Skip to main content Accessibility help

Recurrent Encephalopathy: NAGS (N-Acetylglutamate Synthase) Deficiency in Adults

  • A. Cartagena (a1), A.N. Prasad (a1) (a2) (a3), C.A. Rupar (a4), M. Strong (a1), M. Tuchman (a5), N. Ah Mew (a6) and C. Prasad (a2) (a3)...


N-acetyl-glutamate synthase (NAGS) deficiency is a rare autosomal recessive urea cycle disorder (UCD) that uncommonly presents in adulthood. Adult presentations of UCDs include; confusional episodes, neuropsychiatric symptoms and encephalopathy. To date, there have been no detailed neurological descriptions of an adult onset presentation of NAGS deficiency. In this review we examine the clinical presentation and management of UCDs with an emphasis on NAGS deficiency. An illustrative case is provided. Plasma ammonia levels should be measured in all adult patients with unexplained encephalopathy, as treatment can be potentially life-saving. Availability of N-carbamylglutamate (NCG; carglumic acid) has made protein restriction largely unnecessary in treatment regimens currently employed. Genetic counselling remains an essential component of management of NAGS.

    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Recurrent Encephalopathy: NAGS (N-Acetylglutamate Synthase) Deficiency in Adults
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Recurrent Encephalopathy: NAGS (N-Acetylglutamate Synthase) Deficiency in Adults
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Recurrent Encephalopathy: NAGS (N-Acetylglutamate Synthase) Deficiency in Adults
      Available formats


Corresponding author

Children's Hospital, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, N6C 2V5, Canada, Email:


