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2. ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis

Author

Van Hove, Johan L.K., Friederich, Marisa W., Hock, Daniella H., Stroud, David A., Caruana, Nikeisha J., Christians, Uwe, Schniedewind, Björn, Michel, Cole R., Reisdorph, Richard, Lopez Gonzalez, Edwin D.J., Brenner, Charles, Donovan, Tonia E., Lee, Jessica C., Chatfield, Kathryn C., Larson, Austin A., Baker, Peter R., II, McCandless, Shawn E., and Moore Burk, Meghan F.

Published
2024
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3. Severity-adjusted evaluation of initial dialysis on short-term health outcomes in urea cycle disorders

Author

Schulze, Andreas, Ficicioglu, Can, Harding, Cary O., Lam, Christina, Coughlin, Curtis R., 2nd, Wong, Derek, Diaz, George A., Berry, Gerard T., Enns, Gregory M., Wilkening, Greta, Seminara, Jennifer, Konczal, Laura, Lawrence Merritt, J., 2nd, Burrage, Lindsay C., Breilyn, Margo, Baumgartner, Matthias R., Mew, Nicholas Ah., Gallagher, Renata C., McCandless, Shawn E., Berry, Susan A., Stricker, Tamar, Zielonka, Matthias, Kölker, Stefan, Garbade, Sven F., Gleich, Florian, Nagamani, Sandesh C.S., Gropman, Andrea L., Druck, Ann-Catrin, Ramdhouni, Nesrine, Göde, Laura, Hoffmann, Georg F., and Posset, Roland

Published
2024
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4. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders

Author

Mew, Nicholas Ah, Seminara, Jennifer, Burrage, Lindsay C., Berry, Gerard T., Breilyn, Margo, Schulze, Andreas, Harding, Cary O., Berry, Susan A., Wong, Derek, McCandless, Shawn E., Baumgartner, Matthias R., Konczal, Laura, Ficicioglu, Can, Diaz, George A., Coughlin, Curtis R., 2nd, Enns, Gregory M., Gallagher, Renata C., Lam, Christina, Stricker, Tamar, Wilkening, Greta, Dionisi-Vici, Carlo, Dobbelaere, Dries, Blasco-Alonso, Javier, Burlina, Alberto B., Freisinger, Peter, van Hasselt, Peter M., Skouma, Anastasia, Lund, Allan M., Vara, Roshni, Sarajlija, Adrijan, Morris, Andrew A., Chakrapani, Anupam, Barić, Ivo, Augoustides-Savvopoulou, Persephone, Chien, Yin-Hsiu, Cortès-Saladelafont, Elisenda, Eyskens, Francois, Gramer, Gwendolyn, Zeman, Jiri, Karall, Daniela, Couce, Maria L., Mühlhausen, Chris, Pedrón-Giner, Consuelo, Spiekerkoetter, Ute, Sykut-Cegielska, Jolanta, Wagenmakers, Margreet, Wijburg, Frits A., Posset, Roland, Garbade, Sven F., Gleich, Florian, Scharre, Svenja, Okun, Jürgen G., Gropman, Andrea L., Nagamani, Sandesh C.S., Druck, Ann-Catrin, Epp, Friederike, Hoffmann, Georg F., Kölker, Stefan, and Zielonka, Matthias

Published
2024
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5. Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders

Author

Schulze, Andreas, García-Cazorla, Angeles, Ficicioglu, Can, Harding, Cary O., Lam, Christina, Coughlin, Curtis R., 2<ce:sup loc='post">nd</ce:sup>, Le Mons, Cynthia, Wong, Derek, Dobbelaere, Dries, Diaz, George A., Berry, Gerard T., Enns, Gregory M., Wilkening, Greta, Lawrence Merritt, J., 2<ce:sup loc='post">nd</ce:sup>, Seminara, Jennifer, Konczal, Laura, Burrage, Lindsay C., Breilyn, Margo, Lindner, Martin, Baumgartner, Matthias R., Mew, Nicholas Ah., Gallagher, Renata C., McCandless, Shawn E., Berry, Susan A., Stricker, Tamar, Posset, Roland, Garbade, Sven F., Gleich, Florian, Nagamani, Sandesh C.S., Gropman, Andrea L., Epp, Friederike, Ramdhouni, Nesrine, Druck, Ann-Catrin, Hoffmann, Georg F., Kölker, Stefan, and Zielonka, Matthias

Published
2024
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6. Automated syndrome diagnosis by three-dimensional facial imaging.

Author

Hallgrímsson, Benedikt, Aponte, J, Katz, David, Bannister, Jordan, Riccardi, Sheri, Mahasuwan, Nick, McInnes, Brenda, Ferrara, Tracey, Lipman, Danika, Neves, Amanda, Spitzmacher, Jared, Larson, Jacinda, Bellus, Gary, Pham, Anh, Aboujaoude, Elias, Benke, Timothy, Chatfield, Kathryn, Davis, Shanlee, Elias, Ellen, Enzenauer, Robert, French, Brooke, Pickler, Laura, Shieh, Joseph, Slavotinek, Anne, Harrop, A, Innes, A, McCandless, Shawn, McCourt, Emily, Meeks, Naomi, Tartaglia, Nicole, Tsai, Anne, Wyse, J, Bernstein, Jonathan, Sanchez-Lara, Pedro, Forkert, Nils, Bernier, Francois, Spritz, Richard, and Klein, Ophir

Subjects
deep phenotyping, diagnosis, facial imaging, morphometrics, syndromes, Face, Humans, Imaging, Three-Dimensional, Syndrome
Abstract

PURPOSE: Deep phenotyping is an emerging trend in precision medicine for genetic disease. The shape of the face is affected in 30-40% of known genetic syndromes. Here, we determine whether syndromes can be diagnosed from 3D images of human faces. METHODS: We analyzed variation in three-dimensional (3D) facial images of 7057 subjects: 3327 with 396 different syndromes, 727 of their relatives, and 3003 unrelated, unaffected subjects. We developed and tested machine learning and parametric approaches to automated syndrome diagnosis using 3D facial images. RESULTS: Unrelated, unaffected subjects were correctly classified with 96% accuracy. Considering both syndromic and unrelated, unaffected subjects together, balanced accuracy was 73% and mean sensitivity 49%. Excluding unrelated, unaffected subjects substantially improved both balanced accuracy (78.1%) and sensitivity (56.9%) of syndrome diagnosis. The best predictors of classification accuracy were phenotypic severity and facial distinctiveness of syndromes. Surprisingly, unaffected relatives of syndromic subjects were frequently classified as syndromic, often to the syndrome of their affected relative. CONCLUSION: Deep phenotyping by quantitative 3D facial imaging has considerable potential to facilitate syndrome diagnosis. Furthermore, 3D facial imaging of unaffected relatives may identify unrecognized cases or may reveal novel examples of semidominant inheritance.

Published
2020

8. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders—A successful strategy for clinical research of rare diseases

Author

Posset, Roland, Garbade, Sven F, Boy, Nikolas, Burlina, Alberto B, Dionisi‐Vici, Carlo, Dobbelaere, Dries, Garcia‐Cazorla, Angeles, de Lonlay, Pascale, Teles, Elisa Leão, Vara, Roshni, Mew, Nicholas Ah, Batshaw, Mark L, Baumgartner, Matthias R, McCandless, Shawn E, Seminara, Jennifer, Summar, Marshall, Hoffmann, Georg F, Kölker, Stefan, Burgard, Peter, Berry, Susan A, Burrage, Lindsay, Coughlin, Curtis, Diaz, George A, Gallagher, Renata C, Gropman, Andrea, Harding, Cary O, Lee, Brendan, Le Mons, Cynthia, Lawrence Merritt, J, Nagamani, Sandesh CS, Schulze, Andreas, Stricker, Tamar, Tuchman, Mendel, Waisbren, Susan, WeisfeldAdams, James, Wong, Derek, Yudkoff, Marc, Arnoux, JeanBaptiste, Bari&cacute;, Ivo, Bosch, Annet M, Chabrol, Brigitte, Chakrapani, Anupam, CortèsSaladefont, Elisenda, Couce, Maria L, Eyskens, Francois, Laet, Corine, Meirleir, Linda, Freisinger, Peter, Gleich, Florian, Grünewald, Stephanie, Häberle, Johannes, Hwu, WuhLiang, Jalan, Anil, Karall, Daniela, Lindner, Martin, Lund, Allan M, Martinelli, Diego, Murphy, Elaine, Mühlhausen, Chris, Olivieri, Giorgia, Ottolenghi, Chris, Rodrigues, Esmeralda, Rubert, Laura, Sarajlija, Adrijan, Schiff, Manuel, Sokal, Etienne, SykutCegielska, Jolanta, Walter, John H, Williams, Monique, and Zeman, Jiri

