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2. Quantitative Oculomotor Assessment in Hereditary Ataxia: Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital-motor Biomarkers.

Author

Garces, Pilar, Antoniades, Chrystalina, Sobanska, Anna, Kovacs, Norbert, Ying, Sarah, Gupta, Anoopum, Szmulewicz, David, Pane, Chiara, Németh, Andrea, Jardim, Laura, Coarelli, Giulia, Dankova, Michaela, Traschütz, Andreas, Tarnutzer, Alexander, and Perlman, Susan

Subjects
Eye movement recordings, Hereditary ataxia, Oculomotor, Recommendations, Systematic review, Vestibular, Humans, Consensus, Ocular Motility Disorders, Eye Movements, Biomarkers
Abstract

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias.

Published
2024

3. The parkin V380L variant is a genetic modifier of Machado–Joseph disease with impact on mitophagy

Author

Weber, Jonasz J., Czisch, Leah, Pereira Sena, Priscila, Fath, Florian, Huridou, Chrisovalantou, Schwarz, Natasa, Incebacak Eltemur, Rana D., Würth, Anna, Weishäupl, Daniel, Döcker, Miriam, Blumenstock, Gunnar, Martins, Sandra, Sequeiros, Jorge, Rouleau, Guy A., Jardim, Laura Bannach, Saraiva-Pereira, Maria-Luiza, França, Jr., Marcondes C., Gordon, Carlos R., Zaltzman, Roy, Cornejo-Olivas, Mario R., van de Warrenburg, Bart P. C., Durr, Alexandra, Brice, Alexis, Bauer, Peter, Klockgether, Thomas, Schöls, Ludger, Riess, Olaf, and Schmidt, Thorsten

Published
2024
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4. Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes.

Author

Garces, Pilar, Antoniades, Chrystalina, Sobanska, Anna, Kovacs, Norbert, Ying, Sarah, Gupta, Anoopum, Szmulewicz, David, Pane, Chiara, Németh, Andrea, Jardim, Laura, Coarelli, Giulia, Dankova, Michaela, Traschütz, Andreas, Tarnutzer, Alexander, and Perlman, Susan

Subjects
Eye movement recordings, Hereditary ataxia, Oculomotor, Recommendations, Systematic review, Vestibular, Humans, Eye Movements, Ataxia Telangiectasia, Spinocerebellar Degenerations, Ataxia, Friedreich Ataxia, Genotype, Disease Progression
Abstract

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

Published
2024

5. Huntington disease: DNA analysis in brazilian population

Author

RASKIN SALMO, ALLAN NASSER, TEIVE HÉLIO A.G., CARDOSO FRANCISCO, HADDAD MÔNICA SANTORO, LEVI GILBERTO, BOY RAQUEL, LERENA JR JUAN, SOTOMAIOR VANESSA SANTOS, JANZEN-DÜCK MÔNICA, JARDIM LAURA BANNACH, FELLANDER FLÁVIO R., and ANDRADE LUIZ AUGUSTO FRANCO

Subjects
Huntington disease, CAG repeats, Brazil, DNA, PCR, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Huntington disease (HD) is associated with expansions of a CAG trinucleotide repeat in the HD gene. Accurate measurement of a specific CAG repeat sequence in the HD gene in 92 Brazilian controls without HD, 44 Brazilian subjects with clinical findings suggestive of HD and 40 individuals from 6 putative HD families, showed a range from 7 to 33 repeats in normal subjects and 39 to 88 repeats in affected subjects. A trend between early age at onset of first symptoms and increasing number of repeats was seen. Major increase of repeat size through paternal inheritance than through maternal inheritance was observed. Data generated from this study may have significant implications for the etiology, knowledge of the incidence, diagnosis, prognosis, genetic counseling and treatment of HD Brazilian patients.

Published
2000

6. Clinical and biochemical findings in 7 patients with X-linked adrenoleukodystrophy treated with Lorenzo's Oil

Author

Vargas Carmen R., Barschak Alethéa G., Coelho Daniella M., Furlanetto Vivian, Souza Carolina F.M. de, Karam Simone M., Jardim Laura, Wajner Moacir, and Giugliani Roberto

Subjects
Genetics, QH426-470
Abstract

X-Linked adrenoleukodystrophy (X-ALD) is a hereditary disorder of the peroxisomal metabolism biochemically characterized by the accumulation of very long chain fatty acids (VLCFA) in tissues and biological fluids. The major accumulated acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0). The disorder is characterized clinically by central and peripheral demyelination and adrenal insufficiency closely related to the accumulation of fatty acids. The incidence of X-ALD is estimated to be 1:25,000 males. At least six phenotypes can be distinguished. The most common phenotypes are childhood cerebral ALD and adrenomyeloneuropathy (AMN). The recommended therapy consists of the use of the glyceroltrioleate/glyceroltrierucate (GTO/GTE) mixture, known as Lorenzo's Oil, combined with a VLCFA-poor diet. There are alternative treatments such as bone marrow transplantation and immunosuppression, as well as the use of lovastatin and sodium phenylacetate. In the present study we report the clinical and biochemical course of 7 male patients with X-ALD treated with Lorenzo's Oil and a VLCFA-restricted diet. Treatment produced 50% reduction in C26:0 and 42.8% reduction in the C26:0/C22:0 ratio. Most patients remained clinically well, although approximately 30% of them presented a rapid clinical deterioration. The results showed a poor biochemical-clinical correlation for treatment, indicating that new therapies for X-ALD are needed in order to obtain a better prognosis for patients.

Published
2000

7. Machado Joseph-Disease Is Rare in the Peruvian Population

Author

Cornejo-Olivas, Mario, Solis-Ponce, Lesly, Araujo-Aliaga, Ismael, Milla-Neyra, Karina, Ortega, Olimpio, Illanes-Manrique, Maryenela, Mazzetti, Pilar, Manrique-Enciso, Carla, Cubas-Montecino, Diana, Saraiva-Pereira, Maria Luiza, Jardim, Laura B., and Sarapura-Castro, Elison

Published
2023
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8. The longitudinal progression of MRI changes in pre-ataxic carriers of SCA3/MJD

Author

de Oliveira, Camila Maria, Leotti, Vanessa Bielefeldt, Polita, Sandra, Anes, Mauricio, Cappelli, Amanda Henz, Rocha, Anastacia Guimarães, Ecco, Gabriela, Bolzan, Gabriela, Kersting, Nathalia, Duarte, Juliana Avila, Saraiva-Pereira, Maria-Luiza, Junior, Marcondes Cavalcante França, Rezende, Thiago Junqueira Ribeiro, and Jardim, Laura Bannach

Published
2023
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9. Spinocerebellar ataxia type 2 has multiple ancestral origins

Author

Sena, Lucas Schenatto, Furtado, Gabriel Vasata, Pedroso, José Luiz, Barsottini, Orlando, Cornejo-Olivas, Mario, Nóbrega, Paulo Ribeiro, Braga Neto, Pedro, Soares, Danyela Martins Bezerra, Vargas, Fernando Regla, Godeiro, Clecio, Medeiros, Paula Frassinetti Vasconcelos de, Camejo, Claudia, Toralles, Maria Betania Pereira, Fagundes, Nelson Jurandi Rosa, Jardim, Laura Bannach, and Saraiva-Pereira, Maria Luiza

Published
2024
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10. An Exploratory Survey on the Care for Ataxic Patients in the American Continents and the Caribbean

Author

Jardim, Laura Bannach, Hasan, Ali, Kuo, Sheng-han, Magaña, Jonathan Javier, França, Jr, Marcondes, Marques, Jr, Wilson, Camejo, Claudia, Santana-da-Silva, Luiz Carlos, Leão, Emília Embiruçu, Espíndola, Gisele, Canals, Francisca, Miranda, Marcelo, Salvatierra, Igor, Cornejo-Olivas, Mario, Fernandez-Ruiz, Juan, Braga-Neto, Pedro, Dávila-Ortiz de Montellano, David José, Flores-Lagunes, Luis Leonardo, Dupré, Nicolas, Brais, Bernard, Vargas, Fernando Regla, Godeiro, Clécio, Coutinho, Léo, Teive, Helio G., Kaufmann, Marcelo, Saffie, Paula, Furtado, Gabriel Vasata, Saraiva-Pereira, Maria Luiza, Barsottini, Orlando, Pedroso, José Luiz, Rodríguez-Labrada, Roberto, Velázquez-Pérez, Luis, and Gomez, Christopher