Hide All
1. Brusilow, SW. Urea cycle disorders: clinical paradigm of hyperammonemic encephalopathy. Prog Liver Dis. 1995;13:293309.
2. Caldovic, L, Morizono, H, Panglao, MG, et al. Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles. Hum Mutat. 2005;25:293–8.
3. Caldovic, L, Morizono, H, Tuchman, M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. 2007;28:754–9.
4. Brusilow, SW, Maestri, NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996;43:127–70.
5. Altarescu, G, Brooks, B, Eldar-Geva, T, et al. Polar body-based preimplantation genetic diagnosis for N-acetylglutamate synthase deficiency. Fetal Diagn Ther. 2008;24:170–6.
6. Sniderman King, L, Singh, RH, Rhead, WJ, Smith, W, Lee, B, Summar, ML. Genetic counseling issues in urea cycle disorders. Crit Care Clin. 2005;21:S37–44.
7. Kamoun, P, Fensom, AH, Shin, YS, et al. Prenatal diagnosis of the urea cycle diseases: a survey of the European cases. Am J Med Genet. 1995;55:247–50.
8. Butterworth, RF. Effects of hyperammonaemia on brain function. J Inherit Metab Dis. 1998;21 Suppl 1:620.
9. Tuchman, M, Lee, B, Lichter-Konecki, U, et al. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008;94:397402.
10. Tuchman, M, Yudkoff, M. Blood levels of ammonia and nitrogen scavenging amino acids in patients with inherited hyperammonemia. Mol Genet Metab. 1999;66:1015.
11. Gropman, A. Brain imaging in urea cycle disorders. Mol Genet Metab 2010;100 Suppl 1:S2030.
12. Batshaw, ML, Painter, MJ, Sproul, GT, Schafer, IA, Thomas, GH, Brusilow, S. Therapy of urea cycle enzymopathies: three case studies. Johns Hopkins Med J. 1981;148:3440.
13. Batshaw, ML, MacArthur, RB, Tuchman, M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr. 2001;138:S4654; discussion S54–5.
14. Ah Mew, N, McCarter, R, Daikhin, Y, Nissim, I, Yudkoff, M, Tuchman, M. N-carbamylglutamate augments ureagenesis and reduces ammonia and glutamine in propionic acidemia. Pediatrics. 2010;126:e208–14.
15. Ah Mew, N, Payan, I, Daikhin, Y, Nissim, I, Tuchman, M, Yudkoff, M. Effects of a single dose of N-carbamylglutamate on the rate of ureagenesis. Mol Genet Metab. 2009;98:325–30.
16. Daniotti, M, la Marca, G, Fiorini, P, Filippi, L. New developments in the treatment of hyperammonemia: emerging use of carglumic acid. Int J Gen Med. 2011;4:21–8.
17. Guffon, N, Vianey-Saban, C, Bourgeois, J, Rabier, D, Colombo, JP, Guibaud, P. A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate. J Inherit Metab Dis. 1995;18:61–5.
18. Caldovic, L, Morizono, H, Daikhin, Y, et al. Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. J Pediatr. 2004;145:552–4.
19. Caldovic, L, Ah Mew, N, Shi, D, Morizono, H, Yudkoff, M, Tuchman, M. N-acetylglutamate synthase: structure, function and defects. Mol Genet Metab. 2010;100 Suppl 1:S1319.
20. Bachmann, C, Krahenbuhl, S, Colombo, JP, Schubiger, G, Jaggi, KH, Tonz, O. N-acetylglutamate synthetase deficiency: a disorder of ammonia detoxication. N Engl J Med. 1981;304:543.
21. Bachmann, C, Colombo, JP, Jaggi, K. N-acetylglutamate synthetase (NAGS) deficiency: diagnosis, clinical observations and treatment. Adv Exp Med Biol. 1982;153:3945.
22. Tuchman, M, Caldovic, L, Daikhin, Y, et al. N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers. Pediatr Res. 2008;64:213–17.
23. Haberle, J, Schmidt, E, Pauli, S, et al. Mutation analysis in patients with N-acetylglutamate synthase deficiency. Hum Mutat. 2003;21:593–7.
24. Rogozin, IB, Milanesi, L. Analysis of donor splice sites in different eukaryotic organisms. J Mol Evol. 1997;45:50–9.
25. Ah Mew, N, Caldovic, L. N-acetylglutamate synthase deficiency: an insight into the genetics, epidemiology, pathophysiology, and treatment. The Application of Clinical Genetics. 2011;4:127–35.
26. Haberle, J. Role of carglumic acid in the treatment of acute hyperammonemia due to N-acetylglutamate synthase deficiency. Ther Clin Risk Manag. 2011;7:327–32.
27. Batshaw, ML, Msall, M, Beaudet, AL, Trojak, J. Risk of serious illness in heterozygotes for ornithine transcarbamylase deficiency. J Pediatr. 1986;108:236–41.
28. Msall, M, Monahan, PS, Chapanis, N, Batshaw, ML. Cognitive development in children with inborn errors of urea synthesis. Acta Paediatr Jpn. 1988;30:435–41.
29. Uchino, T, Endo, F, Matsuda, I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis. 1998;21 Suppl 1:151–9.
30. Bachmann, C. Long-term outcome of patients with urea cycle disorders and the question of neonatal screening. Eur J Pediatr. 2003;162 Suppl 1:S2933.
31. Batshaw, ML, Roan, Y, Jung, AL, Rosenberg, LA, Brusilow, SW. Cerebral dysfunction in asymptomatic carriers of ornithine transcarbamylase deficiency. N Engl J Med. 1980;302:482–5.
