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1. Constraints on the Dimensionality of Space

Author

Petway, C. A., Orlando, R. D., McNamara, A. M., Zweig, E. A., Caminada, B. C., Kincaid, E. J., Landgraf, C. V., Mohs, C. M., Schiff, M. L., and Fischbach, E.

Subjects
Physics - Classical Physics
Abstract

Complex structures can only form in a universe that allows for bound states. While this is clearly observed in three-dimensions, added degrees of freedom in a higher-dimensional space preclude the immediate assumption that binding potentials can in fact exist. In this paper, we derive a constraint on the dimensionality of a universe in the presence of an arbitrary set of forces. We then apply this constraint to systems with several example potentials. In doing so, we find that bound states in higher than 3 dimensions are in fact possible under specific circumstances which we characterize., Comment: 13 pages, 4 figures, added clarifying text and a new figure which shows an additional combination of forces

Published
2021
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2. Panorama étiologique et génétique de l’hyperammoniémie chez l’adulte : une étude rétrospective bi-centrique française

Author

Maquet, J., primary, Gobin, S., additional, Arnoux, J.B., additional, Imbard, A., additional, Le Guillou, E., additional, Dubot, P., additional, Brassier, A., additional, Dufeu-Berat, C.M., additional, Altenburger, L., additional, Bouchereau, J., additional, Servais, A., additional, Dao, M., additional, Pontoizeau, C., additional, Ottolenghi, C., additional, Bonnefont, J.P., additional, Benoist, J.F., additional, De Lonlay, P., additional, and Schiff, M., additional

Published
2024
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5. From drug-delivery device to disease management tool: a study of preferences for enhanced features in next-generation self-injection devices

Author

Boeri M, Szegvari B, Hauber B, Mange B, Mountian I, Schiff M, and Maniadakis N

Subjects
Rheumatology, subcutaneous injection, self-administration, patient preference, discrete-choice experiment, Medicine (General), R5-920
Abstract

Marco Boeri,1 Boglarka Szegvari,2 Brett Hauber,3 Brennan Mange,3 Irina Mountian,2 Michael Schiff,4 Nikolaos Maniadakis51RTI Health Solutions, Belfast, UK; 2UCB Pharma, Brussels, Belgium; 3RTI Health Solutions, Research Triangle Park, NC, USA; 4Rheumatology Division, University of Colorado School of Medicine, Denver, CO, USA; 5Health Services Management, National School of Public Health, Athens, GreecePurpose: To quantify rheumatology patient preferences and willingness to pay (WTP) for features differentiating enhanced from standard self-injection devices and to investigate differences among subgroups.Patients and methods: Patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) were recruited in the UK. A discrete-choice experiment was used to elicit preferences; respondents were presented with 10 choices between 3 different devices: a free standard disposable device, and 2 hypothetical reusable devices characterized by presence/absence of skin sensor, injection speed control, on-screen instructions, injection reminders, electronic log, and large grip. Every hypothetical device included a cost component to assess WTP for each enhanced feature. A random-parameters logit model was used to estimate preference weights and WTP.Results: Data were collected from 323 respondents by electronic survey (15/11/2017–15/02/2018; RA: 108; PsA: 103; axSpA: 112). On average, the skin sensor was the most preferred feature (£30), followed by injection speed control, injection reminders, electronic log (∼£20 each), on-screen instructions (∼£12), and a device with a small, rather than large grip (∼£7). Similar preferences for attributes were observed across condition subgroups except for grip size: axSpA patients preferred small grip (∼£27); PsA patients preferred large grip (∼£19). Overall, respondents preferred reusable devices with all enhanced features (WTP value: £85) over the standard device. RA patients exhibited a higher WTP (£145) than PsA (£102) or axSpA (£62) for the same enhanced device.Conclusion: Patients positively valued reusable self-injection devices with enhanced features, which may improve patient experience, potentially improving treatment adherence, clinical, and economic outcomes.Keywords: rheumatology, subcutaneous injection, self-administration, patient preference, discrete-choice experiment