Published
2023
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12. Equaliza\c{c}\~ao das escalas NESSCA e SARA utilizando a Teoria da Resposta ao Item na avalia\c{c}\~ao do comprometimento pela doen\c{c}a de Machado-Joseph

Author

Utpott, Nicole Machado, Leotti, Vanessa Bielefeldt, and Jardim, Laura Bannach

Subjects
Quantitative Biology - Quantitative Methods
Abstract

Background: Scale equating is a statistical technique used to establish equivalence relations between different scales. Its use is quite popular in educational evaluation, however, unusual in the health area, where scales of measures are tools that integrate clinical practice. With the use of different scales, there is a difficulty in comparing scientific results, such as NESSCA and SARA scales, tools for assessing the commitment to Machado-Joseph disease (SCA3/MJD). Objective: Explore the method of scale equating and demonstrate its application through NESSCA and SARA scales, using the Item Response Theory (IRT) approach in assessing SCA3/MJD commitment. Methods: Data came from 227 patients from the Hospital de Cl\'inicas de Porto Alegre with SCA3/MJD who have complete measures for NESSCA and/or SARA scales. The equating design used is that of non-equivalent groups with common items, with separate calibration. The IRT model used in the estimation of the parameters was the generalized partial credit, for NESSCA and SARA. The linear transformation was performed using the Mean/Mean, Mean/Sigma, Haebara and StokingLord methods and the equation of the true score was applied to obtain an estimated relationship between the scores of the scales. Results: Difference between NESSCA score estimated by SARA and observed NESSCA score has shown median of 0.82 points, by Mean/Sigma method. This was the best method of linear transformation among the tested. Conclusions: This study extended the use of scale equating under IRT approach to health outcomes and established an equivalence relationship between NESSCA and SARA scores, making the comparison between patients and scientific results feasible., Comment: in Portuguese

Published
2020

16. Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing

Author

Raposo, Mafalda, Bettencourt, Conceição, Melo, Ana Rosa Vieira, Ferreira, Ana F., Alonso, Isabel, Silva, Paulo, Vasconcelos, João, Kay, Teresa, Saraiva-Pereira, Maria Luiza, Costa, Marta D., Vilasboas-Campos, Daniela, Bettencourt, Bruno Filipe, Bruges-Armas, Jácome, Houlden, Henry, Heutink, Peter, Jardim, Laura Bannach, Sequeiros, Jorge, Maciel, Patrícia, and Lima, Manuela

Published
2022
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20. Planning Future Clinical Trials for Machado-Joseph Disease

Author

Saute, Jonas Alex Morales, Jardim, Laura Bannach, COHEN, IRUN R., Series Editor, LAJTHA, ABEL, Series Editor, LAMBRIS, JOHN D., Series Editor, PAOLETTI, RODOLFO, Series Editor, REZAEI, NIMA, Series Editor, Nóbrega, Clévio, editor, and Pereira de Almeida, Luís, editor

Published
2018
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22. Huntington's disease-like disorders in Latin America and the Caribbean

Author

Walker, Ruth H., Gatto, Emilia M., Bustamante, M. Leonor, Bernal-Pacheco, Oscar, Cardoso, Francisco, Castilhos, Raphael M., Chana-Cuevas, Pedro, Cornejo-Olivas, Mario, Estrada-Bellmann, Ingrid, Jardim, Laura B., López-Castellanos, Ricardo, López-Contreras, Ricardo, Maia, Debora P., Mazzetti, Pilar, Miranda, Marcelo, Rodríguez-Violante, Mayela, Teive, Helio, and Tumas, Vitor

Published
2018
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23. LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study

