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

Published online by Cambridge University Press:  23 September 2014

A. Cartagena ,
A.N. Prasad ,
C.A. Rupar ,
M. Strong ,
M. Tuchman ,
N. Ah Mew  and
C. Prasad
A. Cartagena
Affiliation:
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
A.N. Prasad
Affiliation:
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada Paediatrics, University of Western Ontario, London, Ontario, Canada Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada
C.A. Rupar
Affiliation:
Biochemistry, University of Western Ontario, London, Ontario, Canada
M. Strong
Affiliation:
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
M. Tuchman
Affiliation:
Center for Genetic Medicine Research, Children's Research Institute, Children's National Medical Center, Washington DC, USA
N. Ah Mew
Affiliation:
Center for Clinical an Community Research, Children's Research Institute, Children's National Medical Center, Washington DC, USA
C. Prasad*
Affiliation:
Paediatrics, University of Western Ontario, London, Ontario, Canada Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada
*
Children's Hospital, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, N6C 2V5, Canada, Email: Chitra.Prasad@lhsc.on.ca
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Abstract:

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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.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 40 , Issue 1 , January 2013 , pp. 3 - 9
Copyright
Copyright © The Canadian Journal of Neurological 2013

References

1. Brusilow, SW. Urea cycle disorders: clinical paradigm of hyperammonemic encephalopathy. Prog Liver Dis. 1995;13:293–309.Google Scholar
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.Google Scholar
3. Caldovic, L, Morizono, H, Tuchman, M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. 2007;28:754–9.Google Scholar
4. Brusilow, SW, Maestri, NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996;43:127–70.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
8. Butterworth, RF. Effects of hyperammonaemia on brain function. J Inherit Metab Dis. 1998;21 Suppl 1:6–20.Google Scholar
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;94:397–402.CrossRefGoogle ScholarPubMed
10. Tuchman, M, Yudkoff, M. Blood levels of ammonia and nitrogen scavenging amino acids in patients with inherited hyperammonemia. Mol Genet Metab. 1999;66:10–15.Google Scholar
11. Gropman, A. Brain imaging in urea cycle disorders. Mol Genet Metab 2010;100 Suppl 1:S20–30.Google Scholar
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;148:34–40.Google Scholar
13. Batshaw, ML, MacArthur, RB, Tuchman, M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr. 2001;138:S46–54; discussion S54–5.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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.Google Scholar
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:S13–19.Google Scholar
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.Google Scholar
21. Bachmann, C, Colombo, JP, Jaggi, K. N-acetylglutamate synthetase (NAGS) deficiency: diagnosis, clinical observations and treatment. Adv Exp Med Biol. 1982;153:39–45.CrossRefGoogle ScholarPubMed
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.Google Scholar
23. Haberle, J, Schmidt, E, Pauli, S, et al. Mutation analysis in patients with N-acetylglutamate synthase deficiency. Hum Mutat. 2003;21:593–7.Google Scholar
24. Rogozin, IB, Milanesi, L. Analysis of donor splice sites in different eukaryotic organisms. J Mol Evol. 1997;45:50–9.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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:S29–33.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
33. Gropman, AL, Batshaw, ML. Cognitive outcome in urea cycle disorders. Mol Genet Metab. 2004;81 Suppl 1:S58–62.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google ScholarPubMed
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
49. Hinnie, J, Colombo, JP, Wermuth, B, Dryburgh, FJ. N-Acetylglutamate synthetase deficiency responding to carbamylglutamate. J Inherit Metab Dis. 1997;20:839–40.CrossRefGoogle ScholarPubMed
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;47:38–46.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar