37 results on '"Lichter-Konecki, Uta"'
Search Results
2. Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials
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Nagamani, Sandesh CS, Diaz, George A, Rhead, William, Berry, Susan A, Le Mons, Cynthia, Lichter-Konecki, Uta, Bartley, James, Feigenbaum, Annette, Schulze, Andreas, Longo, Nicola, Berquist, William, Gallagher, Renata, Bartholomew, Dennis, Harding, Cary O, Korson, Mark S, McCandless, Shawn E, Smith, Wendy, Vockley, Jerry, Kronn, David, Zori, Robert, Cederbaum, Stephen, Merritt, J Lawrence, Wong, Derek, Coakley, Dion F, Scharschmidt, Bruce F, Dickinson, Klara, Marino, Miguel, Lee, Brendan H, and Mokhtarani, Masoud
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Chronic Pain ,Pain Research ,Clinical Research ,Neurosciences ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Ammonia ,Antineoplastic Agents ,Child ,Child ,Preschool ,Female ,Glycerol ,Humans ,Infant ,Male ,Middle Aged ,Phenylbutyrates ,Quality of Life ,Self Report ,Surveys and Questionnaires ,Urea Cycle Disorders ,Inborn ,Young Adult ,Treatment-related symptoms ,Glycerol phenylbutyrate ,Sodium phenylbutyrate ,Patient-reported outcomes ,Health-related quality of life ,Clinical Sciences ,Genetics & Heredity - Abstract
BackgroundHealth care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes.MethodsSymptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB).ResultsAfter 3 months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p
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- 2015
3. Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder
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Lee, Brendan, Diaz, George A, Rhead, William, Lichter-Konecki, Uta, Feigenbaum, Annette, Berry, Susan A, Le Mons, Cindy, Bartley, James A, Longo, Nicola, Nagamani, Sandesh C, Berquist, William, Gallagher, Renata, Bartholomew, Dennis, Harding, Cary O, Korson, Mark S, McCandless, Shawn E, Smith, Wendy, Cederbaum, Stephen, Wong, Derek, Merritt, J Lawrence, Schulze, Andreas, Vockley, Gerard, Kronn, David, Zori, Roberto, Summar, Marshall, Milikien, Douglas A, Marino, Miguel, Coakley, Dion F, Mokhtarani, Masoud, and Scharschmidt, Bruce F
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Clinical Research ,Adolescent ,Adult ,Ammonia ,Child ,Child ,Preschool ,Female ,Glutamine ,Humans ,Hyperammonemia ,Infant ,Male ,Middle Aged ,Predictive Value of Tests ,Urea Cycle Disorders ,Inborn ,Young Adult ,glycerol phenylbutyrate ,hyperammonemia ,RAVICTI ,sodium phenylbutyrate ,UCD Consortium ,Genetics ,Clinical Sciences ,Genetics & Heredity - Abstract
PurposeThe aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders.MethodsThe relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders.ResultsFasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations 200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, urea cycle disorder subtype, dietary protein intake, or blood urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis.ConclusionFasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with urea cycle disorder may benefit from tight ammonia control.
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- 2015
4. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate
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Diaz, George A, Krivitzky, Lauren S, Mokhtarani, Masoud, Rhead, William, Bartley, James, Feigenbaum, Annette, Longo, Nicola, Berquist, William, Berry, Susan A, Gallagher, Renata, Lichter‐Konecki, Uta, Bartholomew, Dennis, Harding, Cary O, Cederbaum, Stephen, McCandless, Shawn E, Smith, Wendy, Vockley, Gerald, A., Stephen, Korson, Mark S, Kronn, David, Zori, Roberto, Merritt, J Lawrence, Nagamani, Sandesh CS, Mauney, Joseph, LeMons, Cynthia, Dickinson, Klara, Moors, Tristen L, Coakley, Dion F, Scharschmidt, Bruce F, and Lee, Brendan
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Clinical Research ,Clinical Trials and Supportive Activities ,Neurosciences ,Brain Disorders ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Ammonia ,Child ,Cross-Over Studies ,Double-Blind Method ,Female ,Glutamine ,Glycerol ,Humans ,Male ,Middle Aged ,Neuropsychological Tests ,Phenylbutyrates ,Urea Cycle Disorders ,Inborn ,Young Adult ,Medical Biochemistry and Metabolomics ,Clinical Sciences ,Immunology ,Gastroenterology & Hepatology - Abstract
UnlabelledGlycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. We report the results of a pivotal Phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH3 -AUC0-24hr ), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of four studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Glycerol phenylbutyrate was noninferior to NaPBA with respect to ammonia control in the pivotal study, with mean (standard deviation, SD) NH3 -AUC0-24hr of 866 (661) versus 977 (865) μmol·h/L for glycerol phenylbutyrate and NaPBA, respectively. Among 65 adult and pediatric patients completing three similarly designed short-term comparisons of glycerol phenylbutyrate versus NaPBA, NH3 -AUC0-24hr was directionally lower on glycerol phenylbutyrate in each study, similar among all subgroups, and significantly lower (P < 0.05) in the pooled analysis, as was plasma glutamine. The 24-hour ammonia profiles were consistent with the slow-release behavior of glycerol phenylbutyrate and better overnight ammonia control. During 12 months of open-label glycerol phenylbutyrate treatment, average ammonia was normal in adult and pediatric patients and executive function among pediatric patients, including behavioral regulation, goal setting, planning, and self-monitoring, was significantly improved.ConclusionGlycerol phenylbutyrate exhibits favorable pharmacokinetics and ammonia control relative to NaPBA in UCD patients, and long-term glycerol phenylbutyrate treatment in pediatric UCD patients was associated with improved executive function (ClinicalTrials.gov NCT00551200, NCT00947544, NCT00992459, NCT00947297). (HEPATOLOGY 2012).
