45.4 ± 14.3). We found that patients and pre-HD showed a high PH2AH index as compared to the controls (C mean: 2.9 ± 2.02; HD mean: 10.56 ± 6.9; pre-D: 10.6 ± 7.0); the odds ratio was Conclusions These data, albeit preliminary, suggest an association between a high PH2AX index and HD, being promising as biomarker to characterise HD patients and to monitor disease progression.
Published: 2016
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40. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

Author: L. Calandriello, Guido Palladini, M. Manfredi, Ada Francia, Marina Frontali, G. F. Gualdi, C. Di Biasi, G. Sabbadini, and G. Trasimeni
Subjects: Adult, Genetic Markers, Male, Pathology, medicine.medical_specialty, Central nervous system disease, Neuroimaging, medicine, Humans, Dementia, CADASIL, Stroke, Brain Diseases, business.industry, Vascular disease, Cerebral Infarction, Middle Aged, CADASIL Syndrome, medicine.disease, Penetrance, Pedigree, Cerebrovascular Disorders, Italy, Female, Neurology (clinical), business, Chromosomes, Human, Pair 19
Abstract: Summary Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare hereditary stroke disease. The gene has been recently mapped, in two French families, on chromosome 19q12 between two highly polymorphic genetic markers. We report on a new large Italian family affected with this disease, which is characterized by recurrent stroke episodes, focal neurological deficits progressing to pseudo-bulbar palsy, and dementia. Multiple deep infarcts and diffuse leucoencephalopathy were revealed by MRI and brain histopathology showed abnormalities of arterial media. A genetic study performed with microsatellite markers from region 19q12 showed that the disease locus lies in an interval largely overlapping that already described and is closely linked to two microsatellite markers, D19S212 and D19S222. A joint analysis of genotypic and phenotypic data shows that diffuse leucoencephalopathy is a reliable sign of the disease in otherwise normal 50%-risk subjects over the age 30 years and that penetrance of stroke episodes or dementia is most likely complete around age 60 years.
Published: 1995
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41. Impaired vasoreactivity in mildly disabled CADASIL patients

Author: Antonio Federico, Franco Taroni, Silvia Romano, Jonica Campolo, Caterina Mariotti, Francesca Pescini, Nicola De Stefano, Leonardo Pantoni, Renata De Maria, Alessandra Tavani, Maria Laura Stromillo, Domenico Inzitari, Maria Teresa Dotti, Marina Frontali, Emanuele Puca, Oberdan Parodi, and Chiara Tomasello
Subjects: Adult, Male, AUTOSOMAL-DOMINANT ARTERIOPATHY, medicine.medical_specialty, Pathology, Endothelium, Manometry, FEATURES, CADASIL, Neuroimaging, BLOOD-PRESSURE, HOMOCYSTEINE, Gene mutation, Muscle, Smooth, Vascular, Leukoencephalopathy, Hyperaemia, Internal medicine, LEUKOENCEPHALOPATHY CADASIL, medicine, CARDIOVASCULAR RISK-FACTORS, Humans, Endothelial dysfunction, Stroke, SUBCORTICAL INFARCTS, AUTOSOMAL-DOMINANT ARTERIOPATHY, CARDIOVASCULAR RISK-FACTORS, SUBCORTICAL INFARCTS, ENDOTHELIAL DYSFUNCTION, LEUKOENCEPHALOPATHY CADASIL, CEREBRAL HEMODYNAMICS, BLOOD-PRESSURE, FEATURES, ABNORMALITIES, HOMOCYSTEINE, business.industry, ABNORMALITIES, Case-control study, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Plethysmography, Psychiatry and Mental health, medicine.anatomical_structure, Case-Control Studies, ENDOTHELIAL DYSFUNCTION, Cardiology, cardiovascular system, Blood Vessels, Female, Surgery, Neurology (clinical), medicine.symptom, CEREBRAL HEMODYNAMICS, business
Abstract: Background and purpose CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a rare genetic disease caused by NOTCH3 gene mutations. A dysfunction in vasoreactivity has been proposed as an early event in the pathogenesis of the disease. The aim of this study was to verify whether endothelium dependent and/or independent function is altered in CADASIL patients with respect to controls. Methods Vasoreactivity was studied by a non-invasive pletismographic method in 49 mildly disabled CADASIL patients (30-65 years, 58% male, Rankin scale d2) and 25 controls. Endothelium dependent vasodilatation was assessed by reactive hyperaemia (flow mediated dilation-peripheral arterial tone (FMD-PAT)) and endothelium independent vasoreactivity by glyceryl trinitrate (GTN) administration (GTN-PAT). Results Patients and controls showed comparable age, gender and cardiovascular risk factor distribution. GTN-PAT values were significantly lower in CADASIL patients (1.54 (1.01 to 2.25)) than in controls (1.89 (1.61 to 2.59); p=0.041). FMD-PAT scores did not differ between patients and controls (1.88 (1.57 to 2.43) vs 2.08 (1.81 to 2.58); p=0.126) but 17 CADASIL patients (35%) had FMD-PAT scores below the fifth percentile of controls. FMD-PAT and GTN-PAT values correlated both in controls (Á=0.648, p
Published: 2012

42. Polymorphism analysis of the huntingtin gene in Italian families affected with Huntington disease

Author: Emilia Bellone, F Squitieri, Franco Ajmar, G. Sabbadini, Marina Frontali, G. Campanella, Francesca Persichetti, Andrea Novelletto, Marcy E. MacDonald, Paola Mandich, A Bozza, and James F. Gusella
Subjects: Adult, congenital, hereditary, and neonatal diseases and abnormalities, Linkage disequilibrium, Nerve Tissue Proteins, Minisatellite Repeats, Biology, medicine.disease_cause, Polymerase Chain Reaction, Linkage Disequilibrium, Meiosis, Polymorphism (computer science), Genetics, Huntingtin Protein, medicine, Humans, Age of Onset, Allele, Codon, Molecular Biology, Gene, Genetics (clinical), Sequence Deletion, Mutation, Polymorphism, Genetic, Nuclear Proteins, General Medicine, Middle Aged, Huntington Disease, Genes, Italy, Microsatellite
Abstract: Two sources of variation in the huntingtin gene, the length of the CCG-rich segment downstream to the (CAG)n stretch undergoing expansion in Huntington disease (HD) and the deletion of 3 bp at codon positions 2642-2645 (delta 2642), were analysed on the normal and HD chromosomes of 80 Italian families affected with HD. No instances of meiotic instability of the CCG-rich segment were detected. A strong linkage disequilibrium was found between the HD mutation and alleles at both polymorphic regions: CCG-rich length alleles different from 176 bp are underrepresented while delta 2642 is overrepresented on HD chromosomes. The presence of such alleles on HD chromosomes does not affect age at onset of the disease. Normal chromosomes displayed a non-random association, shorter (CAG)n segments being preferentially followed by longer CCG-rich segments. Finally, the finding, among normal subjects, of carriers of variants on both chromosomes denotes that variation at either of the two polymorphisms does not impair the function of the huntingtin gene product.
Published: 1994
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43. Intensive multidisciplinary rehabilitation for Huntington Disease in Italy. Results in a cohort of HD patients with consecutive treatments along 5 years

Author: Paola Zinzi, Dario Salmaso, Paolo Zappata, Rosa De Grandis, Stefano Maceroni, Liliana Basmagi, Anna Rita Bentivoglio, Marina Frontali, and Gioia Jacopini
Published: 2010

44. Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2

Author: Yusuf A. Rajabally, Barbara Castellotti, Marina Frontali, Sara Caimi, Cinzia Gellera, Caterina Mariotti, Silvia Romano, D. Testa, Marianna Bugiani, Maria J Garcìa Barcina, Margherita Estienne, Elide Mantuano, Liana Veneziano, Giovanna Zorzi, Aurora Panico, and S. Servidei
Subjects: Adult, Male, Ataxia, Adolescent, DNA Mutational Analysis, EA2, CACNB4, Gene mutation, Settore MED/03 - GENETICA MEDICA, CACNA1A, medicine.disease_cause, Episodic ataxia, Young Adult, ea2, acetazolamide, paroxysmal torticollis, cacna1a, episodic ataxia, calcium channel, medicine, Missense mutation, Humans, Child, Aged, Genetics, Mutation, biology, Cerebellar ataxia, Models, Genetic, business.industry, Autosomal dominant trait, Infant, Middle Aged, medicine.disease, Acetazolamide, Settore MED/26 - NEUROLOGIA, Phenotype, Neurology, Calcium channel, Child, Preschool, biology.protein, Female, Neurology (clinical), Calcium Channels, medicine.symptom, business
Abstract: Episodic ataxia type 2 is a rare autosomal dominant disease characterized by recurrent attacks of vertigo and cerebellar ataxia. The disease was caused by mutations in the CACNA1A gene, on chromosome 19p. We perform a mutational screening in a group of 43 unrelated patients. Forty-two patients presented episodes of disequilibrium and ataxia, and one child was studied because of the occurrence of episodic torticollis. The genetic analysis showed 15 mutated patients (35%). In 13 cases we found novel CACNA1A gene mutations, including missense, protein truncating, and aberrant splicing mutations. Two truncating mutations lead to the uppermost premature stop so far reported, challenging recent hypotheses on dominant negative effect. In patients without CACNA1A mutations, molecular testing for CACNB4 gene mutations excluded this genetic subtype. Clinical features of mutated subjects mostly confirmed previous sign and symptoms associated with EA2, including paroxysmal torticollis and mental retardation. CACNA1A mutated patients have an earlier age at onset, interictal nystagmus, and abnormalities of ocular movements. A review of all CACNA1A mutations so far reported showed that they are mainly located downstream exon 18. Our data substantially increase the number of the described CACNA1A mutations, and propose clinical and molecular criteria for a more focused genetic screening.
Published: 2009
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45. Patients' and caregivers' perspectives: assessing an intensive rehabilitation programme and outcomes in Huntington's disease

Author: Dario Salmaso, Marina Frontali, Gioia Jacopini, and Paola Zinzi
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, medicine.medical_treatment, Disease, Huntington's disease, mental disorders, Epidemiology, medicine, ddc:610, Medicine, Social Medicine, Psychiatry, Social sciences, sociology, anthropology, Health policy, Rehabilitation, Sozialwissenschaften, Soziologie, Medizin und Gesundheit, business.industry, Public health, Health Policy, Public Health, Environmental and Occupational Health, Postal survey, Patient and caregiver perspective, Health-care research, medicine.disease, Medizin, Sozialmedizin, Family medicine, Medicine and health, ddc:300, Gesundheitspolitik, business
Abstract: Aim: To investigate the subjective evaluation of an intensive rehabilitation programme and outcomes by people with Huntington’s disease (HD) and their caregivers. Subjects and methods: A written questionnaire was mailed to people with mild-moderate HD (n = 40) who had completed at least one course of the intensive, inpatient rehabilitation protocol carried out at a facility of the Italian National Welfare System in the previous 3 years (on average 8.6 months before). Descriptive and inferential statistics were used. Thematic analyses were also conducted on written texts. Results: The response rate was 93%. A general improvement after discharge was perceived by all of the respondents. Improvements were reported on gait, balance, motor control, and fall reduction. Duration of benefits was estimated to last from 1 to 3 months by 71% of informants with no carry over to the next admission, which occurred on average 5.7 months later. Ameliorations were also reported in speech and swallowing, and several psychosocial aspects: mood, apathy, familiar and social relationships (binomial test, p
Published: 2009

46. Antenatal diagnosis of fetal skeletal malformations in ‘at risk' cases

Author: Marina Frontali, E. Maggi, F. Torcia, Antonella Giancotti, and A. Pachi
Subjects: Gynecology, medicine.medical_specialty, Fetus, education.field_of_study, Obstetrics, business.industry, Genetic counseling, Population, Ultrasound, Obstetrics and Gynecology, Prenatal diagnosis, In utero, medicine, Medical diagnosis, business, education, Pathological
Abstract: SummarySkeletal malformations affect one out of every 500 newborn babies in Italy. Genetic counselling enables identification of women at risk for these abnormalities, and ultrasound scanning permits prenatal diagnosis. Of 49 patients studied between October 1984 and June 1988, 29 women had a greater risk of fetal skeletal abnormalities than that in the general population. With ultrasound scanning, no false positive diagnoses were made. In four women at increased risk, pathological features were found in utero by ultrasound and in two women the diagnosis was missed and made after birth. One of these was a case of hypophosphataemic rickets, diagnosed by X-ray at 10 months of age; the other was monitored for cleft lip and palate, but a cleft lip was found only at birth.
Published: 1991
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47. Newly characterised 5' and 3' regions of CACNA1A gene harbour mutations associated with Familial Hemiplegic Migraine and Episodic Ataxia

Author: Patrizia Tarantino, Marina Frontali, Liana Veneziano, Fuki M. Hisama, Paola Carrera, Carla Jodice, Paola Bernard, Elide Mantuano, Loredana Boccone, and Serena Guida
Subjects: DNA Mutational Analysis, Migraine with Aura, Molecular Sequence Data, Biology, medicine.disease_cause, Cell Line, Exon, Neuroblastoma, Cell Line, Tumor, medicine, Spinocerebellar ataxia type 6, Humans, Analysis of Variance, Computational Biology, Calcium Channels, Italy, Phenotype, Sequence Deletion, Ataxia, Exons, Gene, Familial hemiplegic migraine, Episodic ataxia, Genetics, Mutation, Tumor, Alternative splicing, medicine.disease, Settore BIO/18 - Genetica, Neurology, Spinocerebellar ataxia, Neurology (clinical)
Abstract: The CACNA1A gene codes for the alpha(1A) pore-forming subunit of Ca(2+) voltage-gated Cav2.1 channels. CACNA1A mutations are responsible for Familial Hemiplegic Migraine (FHM) type 1, Episodic Ataxia (EA) type 2 and Spinocerebellar Ataxia type 6. The structure of the human gene includes, at present, 49 exons; however almost nothing is known about the 5' regulatory region, and there is now evidence suggesting the presence of additional exons at the 3' of the gene. The 892 bp fragment upstream of exon 1 and its deletion mutants were characterised for their transcriptional activity by using luciferase as a reporter gene. The 3' region was analysed by Rapid Amplification of the cDNA 3' End. Both regions were screened for mutations in a series of FHM and EA patients by SSCP and sequencing. At the 5' end of the gene a minimal promoter region was identified within the first 497 bp from ATG. By screening a larger fragment for mutations, the 5 bp deletion (g.-757_-753delCTTTC) was identified in a FHM patient. The deletion significantly increased the transcriptional activity, most likely due to the removal of half a turn of the DNA helix, changing the orientation of downstream binding sites for transcriptional factors. At the 3' end of the gene a new exon 48, followed by a strong poly-A signal, was identified as well as a new splice variant. The 5 bp insertion (g.38429_38430insCTTTT) in this exon was found in an EA patient. The two new regions can open the way for the study of human CACNA1A gene expression regulation and can be sites of mutations associated with FHM or EA phenotypes.
Published: 2007
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48. Effects of an intensive rehabilitation programme on patients with Huntington's disease: a pilot study

Author: Rosa De Grandis, Gioia Jacopini, Dario Salmaso, Paolo Zappata, Paola Zinzi, Stefano Maceroni, Anna Rita Bentivoglio, Graziano Graziani, and Marina Frontali
Subjects: Occupational therapy, Male, 030506 rehabilitation, medicine.medical_specialty, Activities of daily living, medicine.medical_treatment, Physical Therapy, Sports Therapy and Rehabilitation, Pilot Projects, Speech Therapy, Breathing Exercises, Speech therapy, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Cognition, Huntington's disease, Occupational Therapy, Activities of Daily Living, Outpatients, medicine, Humans, Cognitive rehabilitation therapy, Depression (differential diagnoses), Physical Therapy Modalities, Rehabilitation, business.industry, Depression, Tinetti test, Middle Aged, medicine.disease, Huntington Disease, Treatment Outcome, Physical therapy, Female, 0305 other medical science, business, 030217 neurology & neurosurgery
Abstract: Objective: To investigate the effects of an intensive, inpatient rehabilitation programme on individuals affected by Huntington's disease. Design: A pilot study. Within-subjects design. Setting: Inpatient rehabilitation home of the Italian welfare system. Subjects: Forty patients, early and middle stage of the disease, were recruited to an intensive, inpatient rehabilitation protocol. Interventions: The treatment programme included respiratory exercises and speech therapy, physical and occupational therapy and cognitive rehabilitation exercises. The programme involved three-week admission periods of intensive treatment that could be repeated three times a year. Main measures: A standard clinical assessment was performed at the beginning of each admission using the Zung Depression Scale, Mini-Mental State Examination (MMSE), Barthel Index, Tinetti Scale and Physical Performance Test (PPT). Tinetti and PPT were also used at the end of each admission to assess the outcomes in terms of motor and functional performance. Results: Each three-week period of treatment resulted in highly significant ( P < 0.001) improvements of motor performance and daily life activities. The average increase was 4.7 for Tinetti and 5.21 for PPT scores. No carry-over effect from one admission to the next was apparent but at the same time, no motor decline was detected over two years, indicating that patients maintained a constant level of functional, cognitive as well as motor performance. Conclusions: Intensive rehabilitation treatments may positively influence the maintenance of functional and motor performance in patients with Huntington's disease.
Published: 2007

49. The Enigma of Spinocerebellar Ataxia Type 6

Author: Marina Frontali
Subjects: Episodic ataxia, medicine, Spinocerebellar ataxia, Spinocerebellar ataxia type 6, Biology, medicine.disease, Neuroscience, Familial hemiplegic migraine
Published: 2007
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50. Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study

Author: Carmen Ayuso García, Martha Nance, Andrea Novelletto, Gang Xu, Oksana Suchowersky, Alice Lazzarini, Jang Ho J. Cha, Steven M. Hersch, Russell L. Margolis, Andrea Zanko, Vanessa C. Wheeler, Anthony J. Lechich, P. Michael Conneally, Ruth K. Abramson, Ferdinando Squitieri, Patrick J. Morrison, Ranjana Prakash, Adam Rosenblatt, John B. Penney, Jayalakshmi S. Mysore, Marina Frontali, Jane S. Paulsen, Marie Saint-Hilaire, Ayana Duckett, Luc Djoussé, Richard H. Myers, Alexandra Durr, Simon C. Warby, Tammy Gillis, Michael R. Hayden, James F. Gusella, Chirstopher A. Ross, Elizabeth McCusker, Ronald J. Trent, Susan Perlman, Marcy E. MacDonald, Michael Hakky, Randi Jones, Luigi Frati, Jian-Liang Li, Tetsuo Ashizawa, Madaline B. Harrison, Karen Marder, L. Adrienne Cupples, Mary Lou Klimek, and Estrella Gómez-Tortosa
Subjects: molecular cloning, Genetic Linkage, correlation analysis, genotype, data analysis, Pedigree chart, genetic analysis, variance, Nervous system--Diseases--Genetic aspects, quantitative trait locus, 0302 clinical medicine, Trinucleotide Repeats, genetic variability, guanine, Genetics(clinical), sibling, Age of Onset, cytosine, Genetics (clinical), Genetics, 0303 health sciences, pathogenesis, Brain--Diseases--Age factors, article, microsatellite marker, Huntington's disease, Middle Aged, Huntington Disease, Microsatellite, Chromosomes, Human, Pair 6, DNA modification, trinucleotide repeat, Research Article, onset age, Adult, Genetic Markers, lcsh:Internal medicine, gene locus, Adolescent, lcsh:QH426-470, huntingtin, heredity, Quantitative Trait Loci, Age factors in disease, Locus (genetics), Biology, Quantitative trait locus, adenine, DNA, adolescent, adult, age, aged, chromosome 18q, chromosome 6q, controlled study, follow up, gene identification, gene interaction, gene replication, genetic epistasis, genetic linkage, human, human cell, Huntington chorea, linkage analysis, major clinical study, pedigree analysis, 03 medical and health sciences, medicine, Humans, lcsh:RC31-1245, 030304 developmental biology, Aged, Linkage (software), Models, Genetic, Genome, Human, FOS: Clinical medicine, Neurosciences, medicine.disease, Settore BIO/18 - Genetica, lcsh:Genetics, Epistasis, Trinucleotide repeat expansion, 030217 neurology & neurosurgery
Abstract: Background Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD. Methods In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs. Results Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci. Conclusion In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.
Published: 2006

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