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2. 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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3. Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease

Author

Hammann, Nicole, Lenz, Dominic, Baric, Ivo, Crushell, Ellen, Vici, Carlo Dionisi, Distelmaier, Felix, Feillet, Francois, Freisinger, Peter, Hempel, Maja, Khoreva, Anna L., Laass, Martin W., Lacassie, Yves, Lainka, Elke, Larson-Nath, Catherine, Li, Zhongdie, Lipiński, Patryk, Lurz, Eberhard, Mégarbané, André, Nobre, Susana, Olivieri, Giorgia, Peters, Bianca, Prontera, Paolo, Schlieben, Lea D., Seroogy, Christine M., Sobacchi, Cristina, Suzuki, Shigeru, Tran, Christel, Vockley, Jerry, Wang, Jian-She, Wagner, Matias, Prokisch, Holger, Garbade, Sven F., Kölker, Stefan, Hoffmann, Georg F., and Staufner, Christian

Published
2024
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4. 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, Barić, 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

5. Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, Vicente A., Gusic, Mirjana, Kopajtich, Robert, Mertes, Christian, Smith, Nicholas H., Alston, Charlotte L., Ban, Rui, Beblo, Skadi, Berutti, Riccardo, Blessing, Holger, Ciara, Elżbieta, Distelmaier, Felix, Freisinger, Peter, Häberle, Johannes, Hayflick, Susan J., Hempel, Maja, Itkis, Yulia S., Kishita, Yoshihito, Klopstock, Thomas, Krylova, Tatiana D., Lamperti, Costanza, Lenz, Dominic, Makowski, Christine, Mosegaard, Signe, Müller, Michaela F., Muñoz-Pujol, Gerard, Nadel, Agnieszka, Ohtake, Akira, Okazaki, Yasushi, Procopio, Elena, Schwarzmayr, Thomas, Smet, Joél, Staufner, Christian, Stenton, Sarah L., Strom, Tim M., Terrile, Caterina, Tort, Frederic, Van Coster, Rudy, Vanlander, Arnaud, Wagner, Matias, Xu, Manting, Fang, Fang, Ghezzi, Daniele, Mayr, Johannes A., Piekutowska-Abramczuk, Dorota, Ribes, Antonia, Rötig, Agnès, Taylor, Robert W., Wortmann, Saskia B., Murayama, Kei, Meitinger, Thomas, Gagneur, Julien, and Prokisch, Holger

Published
2022
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7. Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects

Author

Rujano, Maria A, Serio, Magda Cannata, Panasyuk, Ganna, Péanne, Romain, Reunert, Janine, Rymen, Daisy, Hauser, Virginie, Park, Julien H, Freisinger, Peter, Souche, Erika, Guida, Maria Clara, Maier, Esther M, Wada, Yoshinao, Jäger, Stefanie, Krogan, Nevan J, Kretz, Oliver, Nobre, Susana, Garcia, Paula, Quelhas, Dulce, Bird, Thomas D, Raskind, Wendy H, Schwake, Michael, Duvet, Sandrine, Foulquier, Francois, Matthijs, Gert, Marquardt, Thorsten, and Simons, Matias

Subjects
Liver Disease, Digestive Diseases, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Amino Acid Sequence, Animals, Autophagy, Base Sequence, Blood Proteins, Brain, Cutis Laxa, Drosophila Proteins, Drosophila melanogaster, Endoplasmic Reticulum-Associated Degradation, Fibroblasts, Genes, X-Linked, Glycosylation, Humans, Infant, Lipids, Liver, Liver Diseases, Male, Membrane Proteins, Mice, Mutation, Neural Stem Cells, Protein Binding, Protein Processing, Post-Translational, Proton-Translocating ATPases, Psychomotor Disorders, Receptors, Cell Surface, Vacuolar Proton-Translocating ATPases, Young Adult, Medical and Health Sciences, Immunology
Abstract

The biogenesis of the multi-subunit vacuolar-type H+-ATPase (V-ATPase) is initiated in the endoplasmic reticulum with the assembly of the proton pore V0, which is controlled by a group of assembly factors. Here, we identify two hemizygous missense mutations in the extracellular domain of the accessory V-ATPase subunit ATP6AP2 (also known as the [pro]renin receptor) responsible for a glycosylation disorder with liver disease, immunodeficiency, cutis laxa, and psychomotor impairment. We show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. The introduction of one of the missense mutations into Drosophila led to reduced survival and altered lipid metabolism. We further demonstrate that in the liver-like fat body, the autophagic dysregulation was associated with defects in lysosomal acidification and mammalian target of rapamycin (mTOR) signaling. Finally, both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the V0 assembly complex. Collectively, our data suggest that the missense mutations in ATP6AP2 lead to impaired V-ATPase assembly and subsequent defects in glycosylation and autophagy.

Published
2017

8. Outcomes after newborn screening for propionic and methylmalonic acidemia and homocystinurias

Author

Reischl‐Hajiabadi, Anna T., primary, Schnabel, Elena, additional, Gleich, Florian, additional, Mengler, Katharina, additional, Lindner, Martin, additional, Burgard, Peter, additional, Posset, Roland, additional, Lommer‐Steinhoff, Svenja, additional, Grünert, Sarah C., additional, Thimm, Eva, additional, Freisinger, Peter, additional, Hennermann, Julia B., additional, Krämer, Johannes, additional, Gramer, Gwendolyn, additional, Lenz, Dominic, additional, Christ, Stine, additional, Hörster, Friederike, additional, Hoffmann, Georg F., additional, Garbade, Sven F., additional, Kölker, Stefan, additional, and Mütze, Ulrike, additional

Published
2024
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9. Mitochondriopathien

Author

Sperl, Wolfgang, Freisinger, Peter, Hoffmann, Georg. F., Section editor, Hoffmann, Georg F., editor, Lentze, Michael J., editor, Spranger, Jürgen, editor, Zepp, Fred, editor, Berner, Reinhard, editor, Schaub, Jürgen, Founding Editor, and Schulte, Franz-Josef, Founding Editor

Published
2020
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11. Genetic landscape of pediatric acute liver failure of indeterminate origin

Author

MDL patientenzorg, Lenz, Dominic, Schlieben, Lea D, Shimura, Masaru, Bianzano, Alyssa, Smirnov, Dmitrii, Kopajtich, Robert, Berutti, Riccardo, Adam, Rüdiger, Aldrian, Denise, Baric, Ivo, Baumann, Ulrich, Bozbulut, Neslihan Eksi, Brugger, Melanie, Brunet, Theresa, Bufler, Philip, Burnytė, Birutė, Calvo, Pier Luigi, Crushell, Ellen, Dalgıç, Buket, Das, Anibh M, Dezsőfi, Antal, Distelmaier, Felix, Fichtner, Alexander, Freisinger, Peter, Garbade, Sven F, Gaspar, Harald, Goujon, Louise, Hadzic, Nedim, Hartleif, Steffen, Hegen, Bianca, Hempel, Maja, Henning, Stephan, Hoerning, Andre, Houwen, Roderick, Hughes, Joanne, Iorio, Raffaele, Iwanicka-Pronicka, Katarzyna, Jankofsky, Martin, Junge, Norman, Kanavaki, Ino, Kansu, Aydan, Kaspar, Sonja, Kathemann, Simone, Kelly, Deidre, Kırsaçlıoğlu, Ceyda Tuna, Knoppke, Birgit, Kohl, Martina, Kölbel, Heike, Kölker, Stefan, Konstantopoulou, Vassiliki, Krylova, Tatiana, Kuloğlu, Zarife, Kuster, Alice, Laass, Martin W, Lainka, Elke, Lurz, Eberhard, Mandel, Hanna, Mayerhanser, Katharina, Mayr, Johannes A, McKiernan, Patrick, McLean, Patricia, McLin, Valerie, Mention, Karine, Müller, Hanna, Pasquier, Laurent, Pavlov, Martin, Pechatnikova, Natalia, Peters, Bianca, Petković Ramadža, Danijela, Piekutowska-Abramczuk, Dorota, Pilic, Denisa, Rajwal, Sanjay, Rock, Nathalie, Roetig, Agnès, Santer, René, Schenk, Wilfried, Semenova, Natalia, Sokollik, Christiane, Sturm, Ekkehard, Taylor, Robert W, Tschiedel, Eva, Urbonas, Vaidotas, Urreizti, Roser, Vermehren, Jan, Vockley, Jerry, Vogel, Georg-Friedrich, Wagner, Matias, van der Woerd, Wendy, Wortmann, Saskia B, Zakharova, Ekaterina, Hoffmann, Georg Friedrich, Meitinger, Thomas, Murayama, Kei, Staufner, Christian, Prokisch, Holger, MDL patientenzorg, Lenz, Dominic, Schlieben, Lea D, Shimura, Masaru, Bianzano, Alyssa, Smirnov, Dmitrii, Kopajtich, Robert, Berutti, Riccardo, Adam, Rüdiger, Aldrian, Denise, Baric, Ivo, Baumann, Ulrich, Bozbulut, Neslihan Eksi, Brugger, Melanie, Brunet, Theresa, Bufler, Philip, Burnytė, Birutė, Calvo, Pier Luigi, Crushell, Ellen, Dalgıç, Buket, Das, Anibh M, Dezsőfi, Antal, Distelmaier, Felix, Fichtner, Alexander, Freisinger, Peter, Garbade, Sven F, Gaspar, Harald, Goujon, Louise, Hadzic, Nedim, Hartleif, Steffen, Hegen, Bianca, Hempel, Maja, Henning, Stephan, Hoerning, Andre, Houwen, Roderick, Hughes, Joanne, Iorio, Raffaele, Iwanicka-Pronicka, Katarzyna, Jankofsky, Martin, Junge, Norman, Kanavaki, Ino, Kansu, Aydan, Kaspar, Sonja, Kathemann, Simone, Kelly, Deidre, Kırsaçlıoğlu, Ceyda Tuna, Knoppke, Birgit, Kohl, Martina, Kölbel, Heike, Kölker, Stefan, Konstantopoulou, Vassiliki, Krylova, Tatiana, Kuloğlu, Zarife, Kuster, Alice, Laass, Martin W, Lainka, Elke, Lurz, Eberhard, Mandel, Hanna, Mayerhanser, Katharina, Mayr, Johannes A, McKiernan, Patrick, McLean, Patricia, McLin, Valerie, Mention, Karine, Müller, Hanna, Pasquier, Laurent, Pavlov, Martin, Pechatnikova, Natalia, Peters, Bianca, Petković Ramadža, Danijela, Piekutowska-Abramczuk, Dorota, Pilic, Denisa, Rajwal, Sanjay, Rock, Nathalie, Roetig, Agnès, Santer, René, Schenk, Wilfried, Semenova, Natalia, Sokollik, Christiane, Sturm, Ekkehard, Taylor, Robert W, Tschiedel, Eva, Urbonas, Vaidotas, Urreizti, Roser, Vermehren, Jan, Vockley, Jerry, Vogel, Georg-Friedrich, Wagner, Matias, van der Woerd, Wendy, Wortmann, Saskia B, Zakharova, Ekaterina, Hoffmann, Georg Friedrich, Meitinger, Thomas, Murayama, Kei, Staufner, Christian, and Prokisch, Holger

Published
2024

12. 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

14. Neurological outcome in long‐chain hydroxy fatty acid oxidation disorders

Author

Mütze, Ulrike, primary, Ottenberger, Alina, additional, Gleich, Florian, additional, Maier, Esther M., additional, Lindner, Martin, additional, Husain, Ralf A., additional, Palm, Katja, additional, Beblo, Skadi, additional, Freisinger, Peter, additional, Santer, René, additional, Thimm, Eva, additional, vom Dahl, Stephan, additional, Weinhold, Natalie, additional, Grohmann‐Held, Karina, additional, Haase, Claudia, additional, Hennermann, Julia B., additional, Hörbe‐Blindt, Alexandra, additional, Kamrath, Clemens, additional, Marquardt, Iris, additional, Marquardt, Thorsten, additional, Behne, Robert, additional, Haas, Dorothea, additional, Spiekerkoetter, Ute, additional, Hoffmann, Georg F., additional, Garbade, Sven F., additional, Grünert, Sarah C., additional, and Kölker, Stefan, additional

Published
2024
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15. The biochemical subtype is a predictor for cognitive function in glutaric aciduria type 1: a national prospective follow-up study

Author

Märtner, E. M. Charlotte, Thimm, Eva, Guder, Philipp, Schiergens, Katharina A., Rutsch, Frank, Roloff, Sylvia, Marquardt, Iris, Das, Anibh M., Freisinger, Peter, Grünert, Sarah C., Krämer, Johannes, Baumgartner, Matthias R., Beblo, Skadi, Haase, Claudia, Dieckmann, Andrea, Lindner, Martin, Näke, Andrea, Hoffmann, Georg F., Mühlhausen, Chris, Walter, Magdalena, Garbade, Sven F., Maier, Esther M., Kölker, Stefan, and Boy, Nikolas

Published
2021
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16. Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at < 4 years of age with phenylketonuria: results of the 3-year extension of the SPARK open-label, multicentre, randomised phase IIIb trial

Author

Muntau, Ania C., Burlina, Alberto, Eyskens, François, Freisinger, Peter, Leuzzi, Vincenzo, Sivri, Hatice Serap, Gramer, Gwendolyn, Pazdírková, Renata, Cleary, Maureen, Lotz-Havla, Amelia S., Lane, Paul, Alvarez, Ignacio, and Rutsch, Frank

Published
2021
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17. Publisher Correction: The biochemical subtype is a predictor for cognitive function in glutaric aciduria type 1: a national prospective follow-up study

Author

Märtner, E. M. Charlotte, Thimm, Eva, Guder, Philipp, Schiergens, Katharina A., Rutsch, Frank, Roloff, Sylvia, Marquardt, Iris, Das, Anibh M., Freisinger, Peter, Grünert, Sarah C., Krämer, Johannes, Baumgartner, Matthias R., Beblo, Skadi, Haase, Claudia, Dieckmann, Andrea, Lindner, Martin, Näke, Andrea, Hoffmann, Georg F., Mühlhausen, Chris, Walter, Magdalena, Garbade, Sven F., Maier, Esther M., Kölker, Stefan, and Boy, Nikolas

Published
2021
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18. Genetic landscape of pediatric acute liver failure of indeterminate origin

Author

Lenz, Dominic, primary, Schlieben, Lea D., additional, Shimura, Masaru, additional, Bianzano, Alyssa, additional, Smirnov, Dmitrii, additional, Kopajtich, Robert, additional, Berutti, Riccardo, additional, Adam, Rüdiger, additional, Aldrian, Denise, additional, Baric, Ivo, additional, Baumann, Ulrich, additional, Bozbulut, Neslihan E., additional, Brugger, Melanie, additional, Brunet, Theresa, additional, Bufler, Philip, additional, Burnytė, Birutė, additional, Calvo, Pier L., additional, Crushell, Ellen, additional, Dalgiç, Buket, additional, Das, Anibh M., additional, Dezsőfi, Antal, additional, Distelmaier, Felix, additional, Fichtner, Alexander, additional, Freisinger, Peter, additional, Garbade, Sven F., additional, Gaspar, Harald, additional, Goujon, Louise, additional, Hadzic, Nedim, additional, Hartleif, Steffen, additional, Hegen, Bianca, additional, Hempel, Maja, additional, Henning, Stephan, additional, Hoerning, Andre, additional, Houwen, Roderick, additional, Hughes, Joanne, additional, Iorio, Raffaele, additional, Iwanicka-Pronicka, Katarzyna, additional, Jankofsky, Martin, additional, Junge, Norman, additional, Kanavaki, Ino, additional, Kansu, Aydan, additional, Kaspar, Sonja, additional, Kathemann, Simone, additional, Kelly, Deidre, additional, Kirsaçlioğlu, Ceyda T., additional, Knoppke, Birgit, additional, Kohl, Martina, additional, Kölbel, Heike, additional, Kölker, Stefan, additional, Konstantopoulou, Vassiliki, additional, Krylova, Tatiana, additional, Kuloğlu, Zarife, additional, Kuster, Alice, additional, Laass, Martin W., additional, Lainka, Elke, additional, Lurz, Eberhard, additional, Mandel, Hanna, additional, Mayerhanser, Katharina, additional, Mayr, Johannes A., additional, McKiernan, Patrick, additional, McClean, Patricia, additional, McLin, Valerie, additional, Mention, Karine, additional, Müller, Hanna, additional, Pasquier, Laurent, additional, Pavlov, Martin, additional, Pechatnikova, Natalia, additional, Peters, Bianca, additional, Petković Ramadža, Danijela, additional, Piekutowska-Abramczuk, Dorota, additional, Pilic, Denisa, additional, Rajwal, Sanjay, additional, Rock, Nathalie, additional, Roetig, Agnès, additional, Santer, René, additional, Schenk, Wilfried, additional, Semenova, Natalia, additional, Sokollik, Christiane, additional, Sturm, Ekkehard, additional, Taylor, Robert W., additional, Tschiedel, Eva, additional, Urbonas, Vaidotas, additional, Urreizti, Roser, additional, Vermehren, Jan, additional, Vockley, Jerry, additional, Vogel, Georg-Friedrich, additional, Wagner, Matias, additional, van der Woerd, Wendy, additional, Wortmann, Saskia B., additional, Zakharova, Ekaterina, additional, Hoffmann, Georg F., additional, Meitinger, Thomas, additional, Murayama, Kei, additional, Staufner, Christian, additional, and Prokisch, Holger, additional

Published
2023
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19. Clinical outcomes and survival of individuals with methylmalonic acidemia, propionic acidemia, classic homocystinuria, and remethylation disorders identified through newborn screening

Author

Reischl-Hajiabadi, Anna T, primary, Schnabel, Elena, additional, Gleich, Florian, additional, Mengler, Katharina, additional, Lindner, Martin, additional, Burgard, Peter, additional, Posset, Roland, additional, Lommer-Steinhoff, Svenja, additional, Grunert, Sarah C, additional, Thimm, Eva, additional, Freisinger, Peter, additional, Hennermann, Julia B, additional, Kramer, Johannes, additional, Gramer, Gwendolyn, additional, Lenz, Dominic, additional, Christ, Stine, additional, Horster, Friederike, additional, Hoffmann, Georg F, additional, Garbade, Sven F, additional, Kolker, Stefan, additional, and Mutze, Ulrike, additional

Published
2023
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21. Phenylalanine effects on brain function in adult phenylketonuria

Author

Pilotto, Andrea, Zipser, Carl M., Leks, Edytha, Haas, Dorothea, Gramer, Gwendolyn, Freisinger, Peter, Schaeffer, Eva, Liepelt-Scarfone, Inga, Brockmann, Kathrin, Maetzler, Walter, Schulte, Claudia, Deuschle, Christian, Hauser, Ann Kathrin, Hoffmann, Georg F., Scheffler, Klaus, van Spronsen, Francjan J., Padovani, Alessandro, Trefz, Friedrich, and Berg, Daniela

Published
2020
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22. Delineating MT-ATP6-associated disease: From isolated neuropathy to early onset neurodegeneration

Author

Stendel, Claudia, Neuhofer, Christiane, Floride, Elisa, Yuqing, Shi, Ganetzky, Rebecca D., Park, Joohyun, Freisinger, Peter, Kornblum, Cornelia, Kleinle, Stephanie, Schöls, Ludger, Distelmaier, Felix, Stettner, Georg M., Büchner, Boriana, Falk, Marni J., Mayr, Johannes A., Synofzik, Matthis, Abicht, Angela, Haack, Tobias B., Prokisch, Holger, Wortmann, Saskia B., Murayama, Kei, Fang, Fang, and Klopstock, Thomas

Published
2020
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23. Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy

Author

Feichtinger, René G., Mucha, Bettina E., Hengel, Holger, Orfi, Zakaria, Makowski, Christine, Dort, Junio, D’Anjou, Guy, Nguyen, Thi Tuyet Mai, Buchert, Rebecca, Juenger, Hendrik, Freisinger, Peter, Baumeister, Sarah, Schoser, Benedikt, Ahting, Uwe, Keimer, Reinhard, Nguyen, Cam-Tu Emilie, Fabre, Paul, Gauthier, Julie, Miguet, Marguerite, Lopes, Fátima, AlHakeem, Afnan, AlHashem, Amal, Tabarki, Brahim, Kandaswamy, Krishna Kumar, Bauer, Peter, Steinbacher, Peter, Prokisch, Holger, Sturm, Marc, Strom, Tim M., Ellezam, Benjamin, Mayr, Johannes A., Schöls, Ludger, Michaud, Jacques L., Campeau, Philippe M., Haack, Tobias B., and Dumont, Nicolas A.

Published
2019
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24. Collaborative evaluation study on 18 candidate diseases for newborn screening in 1.77 million samples

Author

Maier, Esther M., primary, Mütze, Ulrike, additional, Janzen, Nils, additional, Steuerwald, Ulrike, additional, Nennstiel, Uta, additional, Odenwald, Birgit, additional, Schuhmann, Elfriede, additional, Lotz‐Havla, Amelie S., additional, Weiss, Katharina J., additional, Hammersen, Johanna, additional, Weigel, Corina, additional, Thimm, Eva, additional, Grünert, Sarah C., additional, Hennermann, Julia B., additional, Freisinger, Peter, additional, Krämer, Johannes, additional, Das, Anibh M., additional, Illsinger, Sabine, additional, Gramer, Gwendolyn, additional, Fang‐Hoffmann, Junmin, additional, Garbade, Sven F., additional, Okun, Jürgen G., additional, Hoffmann, Georg F., additional, Kölker, Stefan, additional, and Röschinger, Wulf, additional

Published
2023
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25. Phenylketonuria (PKU) Urinary Metabolomic Phenotype Is Defined by Genotype and Metabolite Imbalance: Results in 51 Early Treated Patients Using Ex Vivo 1H-NMR Analysis

Author

Cannet, Claire, primary, Bayat, Allan, additional, Frauendienst-Egger, Georg, additional, Freisinger, Peter, additional, Spraul, Manfred, additional, Himmelreich, Nastassja, additional, Kockaya, Musa, additional, Ahring, Kirsten, additional, Godejohann, Markus, additional, MacDonald, Anita, additional, and Trefz, Friedrich, additional

Published
2023
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27. Lower plasma cholesterol, LDL-cholesterol and LDL-lipoprotein subclasses in adult phenylketonuria (PKU) patients compared to healthy controls: results of NMR metabolomics investigation

Author

Cannet, Claire, Pilotto, Andrea, Rocha, Júlio César, Schäfer, Hartmut, Spraul, Manfred, Berg, Daniela, Nawroth, Peter, Kasperk, Christian, Gramer, Gwendolyn, Haas, Dorothea, Piel, David, Kölker, Stefan, Hoffmann, Georg, Freisinger, Peter, and Trefz, Friedrich

Published
2020
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28. 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

31. Isovaleric aciduria identified by newborn screening: Strategies to predict disease severity and stratify treatment.

Author

Mütze, Ulrike, Henze, Lucy, Schröter, Julian, Gleich, Florian, Lindner, Martin, Grünert, Sarah C., Spiekerkoetter, Ute, Santer, René, Thimm, Eva, Ensenauer, Regina, Weigel, Johannes, Beblo, Skadi, Arélin, Maria, Hennermann, Julia B., Marquardt, Iris, Freisinger, Peter, Krämer, Johannes, Dieckmann, Andrea, Weinhold, Natalie, and Schiergens, Katharina A.

Abstract

Newborn screening (NBS) allows early identification of individuals with rare disease, such as isovaleric aciduria (IVA). Reliable early prediction of disease severity of positively screened individuals with IVA is needed to guide therapeutic decision, prevent life‐threatening neonatal disease manifestation in classic IVA and over‐medicalization in attenuated IVA that may remain asymptomatic. We analyzed 84 individuals (median age at last study visit 8.5 years) with confirmed IVA identified by NBS between 1998 and 2018 who participated in the national, observational, multicenter study. Screening results, additional metabolic parameters, genotypes, and clinical phenotypic data were included. Individuals with metabolic decompensation showed a higher median isovalerylcarnitine (C5) concentration in the first NBS sample (10.6 vs. 2.7 μmol/L; p < 0.0001) and initial urinary isovalerylglycine concentration (1750 vs. 180 mmol/mol creatinine; p = 0.0003) than those who remained asymptomatic. C5 was in trend inversely correlated with full IQ (R = −0.255; slope = −0.869; p = 0.0870) and was lower for the "attenuated" variants compared to classic genotypes [median (IQR; range): 2.6 μmol/L (2.1–4.0; 0.7–6.4) versus 10.3 μmol/L (7.4–13.1; 4.3–21.7); N = 73]. In‐silico prediction scores (M‐CAP, MetaSVM, and MetaLR) correlated highly with isovalerylglycine and ratios of C5 to free carnitine and acetylcarnitine, but not sufficiently with clinical endpoints. The results of the first NBS sample and biochemical confirmatory testing are reliable early predictors of the clinical course of IVA, facilitating case definition (attenuated versus classic IVA). Prediction of attenuated IVA is supported by the genotype. On this basis, a reasonable algorithm has been established for neonates with a positive NBS result for IVA, with the aim of providing the necessary treatment immediately, but whenever possible, adjusting the treatment to the individual severity of the disease. [ABSTRACT FROM AUTHOR]

Published
2023
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32. Ex vivo proton spectroscopy ( 1 H‐NMR) analysis of inborn errors of metabolism: Automatic and computer‐assisted analyses

Author

Cannet, Claire, primary, Frauendienst‐Egger, Georg, additional, Freisinger, Peter, additional, Götz, Hermann, additional, Götz, Madalina, additional, Himmelreich, Nastassja, additional, Kock, Vanessa, additional, Spraul, Manfred, additional, Bus, Christine, additional, Biskup, Saskia, additional, and Trefz, Friedrich, additional

Published
2022
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33. Long‐term anthropometric development of individuals with inherited metabolic diseases identified by newborn screening

Author

Mütze, Ulrike, primary, Garbade, Sven F., additional, Gleich, Florian, additional, Lindner, Martin, additional, Freisinger, Peter, additional, Hennermann, Julia B., additional, Thimm, Eva, additional, Gramer, Gwendolyn, additional, Posset, Roland, additional, Krämer, Johannes, additional, Grünert, Sarah C., additional, Hoffmann, Georg F., additional, and Kölker, Stefan, additional

Published
2022
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34. Progressive deafness–dystonia due to SERAC1 mutations: A study of 67 cases

Author

Maas, Roeltje R., Iwanicka‐Pronicka, Katarzyna, Kalkan Ucar, Sema, Alhaddad, Bader, AlSayed, Moeenaldeen, Al‐Owain, Mohammed A., Al‐Zaidan, Hamad I., Balasubramaniam, Shanti, Barić, Ivo, Bubshait, Dalal K., Burlina, Alberto, Christodoulou, John, Chung, Wendy K., Colombo, Roberto, Darin, Niklas, Freisinger, Peter, Garcia Silva, Maria Teresa, Grunewald, Stephanie, Haack, Tobias B., van Hasselt, Peter M., Hikmat, Omar, Hörster, Friederike, Isohanni, Pirjo, Ramzan, Khushnooda, Kovacs‐Nagy, Reka, Krumina, Zita, Martin‐Hernandez, Elena, Mayr, Johannes A., McClean, Patricia, De Meirleir, Linda, Naess, Karin, Ngu, Lock H., Pajdowska, Magdalena, Rahman, Shamima, Riordan, Gillian, Riley, Lisa, Roeben, Benjamin, Rutsch, Frank, Santer, Rene, Schiff, Manuel, Seders, Martine, Sequeira, Silvia, Sperl, Wolfgang, Staufner, Christian, Synofzik, Matthis, Taylor, Robert W., Trubicka, Joanna, Tsiakas, Konstantinos, Unal, Ozlem, Wassmer, Evangeline, Wedatilake, Yehani, Wolff, Toni, Prokisch, Holger, Morava, Eva, Pronicka, Ewa, Wevers, Ron A., de Brouwer, Arjan P., and Wortmann, Saskia B.

