دورية أكاديمية
N-carbamoylglutamate-responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutation's effects
| العنوان: | N-carbamoylglutamate-responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutation's effects |
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| المؤلفون: | Yap, Sufin, Gougeard, Nadine, Hart, Anthony R., Barcelona, Belén, Rubio, Vicente |
| المساهمون: | Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Fundación Inocente Inocente, Rubio, Vicente |
| بيانات النشر: | Wiley-Blackwell |
| سنة النشر: | 2019 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| مصطلحات موضوعية: | Carbamylglutamate, Carglumic acid, Carglumic acid test trial, Hyperammonemia, Novel treatments, Urea cycle disorders |
| الوصف: | 9 páginas, 3 figuras ; N-carbamoyl-l-glutamate (NCG), the N-acetyl-l-glutamate analogue used to treat N-acetylglutamate synthase deficiency, has been proposed as potential therapy of carbamoyl phosphate synthetase 1 deficiency (CPS1D). Previous findings in five CPS1D patients suggest that NCG-responsiveness could be mutation-specific. We report on a patient with CPS1D, homozygous for the novel p.(Pro1211Arg) CPS1 mutation, who presented at 9 days of life with hyperammonemic coma which was successfully treated with emergency measures. He remained metabolically stable on merely oral NCG, arginine, and modest protein restriction. Ammonia scavengers were only added after poor dietary compliance following solid food intake at age 1 year. The patient received a liver transplantation at 3.9 years of age, having normal cognitive, motor, and quality of life scores despite repeated but successfully treated episodes of hyperammonemia. Studies using recombinantly produced mutant CPS1 confirmed the partial nature of the CPS1D triggered by the p.(Pro1211Arg) mutation. This mutation decreased the solubility and yield of CPS1 as expected for increased tendency to misfold, and reduced the thermal stability, maximum specific activity (V max; ~2-fold reduction), and apparent affinity (~5-fold reduction) for ATP of the purified enzyme. By increasing the saturation of the NAG site in vivo, NCG could stabilize CPS1 and minimize the decrease in the effective affinity of the enzyme for ATP. These observations, together with prior experience, support the ascertainment of clinical responsiveness to NCG in CPS1 deficient patients, particularly when decreased stability or lowered affinity for NAG of the mutant enzyme are suspected or proven. ; Grants to V.R. from the Fundación Inocente Inocente2018 (Spain) and BFU2017-84264-P of MINECO-SpanishGovernment. N.G. and B.B. had contracts from CIBERER-ISCIII and Fundación Inocente Inocente. Orphan Europefunded editorial assistance. ; Peer reviewed |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2192-8304 2192-8312 |
| العلاقة: | #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2017-84264-P; Publisher's version; http://dx.doi.org/10.1002/jmd2.12034Test; Sí; JIMD Reports 48(1):36-44 (2019); http://hdl.handle.net/10261/192035Test; http://dx.doi.org/10.13039/501100003329Test |
| DOI: | 10.1002/jmd2.12034 |
| DOI: | 10.13039/501100003329 |
| الإتاحة: | https://doi.org/10.1002/jmd2.12034Test https://doi.org/10.13039/501100003329Test http://hdl.handle.net/10261/192035Test |
| حقوق: | open |
| رقم الانضمام: | edsbas.E47A62CD |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 21928304 21928312 |
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| DOI: | 10.1002/jmd2.12034 |