Subjects
Clinical Research, Pediatric, Digestive Diseases, Neurodegenerative, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Cohort Studies, Data Analysis, Delayed Diagnosis, Europe, Female, Humans, Infant, Newborn, Male, Neonatal Screening, North America, Ornithine Carbamoyltransferase Deficiency Disease, Rare Diseases, Urea, Urea Cycle Disorders, Inborn, Urea cycle Disorders, international registry and database, diagnostic methods, Additional individual contributors of the UCDC and the E-IMD consortium, Clinical Sciences, Genetics & Heredity
Abstract

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.

Published
2019

9. REVIEW: Practical strategies to maintain anabolism by intravenous nutritional management in children with inborn metabolic diseases

Author

Kripps, Kimberly A., Baker, Peter R., II, Thomas, Janet A., Skillman, Heather E., Bernstein, Laurie, Gaughan, Sommer, Burns, Casey, Coughlin, Curtis R., II, McCandless, Shawn E., Larson, Austin A., Kochar, Aaina, Stillman, Chelsey F., Wymore, Erica M., Hendricks, Ellie G., Woontner, Michael, and Van Hove, Johan L.K.

Published
2021
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10. Effects of MetAP2 inhibition on hyperphagia and body weight in Prader–Willi syndrome: A randomized, double‐blind, placebo‐controlled trial

Author

McCandless, Shawn E, Yanovski, Jack A, Miller, Jennifer, Fu, Cary, Bird, Lynne M, Salehi, Parisa, Chan, Christine L, Stafford, Diane, Abuzzahab, M Jennifer, Viskochil, David, Barlow, Sarah E, Angulo, Moris, Myers, Susan E, Whitman, Barbara Y, Styne, Dennis, Roof, Elizabeth, Dykens, Elisabeth M, Scheimann, Ann O, Malloy, Jaret, Zhuang, Dongliang, Taylor, Kristin, Hughes, Thomas E, Kim, Dennis D, and Butler, Merlin G

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Clinical Research, Obesity, Rare Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Cardiovascular, Adolescent, Adult, Aminopeptidases, Appetite Depressants, Body Mass Index, Cinnamates, Cyclohexanes, Dose-Response Relationship, Drug, Double-Blind Method, Early Termination of Clinical Trials, Epoxy Compounds, Female, Glycoproteins, Humans, Hyperphagia, Intention to Treat Analysis, Male, Methionyl Aminopeptidases, Prader-Willi Syndrome, Protease Inhibitors, Sesquiterpenes, Severity of Illness Index, Venous Thrombosis, Weight Loss, Young Adult, antiobesity drug, appetite control, clinical trial, phase III study, randomized trial, Endocrinology & Metabolism, Clinical sciences
Abstract

AimsThere are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib.Materials and methodsParticipants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151.ResultsOne-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo.ConclusionsMetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

Published
2017

14. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders

Author

Posset, Roland, Garbade, Sven F., Gleich, Florian, Scharre, Svenja, Okun, Jürgen G., Gropman, Andrea L., Nagamani, Sandesh C.S., Druck, Ann Catrin, Epp, Friederike, Hoffmann, Georg F., Kölker, Stefan, Zielonka, Matthias, Mew, Nicholas Ah, Seminara, Jennifer, Burrage, Lindsay C., Berry, Gerard T., Breilyn, Margo, Schulze, Andreas, Harding, Cary O., Berry, Susan A., Wong, Derek, McCandless, Shawn E., Baumgartner, Matthias R., Konczal, Laura, Ficicioglu, Can, Diaz, George A., Coughlin, Curtis R., Enns, Gregory M., Gallagher, Renata C., Lam, Christina, Stricker, Tamar, Wilkening, Greta, Dionisi-Vici, Carlo, Dobbelaere, Dries, Blasco-Alonso, Javier, Burlina, Alberto B., Freisinger, Peter, van Hasselt, Peter M., Skouma, Anastasia, Lund, Allan M., Vara, Roshni, Sarajlija, Adrijan, Morris, Andrew A., Chakrapani, Anupam, Barić, Ivo, Augoustides-Savvopoulou, Persephone, Chien, Yin Hsiu, Cortès-Saladelafont, Elisenda, Eyskens, Francois, Wagenmakers, Margreet, Posset, Roland, Garbade, Sven F., Gleich, Florian, Scharre, Svenja, Okun, Jürgen G., Gropman, Andrea L., Nagamani, Sandesh C.S., Druck, Ann Catrin, Epp, Friederike, Hoffmann, Georg F., Kölker, Stefan, Zielonka, Matthias, Mew, Nicholas Ah, Seminara, Jennifer, Burrage, Lindsay C., Berry, Gerard T., Breilyn, Margo, Schulze, Andreas, Harding, Cary O., Berry, Susan A., Wong, Derek, McCandless, Shawn E., Baumgartner, Matthias R., Konczal, Laura, Ficicioglu, Can, Diaz, George A., Coughlin, Curtis R., Enns, Gregory M., Gallagher, Renata C., Lam, Christina, Stricker, Tamar, Wilkening, Greta, Dionisi-Vici, Carlo, Dobbelaere, Dries, Blasco-Alonso, Javier, Burlina, Alberto B., Freisinger, Peter, van Hasselt, Peter M., Skouma, Anastasia, Lund, Allan M., Vara, Roshni, Sarajlija, Adrijan, Morris, Andrew A., Chakrapani, Anupam, Barić, Ivo, Augoustides-Savvopoulou, Persephone, Chien, Yin Hsiu, Cortès-Saladelafont, Elisenda, Eyskens, Francois, and Wagenmakers, Margreet

Abstract

Purpose: Liver transplantation (LTx) is performed in individuals with urea cycle disorders when medical management (MM) insufficiently prevents the occurrence of hyperammonemic events. However, there is a paucity of systematic analyses on the effects of LTx on health-related outcome parameters compared to individuals with comparable severity who are medically managed. Methods: We investigated the effects of LTx and MM on validated health-related outcome parameters, including the metabolic disease course, linear growth, and neurocognitive outcomes. Individuals were stratified into “severe” and “attenuated” categories based on the genotype-specific and validated in vitro enzyme activity. Results: LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. However, neurocognitive outcome in individuals with LTx did not differ from the medically managed counterparts as reflected by the frequency of motor abnormality and cognitive standard deviation score at last observation. Conclusion: Whereas LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy and was associated with a more favorable growth outcome, LTx—as currently performed—was not associated with improved neurocognitive outcomes compared with long-term MM in the investigated urea cycle disorders.

Published
2024

15. Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials

Author

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

Subjects
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

Published
2015

16. Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder

Author

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

Subjects
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.

Published
2015

17. Long-term safety and efficacy of glycerol phenylbutyrate for the management of urea cycle disorder patients

Author

Diaz, George A., Schulze, Andreas, Longo, Nicola, Rhead, William, Feigenbaum, Annette, Wong, Derek, Merritt, J. Lawrence, II, Berquist, William, Gallagher, Renata C., Bartholomew, Dennis, McCandless, Shawn E., Smith, Wendy E., Harding, Cary O., Zori, Roberto, Lichter-Konecki, Uta, Vockley, Jerry, Canavan, Colleen, Vescio, Thomas, Holt, Robert J., and Berry, Susan A.

Published
2019
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18. De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities

Author

Okur, Volkan, Chen, Zefu, Vossaert, Liesbeth, Peacock, Sandra, Rosenfeld, Jill, Zhao, Lina, Du, Haowei, Calamaro, Emily, Gerard, Amanda, Zhao, Sen, Kelsay, Jill, Lahr, Ashley, Mighton, Chloe, Porter, Hillary M., Siemon, Amy, Silver, Josh, Svihovec, Shayna, Fong, Chin-To, Grant, Christina L., Lerner-Ellis, Jordan, Manickam, Kandamurugu, Madan-Khetarpal, Suneeta, McCandless, Shawn E., Morel, Chantal F., Schaefer, G. Bradley, Berry-Kravis, Elizabeth M., Gates, Ryan, Gomez-Ospina, Natalia, Qiu, Guixing, Zhang, Terry Jianguo, Wu, Zhihong, Meng, Linyan, Liu, Pengfei, Scott, Daryl A., Lupski, James R., Eng, Christine M., Wu, Nan, and Yuan, Bo

Published
2021
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25. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate

Author

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

Subjects
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).