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- 2013
5. P018: Phenylketonuria families and researchers evaluating evidence (PHEFREE), the NIH Rare Disease Consortium for PKU
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Arnold, Georgianne, Christ, Shawn, Lichter-Konecki, Uta, Grange, Dorothy, Thomas, Janet, Berry, Gerard, Longo, Nicola, White, Desiree, and Harding, Cary
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- 2024
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6. P007: PP4 criteria specifications for proximal urea cycle disorders*
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Simpson, Kara, Mew, Nicholas Ah, Caldovic, Ljubica, Feigenbaum, Annette, Fernandez, Raquel, Groopman, Emily, Gropman, Andrea, Kudalkar, Emily, Lichter-Konecki, Uta, Kyriss, McKenna, Spector, Elaine, Weaver, Meredith, Warrier, Manya, Zastrow, Diane, and Thomas-Wilson, Amanda
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- 2024
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7. Correction to: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency
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Wortmann, Saskia B., Ziętkiewicz, Szymon, Guerrero-Castillo, Sergio, Feichtinger, René G., Wagner, Matias, Russell, Jacqui, Ellaway, Carolyn, Mróz, Dagmara, Wyszkowski, Hubert, Weis, Denisa, Hannibal, Iris, von Stülpnagel, Celina, Cabrera-Orefice, Alfredo, Lichter-Konecki, Uta, Gaesser, Jenna, Windreich, Randy, Myers, Kasiani C., Lorsbach, Robert, Dale, Russell C., Gersting, Søren, Prada, Carlos E., Christodoulou, John, Wolf, Nicole I., Venselaar, Hanka, Mayr, Johannes A., and Wevers, Ron A.
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- 2021
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8. Newborn Screening for X-Linked Adrenoleukodystrophy: Review of Data and Outcomes in Pennsylvania
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Priestley, Jessica R. C., primary, Adang, Laura A., additional, Drewes Williams, Sarah, additional, Lichter-Konecki, Uta, additional, Menello, Caitlin, additional, Engelhardt, Nicole M., additional, DiPerna, James C., additional, DiBoscio, Brenda, additional, Ahrens-Nicklas, Rebecca C., additional, Edmondson, Andrew C., additional, Reynoso Santos, Francis Jeshira, additional, and Ficicioglu, Can, additional
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- 2022
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9. Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency
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Burrage, Lindsay C., Sun, Qin, Elsea, Sarah H., Jiang, Ming-Ming, Nagamani, Sandesh C.S., Frankel, Arthur E., Stone, Everett, Alters, Susan E., Johnson, Dale E., Rowlinson, Scott W., Georgiou, George, Lee, Brendan H., Batshaw, Mark L., Tuchman, Mendel, Summar, Marshall L., Mew, Nicholas Ah, Baumgartner, Matthias R., Berry, Susan A., Cederbaum, Stephen, Coughlin, Curtis, III, Diaz, George A., Feigenbaum, Annette, Gallagher, Renata C., Harding, Cary O., Hoffmann, Georg, Kerr, Douglas S., Lee, Brendan, Lichter-Konecki, Uta, McCandless, Shawn E., Lawrence Merritt, J., II, Nagamani, Sandesh CS, Schulze, Andreas, Seashore, Margretta R., Stricker, Tamar, Waisbren, Susan, Weisfeld-Adams, James, Wong, Derek, and Yudkoff, Mark
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- 2015
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10. MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline elevated serum creatine kinase
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Lopes Abath Neto, Osorio, primary, Medne, Livija, additional, Donkervoort, Sandra, additional, Rodríguez-García, Maria Elena, additional, Bolduc, Véronique, additional, Hu, Ying, additional, Guadagnin, Eleonora, additional, Foley, A Reghan, additional, Brandsema, John F, additional, Glanzman, Allan M, additional, Tennekoon, Gihan I, additional, Santi, Mariarita, additional, Berger, Justin H, additional, Megeney, Lynn A, additional, Komaki, Hirofumi, additional, Inoue, Michio, additional, Cotrina-Vinagre, Francisco Javier, additional, Hernández-Lain, Aurelio, additional, Martin-Hernández, Elena, additional, Williams, Linford, additional, Borell, Sabine, additional, Schorling, David, additional, Lin, Kimberly, additional, Kolokotronis, Konstantinos, additional, Lichter-Konecki, Uta, additional, Kirschner, Janbernd, additional, Nishino, Ichizo, additional, Banwell, Brenda, additional, Martínez-Azorín, Francisco, additional, Burgon, Patrick G, additional, and Bönnemann, Carsten G, additional
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- 2021
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11. Severe Neonatal Holocarboxylase Synthetase Deficiency in West African Siblings
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De Castro, Mauricio, primary, Zand, Dina J., additional, Lichter-Konecki, Uta, additional, and Kirmse, Brian, additional
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- 2014
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12. The Genetic Landscape and Epidemiology of Phenylketonuria