Published
2019

7. Factors associated with contraceptive nonuse among obese and non-obese WOMEN

Author

Callegari, L, Prager, S, Schwarz, EB, and Schiff, M

Subjects
Biomedical and Clinical Sciences, Health Services and Systems, Clinical Sciences, Health Sciences, Reproductive Medicine, Paediatrics and Reproductive Medicine, Public Health and Health Services, Obstetrics & Reproductive Medicine, Clinical sciences, Reproductive medicine, Health services and systems
Published
2013

8. Renal Involvement in a French Paediatric Cohort of Patients with Lysinuric Protein Intolerance

Author

Nicolas, C., Bednarek, N., Vuiblet, V., Boyer, O., Brassier, A., De Lonlay, P., Galmiche, L., Krug, P., Baudouin, V., Pichard, S., Schiff, M., Pietrement, C., Baumgartner, Matthias R., Series editor, Patterson, Marc, Series editor, Rahman, Shamima, Series editor, Peters, Verena, Series editor, Morava, Eva, Editor-in-chief, Zschocke, Johannes, Series editor, and Baumgartner, Matthias, editor

Published
2016
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9. A novel role for the TIR domain in association with pathogen-derived elicitors

Author

Burch-Smith, TM, Schiff, M, Caplan, JL, Tsao, J, Czymmek, K, and Dinesh-Kumar, SP

Subjects
Amino Acid Sequence, Immunity, Innate, Plant Proteins, Plants, Polymerase Chain Reaction, Tobacco Mosaic Virus, Virulence, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Plant innate immunity is mediated by Resistance (R) proteins, which bear a striking resemblance to animal molecules of similar function. Tobacco N is a TIR-NB-LRR R gene that confers resistance to Tobacco mosaic virus, specifically the p50 helicase domain. An intriguing question is how plant R proteins recognize the presence of pathogen-derived Avirulence (Avr) elicitor proteins. We have used biochemical cell fraction and immunoprecipitation in addition to confocal fluorescence microscopy of living tissue to examine the association between N and p50. Surprisingly, both N and p50 are cytoplasmic and nuclear proteins, and N's nuclear localization is required for its function. We also demonstrate an in planta association between N and p50. Further, we show that N's TIR domain is critical for this association, and indeed, it alone can associate with p50. Our results differ from current models for plant innate immunity that propose detection is mediated solely through the LRR domains of these molecules. The data we present support an intricate process of pathogen elicitor recognition by R proteins involving multiple subcellular compartments and the formation of multiple protein complexes. © 2007 Burch-Smith et al.

Published
2007

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

Author

Huemer, Martina, Diodato, Daria, Martinelli, Diego, Olivieri, Giorgia, Blom, Henk, Gleich, Florian, Kölker, Stefan, Kožich, Viktor, Morris, Andrew A., Seifert, Burkhardt, Froese, D. Sean, Baumgartner, Matthias R., Dionisi-Vici, Carlo, the EHOD consortium, Alcalde Martin, C., Baethmann, M., Ballhausen, D., Blasco-Alonso, J., Boy, N., Bueno, M., Burgos Peláez, R., Cerone, R., Chabrol, B., Chapman, K. A., Couce, M. L., Crushell, E., Dalmau Serra, J., Diogo, L., Ficicioglu, C., García Jimenez, M. C., García Silva, M. T., Gaspar, A. M., Gautschi, M., González-Lamuño, D., Gouveia, S., Grünewald, S., Hendriksz, C., Janssen, M. C. H., Jesina, P., Koch, J., Konstantopoulou, V., Lavigne, C., Lund, A. M., Martins, E. G., Meavilla Olivas, S., Mention, K., Mochel, F., Mundy, H., Murphy, E., Paquay, S., Pedrón-Giner, C., Ruiz Gómez, M. A., Santra, S., Schiff, M., Schwartz, I. V., Scholl-Bürgi, S., Servais, A., Skouma, A., Tran, C., Vives Piñera, I., Walter, J., and Weisfeld-Adams, J.

Published
2018
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11. Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.

Author

Vogel, G.F., Mozer-Glassberg, Y., Landau, Y.E., Schlieben, L.D., Prokisch, H., Feichtinger, R.G., Mayr, J.A., Brennenstuhl, H., Schröter, J., Pechlaner, A., Alkuraya, F.S., Baker, J.J., Barcia, G., Baric, I., Braverman, N., Burnyte, B., Christodoulou, J., Ciara, E., Coman, D., Das, A.M., Darin, N., Marina, A. Della, Distelmaier, F., Eklund, E.A., Ersoy, M., Fang, W., Gaignard, P., Ganetzky, R.D., Gonzales, E., Howard, C., Hughes, J., Konstantopoulou, V., Kose, M., Kerr, M., Khan, A., Lenz, D., McFarland, R., Margolis, M.G., Morrison, K., Müller, T., Murayama, K., Nicastro, E., Pennisi, A., Peters, Heidi, Piekutowska-Abramczuk, D., Rötig, A., Santer, R., Scaglia, F., Schiff, M., Shagrani, M., Sharrard, M., Soler-Alfonso, C., Staufner, C., Storey, I., Stormon, M., Taylor, R.W., Thorburn, D.R., Teles, E.L., Wang, J.S., Weghuber, D., Wortmann, S.B., Vogel, G.F., Mozer-Glassberg, Y., Landau, Y.E., Schlieben, L.D., Prokisch, H., Feichtinger, R.G., Mayr, J.A., Brennenstuhl, H., Schröter, J., Pechlaner, A., Alkuraya, F.S., Baker, J.J., Barcia, G., Baric, I., Braverman, N., Burnyte, B., Christodoulou, J., Ciara, E., Coman, D., Das, A.M., Darin, N., Marina, A. Della, Distelmaier, F., Eklund, E.A., Ersoy, M., Fang, W., Gaignard, P., Ganetzky, R.D., Gonzales, E., Howard, C., Hughes, J., Konstantopoulou, V., Kose, M., Kerr, M., Khan, A., Lenz, D., McFarland, R., Margolis, M.G., Morrison, K., Müller, T., Murayama, K., Nicastro, E., Pennisi, A., Peters, Heidi, Piekutowska-Abramczuk, D., Rötig, A., Santer, R., Scaglia, F., Schiff, M., Shagrani, M., Sharrard, M., Soler-Alfonso, C., Staufner, C., Storey, I., Stormon, M., Taylor, R.W., Thorburn, D.R., Teles, E.L., Wang, J.S., Weghuber, D., and Wortmann, S.B.

Abstract

01 juni 2023, Item does not contain fulltext, PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Published
2023

12. A critical evaluation of the role of subcutaneous abatacept in the treatment of rheumatoid arthritis: patient considerations

Author

Wells AF, Jodat N, and Schiff M

Subjects
Medicine (General), R5-920
Abstract

Alvin F Wells,1,2 Nicole Jodat,1 Michael Schiff3 1Rheumatology and Immunotherapy Center, Franklin, WI, USA; 2Duke University Medical Center, Durham, NC, USA; 3University of Colorado, School of Medicine, Denver, CO, USA Abstract: There are now more therapeutic options for the treatment of rheumatoid arthritis (RA) than ever before, involving a range of mechanisms of action and different routes of administration. The T-cell costimulation modulator abatacept is the first biologic therapy for RA to be available in both subcutaneous (SC) and intravenous (IV) formulations. This review evaluates the utility of SC abatacept, with a particular focus on patient-reported outcomes, including physical function, pain, fatigue, and quality of life. Practical questions relating to the clinical use of SC abatacept are also addressed, including the relevance of abatacept's mechanism of action; whether IV and SC abatacept are comparable; if patients can easily switch from IV to SC abatacept; whether an IV loading dose is needed; and if temporary treatment interruptions or lack of concomitant methotrexate can affect efficacy or safety. Topics that are of particular concern to patients when using SC biologics, such as injection-site reactions, are also discussed. Observational data from registries and meta-analyses of clinical studies suggest comparable clinical efficacy between biologic disease-modifying antirheumatic drugs; however, such analyses rarely focus on key determinants of patient quality of life such as pain, fatigue, and physical function. The head-to-head AMPLE study is one of the first studies powered to directly compare two biologics in patients with RA. Patient-reported outcomes from year 1 of the ongoing study are evaluated, demonstrating comparable improvements in physical function, pain, fatigue, Short Form-36 Health Survey, and Routine Assessment of Patient Index Data 3 scores between SC abatacept and SC adalimumab when administered with concomitant methotrexate. In summary, the data presented herein show that the SC formulation of abatacept provides a valuable addition to the range of available therapy options for patients with RA, capable of significantly improving key patient considerations such as pain, disability, loss of function, fatigue, and quality of life. Keywords: rheumatoid arthritis, abatacept, subcutaneous, biologic DMARD, patient-reported outcomes

Published
2014

13. S230: HUMAN ΒETA-DEFENSIN 2 TREATMENT MODULATES THE INTESTINAL MICROBIOME AND THE ALLOGENEIC T CELL RESPONSE TO LIMIT ACUTE GRAFT-VERSUS-HOST DISEASE

Author

Rückert, T., primary, Andrieux, G., additional, Boerries, M., additional, Woessner, N. M., additional, Minguet, S., additional, Doetsch, S., additional, Aumann, K., additional, Schiff, M, additional, Braun, L. M., additional, Haring, E., additional, Siranosian, B. A., additional, Bhatt, A. S., additional, Nordkild, P., additional, Wehkamp, J., additional, Jensen, B. A. H., additional, Duyster, J., additional, Zeiser, R., additional, and Köhler, N., additional

Published
2022
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14. Very long‐term outcomes in 23 patients with cblA type methylmalonic acidemia

Author

Marelli, C., primary, Fouilhoux, A., additional, Benoist, J. F., additional, De Lonlay, P., additional, Guffon‐Fouilhoux, N., additional, Brassier, Anais, additional, Cano, A., additional, Chabrol, B., additional, Pennisi, A., additional, Schiff, M., additional, Acquaviva, C., additional, Murphy, E., additional, Servais, A., additional, and Lachmann, R., additional

Published
2022
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17. Influence of early identification and therapy on long-term outcomes in early-onset MTHFR deficiency

Author

Yverneau, M., Leroux, S., Imbard, A., Gleich, F., Arion, A., Moreau, C., Nassogne, M.C., Szymanowski, M., Tardieu, M., Touati, G., Bueno, M., Chapman, K.A., Chien, Y.H., Huemer, M., Ješina, P., Janssen, M.C.H., Kölker, S., Kožich, V., Lavigne, C., Lund, A.M., Mochel, F., Morris, A., Pons, M.R., Porras-Hurtado, G.L., Benoist, J.F., Damaj, L., Schiff, M., Yverneau, M., Leroux, S., Imbard, A., Gleich, F., Arion, A., Moreau, C., Nassogne, M.C., Szymanowski, M., Tardieu, M., Touati, G., Bueno, M., Chapman, K.A., Chien, Y.H., Huemer, M., Ješina, P., Janssen, M.C.H., Kölker, S., Kožich, V., Lavigne, C., Lund, A.M., Mochel, F., Morris, A., Pons, M.R., Porras-Hurtado, G.L., Benoist, J.F., Damaj, L., and Schiff, M.

Abstract

Item does not contain fulltext, MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.

Published
2022

20. Constraints on the dimensionality of space

Author

Petway, C. A., primary, Orlando, R. D., additional, McNamara, A. M., additional, Zweig, E. A., additional, Caminada, B. C., additional, Kincaid, E. J., additional, Landgraf, C. V., additional, Mohs, C. M., additional, Schiff, M. L., additional, and Fischbach, E., additional

Published
2022
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21. Post-authorization safety study of Betaine anhydrous

Author

Mütze U, Gleich F, Garbade SF, Plisson C, Aldámiz-Echevarría L, Arrieta F, Ballhausen D, Zielonka M, Ramadža DP, Baumgartner MR, Cano A, Jiménez MCG, Dionisi-Vici C, Ješina P, Blom HJ, Couce ML, Olivas SM, Mention K, Mochel F, Morris AAM, Mundy H, Redonnet-Vernhet I, Santra S, Schiff M, Servais A, Vitoria I, Huemer M, Kožich V, and Kölker S

Subjects
homocystinuria, post-authorization safety study, Betaine anhydrous, rare disease, orphan drug, public private partnership, E-HOD
Abstract

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate post-authorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane®), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects (E-HOD) and the marketing authorization holder (MAH). Prospective data collection, 2013-2016, in a non-interventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. 130 individuals with vitamin B(6) non-responsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B(6) non-responsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 µmoL/L to 81 ± 51 µmoL/L (P < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals older than 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

Published
2022

22. Efficacité d’une supplémentation orale en méthionine chez les patients atteints de protéinose alvéolaire primitive par mutations du gène MARS

Author

Hadchouel, A., primary, Drummond, D., additional, Pontoizeau, C., additional, Hurtado-Nedelec, M., additional, El Benna, J., additional, Gachelin, E., additional, Perisson, C., additional, Vigier, C., additional, Schiff, M., additional, Lacaille, F., additional, Molina, T.J., additional, Berteloot, L., additional, Renolleau, S., additional, Ottolenghi, C., additional, Tréluyer, J.M., additional, De Blic, J., additional, and Delacourt, C., additional

Published
2022
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23. Update on transcobalamin deficiency: clinical presentation, treatment and outcome

Author

Trakadis, Y. J., Alfares, A., Bodamer, O. A., Buyukavci, M., Christodoulou, J., Connor, P., Glamuzina, E., Gonzalez-Fernandez, F., Bibi, H., Echenne, B., Manoli, I., Mitchell, J., Nordwall, M., Prasad, C., Scaglia, F., Schiff, M., Schrewe, B., Touati, G., Tchan, M. C., Varet, B., Venditti, C. P., Zafeiriou, D., Rupar, C. A., Rosenblatt, D. S., Watkins, D., and Braverman, N.

Published
2014
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26. Diagnosing pediatric mitochondrial disease: lessons from 2,000 exomes

Author

Husain Ra, Thomas Meitinger, Wilichowski E, Robert Kopajtich, Smirnov D, Ewa Pronicka, Christine Makowski, Elżbieta Ciara, Michael Wagner, Felix Distelmaier, René Santer, Olsen R, Wolstein T, Theresa Brunet, Muller-Felber W, Buchner B, Wolfgang Sperl, Maja Hempel, Stefan Kölker, Dominic Lenz, Sarah L. Stenton, Saskia B. Wortmann, Leiz S, Kei Murayama, Munoz-Pujol G, Konstantopoulou, Xu M, Tobias B. Haack, Tim M. Strom, Riccardo Berutti, Tsygankova P, Lim Az, Daniele Ghezzi, Robert McFarland, Deen D, Kotzaeridou U, Daniela Karall, Ardissone A, Charlotte L. Alston, Markus Schuelke, Thomas Klopstock, Peter Freisinger, Robert W. Taylor, Ban R, Verloo P, van Coster R, Shimura M, Agnès Rötig, Dariusz Rokicki, Yepez, Mandel H, Akira Ohtake, Angela Pyle, Yasushi Okazaki, Mirjana Gusic, Antonia Ribes, Costanza Lamperti, Fang F, Holger Prokisch, von Kleist-Retzow J, Ivo Barić, Julien Gagneur, Bader Alhaddad, Dorota Piekutowska-Abramczuk, Johannes A. Mayr, Michael Zech, Frederic Tort, and Schiff M

Subjects
0303 health sciences, business.industry, Mitochondrial disease, Precision medicine, medicine.disease, Bioinformatics, Phenotype, 3. Good health, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, medicine, Functional studies, business, Gene, Mitochondrial protein, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