Published
2017
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35. Biallelic variants in WARS2 encoding mitochondrial tryptophanyl‐tRNA synthase in six individuals with mitochondrial encephalopathy

Author

Wortmann, Saskia B., Timal, Sharita, Venselaar, Hanka, Wintjes, Liesbeth T., Kopajtich, Robert, Feichtinger, René G., Onnekink, Carla, Mühlmeister, Mareike, Brandt, Ulrich, Smeitink, Jan A., Veltman, Joris A., Sperl, Wolfgang, Lefeber, Dirk, Pruijn, Ger, Stojanovic, Vesna, Freisinger, Peter, v Spronsen, Francjan, Derks, Terry GJ, Veenstra‐Knol, Hermine E., Mayr, Johannes A, Rötig, Agnes, Tarnopolsky, Mark, Prokisch, Holger, and Rodenburg, Richard J.

Published
2017
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36. Phenylketonuria (PKU) Urinary Metabolomic Phenotype Is Defined by Genotype and Metabolite Imbalance: Results in 51 Early Treated Patients Using Ex Vivo 1 H-NMR Analysis.

Author

Cannet, Claire, Bayat, Allan, Frauendienst-Egger, Georg, Freisinger, Peter, Spraul, Manfred, Himmelreich, Nastassja, Kockaya, Musa, Ahring, Kirsten, Godejohann, Markus, MacDonald, Anita, and Trefz, Friedrich

Subjects
PHENYLKETONURIA, PROTON magnetic resonance, METABOLOMICS, NAD (Coenzyme), PHENOTYPES, OCHRATOXINS, PHENYLALANINE
Abstract

Phenylketonuria (PKU) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase gene. Depending on the severity of the genetic mutation, medical treatment, and patient dietary management, elevated phenylalanine (Phe) may occur in blood and brain tissues. Research has recently shown that high Phe not only impacts the central nervous system, but also other organ systems (e.g., heart and microbiome). This study used ex vivo proton nuclear magnetic resonance (1H-NMR) analysis of urine samples from PKU patients (mean 14.9 ± 9.2 years, n = 51) to identify the impact of elevated blood Phe and PKU treatment on metabolic profiles. Our results found that 24 out of 98 urinary metabolites showed a significant difference (p < 0.05) for PKU patients compared to age-matched healthy controls (n = 51) based on an analysis of urinary metabolome. These altered urinary metabolites were related to Phe metabolism, dysbiosis, creatine synthesis or intake, the tricarboxylic acid (TCA) cycle, end products of nicotinamide-adenine dinucleotide degradation, and metabolites associated with a low Phe diet. There was an excellent correlation between the metabolome and genotype of PKU patients and healthy controls of 96.7% in a confusion matrix model. Metabolomic investigations may contribute to a better understanding of PKU pathophysiology. [ABSTRACT FROM AUTHOR]

Published
2023
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37. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

Author

Repp, Birgit M., Mastantuono, Elisa, Alston, Charlotte L., Schiff, Manuel, Haack, Tobias B., Rötig, Agnes, Ardissone, Anna, Lombès, Anne, Catarino, Claudia B., Diodato, Daria, Schottmann, Gudrun, Poulton, Joanna, Burlina, Alberto, Jonckheere, An, Munnich, Arnold, Rolinski, Boris, Ghezzi, Daniele, Rokicki, Dariusz, Wellesley, Diana, Martinelli, Diego, Wenhong, Ding, Lamantea, Eleonora, Ostergaard, Elsebet, Pronicka, Ewa, Pierre, Germaine, Smeets, Hubert J. M., Wittig, Ilka, Scurr, Ingrid, de Coo, Irenaeus F. M., Moroni, Isabella, Smet, Joél, Mayr, Johannes A., Dai, Lifang, de Meirleir, Linda, Schuelke, Markus, Zeviani, Massimo, Morscher, Raphael J., McFarland, Robert, Seneca, Sara, Klopstock, Thomas, Meitinger, Thomas, Wieland, Thomas, Strom, Tim M., Herberg, Ulrike, Ahting, Uwe, Sperl, Wolfgang, Nassogne, Marie-Cecile, Ling, Han, Fang, Fang, Freisinger, Peter, Van Coster, Rudy, Strecker, Valentina, Taylor, Robert W., Häberle, Johannes, Vockley, Jerry, Prokisch, Holger, and Wortmann, Saskia

Published
2018
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38. Impact of age at onset and newborn screening on outcome in organic acidurias

Author

Heringer, Jana, Valayannopoulos, Vassili, Lund, Allan M., Wijburg, Frits A., Freisinger, Peter, Barić, Ivo, Baumgartner, Matthias R., Burgard, Peter, Burlina, Alberto B., Chapman, Kimberly A., i Saladelafont, Elisenda Cortès, Karall, Daniela, Mühlhausen, Chris, Riches, Victoria, Schiff, Manuel, Sykut-Cegielska, Jolanta, Walter, John H., Zeman, Jiri, Chabrol, Brigitte, Kölker, Stefan, and additional individual contributors of the E-IMD consortium