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Hillert, Alicia, Anikster, Yair, Belanger-Quintana, Amaya, Burlina, Alberto, Burton, Barbara K., Carducci, Carla, Chiesa, Ana E., Christodoulou, John, Đorđević, Maja, Desviat, Lourdes R., Eliyahu, Aviva, Evers, Roeland A. F., Fajkusova, Lena, Feillet, Francois, Bonfim-Freitas, Pedro E., Gizewska, Maria, Gundorova, Polina, Karall, Daniela, Kneller, Katya, Kutsev, Sergey, I, Leuzzi, Vincenzo, Levy, Harvey L., Lichter-Konecki, Uta, Muntau, Ania C., Namour, Fares, Oltarzewski, Mariusz, Paras, Andrea, Perez, Belen, Polak, Emil, Polyakov, Alexander, V, Porta, Francesco, Rohrbach, Marianne, Scholl-Burgi, Sabine, Specola, Norma, Stojiljković, Maja, Shen, Nan, Santana-da Silva, Luiz C., Skouma, Anastasia, van Spronsen, Francjan, Stoppioni, Vera, Thony, Beat, Trefz, Friedrich K., Vockley, Jerry, Yu, Youngguo, Zschocke, Johannes, Hoffmann, Georg F., Garbade, Sven F., Blau, Nenad, Hillert, Alicia, Anikster, Yair, Belanger-Quintana, Amaya, Burlina, Alberto, Burton, Barbara K., Carducci, Carla, Chiesa, Ana E., Christodoulou, John, Đorđević, Maja, Desviat, Lourdes R., Eliyahu, Aviva, Evers, Roeland A. F., Fajkusova, Lena, Feillet, Francois, Bonfim-Freitas, Pedro E., Gizewska, Maria, Gundorova, Polina, Karall, Daniela, Kneller, Katya, Kutsev, Sergey, I, Leuzzi, Vincenzo, Levy, Harvey L., Lichter-Konecki, Uta, Muntau, Ania C., Namour, Fares, Oltarzewski, Mariusz, Paras, Andrea, Perez, Belen, Polak, Emil, Polyakov, Alexander, V, Porta, Francesco, Rohrbach, Marianne, Scholl-Burgi, Sabine, Specola, Norma, Stojiljković, Maja, Shen, Nan, Santana-da Silva, Luiz C., Skouma, Anastasia, van Spronsen, Francjan, Stoppioni, Vera, Thony, Beat, Trefz, Friedrich K., Vockley, Jerry, Yu, Youngguo, Zschocke, Johannes, Hoffmann, Georg F., Garbade, Sven F., and Blau, Nenad
- Abstract
Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A gt G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C gt T (p.Arg408Trp) (22.2%), c.1066-11G gt A (IVS10-11G gt A) (6.4%), and c.782G gt A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G gt A];[1066-11G gt A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.
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- 2020
13. Noncompaction of the Ventricular Myocardium and Hydrops Fetalis in Cobalamin C Disease
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Tanpaiboon, Pranoot, primary, Sloan, Jennifer L., additional, Callahan, Patrick F., additional, McAreavey, Dorothea, additional, Hart, P. Suzanne, additional, Lichter-Konecki, Uta, additional, Zand, Dina, additional, and Venditti, Charles P., additional
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- 2012
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14. A porcine model of phenylketonuria generated by CRISPR/Cas9 genome editing
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Koppes, Erik A., primary, Redel, Bethany K., additional, Johnson, Marie A., additional, Skvorak, Kristen J., additional, Ghaloul-Gonzalez, Lina, additional, Yates, Megan E., additional, Lewis, Dale W., additional, Gollin, Susanne M., additional, Wu, Yijen L., additional, Christ, Shawn E., additional, Yerle, Martine, additional, Leshinski, Angela, additional, Spate, Lee D., additional, Benne, Joshua A., additional, Murphy, Stephanie L., additional, Samuel, Melissa S., additional, Walters, Eric M., additional, Hansen, Sarah A., additional, Wells, Kevin D., additional, Lichter-Konecki, Uta, additional, Wagner, Robert A., additional, Newsome, Joseph T., additional, Dobrowolski, Steven F., additional, Vockley, Jerry, additional, Prather, Randall S., additional, and Nicholls, Robert D., additional
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- 2020
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15. The Genetic Landscape and Epidemiology of Phenylketonuria
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Hillert, Alicia, primary, Anikster, Yair, additional, Belanger-Quintana, Amaya, additional, Burlina, Alberto, additional, Burton, Barbara K., additional, Carducci, Carla, additional, Chiesa, Ana E., additional, Christodoulou, John, additional, Đorđević, Maja, additional, Desviat, Lourdes R., additional, Eliyahu, Aviva, additional, Evers, Roeland A.F., additional, Fajkusova, Lena, additional, Feillet, François, additional, Bonfim-Freitas, Pedro E., additional, Giżewska, Maria, additional, Gundorova, Polina, additional, Karall, Daniela, additional, Kneller, Katya, additional, Kutsev, Sergey I., additional, Leuzzi, Vincenzo, additional, Levy, Harvey L., additional, Lichter-Konecki, Uta, additional, Muntau, Ania C., additional, Namour, Fares, additional, Oltarzewski, Mariusz, additional, Paras, Andrea, additional, Perez, Belen, additional, Polak, Emil, additional, Polyakov, Alexander V., additional, Porta, Francesco, additional, Rohrbach, Marianne, additional, Scholl-Bürgi, Sabine, additional, Spécola, Norma, additional, Stojiljković, Maja, additional, Shen, Nan, additional, Santana-da Silva, Luiz C., additional, Skouma, Anastasia, additional, van Spronsen, Francjan, additional, Stoppioni, Vera, additional, Thöny, Beat, additional, Trefz, Friedrich K., additional, Vockley, Jerry, additional, Yu, Youngguo, additional, Zschocke, Johannes, additional, Hoffmann, Georg F., additional, Garbade, Sven F., additional, and Blau, Nenad, additional
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- 2020
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16. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-A successful strategy for clinical research of rare diseases
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Posset, Roland, Garbade, Sven F., Boy, Nikolas, Burlina, Alberto B., Dionisi-Vici, Carlo, Dobbelaere, Dries, Garcia-Cazorla, Angeles, de Lonlay, Pascale, Teles, Elisa Leao, Vara, Roshni, Mew, Nicholas Ah., Batshaw, Mark L., Baumgartner, Matthias R., McCandless, Shawn, Seminara, Jennifer, Summar, Marshall, Hoffmann, Georg F., Koelker, Stefan, Burgard, Peter, Bloxam, Sondra, Brody, Linnea, Caspi, Liora, Elsbecker, Sara, Fierro, Luca, Lynn, Audrey, Mullins, Mary, Mutze, Ulrike, Papaleo, Cassandra, Payan, Irma, Simpson, Kara, Singer, Rebecca, Wallis, Kimberly, Alber, Fabienne Dietrich, Babikian, Talin, Bender, Heidi, Boys, Christopher, Breiger, David, Buerger, Corinna, Caudle, Susan E., Nguyen-Driver, Mina, Kerr, Elizabeth, Mamak, Eva, Sanz, Jacqueline H., Tangen, Rachel, Wilkening, Greta, Cederbaum, Stephen, Feigenbaum, Annette, Kerr, Douglas S., Lichter-Konecki, Uta, Seashore, Margretta R., Berry, Susan A., Burrage, Lindsay, Coughlin, Curtis, Diaz, George A., Gallagher, Renata C., Gropman, Andrea, Harding, Cary O., Lee, Brendan, Le Mons, Cynthia, Merritt, J. Lawrence, II, Nagamani, Sandesh C. S., Schulze, Andreas, Stricker, Tamar, Tuchman, Mendel, Waisbren, Susan, Weisfeld-Adams, James, Wong, Derek, Yudkoff, Marc, Arnoux, Jean-Baptiste, Baric, Ivo, Bosch, Annet M., Chabrol, Brigitte, Chakrapani, Anupam, Cortes-Saladefont, Elisenda, Couce, Maria L., Eyskens, François, de Laet, Corine, de Meirleir, Linda, Freisinger, Peter, Gleich, Florian, Grunewald, Stephanie, Haberle, Johannes, Hwu, Wuh-Liang, Jalan, Anil, Karall, Daniela, Lindner, Martin, Lund, Allan M., Martinelli, Diego, Murphy, Elaine, Muehlhausen, Chris, Olivieri, Giorgia, Ottolenghi, Chris, Rodrigues, Esmeralda, Rubert, Laura, Sarajlija, Adrijan, Schiff, Manuel, Sokal, Etienne, Sykut-Cegielska, Jolanta, Walter, John H., Williams, Monique, Zeman, Jiri, Pediatric surgery, Clinical chemistry, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Reproduction & Development (AR&D), Pediatrics, Paediatric Metabolic Diseases, University of Zurich, Burgard, Peter, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, UCDC, and E-IMD Consortium
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0301 basic medicine ,Male ,Data Analysis ,Urea Cycle Disorders ,Delayed Diagnosis ,medicine.medical_treatment ,030105 genetics & heredity ,Liver transplantation ,Neurodegenerative ,Cohort Studies ,0302 clinical medicine ,Urea ,Genetics(clinical) ,Urea Cycle Disorders, Inborn ,Genetics (clinical) ,Ornithine transcarbamylase deficiency ,Pediatric ,Genetics & Heredity ,screening and diagnosis ,diagnostic methods ,international registry and database ,Europe ,Detection ,Urea cycle Disorders ,Urea cycle ,Female ,medicine.symptom ,Cohort study ,4.2 Evaluation of markers and technologies ,medicine.medical_specialty ,2716 Genetics (clinical) ,Clinical Sciences ,Late onset ,610 Medicine & health ,Asymptomatic ,Article ,03 medical and health sciences ,Rare Diseases ,Neonatal Screening ,1311 Genetics ,Clinical Research ,Internal medicine ,medicine ,Genetics ,Humans ,Newborn screening ,business.industry ,Infant, Newborn ,Infant ,Additional individual contributors of the UCDC and the E-IMD consortium ,medicine.disease ,Newborn ,Ornithine Carbamoyltransferase Deficiency Disease ,Clinical research ,Inborn ,Good Health and Well Being ,10036 Medical Clinic ,North America ,Human medicine ,business ,Digestive Diseases ,030217 neurology & neurosurgery - Abstract
ollaborators: Bloxam S, Brody L, Caspi L, Elsbecker S, Fierro L, Lynn A, Mullins M, Mütze U, Papaleo C, Payan I, Seminara J, Simpson K, Singer R, Wallis K, Alber FD, Babikian T, Bender H, Boys C, Breiger D, Buerger C, Caudle SE, NguyenDriver M, Kerr E, Mamak E, Sanz JH, Tangen R, Wilkening G, Cederbaum S, Feigenbaum A, Kerr DS, LichterKonecki U, Seashore MR, Berry SA, Burrage L, Coughlin C, Diaz GA, Gallagher RC, Gropman A, Harding CO, Lee B, Le Mons C, Lawrence Merritt J 2nd, Nagamani SCS, Schulze A, Stricker T, Tuchman M, Waisbren S, WeisfeldAdams J, Wong D, Yudkoff M, Arnoux J, Bari Cacute I, Bosch AM, Chabrol B, Chakrapani A, CortèsSaladefont E, Couce ML, Eyskens F, de Laet C, de Meirleir L, Freisinger P, Gleich F, Grünewald S, Häberle J, Hwu W, Jalan A, Karall D, Lindner M, Lund AM, Martinelli D, Murphy E, Mühlhausen C, Olivieri G, Ottolenghi C, Rodrigues E, Rubert L, Sarajlija A, Schiff M, Sokal E, SykutCegielska J, Walter JH, Williams M, Zeman J. BACKGROUND: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.
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- 2019
17. DNA sequence polymorphisms in exonic and intronic regions of the human phenylalanine hydroxylase gene aid in the identification of alleles
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Lichter-Konecki, Uta, Schlotter, Magdalena, and Konecki, David S.
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- 1994
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18. The phenylketonuria locus: current knowledge about alleles and mutations of the phenylalanine hydroxylase gene in various populations
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Konecki, David S. and Lichter-Konecki, Uta
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- 1991
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19. Population genetics of hyperphenylalaninaemia resulting from phenylalanine hydroxylase deficiency in Portugal
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Rivera, Isabel, Leandro, Paula, Lichter-Konecki, Uta, de Almeida, Isabel Tavares, and Lechner, Maria Celeste
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- 1998
20. The phenylketonuria G272X haplotype 7 mutation in European populations
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Apold, Jaran, Eiken, Hans G., Svensson, Elisabeth, Kunert, Erich, Kozak, Libor, Cechak, Petr, Güttler, Flemming, Giltay, Jacques, Lichter-Konecki, Uta, Melle, Dominique, and Jaruzelska, Jadwiga Maria
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- 1993
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21. Haplotype distribution and mutations at the PAH locus in Croatia
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Barić, Ivo, Mardešić, Duško, Gjurić, Gorjana, Samavka, Vladimir, Göbel-Schreiner, Barbara, Lichter-Konecki, Uta, Konecki, David S., and Trefz, Friedrich K.
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- 1992
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22. BLOOD AMMONIA AND GLUTAMINE AS PREDICTORS OF HYPERAMMONEMIC CRISES IN UREA CYCLE DISORDER PATIENTS
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Lee, Brendan, Diaz, George A, Rhead, William, Lichter-Konecki, Uta, Feigenbaum, Annette, Berry, Susan A, Le Mons, Cindy, Bartley, James A, Longo, Nicola, Nagamani, Sandesh C, Berquist, William, Gallagher, Renata, Bartholomew, Dennis, Harding, Cary O, Korson, Mark S, McCandless, Shawn E, Smith, Wendy, Cederbaum, Stephen, Wong, Derek, Merritt, J Lawrence, Schulze, Andreas, Vockley, Jerry, Kronn, David, Zori, Roberto, Summar, Marshall, Milikien, Douglas A, Marino, Miguel, Coakley, Dion F, Mokhtarani, Masoud, UCD Consortium, Scharschmidt, Bruce F, and University of Zurich
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Male ,Urea Cycle Disorders ,Glutamine ,sodium phenylbutyrate ,chemistry.chemical_compound ,0302 clinical medicine ,Glycerol phenylbutyrate ,Child ,Blood urea nitrogen ,Urea Cycle Disorders, Inborn ,Genetics (clinical) ,Genetics & Heredity ,0303 health sciences ,Sodium phenylbutyrate ,Hyperammonemia ,Middle Aged ,Biochemistry ,Urea cycle ,Child, Preschool ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,2716 Genetics (clinical) ,Urea cycle disorder ,Adolescent ,hyperammonemia ,Clinical Sciences ,610 Medicine & health ,Article ,03 medical and health sciences ,Ammonia ,Young Adult ,Clinical Research ,Predictive Value of Tests ,Internal medicine ,medicine ,Genetics ,Humans ,Preschool ,030304 developmental biology ,business.industry ,Infant ,medicine.disease ,glycerol phenylbutyrate ,Endocrinology ,Inborn ,chemistry ,10036 Medical Clinic ,UCD Consortium ,RAVICTI ,business ,030217 neurology & neurosurgery - Abstract
PurposeThe aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders.MethodsThe relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders.ResultsFasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations 200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, urea cycle disorder subtype, dietary protein intake, or blood urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis.ConclusionFasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with urea cycle disorder may benefit from tight ammonia control.
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- 2014
23. Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure
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Reichold, Markus, Klootwijk, Enriko D., Reinders, Joerg, Otto, Edgar A., Milani, Mario, Broeker, Carsten, Laing, Chris, Wiesner, Julia, Devi, Sulochana, Zhou, Weibin, Schmitt, Roland, Tegtmeier, Ines, Sterner, Christina, Doellerer, Hannes, Renner, Kathrin, Oefner, Peter J., Dettmer, Katja, Simbuerger, Johann M., Witzgall, Ralph, Stanescu, Horia C., Dumitriu, Simona, Iancu, Daniela, Patel, Vaksha, Mozere, Monika, Tekman, Mehmet, Jaureguiberry, Graciana, Issler, Naomi, Kesselheim, Anne, Walsh, Stephen B., Gale, Daniel P., Howie, Alexander J., Martins, Joana R., Hall, Andrew M., Kasgharian, Michael, O'Brien, Kevin, Ferreira, Carlos R., Atwal, Paldeep S., Jain, Mahim, Hammers, Alexander, Charles-Edwards, Geoffrey, Choe, Chi-Un, Isbrandt, Dirk, Cebrian-Serrano, Alberto, Davies, Ben, Sandford, Richard N., Pugh, Christopher, Konecki, David S., Povey, Sue, Bockenhauer, Detlef, Lichter-Konecki, Uta, Gahl, William A., Unwin, Robert J., Warth, Richard, Kleta, Robert, Reichold, Markus, Klootwijk, Enriko D., Reinders, Joerg, Otto, Edgar A., Milani, Mario, Broeker, Carsten, Laing, Chris, Wiesner, Julia, Devi, Sulochana, Zhou, Weibin, Schmitt, Roland, Tegtmeier, Ines, Sterner, Christina, Doellerer, Hannes, Renner, Kathrin, Oefner, Peter J., Dettmer, Katja, Simbuerger, Johann M., Witzgall, Ralph, Stanescu, Horia C., Dumitriu, Simona, Iancu, Daniela, Patel, Vaksha, Mozere, Monika, Tekman, Mehmet, Jaureguiberry, Graciana, Issler, Naomi, Kesselheim, Anne, Walsh, Stephen B., Gale, Daniel P., Howie, Alexander J., Martins, Joana R., Hall, Andrew M., Kasgharian, Michael, O'Brien, Kevin, Ferreira, Carlos R., Atwal, Paldeep S., Jain, Mahim, Hammers, Alexander, Charles-Edwards, Geoffrey, Choe, Chi-Un, Isbrandt, Dirk, Cebrian-Serrano, Alberto, Davies, Ben, Sandford, Richard N., Pugh, Christopher, Konecki, David S., Povey, Sue, Bockenhauer, Detlef, Lichter-Konecki, Uta, Gahl, William A., Unwin, Robert J., Warth, Richard, and Kleta, Robert
- Abstract
Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATMaggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.
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- 2018
24. Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure
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Reichold, Markus, primary, Klootwijk, Enriko D., additional, Reinders, Joerg, additional, Otto, Edgar A., additional, Milani, Mario, additional, Broeker, Carsten, additional, Laing, Chris, additional, Wiesner, Julia, additional, Devi, Sulochana, additional, Zhou, Weibin, additional, Schmitt, Roland, additional, Tegtmeier, Ines, additional, Sterner, Christina, additional, Doellerer, Hannes, additional, Renner, Kathrin, additional, Oefner, Peter J., additional, Dettmer, Katja, additional, Simbuerger, Johann M., additional, Witzgall, Ralph, additional, Stanescu, Horia C., additional, Dumitriu, Simona, additional, Iancu, Daniela, additional, Patel, Vaksha, additional, Mozere, Monika, additional, Tekman, Mehmet, additional, Jaureguiberry, Graciana, additional, Issler, Naomi, additional, Kesselheim, Anne, additional, Walsh, Stephen B., additional, Gale, Daniel P., additional, Howie, Alexander J., additional, Martins, Joana R., additional, Hall, Andrew M., additional, Kasgharian, Michael, additional, O’Brien, Kevin, additional, Ferreira, Carlos R., additional, Atwal, Paldeep S., additional, Jain, Mahim, additional, Hammers, Alexander, additional, Charles-Edwards, Geoffrey, additional, Choe, Chi-Un, additional, Isbrandt, Dirk, additional, Cebrian-Serrano, Alberto, additional, Davies, Ben, additional, Sandford, Richard N., additional, Pugh, Christopher, additional, Konecki, David S., additional, Povey, Sue, additional, Bockenhauer, Detlef, additional, Lichter-Konecki, Uta, additional, Gahl, William A., additional, Unwin, Robert J., additional, Warth, Richard, additional, and Kleta, Robert, additional
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- 2018
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25. RFLP-patterns in Japanese PKU families: new polymorphisms for the mutant phenylalanine hydroxylase gene
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Trefz, Friedrich K., Yoshino, M., Nishiyori, A., Aengeneyndt, Frank, Schmidt-Mader, Brigitte, Lichter-Konecki, Uta, and Konecki, David S.
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- 1990
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26. Phenylketonuria Scientific Review Conference:State Of The Science And Future Research Needs
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Camp, Kathryn M., Parisi, Melissa A., Acosta, Phyllis B., Berry, Gerard T., Bilder, Deborah A., Blau, Nenad, Bodamer, Olaf A., Brosco, Jeffrey P., Brown, Christine S., Burlina, Alberto B., Burton, Barbara K., Chang, Christine S., Coates, Paul M., Cunningham, Amy C., Dobrowolski, Steven F., Ferguson, John H., Franklin, Thomas D., Frazier, Dianne M., Grange, Dorothy K., Greene, Carol L., Groft, Stephen C., Harding, Cary O., Howell, R. Rodney, Huntington, Kathleen L., Hyatt-Knorr, Henrietta D., Jevaji, Indira P., Levy, Harvey L., Lichter-Konecki, Uta, Lindegren, Mary Lou, Lloyd-Puryear, Michele A., Matalon, Kimberlee, MacDonald, Anita, McPheeters, Melissa L., Mitchell, John J., Mofidi, Shideh, Moseley, Kathryn D., Mueller, Christine M., Mulberg, Andrew E., Nerurkar, Lata S., Ogata, Beth N., Pariser, Anne R., Prasad, Suyash, Pridjian, Gabriella, Rasmussen, Sonja A., Reddy, Uma M., Rohr, Frances J., Singh, Rani H., Sirrs, Sandra M., Stremer, Stephanie E., Tagle, Danilo A., Thompson, Susan M., Urv, Tiina K., Utz, Jeanine R., van Spronsen, Francjan, Vockley, Jerry, Waisbren, Susan E., Weglicki, Linda S., White, Desiree A., Whitley, Chester B., Wilfond, Benjamin S., Yannicelli, Steven, and Young, Justin M.
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congenital, hereditary, and neonatal diseases and abnormalities ,nutritional and metabolic diseases - Abstract
New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 Rtnol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 [tmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.
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- 2014
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27. Phenylketonuria (PKU): A problem solved?
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Brown, Christine S., primary and Lichter-Konecki, Uta, additional
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- 2016
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28. Mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder
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Wang, Yuexia, primary, Lichter-Konecki, Uta, additional, Anyane-Yeboa, Kwame, additional, Shaw, Jessica E., additional, Lu, Jonathan T., additional, Östlund, Cecilia, additional, Shin, Ji-Yeon, additional, Clark, Lorraine N., additional, Gundersen, Gregg G., additional, Nagy, Peter L., additional, and Worman, Howard J., additional
- Published
- 2016
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29. Linkage disequilibrium between mutation and RFLP haplotype at the phenylalanine hydroxylase locus in the German population
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Lichter-Konecki, Uta, Schlotter, Magdalena, Konecki, David S., Labeit, Sigfried, Woo, Savio L. C., and Trefz, Friedrich K.
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- 1988
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30. DNA haplotype analysis at the phenylalanine hydroxylase locus in the Turkish population
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Lichter-Konecki, Uta, Schlotter, Magdalena, Yaylak, Canan, Özgüç, Meral, Çoskun, Turgay, Özalp, Imran, Wendel, Udo, Batzler, Ulrich, Trefz, Friedrich K., and Konecki, David
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- 1989
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31. Thiamine pyrophosphokinase deficiency causes a Leigh Disease like phenotype in a sibling pair: identification through whole exome sequencing and management strategies
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Fraser, Jamie L., primary, Vanderver, Adeline, additional, Yang, Sandra, additional, Chang, Taeun, additional, Cramp, Laura, additional, Vezina, Gilbert, additional, Lichter-Konecki, Uta, additional, Cusmano-Ozog, Kristina P., additional, Smpokou, Patroula, additional, Chapman, Kimberly A., additional, and Zand, Dina J., additional
- Published
- 2014
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32. A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder.
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Yuexia Wang, Lichter-Konecki, Uta, Anyane-Yeboa, Kwame, Shaw, Jessica E., Lu, Jonathan T., Östlund, Cecilia, Ji-Yeon Shin, Clark, Lorraine N., Gundersen, Gregg G., Nagy, Peter L., and Worman, Howard J.
- Subjects
- *
METALLOPROTEINASES , *LAMINA epithelialis , *CLEAVAGE (Embryology) , *GENETIC disorders , *VALINE , *ARGININE - Abstract
In 1994 in the Journal of Cell Science, Hennekes andNigg reported that changing valine to arginine at the endoproteolytic cleavage site in chicken prelamin A abolishes its conversion to lamin A. The consequences of this mutation in an organism have remained unknown. We now report that the corresponding mutation in a human subject leads to accumulation of prelamin A and causes a progeroid disorder. Next generation sequencing of the subject and her parents' exomes identified a de novo mutation in the lamin A/C gene (LMNA) that resulted in a leucine to arginine amino acid substitution at residue 647 in prelamin A. The subject's fibroblasts accumulated prelamin A, a farnesylated protein, which led to an increased percentage of cultured cells with morphologically abnormal nuclei. Treatment with a protein farnesyltransferase inhibitor improved abnormal nuclear morphology. This case demonstrates that accumulation of prelamin A, independent of the loss of function of ZMPSTE24 metallopeptidase that catalyzes processing of prelamin A, can cause a progeroid disorder and that a cell biology assay could be used in precision medicine to identify a potential therapy. [ABSTRACT FROM AUTHOR]
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- 2016
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33. Utility of Oligonucleotide Array–Based Comparative Genomic Hybridization for Detection of Target Gene Deletions
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Wong, Lee-Jun C, primary, Dimmock, David, primary, Geraghty, Michael T, primary, Quan, Richard, primary, Lichter-Konecki, Uta, primary, Wang, Jing, primary, Brundage, Ellen K, primary, Scaglia, Fernando, primary, and Chinault, A Craig, primary
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- 2008
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34. A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder.