BackgroundThe spectrum of mitochondrial disease is genetically and phenotypically diverse, resulting from pathogenic variants in over 400 genes, with aerobic energy metabolism defects as a common denominator. Such heterogeneity poses a significant challenge in making an accurate diagnosis, critical for precision medicine.MethodsIn an international collaboration initiated by the European Network for Mitochondrial Diseases (GENOMIT) we recruited 2,023 pediatric patients at 11 specialist referral centers between October 2010 and January 2021, accumulating exome sequencing and HPO-encoded phenotype data. An exome-wide search for variants in known and potential novel disease genes, complemented by functional studies, followed ACMG guidelines.Results1,109 cases (55%) received a molecular diagnosis, of which one fifth have potential disease-modifying treatments (236/1,109, 21%). Functional studies enabled diagnostic uplift from 36% to 55% and discovery of 62 novel disease genes. Pathogenic variants were identified within genes encoding mitochondrial proteins or RNAs in 801 cases (72%), while, given extensive phenotype overlap, the remainder involved proteins targeted to other cellular compartments. To delineate genotype-phenotype associations, our data was complemented with registry and literature data to develop “GENOMITexplorer”, an open access resource detailing patient- (n=3,940), gene- (n=427), and variant-level (n=1,492) associations (prokischlab.github.io/GENOMITexplorer/).ConclusionsReaching a molecular diagnosis was essential for implementation of precision medicine and clinical trial eligibility, underlining the need for genome-wide screening given inability to accurately define mitochondrial diseases clinically. Key to diagnostic success were functional studies, encouraging early acquisition of patient- derived tissues and routine integration of high-throughput functional data to improve patient care by uplifting diagnostic rate.

Published
2021

27. Evaluation of dietary treatment and amino acid supplementation in organic acidurias and urea‐cycle disorders: On the basis of information from a European multicenter registry

Author

Molema, Femke, Gleich, Florian, Burgard, Peter, van der Ploeg, Ans T., Summar, Marshall L., Chapman, Kimberly A., Barić, Ivo, Lund, Allan M., Kölker, Stefan, Williams, Monique, Hörster, F., Jelsig, A.M., de Lonlay, P., Wijburg, F.A., Bosch, A., Freisinger, P., Posset, R., Augoustides‐Savvopoulou, P., Avram, P., Deleanu, C., Baumgartner, M.R., Häberle, J., Blasco‐ Alonso, J., Burlina, A.B., Rubert, L., Cazorla, A. Garcia, Saladelafont, E. Cortes i, Dionisi‐ Vici, C., Martinelli, D., Dobbelaere, D., Mention, K., Grünewald, S., Chakrapani, A., Hwu, Wuh‐Liang, Chien, Yin‐Hsiu, Lee, Ni‐Chung, Karall, D., Scholl‐Bürgi, S., Lachmann, R., De Laet, C., Matsumoto, S., de Meirleir, L., Mühlhausen, C., Schiff, M., Peña‐Quintana, L., Djordjevic, M., Sarajlija, A., Sykut‐Cegielska, J., Wisniewska, A., Leao‐Teles, E., Alves, S., Vara, R., Vives‐Pinera, I., Ortega, D.G., Morris, A., Zeman, J., Honzik, T., Chabrol, B., Arnaudo, F., Cano, A., Thompson, N., Eyskens, F., Lindner, M., Lüsebrink, N., Jalan, A., Sokal, E., Legros, V., Nassogne, M.C., Additional individual contributors from E‐IMD, Pediatrics, Paediatric Metabolic Diseases, AGEM - Inborn errors of metabolism, ARD - Amsterdam Reproduction and Development, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), and E-IMD

Subjects
Adult, Male, Ornithine, medicine.medical_specialty, Propionic Acidemia, Adolescent, organic acidurias, Protein metabolism, Ornithine transcarbamylase, amino acid mixtures, Gastroenterology, Reference Daily Intake, Young Adult, chemistry.chemical_compound, Valine, Internal medicine, Genetics, medicine, Humans, Hyperammonemia, dietary and supplemental treatment, Registries, Amino Acids, branched-chain amino acids, Child, Amino Acid Metabolism, Inborn Errors, Urea Cycle Disorders, Inborn, Genetics (clinical), Retrospective Studies, L-citrulline and L-arginine, business.industry, urea-cycle disorders, Infant, Europe, Cross-Sectional Studies, Treatment Outcome, chemistry, Methylmalonic aciduria, Child, Preschool, Urea cycle, Dietary Supplements, Feasibility Studies, Female, Human medicine, Leucine, business
Abstract

Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D, and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation.

Published
2019

33. Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Author

Posset, R. (Roland), Garbade, S.F. (Sven), Gleich, F. (Florian), Gropman, A.L. (Andrea L.), Lonlay, P. (Pascale) de, Hoffmann, G.F. (Georg), Garcia-Cazorla, A. (Angeles), Nagamani, S.C.S. (Sandesh C. S.), Baumgartner, M.R. (Matthias), Schulze, A. (Andreas), Dobbelaere, D. (Dries), Yudkoff, M. (Marc), Kölker, S. (Stefan), Zielonka, M. (Matthias), Ah Mew, N. (Nicholas), Berry, S.A. (Susan A.), McCandless, S.E. (Shawn E.), Coughlin, C. (Curtis), Enns, G. (Gregory), Gallagher, R.C. (Renata C.), Burrage, L.C. (Lindsay C.), Seminara, J. (Jennifer), Harding, C.O. (Cary O.), Burgard, P. (Peter), Le Mons, C. (Cynthia), Merritt, J.L. (J. Lawrence), Stricker, T. (Tamar), Bedoyan, J. (Jirair), Berry, G.T. (Gerard T.), Diaz, G.A. (George A.), Wong, D. (Derek), Tuchman, M. (Mendel), Waisbren, S. (Susan), Weisfeld-Adams, J.D. (James D), Burlina, A.B. (Alberto), Leão Teles, E. (Elisa), Pedrón-Giner, C. (Consuelo), Lund, A.M. (Allan M.), Dionisi-Vici, C. (Carlo), Williams, M. (Monique), Mütze, U. (Ulrike), Karall, D. (Daniela), Blasco-Alonso, J. (Javier), Couce, M.L. (Maria L.), Sykut-Cegielska, J. (Jolanta), Augoustides-Savvopoulou, P. (Persa), Ruiz Gomez, A. (Angeles), Barić, I. (Ivo), Schiff, M. (Manuel), Chien, Y.-H. (Yin-Hsiu), Lindner, M. (Martin), Chabrol, B. (Brigitte), Skouma, A. (Anastasia), Zeman, J. (Jiri), Sokal, E. (Etienne), Santer, R. (Rene), Eyskens, F. (François), Freisinger, P. (Peter), Peña-Quintana, L. (Luis), Roland, D. (Dominique), Cortès-Saladelafont, E. (Elisenda), Djordjevic, M. (Maja), Posset, R. (Roland), Garbade, S.F. (Sven), Gleich, F. (Florian), Gropman, A.L. (Andrea L.), Lonlay, P. (Pascale) de, Hoffmann, G.F. (Georg), Garcia-Cazorla, A. (Angeles), Nagamani, S.C.S. (Sandesh C. S.), Baumgartner, M.R. (Matthias), Schulze, A. (Andreas), Dobbelaere, D. (Dries), Yudkoff, M. (Marc), Kölker, S. (Stefan), Zielonka, M. (Matthias), Ah Mew, N. (Nicholas), Berry, S.A. (Susan A.), McCandless, S.E. (Shawn E.), Coughlin, C. (Curtis), Enns, G. (Gregory), Gallagher, R.C. (Renata C.), Burrage, L.C. (Lindsay C.), Seminara, J. (Jennifer), Harding, C.O. (Cary O.), Burgard, P. (Peter), Le Mons, C. (Cynthia), Merritt, J.L. (J. Lawrence), Stricker, T. (Tamar), Bedoyan, J. (Jirair), Berry, G.T. (Gerard T.), Diaz, G.A. (George A.), Wong, D. (Derek), Tuchman, M. (Mendel), Waisbren, S. (Susan), Weisfeld-Adams, J.D. (James D), Burlina, A.B. (Alberto), Leão Teles, E. (Elisa), Pedrón-Giner, C. (Consuelo), Lund, A.M. (Allan M.), Dionisi-Vici, C. (Carlo), Williams, M. (Monique), Mütze, U. (Ulrike), Karall, D. (Daniela), Blasco-Alonso, J. (Javier), Couce, M.L. (Maria L.), Sykut-Cegielska, J. (Jolanta), Augoustides-Savvopoulou, P. (Persa), Ruiz Gomez, A. (Angeles), Barić, I. (Ivo), Schiff, M. (Manuel), Chien, Y.-H. (Yin-Hsiu), Lindner, M. (Martin), Chabrol, B. (Brigitte), Skouma, A. (Anastasia), Zeman, J. (Jiri), Sokal, E. (Etienne), Santer, R. (Rene), Eyskens, F. (François), Freisinger, P. (Peter), Peña-Quintana, L. (Luis), Roland, D. (Dominique), Cortès-Saladelafont, E. (Elisenda), and Djordjevic, M. (Maja)

Abstract

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.

