Long-term continuous N-carbamylglutamate treatment in frequently decompensated propionic acidemia: a case report

Albina Tummolo, Livio Melpignano, Antonella Carella, Anna Maria Di Mauro, Elvira Piccinno, Marcella Vendemiale, Federica Ortolani, Stefania Fedele, Maristella Masciopinto, Francesco Papadia, Albina Tummolo, Livio Melpignano, Antonella Carella, Anna Maria Di Mauro, Elvira Piccinno, Marcella Vendemiale, Federica Ortolani, Stefania Fedele, Maristella Masciopinto, Francesco Papadia

Abstract

Background: Propionic acidemia is a rare autosomal recessive inherited metabolic disorder that can inhibit the synthesis of N-acetylglutamate, the obligatory activator in urea synthesis, leading to hyperammonemia. N-carbamylglutamate ameliorates hyperammonemia in decompensated propionic acidemia. The effects of long-term continuous N-acetylglutamate administration in such patients are unknown. We report our clinical experience with continuous administration of N-acetylglutamate for 6 years in a patient with propionic acidemia frequently presenting with hyperammonemia.

Case presentation: A male Caucasian patient with frequently decompensated propionic acidemia and hyperammonemia was admitted 78 times for acute attacks during the first 9 years of his life. Continuous daily treatment with oral N-carbamylglutamate 100 mg/kg (50 mg/kg after 6 months) was initiated. During 6 years of treatment, he had a significant decrease in his mean plasma ammonia levels (75.7 μmol/L vs. 140.3 μmol/L before N-carbamylglutamate therapy, p < 0.005 [normal range 50-80 μmol/L]) and fewer acute episodes (two in 6 years).

Conclusion: Our results suggest a benefit of N-acetylglutamate administration outside the emergency setting. If this observation is confirmed, future studies should aim to optimize the dosage and explore effects of the dosage requirements on other drugs and on protein tolerance.

Keywords: Hyperammonemia; Long-term treatment; N-carbamylglutamate; Propionic acidemia.

Conflict of interest statement

Ethics approval and consent to participate

Ethic approval was obtained from the local ethics committee, and written consent to participate was obtained from the patient’s parents.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

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References

    1. Ogier de Baulny H, Dionisi-Vici C, Wendel U. Branched-chain organic acidurias/acidaemias. In: Saudubray JM, van den Berghe G, Walter JH, editors. Inborn metabolic diseases: diagnosis and management. 5. Berlin: Springer-Verlag; 2012. pp. 277–296.
    1. Coude FX, Sweetman L, Nyhan WL. Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria: a possible explanation for hyperammonemia in propionic and methylmalonic acidemia. J Clin Invest. 1979;64(6):1544–1551. doi: 10.1172/JCI109614.
    1. Dercksen M, IJlst L, Duran M, et al. Inhibition of N-acetylglutamate synthase by various monocarboxylic and dicarboxylic short-chain coenzyme A esters and the production of alternative glutamate esters. Biochim Biophys Acta. 2014;1842(12 Pt A):2510–2516. doi: 10.1016/j.bbadis.2013.04.027.
    1. Baumgartner MR, Hörster F, Dionisi-Vici C, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130. doi: 10.1186/s13023-014-0130-8.
    1. 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. doi: 10.1016/j.ymgme.2013.05.018.
    1. Pérez B, Desviat LR, Rodríguez-Pombo P, et al. Propionic acidemia: identification of twenty-four novel mutations in Europe and North America. Mol Genet Metab. 2003;78:59–67. doi: 10.1016/S1096-7192(02)00197-X.
    1. Filippi L, Gozzini E, Fiorini P, et al. N-carbamylglutamate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria. Neonatology. 2010;97:286–290. doi: 10.1159/000255168.
    1. Tummolo A, Favia V, Bellantuono R, et al. Successful early management of a female patient with a metabolic stroke due to ornithine transcarbamylase deficiency. Pediatr Emerg Care. 2013;29:656–658. doi: 10.1097/PEC.0b013e31828ec2b9.
    1. Burlina A, Cazzorla C, Zanonato E, et al. Clinical experience with N-carbamylglutamate in a single-centre cohort of patients with propionic and methylmalonic aciduria. Mol Genet Metab Rep. 2016;8:34–40. doi: 10.1016/j.ymgmr.2016.06.007.
    1. Valayannopoulos V, Baruteau J, Delgado MB, 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. doi: 10.1186/s13023-016-0406-2.
    1. Yap S, Leong HY, Abdul Aziz F, et al. N-carbamylglutamate is an effective treatment for acute neonatal hyperammonaemia in a patient with methylmalonic aciduria. Neonatology. 2016;109:303–307. doi: 10.1159/000443630.
    1. Ierardi-Curto L, Kaplan P, Saitta S, et al. The glutamine paradox in a neonate with propionic acidaemia and severe hyperammonaemia. J Inherit Metab Dis. 2000;23:85–86. doi: 10.1023/A:1005659132147.
    1. Filipowicz HR, Ernst SL, Ashurst CL, et al. Metabolic changes associated with hyperammonemia in patients with propionic acidemia. Mol Genet Metab. 2006;88:123–130. doi: 10.1016/j.ymgme.2005.11.016.
    1. Corbeel L, Tada K, Colombo JP, et al. Methylmalonic acidaemia and nonketotic hyperglycinaemia: clinical and biochemical aspects. Arch Dis Child. 1975;50:103–109. doi: 10.1136/adc.50.2.103.
    1. Kølvraa S. Inhibition of the glycine cleavage system by branched-chain amino acid metabolites. Pediatr Res. 1979;13:889–893. doi: 10.1203/00006450-197908000-00004.
    1. Hayasaka K, Narisawa K, Satoh T, et al. Glycine cleavage system in ketotic hyperglycinemia: a reduction of H-protein activity. Pediatr Res. 1982;16:5–7. doi: 10.1203/00006450-198201001-00002.

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