Natural course of glutamine synthetase deficiency in a 3 year old patient

Häberle, Johannes; Shahbeck, Noora; Ibrahim, Khalid; Hoffmann, Georg F.; Ben‐Omran, Tawfeg

doi:10.1016/j.ymgme.2011.02.001

Cited by 51 publications

(73 citation statements)

References 10 publications

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“…The evidence that GS levels are significantly decreased in the human hippocampus and amygdala in temporal lobe epilepsy further corroborated critical role of this enzyme in epileptogenesis (Eid et al ., 2013). Such assumption was aslo supported by the observation that reduced GS expression induced by gene mutations resulted in severe seizures (Haberle et al ., 2011). …”

Section: Epilepsymentioning

confidence: 74%

Translational potential of astrocytes in brain disorders

Verkhratsky

Steardo²,

Parpura

et al. 2016

Progress in Neurobiology

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Fundamentally, all brain disorders can be broadly defined as the homeostatic failure of this organ. As the brain is composed of many different cells types, including but not limited to neurons and glia, it is only logical that all the cell types/constituents could play a role in health and disease. Yet, for a long time the sole conceptualization of brain pathology was focused on the well-being of neurons. Here, we challenge this neuron-centric view and present neuroglia as a key element in neuropathology, a process that has a toll on astrocytes, which undergo complex morpho-functional changes that can in turn affect the course of the disorder. Such changes can be grossly identified as reactivity, atrophy with loss of function and pathological remodeling. We outline the pathogenic potential of astrocytes in variety of disorders, ranging from neurotrauma, infection, toxic damage, stroke, epilepsy, neurodevelopmental, neurodegenerative and psychiatric disorders, Alexander disease to neoplastic changes seen in gliomas. We hope that in near future we would witness glial-based translational medicine with generation of deliverables for the containment and cure of disorders. We point out that such as a task will require a holistic and multi-disciplinary approach that will take in consideration the concerted operation of all the cell types in the brain.

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Section: Epilepsymentioning

confidence: 74%

Translational potential of astrocytes in brain disorders

Verkhratsky

Steardo²,

Parpura

et al. 2016

Progress in Neurobiology

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“…It should be noted that, in the patient with the mild phenotype, analysis of plasma amino acids at the age of 6 months demonstrated glutamine values just below the reference range, indicating that marginally low concentrations of glutamine should alert us to suspect this diagnosis (Häberle et al 2011).…”

Section: Diagnosismentioning

confidence: 95%

“…Since this disorder was first reported by Häberle et al 2005, only three patients in total have been described in the literature (Häberle et al 2005;Häberle et al 2011).…”

Section: Glutamine Deficiencymentioning

confidence: 99%

Amino acid synthesis deficiencies

Koning

2013

Handbook of Clinical Neurology

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“…(Note: NH 3 is protonated for 98% to NH 4 1 at physiological pH. We use the term "ammonia" to refer to the sum of NH 3 and NH 4 1 unless specified as either "NH 3 " or "NH 4 1 .") Glutamine serves, with alanine, as a major nontoxic interorgan ammonia shuttle in the body (1) and as an aminomoiety donor for the synthesis of nucleotides, amino acids, amino-sugars, and oxidized nicotinamide adenine dinucleotide.…”

mentioning

confidence: 99%

“…GS deficiency causes only moderate hyperammonemia, but affected humans and mice suffer from encephalopathy and die neonatally. (2,3) GS is predominantly expressed in the nervous system, kidney, and liver, that is, in established glutamine-consuming organs, (4)(5)(6) whereas skeletal muscle, with a much lower expression but large mass, is considered the main net producer of glutamine. (7) The nervous system synthesizes glutamine to scavenge /Gs fl/fl mice; GS-KO/0.5, Gs fl/LacZ mice; K 0.5 , substrate concentration at which process proceeds at 50% of maximum velocity; KO, knockout; MSO, methionine sulfoximine.…”

mentioning

confidence: 99%

Pivotal role of glutamine synthetase in ammonia detoxification

et al. 2016

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Glutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. Glutamine serves, with alanine, as a major nontoxic interorgan ammonia carrier. Elimination of hepatic GS expression in mice causes only mild hyperammonemia and hypoglutaminemia but a pronounced decrease in the whole-body muscle-to-fat ratio with increased myostatin expression in muscle. Using GS-knockout/liver and control mice and stepwise increments of enterally infused ammonia, we show that 35% of this ammonia is detoxified by hepatic GS and 35% by urea-cycle enzymes, while 30% is not cleared by the liver, independent of portal ammonia concentrations £ 2 mmol/L. Using both genetic (GSknockout/liver and GS-knockout/muscle) and pharmacological (methionine sulfoximine and dexamethasone) approaches to modulate GS activity, we further show that detoxification of stepwise increments of intravenously (jugular vein) infused ammonia is almost totally dependent on GS activity. Maximal ammonia-detoxifying capacity through either the enteral or the intravenous route is 160 lmol/hour in control mice. Using stable isotopes, we show that disposal of glutaminebound ammonia to urea (through mitochondrial glutaminase and carbamoylphosphate synthetase) depends on the rate of glutamine synthesis and increases from 7% in methionine sulfoximine-treated mice to 500% in dexamethasone-treated mice (control mice, 100%), without difference in total urea synthesis. Conclusions: Hepatic GS contributes to both enteral and systemic ammonia detoxification. Glutamine synthesis in the periphery (including that in pericentral hepatocytes) and glutamine catabolism in (periportal) hepatocytes represents the high-affinity ammonia-detoxifying system of the body. The dependence of glutamine-bound ammonia disposal to urea on the rate of glutamine synthesis suggests that enhancing peripheral glutamine synthesis is a promising strategy to treat hyperammonemia. Because total urea synthesis does not depend on glutamine synthesis, we hypothesize that glutamate dehydrogenase complements mitochondrial ammonia production. (HEPATOLOGY 2017;65:281-293). G lutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. (Note: NH 3 is protonated for 98% to NH 4 1 at physiological pH. We use the term "ammonia" to refer to the sum of NH 3 and NH 4 1 unless specified as either "NH 3 " or "NH 41 .") Glutamine serves, with alanine, as a major nontoxic interorgan ammonia shuttle in the body (1) and as an aminomoiety donor for the synthesis of nucleotides, amino acids, amino-sugars, and oxidized nicotinamide adenine dinucleotide. Its intracellular turnover rate exceeds that of all other amino acids. GS deficiency causes only moderate hyperammonemia, but affected humans and mice suffer from encephalopathy and die neonatally. (2,3) GS is predominantly expressed in the nervous system, kidney, and liver, that is, in established glutamine-consuming organs, (4)(5)(6) whereas skeletal muscle, with a much lower expression but large mass, is considered the main net ...

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Natural course of glutamine synthetase deficiency in a 3 year old patient

Cited by 51 publications

References 10 publications

Translational potential of astrocytes in brain disorders

Translational potential of astrocytes in brain disorders

Amino acid synthesis deficiencies

Pivotal role of glutamine synthetase in ammonia detoxification

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