Published
2020
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34. Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Author

Posset, R, Garbade, SF, Gleich, F, Gropman, AL, de Lonlay, P, Hoffmann, GF, Garcia-Cazorla, A, Nagamani, SCS, Baumgartner, MR, Schulze, A, Dobbelaere, D, Yudkoff, M, Kölker, S, Zielonka, M, Ah Mew, N, Berry, SA, McCandless, SE, Coughlin, C, Enns, G, Gallagher, RC, Burrage, LC, Seminara, J, Harding, CO, Burgard, P, Le Mons, C, Merritt, JL, II, Stricker, T, Bedoyan, JK, Berry, GT, Diaz, GA, Wong, D, Tuchman, M, Waisbren, S, Weisfeld-Adams, JD, Burlina, AB, Leão Teles, E, Pedrón-Giner, C, Lund, AM, Dionisi-Vici, C, Williams, Monique, Mütze, U, Karall, D, Blasco-Alonso, J, Couce, ML, Sykut-Cegielska, J, Augoustides-Savvopoulou, P, Ruiz Gomez, A, Bari?, I, Schiff, M, Chien, YH, Lindner, M, Chabrol, B, Skouma, A, Zeman, J, Sokal, E, Santer, R, Eyskens, F, Freisinger, P, Peña-Quintana, L, Roland, D, Cortès-Saladelafont, E, Djordjevic, M, Posset, R, Garbade, SF, Gleich, F, Gropman, AL, de Lonlay, P, Hoffmann, GF, Garcia-Cazorla, A, Nagamani, SCS, Baumgartner, MR, Schulze, A, Dobbelaere, D, Yudkoff, M, Kölker, S, Zielonka, M, Ah Mew, N, Berry, SA, McCandless, SE, Coughlin, C, Enns, G, Gallagher, RC, Burrage, LC, Seminara, J, Harding, CO, Burgard, P, Le Mons, C, Merritt, JL, II, Stricker, T, Bedoyan, JK, Berry, GT, Diaz, GA, Wong, D, Tuchman, M, Waisbren, S, Weisfeld-Adams, JD, Burlina, AB, Leão Teles, E, Pedrón-Giner, C, Lund, AM, Dionisi-Vici, C, Williams, Monique, Mütze, U, Karall, D, Blasco-Alonso, J, Couce, ML, Sykut-Cegielska, J, Augoustides-Savvopoulou, P, Ruiz Gomez, A, Bari?, I, Schiff, M, Chien, YH, Lindner, M, Chabrol, B, Skouma, A, Zeman, J, Sokal, E, Santer, R, Eyskens, F, Freisinger, P, Peña-Quintana, L, Roland, D, Cortès-Saladelafont, E, and Djordjevic, M

Published
2020

35. Analgésiques morphiniques

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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36. La dépression

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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37. Fracture de jambe

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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38. Syndrome de Turner

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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39. Alcaloïdes de la Pervenche

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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40. Insuffisance surrénalienne

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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41. Diphtérie

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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42. Lésions ligamentaires et méniscales du genou

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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43. Sulfasalazine

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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44. Polyarthrite rhumatoïde

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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45. Fracture du fémur

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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46. Diagnostic des méningites bactériennes communautaires

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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47. Gale

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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48. Prolapsus génitaux

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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49. Anticortisoliques de synthèse

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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50. Polysomnographie

Author

Alexandre, J., primary, Balian, A., additional, Bensoussan, L., additional, Chaïb, A., additional, Gridel, G., additional, Kinugawa, K., additional, Lamazou, F., additional, Lim-Sabbah, I., additional, Mink, V., additional, Planquette, B., additional, Rouprêt, M., additional, Rousseau, M.-A., additional, Roze, E., additional, Salama, S., additional, Schiff, M., additional, Simon, D., additional, Skurnik, D., additional, and Soria, A., additional

Published
2009
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