Author

Bonifati, Vincenzo, Quadri, Marialuisa, Mandemakers, Wim, Kievit, Anneke J.A., Boon, Agnita J.W., Rood, Janneke P.A, Vergouw, Leonie J.M., de Jong, Frank J., van Swieten, John C., Mattace-Raso, Francesco U.S., Leenders, Klaus L., Ferreira, Joaquim J., Correia Guedes, Leonor, Puschmann, Andreas, Ygland, Emil, Nilsson, Christer, Chien, Hsin F., Barbosa, Egberto, Bannach Jardim, Laura, Rieder, Carlos R.M., Chang, Hsiu-Chen, Lu, Chin-Song, Wu-Chou, Yah-Huei, Yeh, Tu-Hsueh, Lopiano, Leonardo, Tassorelli, Cristina, Pacchetti, Claudio, Riboldazzi, Giulio, Bono, Giorgio, Comi, Cristoforo, Padovani, Alessandro, Borroni, Barbara, Raudino, Francesco, Fincati, Emiliana, Tinazzi, Michele, Bonizzato, Alberto, Ferracci, Carlo, Dalla Libera, Alessio, Abbruzzese, Giovanni, Cortelli, Pietro, Capellari, Sabina, Marconi, Roberto, Guidi, Marco, Onofrj, Marco, Thomas, Astrid, Vanacore, Nicola, Meco, Giuseppe, Fabrizio, Edito, Fabbrini, Giovanni, Berardelli, Alfredo, Stocchi, Fabrizio, Vacca, Laura, Barone, Paolo, Picillo, Marina, De Michele, Giuseppe, Criscuolo, Chiara, De Mari, Michele, Dell'Aquila, Claudia, Iliceto, Gianni, Toni, Vincenzo, Trianni, Giorgio, Gagliardi, Monica, Annesi, Grazia, Quattrone, Aldo, Saddi, Valeria, Cossu, Gianni, Melis, Maurizio, Grochowska, Martyna M, Masius, Roy, Geut, Hanneke, Breedveld, Guido J, Kuipers, Demy, Minneboo, Michelle, Vergouw, Leonie J M, Carreras Mascaro, Ana, Yonova-Doing, Ekaterina, Simons, Erik, Zhao, Tianna, Di Fonzo, Alessio B, Parchi, Piero, Melis, Marta, Brouwer, Rutger W W, Heijsman, Daphne, Ingrassia, Angela M T, Calandra Buonaura, Giovanna, Rood, Janneke P, Rozemuller, Annemieke J, Sarchioto, Marianna, Fen Chien, Hsin, Olgiati, Simone, Boon, Agnita J W, Hoogers, Susanne E, Ghazvini, Mehrnaz, IJpma, Arne S, van IJcken, Wilfred F J, Nicholl, David J, Kievit, Anneke J, Majoor-Krakauer, Danielle, van Swieten, John C, de Jong, Frank J, Ferreira, Joaquim J, Cossu, Giovanni, and van de Berg, Wilma D J

Published
2018
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29. PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