32. Gyato, K, Wray, J, Huang, ZJ, Yudkoff, M, Batshaw, ML. Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol. 2004;55:80–6.
33. Gropman, AL, Batshaw, ML. Cognitive outcome in urea cycle disorders. Mol Genet Metab. 2004;81 Suppl 1:S5862.
34. Corne, C, Fouilhoux, A, Aquaviva, C, Besson, G. First French case of NAGS deficiency. 20 years of follow up. Mol Genet Metab. 2011;102:275.
35. Gessler, P, Buchal, P, Schwenk, HU, Wermuth, B. Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency. Eur J Pediatr. 2010;169:197–9.
36. Nordenstrom, A, Halldin, M, Hallberg, B, Alm, J. A trial with N-carbamylglutamate may not detect all patients with NAGS deficiency and neonatal onset. J Inherit Metab Dis. 2007;30:400.
37. Grody, WW, Chang, RJ, Panagiotis, NM, Matz, D, Cederbaum, SD. Menstrual cycle and gonadal steroid effects on symptomatic hyperammonaemia of urea-cycle-based and idiopathic aetiologies. J Inherit Metab Dis. 1994;17:566–74.
38. Guffon, N, Schiff, M, Cheillan, D, Wermuth, B, Haberle, J, Vianey-Saban, C. Neonatal hyperammonemia: the N-carbamoyl-Lglutamic acid test. J Pediatr. 2005;147:260–62.
39. Schmidt, E, Nuoffer, JM, Haberle, J, et al. Identification of novel mutations of the human N-acetylglutamate synthase gene and their functional investigation by expression studies. Biochim Biophys Acta. 2005;1740:54–9.
40. Belanger-Quintana, A, Martinez-Pardo, M, Garcia, MJ, et al. Hyperammonaemia as a cause of psychosis in an adolescent. Eur J Pediatr. 2003;162:773–5.
41. Heckmann, M, Wermuth, B, Haberle, J, Koch, HG, Gortner, L, Kreuder, JG. Misleading diagnosis of partial N-acetylglutamate synthase deficiency based on enzyme measurement corrected by mutation analysis. Acta Paediatr. 2005;94:121–4.
42. Haberle, J, Denecke, J, Schmidt, E, Koch, HG. Diagnosis of N-acetylglutamate synthase deficiency by use of cultured fibroblasts and avoidance of nonsense-mediated mRNA decay. J Inherit Metab Dis. 2003;26:601–5.
43. Caldovic, L, Morizono, H, Panglao, MG, Cheng, SF, Packman, S, Tuchman, M. Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum Genet. 2003;112:364–8.
44. Takanashi, J, Barkovich, AJ, Cheng, SF, et al. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. Am J Neuroradiol. 2003;24:1184–7.
45. Elpeleg, O, Shaag, A, Ben-Shalom, E, Schmid, T, Bachmann, C. N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy. Ann Neurol. 2002;52:845–9.
46. Forget, PP, van Oosterhout, M, Bakker, JA, Wermuth, B, Vles, JS, Spaapen, LJ. Partial N-acetyl-glutamate synthetase deficiency masquerading as a valproic acid-induced Reye-like syndrome. Acta Paediatr. 1999;88:1409–11.
47. Plecko, B, Erwa, W, Wermuth, B. Partial N-acetylglutamate synthetase deficiency in a 13-year-old girl: diagnosis and response to treatment with N-carbamylglutamate. Eur J Pediatr. 1998;157:996–8.
48. Morris, AA, Richmond, SW, Oddie, SJ, Pourfarzam, M, Worthington, V, Leonard, JV. N-acetylglutamate synthetase deficiency: favourable experience with carbamylglutamate. J Inherit Metab Dis. 1998;21:867–8.
49. Hinnie, J, Colombo, JP, Wermuth, B, Dryburgh, FJ. N-Acetylglutamate synthetase deficiency responding to carbamylglutamate. J Inherit Metab Dis. 1997;20:839–40.
50. Vockley, J, Vockley, CM, Lin, SP, et al. Normal N-acetylglutamate concentration measured in liver from a new patient with N-acetylglutamate synthetase deficiency: physiologic and biochemical implications. Biochem Med Metab Biol. 1992;47:3846.
51. Burlina, AB, Bachmann, C, Wermuth, B, et al. Partial N-acetylglutamate synthetase deficiency: a new case with uncontrollable movement disorders. J Inherit Metab Dis. 1992;15:395–8.
52. Pandya, AL, Koch, R, Hommes, FA, Williams, JC. N-acetylglutamate synthetase deficiency: clinical and laboratory observations. J Inherit Metab Dis. 1991;14:685–90.
53. Elpeleg, ON, Colombo, JP, Amir, N, Bachmann, C, Hurvitz, H. Late-onset form of partial N-acetylglutamate synthetase deficiency. Eur J Pediatr. 1990;149:634–6.
54. Bachmann, C, Brandis, M, Weissenbarth-Riedel, E, Burghard, R, Colombo, JP. N-acetylglutamate synthetase deficiency, a second patient. J Inherit Metab Dis. 1988;11:191–3.
55. Schubiger, G, Bachmann, C, Barben, P, Colombo, JP, Tonz, O, Schupbach, D. N-acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxication. Eur J Pediatr. 1991;150:353–6.

Recurrent Encephalopathy: NAGS (N-Acetylglutamate Synthase) Deficiency in Adults

  • A. Cartagena (a1), A.N. Prasad (a1) (a2) (a3), C.A. Rupar (a4), M. Strong (a1), M. Tuchman (a5), N. Ah Mew (a6) and C. Prasad (a2) (a3)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed