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1. Congenital Disorders of Glycosylation in Portugal—Two Decades of Experience

Author

Quelhas, Dulce, Martins, Esmeralda, Azevedo, Luísa, Bandeira, Anabela, Diogo, Luísa, Garcia, Paula, Sequeira, Sílvia, Ferreira, Ana Cristina, Teles, Elisa Leão, Rodrigues, Esmeralda, Fortuna, Ana Maria, Mendonça, Carla, Fernandes, Helena Cabral, Medeira, Ana, Gaspar, Ana, Janeiro, Patrícia, Oliveira, Anabela, Laranjeira, Francisco, Ribeiro, Isaura, Souche, Erica, Race, Valérie, Keldermans, Liesbeth, Matthijs, Gert, and Jaeken, Jaak

Published
2021
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2. ALG1‐CDG: Clinical and Molecular Characterization of 39 Unreported Patients

Author

Ng, Bobby G, Shiryaev, Sergey A, Rymen, Daisy, Eklund, Erik A, Raymond, Kimiyo, Kircher, Martin, Abdenur, Jose E, Alehan, Fusun, Midro, Alina T, Bamshad, Michael J, Barone, Rita, Berry, Gerard T, Brumbaugh, Jane E, Buckingham, Kati J, Clarkson, Katie, Cole, F Sessions, O'Connor, Shawn, Cooper, Gregory M, Coster, Rudy, Demmer, Laurie A, Diogo, Luisa, Fay, Alexander J, Ficicioglu, Can, Fiumara, Agata, Gahl, William A, Ganetzky, Rebecca, Goel, Himanshu, Harshman, Lyndsay A, He, Miao, Jaeken, Jaak, James, Philip M, Katz, Daniel, Keldermans, Liesbeth, Kibaek, Maria, Kornberg, Andrew J, Lachlan, Katherine, Lam, Christina, Yaplito‐Lee, Joy, Nickerson, Deborah A, Peters, Heidi L, Race, Valerie, Régal, Luc, Rush, Jeffrey S, Rutledge, S Lane, Shendure, Jay, Souche, Erika, Sparks, Susan E, Trapane, Pamela, Sanchez‐Valle, Amarilis, Vilain, Eric, Vøllo, Arve, Waechter, Charles J, Wang, Raymond Y, Wolfe, Lynne A, Wong, Derek A, Wood, Tim, Yang, Amy C, Genomics, University of Washington Center for Mendelian, Matthijs, Gert, and Freeze, Hudson H

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Pediatric, Clinical Research, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, Aetiology, Biomarkers, Congenital Disorders of Glycosylation, Female, Genes, Lethal, Glycosylation, Humans, Male, Mannosyltransferases, Mutation, Polysaccharides, Sequence Analysis, DNA, Survival Analysis, CDG, asparagine-linked glycosylation protein 1, carbohydrate-deficient transferrin, xeno-tetrasaccharide, University of Washington Center for Mendelian Genomics, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Published
2016

4. Galactose Epimerase Deficiency: Expanding the Phenotype

Author

Dias Costa, Filipa, Ferdinandusse, Sacha, Pinto, Carla, Dias, Andrea, Keldermans, Liesbeth, Quelhas, Dulce, Matthijs, Gert, Mooijer, Petra A., Diogo, Luísa, Jaeken, Jaak, Garcia, Paula, Baumgartner, Matthias, Series editor, Patterson, Marc, Series editor, Rahman, Shamima, Series editor, Peters, Verena, Series editor, Morava, Eva, Editor-in-chief, and Zschocke, Johannes, Series editor

Published
2017
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5. Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features

Author

Oliveira, Renata, Sommerville, Ewen W., Thompson, Kyle, Nunes, Joana, Pyle, Angela, Grazina, Manuela, Chinnery, Patrick F., Diogo, Luísa, Garcia, Paula, Taylor, Robert W., Baumgartner, Matthias R., Series editor, Patterson, Marc, Series editor, Rahman, Shamima, Series editor, Peters, Verena, Series editor, Morava, Eva, Editor-in-chief, Zschocke, Johannes, Series editor, and Baumgartner, Matthias, editor

Published
2017
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11. Brief Report: High Frequency of Biochemical Markers for Mitochondrial Dysfunction in Autism: No Association with the Mitochondrial Aspartate/Glutamate Carrier 'SLC25A12' Gene

Author

Correia, Catarina, Coutinho, Ana M., and Diogo, Luisa

Abstract

In the present study we confirm the previously reported high frequency of biochemical markers of mitochondrial dysfunction, namely hyperlactacidemia and increased lactate/pyruvate ratio, in a significant fraction of 210 autistic patients. We further examine the involvement of the mitochondrial aspartate/glutamate carrier gene ("SLC25A12") in mitochondrial dysfunction associated with autism. We found no evidence of association of the "SLC25A12" gene with lactate and lactate/pyruvate distributions or with autism in 241 nuclear families with one affected individual. We conclude that while mitochondrial dysfunction may be one of the most common medical conditions associated with autism, variation at the "SLC25A12" gene does not explain the high frequency of mitochondrial dysfunction markers and is not associated with autism in this sample of autistic patients.