Author

Fevga, Christina, Tesson, Christelle, Carreras Mascaro, Ana, Courtin, Thomas, Van Coller, Riaan, Sakka, Salma, Ferraro, Federico, Farhat, Nouha, Bardien, Soraya, Damak, Mariem, Carr, Jonathan, Ferrien, Melanie, Boumeester, Valerie, Hundscheid, Jasmijn, Grillenzoni, Nicola, Kessissoglou, Irini A., Kuipers, Demy J.S., Quadri, Marialuisa, Agid, Yves, Anheim, Mathieu, Borg, Michel, Brice, Alexis, Broussolle, Emmanuel, Corvol, Jean Christophe, Damier, Philippe, Defebvre, Luc, Dürr, Alexandra, Durif, Franck, Houeto, Jean Luc, Krack, Paul, Klebe, Stephan, Lesage, Suzanne, Lohmann, Ebba, Martinez, Maria, Mangone, Graziella, Mariani, Louise Laure, Pollak, Pierre, Rascol, Olivier, Tison, François, Tranchant, Christine, Verin, Marc, Viallet, François, Vidailhet, Marie, Emre, Murat, Hanagasi, Hasmet, Bilgic, Basar, Lu, Bedia Marangozog, Benmahdjoub, Mustapha, Arezki, Mohammed, Bouchetara, Sofiane A., Benhassine, Traki, Tazir, Meriem, Djebara, Mouna Ben, Gouider, Riadh, Romdhan, Sawssan Ben, Mhiri, Chokri, Bouhouche, Ahmed, Bonifati, Vincenzo, Mandemakers, Wim, Kievit, Anneke J.A., Boon, Agnita J.W., Ferreira, Joaquim J., Guedes, Leonor Correia, Hanagasi, Hasmet A., Tufekcioglu, Zeynep, Elibol, Bulent, Dog.u, Okan, Gultekin, Murat, Chien, Hsin F., Barbosa, Egberto, Jardim, Laura Bannach, Rieder, Carlos R.M., Chang, Hsiu Chen, Lu, Chin Song, Wu-Chou, Yah Huei, Yeh, Tu Hsueh, Lopiano, Leonardo, Tassorelli, Cristina, Pacchetti, Claudio, Comi, Cristoforo, Raudino, Francesco, Bertolasi, Laura, Tinazzi, Michele, Bonizzato, Alberto, Ferracci, Carlo, Marconi, Roberto, Guidi, Marco, Onofrj, Marco, Thomas, Astrid, Vanacore, Nicola, Meco, Giuseppe, Fabrizio, Edito, Fabbrini, Giovanni, Berardelli, Alfredo, Stocchi, Fabrizio, Vacca, Laura, Barone, Paolo, Picillo, Marina, De Michele, Giuseppe, Criscuolo, Chiara, De Mari, Michele, Dell'aquila, Claudia, Iliceto, Giovanni, Toni, Vincenzo, Trianni, Giorgio, Saddi, Valeria, Cossu, Gianni, Melis, Maurizio, Hassan, Bassem A., Breedveld, Guido J., Erasmus University Medical Center [Rotterdam] (Erasmus MC), 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), Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Faculty of Health Sciences [Pretoria], University of Pretoria [South Africa], Hopital Habib Bourguiba - Habib Bourguiba Hospital [Sfax], Stellenbosch University, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Motivation, cerveau et comportement = Motivation, Brain and Behavior [ICM Paris] (MBB), 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], Tesson, Christelle, Clinical Genetics, and Neurology

Subjects
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, PTPA, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], PPP2R4, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, parkinsonism, PP2A
Abstract

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C>A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.

Published
2023
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32. Spinocerebellar ataxia type 2 has multiple ancestral origins

Author

Sena, Lucas Schenatto, primary, Furtado, Gabriel Vasata, additional, Pedroso, José Luiz, additional, Barsottini, Orlando, additional, Cornejo-Olivas, Mario, additional, Nobrega, Paulo Ribeiro, additional, Neto, Pedro Braga, additional, Soares, Danyela Bezerra, additional, Vargas, Fernando Regla, additional, Godeiro, Clecio, additional, Medeiros, Paula Frassinetti, additional, Camejo, Claudia, additional, Toralles, Maria Betania, additional, Fagundes, Nelson Rosa, additional, Jardim, Laura Bannach, additional, and Saraiva-Pereira, Maria Luiza, additional

Published
2023
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38. Differences in spontaneous speech fluency between Parkinson's disease and spinocerebellar ataxia type 3

Author

dos Santos, Vanessa Brzoskowski, primary, Ayres, Annelise, additional, Kieling, Maiara Laís Mallmann, additional, Miglorini, Elaine Cristina, additional, Jardim, Laura Bannach, additional, Schumacher-Schuh, Artur Francisco, additional, Rieder, Carlos Roberto de Mello, additional, Castilhos, Raphael Machado de, additional, Spencer, Kristie, additional, Rothe-Neves, Rui, additional, and Olchik, Maira Rozenfeld, additional

Published
2023
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39. Quantitative Oculomotor Assessment in Hereditary Ataxia: Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital-motor Biomarkers

Author

Garces, Pilar, primary, Antoniades, Chrystalina A., additional, Sobanska, Anna, additional, Kovacs, Norbert, additional, Ying, Sarah H., additional, Gupta, Anoopum S., additional, Perlman, Susan, additional, Szmulewicz, David J., additional, Pane, Chiara, additional, Németh, Andrea H., additional, Jardim, Laura B., additional, Coarelli, Giulia, additional, Dankova, Michaela, additional, Traschütz, Andreas, additional, and Tarnutzer, Alexander A., additional

Published
2023
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40. Planning future clinical trials in Machado Joseph disease: Lessons from a phase 2 trial

Author

Saute, Jonas Alex Morales, Rieder, Carlos R.M., Castilhos, Raphael Machado, Monte, Thais Lampert, Schumacher-Schuh, Artur Francisco, Donis, Karina Carvalho, D'Ávila, Rui, Souza, Gabriele Nunes, Russo, Aline Dutra, Furtado, Gabriel Vasata, Gheno, Tailise Conte, Souza, Diogo Onofre Gomes, Saraiva-Pereira, Maria Luiza, Portela, Luis Valmor Cruz, Camey, Suzi, Torman, Vanessa Bielefeld Leotti, and Jardim, Laura Bannach

Published
2015
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45. Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes

Author

Garces, Pilar, primary, Antoniades, Chrystalina A., additional, Sobanska, Anna, additional, Kovacs, Norbert, additional, Ying, Sarah H., additional, Gupta, Anoopum S., additional, Perlman, Susan, additional, Szmulewicz, David J., additional, Pane, Chiara, additional, Németh, Andrea H., additional, Jardim, Laura B., additional, Coarelli, Giulia, additional, Dankova, Michaela, additional, Traschütz, Andreas, additional, and Tarnutzer, Alexander A., additional

Published
2023
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47. Nonneurological Involvement in Late-Onset Friedreich Ataxia (LOFA): Exploring the Phenotypes

Author

Martinez, Alberto R. M., Moro, Adriana, Abrahao, Agessandro, Faber, Ingrid, Borges, Conrado R., Rezende, Thiago J. R., Martins, Jr, Carlos R., Moscovich, Mariana, Munhoz, Renato P., Segal, Sandra Leistner, Arruda, Walter O., Saraiva-Pereira, Maria Luiza, Karuta, Simone, Pedroso, José Luiz, D’Abreu, Anelyssa, Jardim, Laura B., Lopes-Cendes, Íscia, Barsottini, Orlando G., Teive, Hélio A. G., and França, Jr, Marcondes C.

Published
2017
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48. Non-motor and Extracerebellar Features in Spinocerebellar Ataxia Type 2

Author

Pedroso, José Luiz, Braga-Neto, Pedro, Escorcio-Bezerra, Marcio Luiz, Abrahão, Agessandro, de Albuquerque, Marcus Vinicius Cristino, Filho, Flavio Moura Rezende, de Souza, Paulo Victor Sgobbi, de Rezende Pinto, Wladimir Bocca Vieira, Borges, Jr., Franklin Roberto Pereira, Saraiva-Pereira, Maria Luiza, Jardim, Laura Bannach, and Barsottini, Orlando G. P.

Published
2017
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50. Cytokines in Machado Joseph Disease/Spinocerebellar Ataxia 3

Author

da Silva Carvalho, Gerson, Saute, Jonas Alex Morales, Haas, Clarissa Branco, Torrez, Vitor Rocco, Brochier, Andressa Wigner, Souza, Gabriele Nunes, Furtado, Gabriel Vasata, Gheno, Tailise, Russo, Aline, Monte, Thais Lampert, Schumacher-Schuh, Artur, D’Avila, Rui, Donis, Karina Carvalho, Castilhos, Raphael Machado, Souza, Diogo Onofre, Saraiva-Pereira, Maria Luiza, Torman, Vanessa Leotti, Camey, Suzi, Portela, Luis Valmor, and Jardim, Laura Bannach

Published
2016
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