OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULAS AND STRUCTURES

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Carglumic Acid	1188-38-1	C6-H10-N2-O5
N-acetylglutamate	1188-37-1	C7-H11-N-O5

ANNOTATED BIBLIOGRAPHY

References updated: 10 October 2016

Abbreviation used for urea cycle enzyme deficiencies: N-acetylglutamate synthase (NAGS).

• Bachmann C, Krähenbühl S, Colombo JP, Schubiger G, Jaggi KH, Tönz O. N-acetylglutamate synthetase deficiency: a disorder of ammonia detoxication. N Engl J Med 1981; 304: 543. [PubMed: 7453791]

  ( Initial description of a newborn with hyperammonemia that could not be attributed to a known urea cycle defect, but was associated with lack of N-acetylglutamate synthase (NAGS), N-acetylglutamate being the activator of cabamylphosphate synthetase [CPS], the first enzyme in the urea cycle).
• Schubiger G, Bachmann C, Barben P, Colombo JP, Tönz O, Schüpbach D. N-acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxication. Eur J Pediatr 1991; 150: 353-6. [PubMed: 2044610]

  (Nine year follow up of a patient with NAGS deficiency [Bachman 1981] who was maintained on a protein restricted diet and oral N-carbamylglutamate, but who died during an episode of coma after seizures).
• Colombo JP. N-acetylglutamate synthetase (NAGS) deficiency. Adv Exp Med Biol 1994; 368: 135-43. [PubMed: 7741005]

  (Review of the pathogenesis, clinical features and potential therapies of NAGS deficiency which includes use of oral N-carbamylglutamate which is taken up by mitochondria and activates CPS-1 and urea cycle consumption of ammonia).
• Levrat V, Forest I, Fouilhoux A, Acquaviva C, Vianey-Saban C, Guffon N. Carglumic acid: an additional therapy in the treatment of organic acidurias with hyperammonemia? Orphanet J Rare Dis 2008; 3: 2. [PMC free article: PMC2262878] [PubMed: 18234091]

  (Two newborns with severe hyperammonemia were treated successfully with carglumic acid; one with methylmalonic and one propionic aciduria, both associated with decrease in NAGS).
• Thompson CA. Carglumic acid approved to treat genetic hyperammonemia. Am J Health Syst Pharm 2010; 67: 690. [PubMed: 20410539]

  (News report announcing approval of carglumic acid by the FDA and explaining its mechanism of action and clinical use).
• Kasapkara CS, Ezgu FS, Okur I, Tumer L, Biberoglu G, Hasanoglu A. N-carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia. Eur J Pediatr 2011; 170: 799-801. [PubMed: 21207059]

  (A newborn who developed severe hyperammonemia on the 3rd day of life was found to have isovaleric acidemia and was treated with a single dose of carglumic acid [150 mg/kg], with rapid decline in ammonia levels [568 to 72 µg/dL] within 6 hours and the child remained well thereafter on a protein restricted diet).
• Gramage Caro T, Vélez-Díaz-Pallarés M, Serna Pérez J, Bermejo Vicedo T. [Carglumic acid for treatment of valproic acid-induced hyperammonaemia in a paediatric patient]. Farm Hosp 2012; 36: 437-8. Spanish. [PubMed: 22858088]

  (A 30 month old boy with refractory epilepsy was treated with valproate for several months and developed hyperammonemia [165.9 µmol/L] with normal routine liver tests, and was treated with carglumic acid while slowly withdrawn from valproate, which was withdrawn with carglumic acid after 58 days with no subsequent increase in ammonia levels).
• Cartagena A, Prasad AN, Rupar CA, Strong M, Tuchman M, Ah Mew N, Prasad C. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. Can J Neurol Sci 2013; 40: 3-9. [PMC free article: PMC4131410] [PubMed: 23250120]

  (Review of the pathogenesis of NAGS and individual case report in a 38 year old man with long history of fluctuating neurologic symptoms who was found to have hyperammonemia [434 µmol/L] and treated successfully with long term carglumic acid).
• Abacan M, Boneh A. Use of carglumic acid in the treatment of hyperammonaemia during metabolic decompensation of patients with propionic acidaemia. Mol Genet Metab 2013; 109: 397-401. [PubMed: 23791308]

  (Three children with propionic acidemia with episodic bouts of hyperammonemia were treated with carglumic acid and had improvements in ammonia levels within 24 hours of starting treatment).
• Fernández Colomer B, Rekarte García S, García López JE, Pérez González C, Montes Granda M, Coto Cotallo GD. [Valproate-induced hyperammonemic encephalopathy in a neonate: treatment with carglumic acid]. An Pediatr (Barc) 2014; 81: 251-5. [PubMed: 24315420]

  (A 20 day old boy with subdural hematoma and seizures developed hyperammonemia within 2 days of starting valproate [398 µmol/L] and improved rapidly and remained normal after stopping valproate and administration of carnitine, carglumic acid and phenylbutyrate; no mention of adverse events).
• Kasapkara CS, Kanğın M, Taş FF, Topçu Y, Demir R, Ozbek MN. Unusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid. J Pediatr Neurosci 2013; 8: 250-2. [PMC free article: PMC3888049] [PubMed: 24470826]

  (Two boys, ages 1.5 and 15 years, developed hyperammonemia [189 and 283 µg/dL] and confusion while taking valproate for seizures, both responding rapidly without relapse after stopping valproate and administration of a single dose of carglumic acid [100 mg/kg]).
• van Karnebeek CD, Sly WS, Ross CJ, Salvarinova R, Yaplito-Lee J, Santra S, Shyr C, et al. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet 2014; 94: 453-61. [PMC free article: PMC3951944] [PubMed: 24530203]

  (Description of 4 children with early onset hyperammonemia who had deficiency of carbonic anhydrase VA, 3 of whom responded to carglumic acid with control of hyperammonemia).
• Lazier J, Lupichuk SM, Sosova I, Khan AA. Hyperammonemic encephalopathy in an adenocarcinoma patient managed with carglumic acid. Curr Oncol 2014; 21: e736-9. [PMC free article: PMC4189581] [PubMed: 25302046]

  (A 24 year old man with metastatic gastric carcinoma developed encephalopathy and hyperammonemia after treatment with cisplatin, epirubicin and capecitabine, and responded to carglumic acid therapy but relapsed on stopping and died in hyperammonemic coma 2 weeks later; genetic testing failed to show a urea cycle disorder or NAGS deficiency).
• Martín-Hernández E, Aldámiz-Echevarría L, Castejón-Ponce E, Pedrón-Giner C, Couce ML, Serrano-Nieto J, Pintos-Morell G, et al. Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases. Orphanet J Rare Dis 2014; 9: 187. [PMC free article: PMC4258263] [PubMed: 25433810]

  (Cross sectional analysis of 104 patients with urea cycle disorders from 98 families and 21 centers in Spain found most common form was ornithine transcarbamylase deficiency [64%], followed by type 1 citrullinemia [21%] and argininosuccinic aciduria [10%], most were treated with essential amino acid replacement, some with sodium benzoate or phenylbutyrate and one with carglumic acid [with NAGS deficiency]).
• Valayannopoulos V, Baruteau J, Delgado MB, Cano A, Couce ML, Del Toro M, Donati MA, et al. Carglumic acid enhances rapid ammonia detoxification in classical organic acidurias with a favourable risk-benefit profile: a retrospective observational study. Orphanet J Rare Dis 2016; 11: 32. [PMC free article: PMC4815113] [PubMed: 27030250]

  (Among 41 patients with organic acidurias who were treated during 48 episodes of hyperammonemia with carglumic acid for 1-15 [mean=5.5] days, all had prompt normalization of ammonia levels [median time to normal 1.5 days] and most adverse events were considered unrelated; no mention of ALT elevations or hepatotoxicity).
• Matoori S, Leroux JC. Recent advances in the treatment of hyperammonemia. Adv Drug Deliv Rev 2015; 90: 55-68. [PubMed: 25895618]

  (Review of the causes and treatments of hyperammonemia focusing upon newer agents such as rifaximin, sodium benzoate and phenylbutyrate; carglumic acid is indicated for the rare genetic defect of N-acetylglutamate synthetase deficiency, acting to replace NAG and activate the first enzyme of the urea cycle; no discussion of side effects except for bitter taste).