Unusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid

Kasapkara, Çiğdem Seher; Kanğın, Murat; Taş, Funda Feryal; Topçu, Yasemin; Demir, Remezan; Özbek, Mehmet Nuri

doi:10.4103/1817-1745.123697

Cited by 12 publications

(18 citation statements)

References 12 publications

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“…Arginine, furosemide, mannitol, carglumic acid, lactulose, neomycin, protein restriction, hemodialysis are used for the treatment of hyperammonaemia in patients with VHE in previous reports (3,13). Underlying urea cycle enzyme deficiencies creates predispositions for VHE (14).…”

Section: Discussionmentioning

confidence: 99%

Case: Valproat-Induced Hyperammonemic Encephalopathy

Aksu

Arhan

Demir

et al. 2016

GMJ

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Valproate induced hyperammonemic encephalopathy (VHE) is a severe adverse effect of medicine. An epileptic patient with an acute hyperammonemia after the addition of valproic acid to his treatment presented with acute mental status changes consistent with encephalopathy. Notably, plasma ammonia level was 2 times of the upper limit, despite normal liver function tests. Plasma valproic acid level was in the therapeutic range. His symptoms resolved with the discontinuation of valproic acid and Lcarnitine administration. We discuss this case and review the possible mechanisms of valproic acid-associated encephalopathy and the efficacy of L-carnitine.

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Section: Discussionmentioning

confidence: 99%

Case: Valproat-Induced Hyperammonemic Encephalopathy

Aksu

Arhan

Demir

et al. 2016

GMJ

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“…This well-known adverse effect of valproic acid is caused by inhibition of NAGS by the drug metabolite, valproyl-CoA [63]. Hyperammonemia caused by short- or long-term use of valproic acid in children has been successfully managed with NCG [64]. …”

Section: Other Conditions and Future Potentialmentioning

confidence: 99%

“…In addition to its use for IEM, NCG may be useful to treat secondary NAGS deficiency caused by medications such as valproate or chemotherapeutics [64,68]. Additional indications for the use of this drug may arise as research into causes of drug-induced hyperammonemia advances.…”

Section: Five-year Viewmentioning

confidence: 99%

Efficacy of N-carbamoyl-L-glutamic acid for the treatment of inherited metabolic disorders

Chapel-Crespo

Diaz

Oishi

2016

Expert Review of Endocrinology & Metabolism

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Introduction N-carbamoyl-L-glutamic acid (NCG) is a synthetic analogue of N-acetyl glutamate (NAG) that works effectively as a cofactor for carbamoyl phosphate synthase 1 and enhances ureagenesis by activating the urea cycle. NCG (brand name, Carbaglu) was recently approved by the United States Food and Drug Administration (US FDA) for the management of NAGS deficiency and by the European Medicines Agency (EMA) for the treatment of NAGS deficiency as well as for the treatment of hyperammonenia in propionic, methylmalonic and isovaleric acidemias in Europe. Areas covered The history, mechanism of action, and efficacy of this new drug are described. Moreover, clinical utility of NCG in a variety of inborn errors of metabolism with secondary NAGS deficiency is discussed. Expert commentary NCG has favorable pharmacological features including better bioavailability compared to NAG. The clinical use of NCG has proven to be so effective as to make dietary protein restriction unnecessary for patients with NAGS deficiency. It has been also demonstrated to be effective for hyperammonemia secondary to other types of inborn errors of metabolism. NCG may have additional therapeutic potential in conditions such as hepatic hyperammonemic encephalopathy secondary to chemotherapies or other liver pathology.

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“…Even though in vitro , NCG has less than a tenth of the affinity to CPS1 than NAG [8] and activates CPS1 at only about 60% ( V max ) compared to NAG, patients with NAGS deficiency respond remarkably well to NCG, as evidenced by normalized blood ammonia and restoration of ureagenesis [9–11]. NCG supplementation has also been used successfully in other conditions with hyperammonemia, particularly for the conditions with hypothesized reductions in NAG levels, such as organic acidemias (propionic acidemia [12–19], methylmalonic acidemia [14,20–22] and isovaleric acidemia [23], hyperinsulinism hyperammonemia (HIHA) syndrome [24–26] and valproate-induced hyperammonemia [27–29]). NCG was also used successfully to treat the hyperammonemia caused by mitochondrial carbonic anhydrase VA deficiency [30].…”

Section: Introductionmentioning

confidence: 99%

Precision medicine in rare disease: Mechanisms of disparate effects of N -carbamyl- l -glutamate on mutant CPS1 enzymes

Shi

Zhao

Mew

et al. 2017

Molecular Genetics and Metabolism

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This study documents the disparate therapeutic effect of N-carbamyl-L-glutamate (NCG) in the activation of two different disease-causing mutants of carbamyl phosphate synthetase 1 (CPS1). We investigated the effects of NCG on purified recombinant wild-type (WT) mouse CPS1 and its human corresponding E1034G (increased ureagenesis on NCG) and M792I (decreased ureagenesis on NCG) mutants. NCG activates WT CPS1 sub-optimally compared to NAG. Similar to NAG, NCG, in combination with MgATP, stabilizes the enzyme, but competes with NAG binding to the enzyme. NCG supplementation activates available E1034G mutant CPS1 molecules not bound to NAG enhancing ureagenesis. Conversely, NCG competes with NAG binding to the scarce M792I mutant enzyme further decreasing residual ureagenesis. These results correlate with the respective patient’s response to NCG. Particular caution should be taken in the administration of NCG to patients with hyperammonemia before their molecular bases of their urea cycle disorders is known.

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Unusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid

Cited by 12 publications

References 12 publications

Case: Valproat-Induced Hyperammonemic Encephalopathy

Case: Valproat-Induced Hyperammonemic Encephalopathy

Efficacy of N-carbamoyl-L-glutamic acid for the treatment of inherited metabolic disorders

Precision medicine in rare disease: Mechanisms of disparate effects of N -carbamyl- l -glutamate on mutant CPS1 enzymes

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