- Author
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Wang Y, Lichter-Konecki U, Anyane-Yeboa K, Shaw JE, Lu JT, Östlund C, Shin JY, Clark LN, Gundersen GG, Nagy PL, and Worman HJ
- Subjects
- Adolescent, Amino Acid Substitution genetics, Female, Fibroblasts, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Mutation, Protein Prenylation, Lamin Type A genetics, Membrane Proteins genetics, Metalloendopeptidases genetics, Progeria genetics
- Abstract
In 1994 in the Journal of Cell Science, Hennekes and Nigg reported that changing valine to arginine at the endoproteolytic cleavage site in chicken prelamin A abolishes its conversion to lamin A. The consequences of this mutation in an organism have remained unknown. We now report that the corresponding mutation in a human subject leads to accumulation of prelamin A and causes a progeroid disorder. Next generation sequencing of the subject and her parents' exomes identified a de novo mutation in the lamin A/C gene (LMNA) that resulted in a leucine to arginine amino acid substitution at residue 647 in prelamin A. The subject's fibroblasts accumulated prelamin A, a farnesylated protein, which led to an increased percentage of cultured cells with morphologically abnormal nuclei. Treatment with a protein farnesyltransferase inhibitor improved abnormal nuclear morphology. This case demonstrates that accumulation of prelamin A, independent of the loss of function of ZMPSTE24 metallopeptidase that catalyzes processing of prelamin A, can cause a progeroid disorder and that a cell biology assay could be used in precision medicine to identify a potential therapy., (© 2016. Published by The Company of Biologists Ltd.)
- Published
- 2016
- Full Text
- View/download PDF
35. Phenylketonuria (PKU): A problem solved?
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Brown CS and Lichter-Konecki U
- Abstract
Phenylketonuria (PKU) is a rare metabolic disorder characterized by impaired conversion of phenylalanine (Phe) to tyrosine. If left untreated, the resultant accumulation of excess blood Phe can cause physiological, neurological, and intellectual disabilities. The National PKU Alliance (NPKUA) conducted a survey of its membership to assess current health status and interest in new treatments for PKU. Of the 625 survey respondents, less than half (46.7%) reported blood Phe within (120-360 μmol/L) - the range recommended by the American College of Medical Genetics and Genomics (ACMG). The survey results also showed that younger (≤ 18 years) individuals were about 3-times as successful in keeping their blood Phe concentrations within the recommended clinical range compared with adults. Blood Phe over 360 μmol/L was reported in one-quarter (25.5%) of ≤ 18 year old individuals and almost two-thirds (61.5%) of adults. A little more than half (51.7%) of respondents reported having difficulty in managing their PKU, including the maintenance of a Phe-restricted diet. Individuals with PKU desire new treatments that would allow them to increase their intake of natural protein, discontinue or reduce their intake of medical foods (medical formula and foods modified to be low in protein), improve their mental health (including a reduction in depression and anxiety), and a reduction of their blood Phe concentrations. Respondents preferred oral administration of any newly developed therapies and, in general, disliked therapeutic injections. Injections at home were preferred over injections at a clinic. Payers, government agencies, clinicians, and industry partners should consider patient input when developing and approving new therapies and treatments for PKU.
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- 2015
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36. Severe neonatal holocarboxylase synthetase deficiency in west african siblings.
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De Castro M, Zand DJ, Lichter-Konecki U, and Kirmse B
- Abstract
In multiple carboxylase deficiency (MCD), the biotin-dependent carboxylases have decreased activity due to either biotinidase deficiency or holocarboxylase synthetase (HS) deficiency. We report the case of two siblings from Ghana, the first of which presented shortly after birth with profound lactic acidosis and a urine organic acid profile consistent with MCD. In the first sibling, treatment with pulverized biotin tablets (20 mg) was begun immediately, but the patient died at 10 days of age from cardiac arrest secondary to refractory metabolic acidosis. Autopsy revealed a biotin bezoar. Sequencing of HCLS showed homozygosity for a novel missense variant (p.G241W). The second sibling had a similar presentation at birth: severe metabolic acidosis and respiratory distress. A urine organic acid profile was consistent with HS deficiency; he was treated with biotin powder (20 mg), and after 24 h, the lactate decreased significantly; by day 5 of life, the patient was tolerating 40 mg of biotin, feeding by mouth and off all other medications and support. This is the first report of the p.G241W mutation. To our knowledge, this is also the first mutation described in West African patients with HS deficiency and the cases demonstrate that it is biotin responsive. Additionally, our experience suggests that the powdered form of biotin supplementation may be more digestible than tablets for the treatment of severe neonatal HS deficiency.
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- 2015
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37. Noncompaction of the ventricular myocardium and hydrops fetalis in cobalamin C disease.
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Tanpaiboon P, Sloan JL, Callahan PF, McAreavey D, Hart PS, Lichter-Konecki U, Zand D, and Venditti CP
- Abstract
Cobalamin C disease (cblC), a form of combined methylmalonic acidemia and hyperhomocysteinemia caused by mutations in the MMACHC gene, may be the most common inborn error of intracellular cobalamin metabolism. The clinical manifestations of cblC disease are diverse and range from intrauterine growth retardation to adult onset neurological disease. The occurrence of structural heart defects appears to be increased in cblC patients and may be related to the function of the MMACHC enzyme during cardiac embryogenesis, a concept supported by the observation that Mmachc is expressed in the bulbis cordis of the developing mouse heart. Here we report an infant who presented with hydrops fetalis, ventricular dysfunction, and echocardiographic evidence of LVNC, a rare congenital cardiomyopathy. Metabolic evaluations, complementation studies, and mutation analysis confirmed the diagnosis of cblC disease. These findings highlight an intrauterine cardiac phenotype that can be displayed in cblC disease in association with nonimmune hydrops.
- Published
- 2013
- Full Text
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