Abstract
Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that has been described in only three patients so far. The disease is characterized by neonatal onset of severe encephalopathy, low levels of glutamine in blood and cerebrospinal fluid, chronic moderate hyperammonemia, and an overall poor prognosis in the absence of an effective treatment. Recently, enteral glutamine supplementation was shown to be a safe and effective therapy for this disease but there are no data available on the long-term effects of this intervention. The amino acid glutamine, severely lacking in this disorder, is central to many metabolic pathways in the human organism and is involved in the synthesis of nicotinamide adenine dinucleotide (NAD+) starting from tryptophan or niacin as nicotinate, but not nicotinamide. Using fibroblasts, leukocytes, and immortalized peripheral blood stem cells (PBSC) from a patient carrying a GLUL gene point mutation associated with impaired GS activity, we tested whether glutamine deficiency in this patient results in NAD+ depletion and whether it can be rescued by supplementation with glutamine, nicotinamide or nicotinate. The present study shows that congenital GS deficiency is associated with NAD+ depletion in fibroblasts, leukocytes and PBSC, which may contribute to the severe clinical phenotype of the disease. Furthermore, it shows that NAD+ depletion can be rescued by nicotinamide supplementation in fibroblasts and leukocytes, which may open up potential therapeutic options for the treatment of this disorder.
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Abbreviations
- GS:
-
Glutamine synthetase
- NAD+ :
-
Nicotinamide adenine dinucleotide
- PBSC:
-
Peripheral blood stem cells
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Acknowledgments
This study was supported by grants from Qatar Foundation and from Hartmann Müller Stiftung (Grant 1492 to JH). Grant sponsors had no influence on study design, interpretation of data or manuscript writing.
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Human and Animal Rights and Informed Consent
This article does not contain any studies with animal subjects. Studies with human material are in accordance with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from the legal guardians of the patient for being included in the study.
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Communicated by: Jerry Vockley
DedicationThe authors want to dedicate this work to the late Hamad Ajool, the then only known patient with inherited GS deficiency, who was able to give so much to his family and to science.
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Hu, L., Ibrahim, K., Stucki, M. et al. Secondary NAD+ deficiency in the inherited defect of glutamine synthetase. J Inherit Metab Dis 38, 1075–1083 (2015). https://doi.org/10.1007/s10545-015-9846-4
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DOI: https://doi.org/10.1007/s10545-015-9846-4