Published
2006
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17. Phenotype, treatment practice and outcome in the cobalamin‐dependent remethylation disorders and MTHFR deficiency: data from the E‐HOD registry

Author

Huemer, Martina, Diodato, Daria, Martinelli, Diego, Olivieri, Giorgia, Blom, Henk, Gleich, Florian, Kölker, Stefan, Kožich, Viktor, Morris, Andrew A., Seifert, Burkhardt, Froese, D. Sean, Baumgartner, Matthias R., Dionisi‐Vici, Carlo, Martin, Carlos Alcalde, Baethmann, Martina, Ballhausen, Diana, Blasco‐Alonso, Javier, Boy, Nikolas, Bueno, Maria, Burgos Peláez, Rosa, Cerone, Roberto, Chabrol, Brigitte, Chapman, Kimberly A., Couce, Maria Luz, Crushell, Ellen, Dalmau Serra, Jaime, Diogo, Luisa, Ficicioglu, Can, García Jimenez, Maria Concepcion, García Silva, Maria Teresa, Gaspar, Ana, Gautschi, Matthias, González‐Lamuño, Domingo, Gouveia, Sofia, Grünewald, Stephanie, Hendriksz, Chris, Janssen, Mirian C. H., Jesina, Pavel, Koch, Johannes, Konstantopoulou, Vassiliki, Lavigne, Christian, Lund, Allan M., Martins, Esmeralda G., Meavilla Olivas, Silvia, Mention, Karine, Mochel, Fanny, Mundy, Helen, Murphy, Elaine, Paquay, Stephanie, Pedrón‐Giner, Consuelo, Ruiz Gómez, Maria Angeles, Santra, Saikat, Schiff, Manuel, Schwartz, Ida Vanessa, Scholl‐Bürgi, Sabine, Servais, Aude, Skouma, Anastasia, Tran, Christel, Vives Piñera, Inmaculada, Walter, John, Weisfeld‐Adams, James, and Repositório da Universidade de Lisboa

Abstract

© 2018 SSIEM, Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design., This publication arises from the project E-HOD that has received funding from the European Union in the framework of the Health Programme. VK and PJ were supported by Institutional Research Programme RVO/VFN64165.

Published
2019

18. Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

Author

UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - (SLuc) Service de neurologie pédiatrique, Huemer, Martina, Diodato, Daria, Martinelli, Diego, Olivieri, Giorgia, Blom, Henk, Gleich, Florian, Kölker, Stefan, Kožich, Viktor, Morris, Andrew A, Seifert, Burkhardt, Froese, D Sean, Baumgartner, Matthias R, Dionisi-Vici, Carlo, EHOD consortium, Martin, Carlos Alcalde, Baethmann, Martina, Ballhausen, Diana, Blasco-Alonso, Javier, Boy, Nikolas, Bueno, Maria, Burgos Peláez, Rosa, Cerone, Roberto, Chabrol, Brigitte, Chapman, Kimberly A, Couce, Maria Luz, Crushell, Ellen, Dalmau Serra, Jaime, Diogo, Luisa, Ficicioglu, Can, García Jimenez, Maria Concepcion, García Silva, Maria Teresa, Gaspar, Ana Maria, Gautschi, Matthias, González-Lamuño, Domingo, Gouveia, Sofia, Grünewald, Stephanie, Hendriksz, Chris, Janssen, Mirian C H, Jesina, Pavel, Koch, Johannes, Konstantopoulou, Vassiliki, Lavigne, Christian, Lund, Allan M, Martins, Esmeralda G, Meavilla Olivas, Silvia, Mention, Karine, Mochel, Fanny, Mundy, Helen, Murphy, Elaine, Paquay, Stéphanie, Pedrón-Giner, Consuelo, Ruiz Gómez, Maria Angeles, Santra, Saikat, Schiff, Manuel, Schwartz, Ida Vanessa, Scholl-Bürgi, Sabine, Servais, Aude, Skouma, Anastasia, Tran, Christel, Vives Piñera, Inmaculada, Walter, John, Weisfeld-Adams, James, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - (SLuc) Service de neurologie pédiatrique, Huemer, Martina, Diodato, Daria, Martinelli, Diego, Olivieri, Giorgia, Blom, Henk, Gleich, Florian, Kölker, Stefan, Kožich, Viktor, Morris, Andrew A, Seifert, Burkhardt, Froese, D Sean, Baumgartner, Matthias R, Dionisi-Vici, Carlo, EHOD consortium, Martin, Carlos Alcalde, Baethmann, Martina, Ballhausen, Diana, Blasco-Alonso, Javier, Boy, Nikolas, Bueno, Maria, Burgos Peláez, Rosa, Cerone, Roberto, Chabrol, Brigitte, Chapman, Kimberly A, Couce, Maria Luz, Crushell, Ellen, Dalmau Serra, Jaime, Diogo, Luisa, Ficicioglu, Can, García Jimenez, Maria Concepcion, García Silva, Maria Teresa, Gaspar, Ana Maria, Gautschi, Matthias, González-Lamuño, Domingo, Gouveia, Sofia, Grünewald, Stephanie, Hendriksz, Chris, Janssen, Mirian C H, Jesina, Pavel, Koch, Johannes, Konstantopoulou, Vassiliki, Lavigne, Christian, Lund, Allan M, Martins, Esmeralda G, Meavilla Olivas, Silvia, Mention, Karine, Mochel, Fanny, Mundy, Helen, Murphy, Elaine, Paquay, Stéphanie, Pedrón-Giner, Consuelo, Ruiz Gómez, Maria Angeles, Santra, Saikat, Schiff, Manuel, Schwartz, Ida Vanessa, Scholl-Bürgi, Sabine, Servais, Aude, Skouma, Anastasia, Tran, Christel, Vives Piñera, Inmaculada, Walter, John, and Weisfeld-Adams, James

Abstract

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

Published
2019

19. Projet FIND - the first year

Author

Gaspar, Paulo, alves, sandra, Teles, Elisa Leão, Diogo, Luisa, and Vilarinho, Laura

Subjects
Mucopolissacaridoses, Pediatria, Hurler, MPSs, Glicosaminoglicanos, Doenças Genéticas
Abstract

The first year of the project FIND about Lysosomal Storage Disorders. N/A

Published
2018

22. Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection

Author

Zhang, Shen-Ying, primary, Clark, Nathaniel E., additional, Freije, Catherine A., additional, Pauwels, Elodie, additional, Taggart, Allison J., additional, Okada, Satoshi, additional, Mandel, Hanna, additional, Garcia, Paula, additional, Ciancanelli, Michael J., additional, Biran, Anat, additional, Lafaille, Fabien G., additional, Tsumura, Miyuki, additional, Cobat, Aurélie, additional, Luo, Jingchuan, additional, Volpi, Stefano, additional, Zimmer, Bastian, additional, Sakata, Sonoko, additional, Dinis, Alexandra, additional, Ohara, Osamu, additional, Garcia Reino, Eduardo J., additional, Dobbs, Kerry, additional, Hasek, Mary, additional, Holloway, Stephen P., additional, McCammon, Karen, additional, Hussong, Stacy A., additional, DeRosa, Nicholas, additional, Van Skike, Candice E., additional, Katolik, Adam, additional, Lorenzo, Lazaro, additional, Hyodo, Maki, additional, Faria, Emilia, additional, Halwani, Rabih, additional, Fukuhara, Rie, additional, Smith, Gregory A., additional, Galvan, Veronica, additional, Damha, Masad J., additional, Al-Muhsen, Saleh, additional, Itan, Yuval, additional, Boeke, Jef D., additional, Notarangelo, Luigi D., additional, Studer, Lorenz, additional, Kobayashi, Masao, additional, Diogo, Luisa, additional, Fairbrother, William G., additional, Abel, Laurent, additional, Rosenberg, Brad R., additional, Hart, P. John, additional, Etzioni, Amos, additional, and Casanova, Jean-Laurent, additional

Published
2018
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24. ALG1-CDG:Clinical and Molecular Characterization of 39 Unreported Patients

Author

Ng, Bobby G, Shiryaev, Sergey A, Rymen, Daisy, Eklund, Erik A, Raymond, Kimiyo, Kircher, Martin, Abdenur, Jose E, Alehan, Fusun, Midro, Alina T, Bamshad, Michael J, Barone, Rita, Berry, Gerard T, Brumbaugh, Jane E, Buckingham, Kati J, Clarkson, Katie, Cole, F Sessions, O'Connor, Shawn, Cooper, Gregory M, Van Coster, Rudy, Demmer, Laurie A, Diogo, Luisa, Fay, Alexander J, Ficicioglu, Can, Fiumara, Agata, Gahl, William A, Ganetzky, Rebecca, Goel, Himanshu, Harshman, Lyndsay A, He, Miao, Jaeken, Jaak, James, Philip M, Katz, Daniel, Keldermans, Liesbeth, Kibæk, Maria, Kornberg, Andrew J, Lachlan, Katherine, Lam, Christina, Yaplito-Lee, Joy, Nickerson, Deborah A, Peters, Heidi L, Race, Valerie, Régal, Luc, Rush, Jeffrey S, Rutledge, S Lane, Shendure, Jay, Souche, Erika, Sparks, Susan E, Trapane, Pamela, Sanchez-Valle, Amarilis, and Vilain, Eric

Subjects
xeno-tetrasaccharide, asparagine-linked glycosylation protein 1, CDG, carbohydrate-deficient transferrin
Abstract

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Published
2016
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25. ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients

Author

Ng, Bobby G., Shiryaev, Sergey A., Rymen, Daisy, Eklund, Erik A., Raymond, Kimiyo, Kircher, Martin, Abdenur, Jose E., Alehan, Fusun, Midro, Alina T., Bamshad, Michael J., Barone, Rita, Berry, Gerard T., Brumbaugh, Jane E., Buckingham, Kati J., Clarkson, Katie, Cole, F. Sessions, O'Connor, Shawn, Cooper, Gregory M., Van Coster, Rudy, Demmer, Laurie A., Diogo, Luisa, Fay, Alexander J., Ficicioglu, Can, Fiumara, Agata, Gahl, William A., Ganetzky, Rebecca, Goel, Himanshu, Harshman, Lyndsay A., He, Miao, Jaeken, Jaak, James, Philip M., Katz, Daniel, Keldermans, Liesbeth, Kibaek, Maria, Kornberg, Andrew J., Lachlan, Katherine, Lam, Christina, Yaplito-Lee, Joy, Nickerson, Deborah A., Peters, Heidi L., Race, Valerie, Régal, Luc, Rush, Jeffrey S., Rutledge, S. Lane, Shendure, Jay, Souche, Erika, Sparks, Susan E., Trapane, Pamela, Sanchez-Valle, Amarilis, Vilain, Eric, Vollo, Arve, Waechter, Charles J., Wang, Raymond Y., Wolfe, Lynne A., Wong, Derek A., Wood, Tim, Yang, Amy C., Washington, Univ, Matthijs, Gert, Freeze, Hudson H., and Pediatrics

Subjects
Male, Glycosylation, Clinical Sciences, Lethal, Mannosyltransferases, Congenital Disorders of Glycosylation, Rare Diseases, xeno-tetrasaccharide, Polysaccharides, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Aetiology, University of Washington Center for Mendelian Genomics, carbohydrate-deficient transferrin, Pediatric, Genetics & Heredity, asparagine-linked glycosylation protein 1, DNA, Survival Analysis, Genes, Mutation, Female, CDG, Sequence Analysis, Biomarkers
Abstract

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Published
2016

26. ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients

Author

Ng, Bobby G., Shiryaev, Sergey A., Rymen, Daisy, Eklund, Erik A., Raymond, Kimiyo, Kircher, Martin, Abdenur, Jose E., Alehan, Fusun, Midro, Alina T., Bamshad, Michael J., Barone, Rita, Berry, Gerard T., Brumbaugh, Jane E., Buckingham, Kati J., Clarkson, Katie, Cole, F. Sessions, O'Connor, Shawn, Cooper, Gregory M., Van Coster, Rudy, Demmer, Laurie A., Diogo, Luisa, Fay, Alexander J., Ficicioglu, Can, Fiumara, Agata, Gahl, William A., Ganetzky, Rebecca, Goel, Himanshu, Harshman, Lyndsay A., He, Miao, Jaeken, Jaak, James, Philip M., Katz, Daniel, Keldermans, Liesbeth, Kibaek, Maria, Kornberg, Andrew J., Lachlan, Katherine, Lam, Christina, Yaplito-Lee, Joy, Nickerson, Deborah A., Peters, Heidi L., Race, Valerie, Régal, Luc, Rush, Jeffrey S., Rutledge, S. Lane, Shendure, Jay, Souche, Erika, Sparks, Susan E., Trapane, Pamela, Sanchez-Valle, Amarilis, Vilain, Eric, Vøllo, Arve, Waechter, Charles J., Wang, Raymond Y., Wolfe, Lynne A., Wong, Derek A., Wood, Tim, Yang, Amy C., Matthijs, Gert, and Freeze, Hudson H.

Subjects
Male, Glycosylation, Xenotetrasacharide, Sequence Analysis, DNA, Mannosyltransferases, Survival Analysis, CDG, Asparagine-linked glycosylation protein 1, Carbohydrate-deficient transferrin, Article, Congenital Disorders of Glycosylation, Polysaccharides, Mutation, Humans, CDG, Female, Genes, Lethal, Asparagine-linked glycosylation protein 1, Biomarkers
Abstract

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate (DLO) required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date thirteen mutations in eighteen patients from fourteen families have been described with varying degrees of clinical severity. We identified and characterized thirty-nine previously unreported cases of ALG1-CDG from thirty-two families and add twenty-six new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2, was seen in all twenty-seven patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Published
2015

27. CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, Jansen, Jos C., Cirak, Sebahattin, van Scherpenzeel, Monique, Timal, Sharita, Reunert, Janine, Rust, Stephan, Pérez, Belén, Vicogne, Dorothée, Krawitz, Peter, Wada, Yoshinao, Ashikov, Angel, Pérez-Cerdá, Celia, Medrano, Celia, Arnoldy, Andrea, Hoischen, Alexander, Huijben, Karin, Steenbergen, Gerry, Quelhas, Dulce, Diogo, Luisa, Rymen, Daisy, Jaeken, Jaak, Guffon, Nathalie, Cheillan, David, van den Heuvel, Lambertus P., Maeda, Yusuke, Kaiser, Olaf, Schara, Ulrike, Gerner, Patrick, van den Boogert, Marjolein A.W., Holleboom, Adriaan G., Nassogne, Marie-Cécile, Sokal, Etienne, Salomon, Jody, van den Bogaart, Geert, Drenth, Joost P.H., Huynen, Martijn A., Veltman, Joris A., Wevers, Ron A., Morava, Eva, Matthijs, Gert, Foulquier, François, Marquardt, Thorsten, Lefeber, Dirk J., UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, Jansen, Jos C., Cirak, Sebahattin, van Scherpenzeel, Monique, Timal, Sharita, Reunert, Janine, Rust, Stephan, Pérez, Belén, Vicogne, Dorothée, Krawitz, Peter, Wada, Yoshinao, Ashikov, Angel, Pérez-Cerdá, Celia, Medrano, Celia, Arnoldy, Andrea, Hoischen, Alexander, Huijben, Karin, Steenbergen, Gerry, Quelhas, Dulce, Diogo, Luisa, Rymen, Daisy, Jaeken, Jaak, Guffon, Nathalie, Cheillan, David, van den Heuvel, Lambertus P., Maeda, Yusuke, Kaiser, Olaf, Schara, Ulrike, Gerner, Patrick, van den Boogert, Marjolein A.W., Holleboom, Adriaan G., Nassogne, Marie-Cécile, Sokal, Etienne, Salomon, Jody, van den Bogaart, Geert, Drenth, Joost P.H., Huynen, Martijn A., Veltman, Joris A., Wevers, Ron A., Morava, Eva, Matthijs, Gert, Foulquier, François, Marquardt, Thorsten, and Lefeber, Dirk J.

Abstract

Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glyc

Published
2016

28. CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation

Author

Jansen, Jos C., Cirak, Sebahattin, van Scherpenzeel, Monique, Timal, Sharita, Reunert, Janine, Rust, Stephan, Perez, Belen, Vicogne, Dorothee, Krawitz, Peter, Wada, Yoshinao, Ashikov, Angel, Perez-Cerda, Celia, Medrano, Celia, Arnoldy, Andrea, Hoischen, Alexander, Huijben, Karin, Steenbergen, Gerry, Quelhas, Dulce, Diogo, Luisa, Rymen, Daisy, Jaeken, Jaak, Guffon, Nathalie, Cheillan, David, van den Heuvel, Lambertus P., Maeda, Yusuke, Kaiser, Olaf, Schara, Ulrike, Gerner, Patrick, van den Boogert, Marjolein A. W., Holleboom, Adriaan G., Nassogne, Marie-Cecile, Sokal, Etienne, Salomon, Jody, van den Bogaart, Geert, Drenth, Joost P. H., Huynen, Martijn A., Veltman, Joris A., Wevers, Ron A., Morava, Eva, Matthijs, Gert, Foulquier, Francois, Marquardt, Thorsten, Lefeber, Dirk J., Jansen, Jos C., Cirak, Sebahattin, van Scherpenzeel, Monique, Timal, Sharita, Reunert, Janine, Rust, Stephan, Perez, Belen, Vicogne, Dorothee, Krawitz, Peter, Wada, Yoshinao, Ashikov, Angel, Perez-Cerda, Celia, Medrano, Celia, Arnoldy, Andrea, Hoischen, Alexander, Huijben, Karin, Steenbergen, Gerry, Quelhas, Dulce, Diogo, Luisa, Rymen, Daisy, Jaeken, Jaak, Guffon, Nathalie, Cheillan, David, van den Heuvel, Lambertus P., Maeda, Yusuke, Kaiser, Olaf, Schara, Ulrike, Gerner, Patrick, van den Boogert, Marjolein A. W., Holleboom, Adriaan G., Nassogne, Marie-Cecile, Sokal, Etienne, Salomon, Jody, van den Bogaart, Geert, Drenth, Joost P. H., Huynen, Martijn A., Veltman, Joris A., Wevers, Ron A., Morava, Eva, Matthijs, Gert, Foulquier, Francois, Marquardt, Thorsten, and Lefeber, Dirk J.

Abstract

Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum(ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glyco

Published
2016

29. Acidémia Metilmalónica — Forma Tardia Caso Clínico

Author

Brito, Manuel João, Diogo, Luisa, Almeida, Isabel Tavares, and Ganha, Jeni

Subjects
lcsh:R5-920, acidémia metilmalónica, síndroma extrapiramidal, lcsh:RJ1-570, lcsh:Pediatrics, lcsh:Medicine (General)
Abstract

Descreve-se um caso de acidémia metilmalónica de manifestação tardia em que foi inicialmente colocado erroneamente o diagnóstico de fibrosequística. Embora anteriormente tivesse sido evocada uma possível doença hereditária do metabolismo, o diagnóstico de acidémia metilmalónica foi feitoaos 25 meses de idade, aquando de uma grave crise de acidose metabólica da qual resultou uma síndroma extrapiramidal.Chama-se a atenção para a necessidade e urgência de ponderar a hipótese de acidémia orgânica nos casos com uma clínica compatível, uma vezque a instituição precoce de uma terapêutica dietética poderá melhorar o prognóstico., Portuguese Journal of Pediatrics, Vol 27 No 1 (1996)

Published
2014

30. Secondary coenzyme Q 10 deficiencies in oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders

Author

Yubero, Delia, primary, Montero, Raquel, additional, Martín, Miguel A., additional, Montoya, Julio, additional, Ribes, Antonia, additional, Grazina, Manuela, additional, Trevisson, Eva, additional, Rodriguez-Aguilera, Juan Carlos, additional, Hargreaves, Iain P., additional, Salviati, Leonardo, additional, Navas, Plácido, additional, Artuch, Rafael, additional, Jou, Cristina, additional, Jimenez-Mallebrera, Cecilia, additional, Nascimento, Andres, additional, Pérez-Dueñas, Belén, additional, Ortez, Carlos, additional, Ramos, Federico, additional, Colomer, Jaume, additional, O’Callaghan, Mar, additional, Pineda, Mercè, additional, García-Cazorla, Angels, additional, Espinós, Carmina, additional, Ruiz, Angels, additional, Macaya, Alfons, additional, Marcé-Grau, Anna, additional, Garcia-Villoria, Judit, additional, Arias, Angela, additional, Emperador, Sonia, additional, Ruiz-Pesini, Eduardo, additional, Lopez-Gallardo, Ester, additional, Neergheen, Viruna, additional, Simões, Marta, additional, Diogo, Luisa, additional, Blázquez, Alberto, additional, González-Quintana, Adrián, additional, Delmiro, Aitor, additional, Domínguez-González, Cristina, additional, Arenas, Joaquín, additional, García-Silva, Mª Teresa, additional, Martín, Elena, additional, Quijada, Pilar, additional, Hernández-Laín, Aurelio, additional, Morán, María, additional, Rivas Infante, Eloy, additional, Ávila Polo, Rainiero, additional, Paradas Lópe, Carmen, additional, Bautista Lorite, Juan, additional, Martínez Fernández, Eva M., additional, Cortés, Ana B., additional, Sánchez-Cuesta, Ana, additional, Cascajo, Maria V., additional, Alcázar, María, additional, and Brea-Calvo, Gloria, additional

Published
2016
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31. CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation

Author

Jansen, Jos C., primary, Cirak, Sebahattin, additional, van Scherpenzeel, Monique, additional, Timal, Sharita, additional, Reunert, Janine, additional, Rust, Stephan, additional, Pérez, Belén, additional, Vicogne, Dorothée, additional, Krawitz, Peter, additional, Wada, Yoshinao, additional, Ashikov, Angel, additional, Pérez-Cerdá, Celia, additional, Medrano, Celia, additional, Arnoldy, Andrea, additional, Hoischen, Alexander, additional, Huijben, Karin, additional, Steenbergen, Gerry, additional, Quelhas, Dulce, additional, Diogo, Luisa, additional, Rymen, Daisy, additional, Jaeken, Jaak, additional, Guffon, Nathalie, additional, Cheillan, David, additional, van den Heuvel, Lambertus P., additional, Maeda, Yusuke, additional, Kaiser, Olaf, additional, Schara, Ulrike, additional, Gerner, Patrick, additional, van den Boogert, Marjolein A.W., additional, Holleboom, Adriaan G., additional, Nassogne, Marie-Cécile, additional, Sokal, Etienne, additional, Salomon, Jody, additional, van den Bogaart, Geert, additional, Drenth, Joost P.H., additional, Huynen, Martijn A., additional, Veltman, Joris A., additional, Wevers, Ron A., additional, Morava, Eva, additional, Matthijs, Gert, additional, Foulquier, François, additional, Marquardt, Thorsten, additional, and Lefeber, Dirk J., additional

Published
2016
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33. A novel missense mutation in SUCLA2 associated with mild methylmalonic aciduria

Author

Nogueira, Célia, Garcia, Paula, Diogo, Luisa, Valongo, Carla, Santorelli, Filippo, and Vilarinho, Laura

Subjects
SUCLA2, Doenças genéticas
Abstract

Livro de abstracts da 16ª reunião da SPGH 2012 Introduction Succinyl CoA synthase is a mitochondrial matrix enzyme that catalyzes the reversible synthesis of succinate and ATP or GTP from succinyl-CoA and ADP in the tricarboxylic acid cycle (TCA). This enzyme is made up of two subunits, α and β, encoded by SUCLG1 and SUCLA2, respectively. The clinical features of patients with mutations in SUCLA2 include early childhood hypotonia, developmental delay, and almost invariably, progressive dystonia and sensorineural deafness. Mutations in SUCLA2 and SUCLG1 cause an encephalomyopathic form of infantile mtDNA depletion syndrome. A useful diagnostic clue in succinyl CoA synthase disorders is a ‘‘mildly’’ elevated urinary methylmalonic acid (MMA), and presence of TCA intermediates. To date, two patients with SUCLG1 mutations have been reported, whereas mutations in SUCLA2 have been reported in 17 patients. We here present an additional patient with a novel SUCLA2 mutation. Methods We report a 17-month-old-boy, who presented severe muscular hypotonia, failure to thrive, developmental delay, weight loss during a gastroenteritis crises, dysmorphisms and muscular atrophy. A clinical investigation disclosed hyperlactacidemia together with moderate excretion of MMA and elevated C4-dicarboxylic carnitine. Sequencing analysis of SUCLA2 and SUCLG1 was performed using standard methods. Results Mutation analysis of SUCLA2 revealed a homozygous c.985A>G mutation in exon 8 (p.M329V). This missense mutation affects an amino acid that is highly conserved in different species and was not found in controls. The analysis by bioinformatics tools also confirmed a pathogenic mutation. Discussion The clinical and biochemical phenotype of our patient is strikingly similar to other reported patients with SUCLA2 mutations. In addition, the mildly elevated levels of methylmalonate and lactate raised the suspicion of this disease. Our study contributed to expand the spectrum of patients with SUCLA2 mutations, and will be important for an accurate genetic counseling and a prenatal diagnosis to the affected family.

Published
2012

34. Molecular study of portuguese patients with clinical diagnosis of Shwachman-Diamond syndrome

Author

Costa, Elísio, Oliveira, Jorge, Vieira, Emília, Garcia, Paula, Gonçalves, Isabel, Diogo, Luisa, Barbot, José, and Santos, Rosário

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Portugal, Shwachman-Diamond syndrome, hemic and lymphatic diseases, otorhinolaryngologic diseases
Abstract

Shwadurun-Diamond syndrome (SDS; MIM# 260400) is a rare autosomal recessive disorder characterized by the association of exocrine pancreatic and bone marrow disfunction.

Published
2007

36. Guanidinoacetate methyltransferase (GAMT) deficiency: Outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring

Author

Stockler-Ipsiroglu, Sylvia, primary, van Karnebeek, Clara, additional, Longo, Nicola, additional, Korenke, G. Christoph, additional, Mercimek-Mahmutoglu, Saadet, additional, Marquart, Iris, additional, Barshop, Bruce, additional, Grolik, Christiane, additional, Schlune, Andrea, additional, Angle, Brad, additional, Araújo, Helena Caldeira, additional, Coskun, Turgay, additional, Diogo, Luisa, additional, Geraghty, Michael, additional, Haliloglu, Goknur, additional, Konstantopoulou, Vassiliki, additional, Leuzzi, Vincenzo, additional, Levtova, Alina, additional, MacKenzie, Jennifer, additional, Maranda, Bruno, additional, Mhanni, Aizeddin A., additional, Mitchell, Grant, additional, Morris, Andrew, additional, Newlove, Theresa, additional, Renaud, Deborah, additional, Scaglia, Fernando, additional, Valayannopoulos, Vassili, additional, van Spronsen, Francjan J., additional, Verbruggen, Krijn T., additional, Yuskiv, Nataliya, additional, Nyhan, William, additional, and Schulze, Andreas, additional

Published
2014
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37. Coenzyme Q10 deficiency in mitochondrial DNA depletion syndromes

Author

Montero, Raquel, primary, Grazina, Manuela, additional, López-Gallardo, Ester, additional, Montoya, Julio, additional, Briones, Paz, additional, Navarro-Sastre, Aleix, additional, Land, John M., additional, Hargreaves, Iain P., additional, Artuch, Rafael, additional, del Mar O'Callaghan, Maria, additional, Jou, Cristina, additional, Jimenez, Cecilia, additional, Buján, Nuria, additional, Pineda, Mercè, additional, García-Cazorla, Angels, additional, Nascimento, Andrés, additional, Perez-Dueñas, Belen, additional, Ruiz-Pesini, Eduardo, additional, Fratter, Carl, additional, Salviati, Leonardo, additional, Simões, Marta, additional, Mendes, Cândida, additional, Santos, Maria João, additional, Diogo, Luisa, additional, Garcia, Paula, additional, and Navas, Plácido, additional

Published
2013
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38. Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency

Author

Couce, Maria, primary, Sánchez-Pintos, Paula, additional, Diogo, Luisa, additional, Leão-Teles, Elisa, additional, Martins, Esmeralda, additional, Santos, Helena, additional, Bueno, Maria, additional, Delgado-Pecellín, Carmen, additional, Castiñeiras, Daisy E, additional, Cocho, José A, additional, García-Villoria, Judit, additional, Ribes, Antonia, additional, Fraga, José M, additional, and Rocha, Hugo, additional

Published
2013
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40. Identification of novel L2HGDH gene mutations and update of the pathological spectrum

Author

Vilarinho, Laura, primary, Tafulo, Sandra, additional, Sibilio, Michelina, additional, Kok, Fernando, additional, Fontana, Federica, additional, Diogo, Luisa, additional, Venâncio, Margarida, additional, Ferreira, Mariana, additional, Nogueira, Celia, additional, Valongo, Carla, additional, Parenti, Giancarlo, additional, Amorim, António, additional, and Azevedo, Luisa, additional

Published
2009
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41. Null mutations and lethal congenital form of glycogen storage disease type IV

Author

Assereto, Stefania, primary, van Diggelen, Otto P., additional, Diogo, Luisa, additional, Morava, Eva, additional, Cassandrini, Denise, additional, Carreira, Isabel, additional, de Boode, Willem-Pieter, additional, Dilling, Jildau, additional, Garcia, Paula, additional, Henriques, Margarida, additional, Rebelo, Olinda, additional, ter Laak, Henk, additional, Minetti, Carlo, additional, and Bruno, Claudio, additional

Published
2007
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43. A Novel SUCLA2 Mutation in a Portuguese Child Associated With “Mild” Methylmalonic Aciduria.

Author

Nogueira, Célia, Meschini, Maria Chiara, Nesti, Claudia, Garcia, Paula, Diogo, Luisa, Valongo, Carla, Costa, Ricardo, Videira, Arnaldo, Vilarinho, Laura, and Santorelli, Filippo M.

Subjects
SUCCINYL-CoA synthetase, LIGASES, CARBOXAMIDES, NEUROLOGY, PEDIATRIC neurology
Abstract

Succinyl–coenzyme A synthase is a mitochondrial matrix enzyme that catalyzes the reversible synthesis of succinate and adenosine triphosphate (ATP) from succinyl–coenzyme A and adenosine diphosphate (ADP) in the tricarboxylic acid cycle. This enzyme is made up of α and β subunits encoded by SUCLG1 and SUCLA2, respectively. We present a child with severe muscular hypotonia, dystonia, failure to thrive, sensorineural deafness, and dysmorphism. Metabolic investigations disclosed hyperlactacidemia, moderate urinary excretion of methylmalonic acid, and elevated levels of C4-dicarboxylic carnitine in blood. We identified a novel homozygous p.M329V in SUCLA2. In cultured cells, the p.M329V resulted in a reduced amount of the SUCLA2 protein, impaired production of mitochondrial ATP, and enhanced production of reactive oxygen species, which was partially reduced by using 5-aminoimidazole-4-carboxamide ribonucleotide in the culture medium. Expanding the array of SUCLA2 mutations, we suggested that reactive oxygen species scavengers are likely to impact on disease prognosis. [ABSTRACT FROM PUBLISHER]

Published
2015
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44. NMR Derivatives for Quantification of 2H and 13C‐Enrichment of Human Glucuronide from Metabolic Tracers

Author

Jones, John G., primary, Barosa, Cristina, additional, Gomes, Filipe, additional, Carina Mendes, Ana, additional, Delgado, Teresa C., additional, Diogo, Luisa, additional, Garcia, Paula, additional, Bastos, Margarida, additional, Barros, Luisa, additional, Fagulha, Ana, additional, Baptista, Carla, additional, Carvalheiro, Manuela, additional, and Madalena Caldeira, M., additional

Published
2006
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46. Identification of novel L2HGDH gene mutations and update of the pathological spectrum.

Author

Vilarinho, Laura, Tafulo, Sandra, Sibilio, Michelina, Kok, Fernando, Fontana, Federica, Diogo, Luisa, Venâncio, Margarida, Ferreira, Mariana, Nogueira, Celia, Valongo, Carla, Parenti, Giancarlo, Amorim, António, and Azevedo, Luisa

Subjects
CEREBROSPINAL fluid, PHENOTYPES, HUMAN genetics, MAGNETIC resonance imaging, GENES
Abstract

L-2-hydroxyglutaric aciduria (L-2-HGA, MIM 236792) is a neurometabolic disorder caused by the toxic accumulation of high concentration of L-2-hydroxyglutaric acid in plasma and cerebrospinal fluid. Distinct mutations on the L2HGDH gene have been associated with the clinical and biochemical phenotype. Here we present three novel mutations (Gln197X, Gly211Val and c.540+1 G>A), which increase the present deleterious collection of L2HGDH gene up to 35 mutations that we have compiled in this study. In addition, we used the haplotypic information based on polymorphic markers to demonstrate the common origin of Gly57Arg harboring chromosomes. [ABSTRACT FROM AUTHOR]

Published
2010
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47. Metabolic characterisation of plasma in juveniles with glycogen storage disease type 1a (GSD1a) by high-resolution 1H NMR spectroscopy.

Author

Duarte, Iola F., Goodfellow, Brian J., Barros, António, Jones, John G., Barosa, Cristina, Diogo, Luisa, Garcia, Paula, and Gil, Ana M.

Abstract

This paper reports the first application of high-resolution 1H NMR spectroscopy to the plasma of five juveniles with glycogen storage disease type 1a (GSD1a), permitting the characterisation of the plasma metabolic profile and the identification of alterations relative to a set of control samples. The relaxation-weighted spectra allowed changes in low molecular weight compounds to be detected more clearly, whereas diffusion-edited spectra were used to characterise the plasma lipoprotein profile. Low molecular weight metabolites with altered levels in most patients were lactate, ketone bodies, acetate, creatine/creatinine and glucose. One of the patients showed distinctively lower glucose levels and higher lactate and ketone body contents, suggesting poorer metabolic control of the disease compared with other patients. In addition, a metabolite tentatively identified as α-hydroxyisobutyrate was only detected in the spectra of GSD1a plasmas, representing, therefore, a possible novel GSD1a biomarker. Total lipoprotein contents were higher in the plasma from GSD1a patients. Furthermore, lower HDL and higher VLDL + LDL levels also characterised the plasma of these patients. Preliminary results on principal component analysis of 1H NMR spectra allowed a clear separation between GSD1a and control plasmas. The specificity of the changes observed to GSD1a is discussed, together with the recognised potential of NMR and pattern recognition methods for aiding the diagnosis of GSD1a. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2007
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48. NMR Derivatives for Quantification of 2 H and 13 C‐Enrichment of Human Glucuronide from Metabolic Tracers.

Author

Jones, JohnG., Barosa, Cristina, Gomes, Filipe, Carina Mendes, Ana, Delgado, TeresaC., Diogo, Luisa, Garcia, Paula, Bastos, Margarida, Barros, Luisa, Fagulha, Ana, Baptista, Carla, Carvalheiro, Manuela, and Madalena Caldeira, M.

Subjects
GLUCONEOGENESIS, METABOLISM, GLYCOGEN, LIVER, GLUCOSE synthesis
Abstract

Quantification of 2 H and 13 C enrichment distributions in human urinary glucuronide following ingestion of 2 H 2 O and 13 C gluconeogenic tracers was achieved by NMR spectroscopy of the 1,2‐ O ‐isopropylidene‐ α ‐D‐glucofuranurono‐6,3‐lactone and 5‐ O ‐acetyl‐1,2‐ O ‐isopropylidene‐ α ‐D‐glucofuranurono‐6,3‐lactone derivatives. The derivatization process is simple and can be applied to any glucuronide species. The derivatives are highly soluble in acetonitrile and generate well‐resolved and narrow 2 H and 13 C NMR signals. The 1,2‐ O ‐isopropylidene‐α‐D‐glucofuranurono‐6,3‐lactone derivative provided resolution of the six glucuronide 13 C signals and numerous 13 C isotopomer populations through one‐ and two‐bond 13 C‐ 13 C‐coupling, while the 5‐ O ‐acetyl‐1,2‐ O ‐isopropylidene‐α‐D‐glucofuranurono‐6,3‐lactone derivative provided complete resolution of the 2 H NMR signals for the five glucuronide hydrogens. The isopropylidene methyl signals were also resolved and provided an internal 2 H enrichment standard following the acetonation of glucuronolactone with deuterated acetone. [ABSTRACT FROM AUTHOR]

Published
2006
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49. Overcoming the Obstacles.

Author

Johnson, Hilde F., Northover, Henry, Diogo, Luisa, and Rahman, M. Saifur

Subjects
ECONOMIC development, POVERTY, LITERACY, INTERNATIONAL cooperation
Abstract

Presents several essays discussing the possible obstacles in the achievement of the Millenium Development Goals. Complications of state affairs in poverty alleviation; Ineffectivity of the criterion used to assess debt sustainability; Association of absolute poverty with high illiteracy rate. INSET: Promises, promises…..

Published
2003

50. Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

Author

Huemer M, Diodato D, Martinelli D, Olivieri G, Blom H, Gleich F, Kölker S, Kožich V, Morris AA, Seifert B, Froese DS, Baumgartner MR, Dionisi-Vici C, Martin CA, Baethmann M, Ballhausen D, Blasco-Alonso J, Boy N, Bueno M, Burgos Peláez R, Cerone R, Chabrol B, Chapman KA, Couce ML, Crushell E, Dalmau Serra J, Diogo L, Ficicioglu C, García Jimenez MC, García Silva MT, Gaspar AM, Gautschi M, González-Lamuño D, Gouveia S, Grünewald S, Hendriksz C, Janssen MCH, Jesina P, Koch J, Konstantopoulou V, Lavigne C, Lund AM, Martins EG, Meavilla Olivas S, Mention K, Mochel F, Mundy H, Murphy E, Paquay S, Pedrón-Giner C, Ruiz Gómez MA, Santra S, Schiff M, Schwartz IV, Scholl-Bürgi S, Servais A, Skouma A, Tran C, Vives Piñera I, Walter J, and Weisfeld-Adams J

Subjects
Adolescent, Adult, Age of Onset, Child, Child, Preschool, Cross-Sectional Studies, Disease Progression, Europe, Female, Humans, Infant, Infant, Newborn, Male, Methylation, Methylenetetrahydrofolate Reductase (NADPH2) metabolism, Methylmalonic Acid urine, Phenotype, Pregnancy, Psychotic Disorders metabolism, Registries, Retrospective Studies, Young Adult, Amino Acid Metabolism, Inborn Errors diagnosis, Amino Acid Metabolism, Inborn Errors therapy, Homocystinuria metabolism, Methylenetetrahydrofolate Reductase (NADPH2) deficiency, Muscle Spasticity metabolism, Vitamin B 12 metabolism
Abstract

Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry., Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities., Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design., (© 2018 SSIEM.)

Published
2019
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