Published
2013

28. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders—a successful strategy for clinical research of rare diseases

Author

Posset, Roland, Garbade, Sven F., Boy, Nikolas, Burlina, Alberto B., Dionisi-Vici, Carlo, Dobbelaere, Dries, Garcia-Cazorla, Angeles, de Lonlay, Pascale, Teles, Elisa Leão, Vara, Roshni, Ah Mew, Nicholas, Batshaw, Mark L., Baumgartner, Matthias R., McCandless, Shawn, Seminara, Jennifer, Summar, Marshall, Hoffmann, Georg F., Kölker, Stefan, Burgard, Peter, and Additional individual contributors of the UCDC and the E-IMD consortium

Published
2018
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29. Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency

Author

Scharre, Svenja, Posset, Roland, Garbade, Sven F., Gleich, Florian, Seidl, Marie J., Druck, Ann‐Catrin, Okun, Jürgen G., Gropman, Andrea L., Nagamani, Sandesh C. S., Hoffmann, Georg F., Kölker, Stefan, Zielonka, Matthias, Ah Mew, Nicholas, Baumgartner, Matthias R., Berry, Gerard T., Berry, Susan A., Burrage, Lindsay, Diaz, George A., Ficicioglu, Can, Kisin, Genya, Konczal, Laura, Lam, Christina, McCandless, Shawn E., Merritt, J. Lawrence, Schulze, Andreas, Walter, Magdalena E., Wilson, Ashley, Wong, Derek, Arnaudo, Florence, Augoustides‐ Savvopoulou, Persephone, Barić, Ivo, Bosch, Annet M., Cano, Aline, Chien, Yin‐Hsiu, Dionisi‐Vici, Carlo, Dobbelaere, Dries, Eyskens, Francois, Freisinger, Peter, Garcia‐Cazorla, Angeles, Honzik, Tomas, Karall, Daniela, Lund, Allan M., Murphy, Elaine, Santer, René, Schiff, Manuel, Skouma, Anastasia, Sykut‐Cegielska, Jolanta, Wijburg, Frits A., Zeman, Jiri, for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) Consortia Study Group, VU University medical center, Paediatric Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and ARD - Amsterdam Reproduction and Development

Subjects
Male, Phenotype, ornithine transcarbamylase deficiency, disease severity, prediction, General Neuroscience, Humans, Hyperammonemia, Neurology (clinical), Severity of Illness Index, Ornithine Carbamoyltransferase Deficiency Disease
Abstract

Objective: Ornithine transcarbamylase deficiency (OTC-D) is an X-linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity-adjusted classification system based on in vitro residual enzymatic OTC activity. Methods: Applying a cell-based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC-D (mOTC-D) as reported in the UCDC and E-IMD registries. Results: Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC-D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. Interpretation: Residual enzymatic OTC activity reliably predicts the disease severity in mOTC-D and could thus serve as a tool for severity- adjusted evaluation of therapeutic strategies and counselling patients and parents.

Published
2022
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32. Piloting a multidisciplinary approach to improve outcomes of fetal whole exome sequencing: An overview of workflow and case example

Author

Micke, Kestutis C., primary, Elfman, Hannah M., additional, Fantauzzo, Katherine A, additional, McGrath, Patrick S., additional, Clouthier, David E., additional, McCandless, Shawn E., additional, Larson, Austin, additional, Putra, Manesha, additional, Cuneo, Bettina F., additional, Reynolds, Regina M., additional, and Zaretsky, Michael V., additional

Published
2023
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33. Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial

Author

Roof, Elizabeth, primary, Deal, Cheri L, additional, McCandless, Shawn E, additional, Cowan, Ronald L, additional, Miller, Jennifer L, additional, Hamilton, Jill K, additional, Roeder, Elizabeth R, additional, McCormack, Shana E, additional, Roshan Lal, Tamanna R, additional, Abdul-Latif, Hussein D, additional, Haqq, Andrea M, additional, Obrynba, Kathryn S, additional, Torchen, Laura C, additional, Vidmar, Alaina P, additional, Viskochil, David H, additional, Chanoine, Jean-Pierre, additional, Lam, Carol K L, additional, Pierce, Melinda J, additional, Williams, Laurel L, additional, Bird, Lynne M, additional, Butler, Merlin G, additional, Jensen, Diane E, additional, Myers, Susan E, additional, Oatman, Oliver J, additional, Baskaran, Charumathi, additional, Chalmers, Laura J, additional, Fu, Cary, additional, Alos, Nathalie, additional, McLean, Scott D, additional, Shah, Ajay, additional, Whitman, Barbara Y, additional, Blumenstein, Brent A, additional, Leonard, Sarah F, additional, Ernest, Jessica P, additional, Cormier, Joseph W, additional, Cotter, Sara P, additional, and Ryman, Davis C, additional

Published
2023
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35. Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders.

Author

Lichter-Konecki, Uta, Sanz, Jacqueline H., Ah Mew, Nicholas, Baumgartner, Matthias R., Bedoyan, Jirair K., Berry, Gerard, Berry, Susan A., Burgard, Peter, Burrage, Lindsay, Coughlin, Curtis, Diaz, George A., Enns, Gregory, Gallagher, Renata C., Gropman, Andrea, Harding, Cary O., Hoffmann, Georg F., Le Mons, Cynthia, McCandless, Shawn E., Merritt II, J. Lawrence, and Nagamani, Sandesh C. S.

Published
2023
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41. Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire

Author

Grünert, Sarah C., Derks, Terry G.J., Adrian, Katarina, Al-Thihli, Khalid, Ballhausen, Diana, Bidiuk, Joanna, Bordugo, Andrea, Boyer, Monica, Bratkovic, Drago, Brunner-Krainz, Michaela, Burlina, Alberto, Chakrapani, Anupam, Corpeleijn, Willemijn, Cozens, Alison, Dawson, Charlotte, Dhamko, Helena, Milosevic, Maja Djordjevic, Eiroa, Hernan, Finezilber, Yael, Moura de Souza, Carolina Fischinger, Garcia-Jiménez, Maria Concepción, Gasperini, Serena, Haas, Dorothea, Häberle, Johannes, Halligan, Rebecca, Fung, Law Hiu, Hörbe-Blindt, Alexandra, Horka, Laura Maria, Huemer, Martina, Uçar, Sema Kalkan, Kecman, Bozica, Kilavuz, Sebile, Kriván, Gergely, Lindner, Martin, Lüsebrink, Natalia, Makrilakis, Konstantinos, Mei-Kwun Kwok, Anne, Maier, Esther M., Maiorana, Arianna, McCandless, Shawn E., Mitchell, John James, Mizumoto, Hiroshi, Mundy, Helen, Ochoa, Carlos, Pierce, Kathryn, Fraile, Pilar Quijada, Regier, Debra, Rossi, Alessandro, Santer, René, Schuman, Hester C., Sobieraj, Piotr, Spenger, Johannes, Spiegel, Ronen, Stepien, Karolina M., Tal, Galit, Tanšek, Mojca Zerjav, Torkar, Ana Drole, Tchan, Michel, Thyagu, Santhosh, Schrier Vergano, Samantha A., Vucko, Erika, Weinhold, Natalie, Zsidegh, Petra, and Wortmann, Saskia B.

Published
2022
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49. Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium

Author

Seminara, Jennifer, Tuchman, Mendel, Krivitzky, Lauren, Krischer, Jeffrey, Lee, Hye-Seung, LeMons, Cynthia, Baumgartner, Matthias, Cederbaum, Stephen, Diaz, George A., Feigenbaum, Annette, Gallagher, Renata C., Harding, Cary O., Kerr, Douglas S., Lanpher, Brendan, Lee, Brendan, Lichter-Konecki, Uta, McCandless, Shawn E., Merritt, J. Lawrence, Oster-Granite, Mary Lou, Seashore, Margretta R., Stricker, Tamar, Summar, Marshall, Waisbren, Susan, Yudkoff, Marc, and Batshaw, Mark L.

Published
2010
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50. Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency

Author

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

Published
2015
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