Published
2016
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40. Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts

Author

Staufner, Christian, Haack, Tobias B., Köpke, Marlies G., Straub, Beate K., Kölker, Stefan, Thiel, Christian, Freisinger, Peter, Baric, Ivo, McKiernan, Patrick J., Dikow, Nicola, Harting, Inga, Beisse, Flemming, Burgard, Peter, Kotzaeridou, Urania, Lenz, Dominic, Kühr, Joachim, Himbert, Urban, Taylor, Robert W., Distelmaier, Felix, Vockley, Jerry, Ghaloul-Gonzalez, Lina, Ozolek, John A., Zschocke, Johannes, Kuster, Alice, Dick, Anke, Das, Anib M., Wieland, Thomas, Terrile, Caterina, Strom, Tim M., Meitinger, Thomas, Prokisch, Holger, and Hoffmann, Georg F.

Published
2016
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41. Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier

Author

Bölsterli, Bigna K., primary, Boltshauser, Eugen, additional, Palmieri, Luigi, additional, Spenger, Johannes, additional, Brunner-Krainz, Michaela, additional, Distelmaier, Felix, additional, Freisinger, Peter, additional, Geis, Tobias, additional, Gropman, Andrea L., additional, Häberle, Johannes, additional, Hentschel, Julia, additional, Jeandidier, Bruno, additional, Karall, Daniela, additional, Keren, Boris, additional, Klabunde-Cherwon, Annick, additional, Konstantopoulou, Vassiliki, additional, Kottke, Raimund, additional, Lasorsa, Francesco M., additional, Makowski, Christine, additional, Mignot, Cyril, additional, O’Gorman Tuura, Ruth, additional, Porcelli, Vito, additional, Santer, René, additional, Sen, Kuntal, additional, Steinbrücker, Katja, additional, Syrbe, Steffen, additional, Wagner, Matias, additional, Ziegler, Andreas, additional, Zöggeler, Thomas, additional, Mayr, Johannes A., additional, Prokisch, Holger, additional, and Wortmann, Saskia B., additional

Published
2022
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42. Impact of pregnancy planning and preconceptual dietary training on metabolic control and offspring's outcome in phenylketonuria

Author

Grohmann‐Held, Karina, primary, Burgard, Peter, additional, Baerwald, Christoph G. O., additional, Beblo, Skadi, additional, vom Dahl, Stephan, additional, Das, Anibh, additional, Dokoupil, Katharina, additional, Fleissner, Sandra, additional, Freisinger, Peter, additional, Heddrich‐Ellerbrok, Margret, additional, Jung, Alexandra, additional, Korpel, Vanessa, additional, Krämer, Johannes, additional, Lier, Dinah, additional, Maier, Esther M., additional, Meyer, Uta, additional, Mühlhausen, Chris, additional, Newger, Martha, additional, Och, Ulrike, additional, Plöckinger, Ursula, additional, Rosenbaum‐Fabian, Stefanie, additional, Rutsch, Frank, additional, Santer, René, additional, Schick, Petra, additional, Schwarz, Martin, additional, Spiekerkötter, Ute, additional, Strittmatter, Ursula, additional, Thiele, Alena G., additional, Ziagaki, Athanasia, additional, Mütze, Ulrike, additional, Gleich, Florian, additional, Garbade, Sven F., additional, and Kölker, Stefan, additional

Published
2022
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44. Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier

Author

Bölsterli, Bigna K., Boltshauser, Eugen, Palmieri, Luigi, Spenger, Johannes, Brunner-Krainz, Michaela, Distelmaier, Felix, Freisinger, Peter, Geis, Tobias, Gropman, Andrea L., Häberle, Johannes, Hentschel, Julia, Jeandidier, Bruno, Karall, Daniela, Keren, Boris, Klabunde-Cherwon, Annick, Konstantopoulou, Vassiliki, Kottke, Raimund, Lasorsa, Francesco M., Makowski, Christine, Mignot, Cyril, O'Gorman Tuura, Ruth, Porcelli, Vito, Santer, René, Sen, Kuntal, Steinbrücker, Katja, Syrbe, Steffen, Wagner, Matias, Ziegler, Andreas, Zöggeler, Thomas, Mayr, Johannes A., Prokisch, Holger, Wortmann, Saskia B., Bölsterli, Bigna K., Boltshauser, Eugen, Palmieri, Luigi, Spenger, Johannes, Brunner-Krainz, Michaela, Distelmaier, Felix, Freisinger, Peter, Geis, Tobias, Gropman, Andrea L., Häberle, Johannes, Hentschel, Julia, Jeandidier, Bruno, Karall, Daniela, Keren, Boris, Klabunde-Cherwon, Annick, Konstantopoulou, Vassiliki, Kottke, Raimund, Lasorsa, Francesco M., Makowski, Christine, Mignot, Cyril, O'Gorman Tuura, Ruth, Porcelli, Vito, Santer, René, Sen, Kuntal, Steinbrücker, Katja, Syrbe, Steffen, Wagner, Matias, Ziegler, Andreas, Zöggeler, Thomas, Mayr, Johannes A., Prokisch, Holger, and Wortmann, Saskia B.

Abstract

Themitochondrialmalate aspartate shuttle system(MAS)maintains the cytosolicNAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1- individuals with a neurological phenotype treated with KD, 11 experienced benefits—mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1- defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.

Published
2022

45. Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, Vicente A, Gusic, Mirjana, Kopajtich, Robert, Mertes, Christian, Smith, Nicholas H, Alston, Charlotte L, Ban, Rui, Beblo, Skadi, Berutti, Riccardo, Blessing, Holger, Ciara, Elżbieta, Distelmaier, Felix, Freisinger, Peter, Häberle, Johannes; https://orcid.org/0000-0003-0635-091X, Hayflick, Susan J, Hempel, Maja, Itkis, Yulia S, Kishita, Yoshihito, Klopstock, Thomas; https://orcid.org/0000-0003-2805-4652, Krylova, Tatiana D, Lamperti, Costanza, Lenz, Dominic, Makowski, Christine, Mosegaard, Signe, Müller, Michaela F, Muñoz-Pujol, Gerard, Nadel, Agnieszka, Ohtake, Akira, Okazaki, Yasushi, Procopio, Elena, et al, Yépez, Vicente A, Gusic, Mirjana, Kopajtich, Robert, Mertes, Christian, Smith, Nicholas H, Alston, Charlotte L, Ban, Rui, Beblo, Skadi, Berutti, Riccardo, Blessing, Holger, Ciara, Elżbieta, Distelmaier, Felix, Freisinger, Peter, Häberle, Johannes; https://orcid.org/0000-0003-0635-091X, Hayflick, Susan J, Hempel, Maja, Itkis, Yulia S, Kishita, Yoshihito, Klopstock, Thomas; https://orcid.org/0000-0003-2805-4652, Krylova, Tatiana D, Lamperti, Costanza, Lenz, Dominic, Makowski, Christine, Mosegaard, Signe, Müller, Michaela F, Muñoz-Pujol, Gerard, Nadel, Agnieszka, Ohtake, Akira, Okazaki, Yasushi, Procopio, Elena, and et al

Abstract

BACKGROUND: Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics. METHODS: We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage. RESULTS: We detected on average 12,500 genes per sample including around 60% of all disease genes-a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions. CONCLUSION: Together, these results show that streamlined experimental and computational processes can

Published
2022

46. Ex vivo proton spectroscopy (1H‐NMR) analysis of inborn errors of metabolism: Automatic and computer‐assisted analyses.

Author

Cannet, Claire, Frauendienst‐Egger, Georg, Freisinger, Peter, Götz, Hermann, Götz, Madalina, Himmelreich, Nastassja, Kock, Vanessa, Spraul, Manfred, Bus, Christine, Biskup, Saskia, and Trefz, Friedrich

Subjects
INBORN errors of metabolism, LIQUID chromatography-mass spectrometry, LYSOSOMAL storage diseases, HIGH performance liquid chromatography, METABOLIC disorders, GLYCOGEN storage disease type II, CONGENITAL hypothyroidism
Abstract

There are about 1500 genetic metabolic diseases. A small number of treatable diseases are diagnosed by newborn screening programs, which are continually being developed. However, most diseases can only be diagnosed based on clinical symptoms or metabolic findings. The main biological fluids used are urine, plasma and, in special situations, cerebrospinal fluid. In contrast to commonly used methods such as gas chromatography and high performance liquid chromatography mass spectrometry, ex vivo proton spectroscopy (1H‐NMR) is not yet used in routine clinical practice, although it has been recommended for more than 30 years. Automatic analysis and improved NMR technology have also expanded the applications used for the diagnosis of inborn errors of metabolism. We provide a mini‐overview of typical applications, especially in urine but also in plasma, used to diagnose common but also rare genetic metabolic diseases with 1H‐NMR. The use of computer‐assisted diagnostic suggestions can facilitate interpretation of the profiles. In a proof of principle, to date, 182 reports of 59 different diseases and 500 reports of healthy children are stored. The percentage of correct automatic diagnoses was 74%. Using the same 1H‐NMR profile‐targeted analysis, it is possible to apply an untargeted approach that distinguishes profile differences from healthy individuals. Thus, additional conditions such as lysosomal storage diseases or drug interferences are detectable. Furthermore, because 1H‐NMR is highly reproducible and can detect a variety of different substance categories, the metabolomic approach is suitable for monitoring patient treatment and revealing additional factors such as nutrition and microbiome metabolism. Besides the progress in analytical techniques, a multiomics approach is most effective to combine metabolomics with, for example, whole exome sequencing, to also diagnose patients with nondetectable metabolic abnormalities in biological fluids. In this mini review we also provide our own data to demonstrate the role of NMR in a multiomics platform in the field of inborn errors of metabolism. [ABSTRACT FROM AUTHOR]

Published
2023
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47. Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations

Author

Huemer, Martina, Karall, Daniela, Schossig, Anna, Abdenur, Jose E., Al Jasmi, Fatma, Biagosch, Caroline, Distelmaier, Felix, Freisinger, Peter, Graham, Brett H., Haack, Tobias B., Hauser, Natalie, Hertecant, Jozef, Ebrahimi-Fakhari, Darius, Konstantopoulou, Vassiliki, Leydiker, Karen, Lourenco, Charles M., Scholl-Bürgi, Sabine, Wilichowski, Ekkehard, Wolf, Nicole I., Wortmann, Saskia B., Taylor, Robert W., Mayr, Johannes A., Bonnen, Penelope E., Sperl, Wolfgang, Prokisch, Holger, and McFarland, Robert

Published
2015
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48. Spectrum of combined respiratory chain defects

Author

Mayr, Johannes A., Haack, Tobias B., Freisinger, Peter, Karall, Daniela, Makowski, Christine, Koch, Johannes, Feichtinger, René G., Zimmermann, Franz A., Rolinski, Boris, Ahting, Uwe, Meitinger, Thomas, Prokisch, Holger, and Sperl, Wolfgang

Published
2015
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