Alternative titles; symbols
SNOMEDCT: 57119000; ORPHA: 927; DO: 0112258;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.31 | N-acetylglutamate synthase deficiency | 237310 | Autosomal recessive | 3 | NAGS | 608300 |
A number sign (#) is used with this entry because N-acetylglutamate synthase deficiency (NAGSD) is caused by homozygous or compound heterozygous mutation in the NAGS gene (608300) on chromosome 17q21.
N-acetylglutamate synthase deficiency (NAGSD) is an autosomal recessive disorder of the urea cycle. The clinical and biochemical features of the disorder are indistinguishable from carbamoyl phosphate synthase I deficiency (237300), since the CPS1 enzyme (608307) has an absolute requirement for NAGS (Caldovic et al., 2007).
Bachmann et al. (1981) reported hyperammonemia due to deficiency of N-acetylglutamate synthetase in a newborn male and presumably in 2 of his sibs who died in the neonatal period. Autopsy in 1 of the sibs suggested hyperammonemia. The authors suggested that a deficiency of N-acetylglutamate synthetase should be considered in cases of hyperammonemia without increased excretion of orotic acid. The patient was successfully treated with benzoate, and later with carbamylglutamate and arginine. Reduction of the dose of carbamylglutamate again led to hyperammonemia.
Bachmann et al. (1988) reported an additional patient who presented at the age of 6 days with somnolence, tachypnea, and feeding difficulties. Hyperammonemia with high plasma concentrations of alanine and glutamine was present. Organic acid and orotic acid excretion was normal. Therapy with sodium benzoate, arginine hydrochloride, glucose, and insulin as well as peritoneal dialysis initially improved the hyperammonemia. Nonetheless, the child died at 8 days of age. N-acetylglutamate synthetase deficiency was documented on a postmortem hepatic liver biopsy sample.
Elpeleg et al. (1990) described a late-onset form of N-acetylglutamate synthetase deficiency. Autosomal recessive inheritance was strongly supported by the occurrence of 3 affected individuals in 2 sibships, each derived from first-cousin parents. Schubiger et al. (1991) provided follow-up of one of the patients.
Burlina et al. (1992) described a patient with NAGS deficiency who had a severe neurologic presentation characterized by uncontrollable movements, developmental delay, visual impairment, failure to thrive, and hyperammonemia precipitated by the introduction of high-protein diet or febrile illness.
Plecko et al. (1998) described a girl who presented with recurrent episodes of vomiting, psychotic behavior, and confusion during puberty until the diagnosis of partial NAGS deficiency was established at the age of 13 years. She had suffered 1 prior episode of acute vomiting, lethargy, and somnolence at the age of 13 months, and from childhood on had an aversion to high protein food. Orotic acid as well as orotidine was not increased, and amino acid analysis was inconclusive, requiring liver biopsy to establish the diagnosis. Oral substitution of the missing metabolic product by its analog N-carbamylglutamate improved ammonia detoxification and thus protein tolerance. Plecko et al. (1998) stated that only 7 patients with NAGS deficiency had been reported to that time.
Reye syndrome (228100) is characterized by acute encephalopathy, fatty degeneration of the viscera, and impaired liver function often accompanied by hypoglycemia and hyperammonemia. Forget et al. (1999) described a patient presenting with a Reye-like illness following valproate medication, which turned out to be associated with a partial NAGS deficiency.
Batshaw et al. (2014) reported the results of an analysis of 614 patients with urea cycle disorders (UCDs) enrolled in the Urea Cycle Disorders Consortium's longitudinal study protocol. NAGS deficiency occurred in 3 patients (0.5%), all with a late-onset form.
Bachmann et al. (1981) reported successful treatment of NAGS deficiency with carbamylglutamate.
Guffon et al. (1995) reported a neonatal case of hyperammonemic coma in which protein restriction and supply of essential amino acids, in combination with oral benzoate and arginine, did not result in normalization of plasma ammonia. However, a carbamylglutamate test performed at 25 days of life showed normalization of plasma ammonia. Treatment with carbamylglutamate was continued thereafter with normal somatic and neurologic development and good metabolic balance.
The transmission pattern of NAGSD in the families reported by Caldovic et al. (2003) and Haberle et al. (2003) was consistent with autosomal recessive inheritance.
In each of 2 patients with NAGS deficiency, Caldovic et al. (2003) identified a homozygous mutation in the NAGS gene (608300.0001-608300.0002). In 6 families with NAGS deficiency, Haberle et al. (2003) identified 7 mutations in the NAGS gene (608300.0002-608300.0008). In 5 families the affected individuals were apparently homozygous and in 1 doubly heterozygous. One of the patients displayed an atypically late onset of the disorder.
Caldovic et al. (2007) provided a report of 21 disease-associated mutations in the NAGS gene, including 16 previously reported mutations. Ten mutations were associated with acute neonatal hyperammonemia, whereas the remaining mutations were found in patients with late-onset disease. Mutations were distributed throughout the reading frame. Decreased enzyme activity ranged from less than 5% to about 74%.
Bachmann, C., Brandis, M., Weissenbarth-Riedel, E., Burghard, R., Colombo, J. P. N-acetylglutamate synthetase deficiency, a second patient. J. Inherit. Metab. Dis. 11: 191-193, 1988. [PubMed: 3139931] [Full Text: https://doi.org/10.1007/BF01799871]
Bachmann, C., Colombo, J. P., Jaggi, K. N-acetylglutamate synthetase (NAGS) deficiency: diagnosis, clinical observations and treatment. Adv. Exp. Med. Biol. 153: 39-45, 1982. [PubMed: 7164912] [Full Text: https://doi.org/10.1007/978-1-4757-6903-6_6]
Bachmann, C., Krahenbuhl, S., Colombo, J. P., Schubiger, G., Jaggi, K. H., Tonz, O. N-acetylglutamate synthetase deficiency: a disorder of ammonia detoxication. (Letter) New Eng. J. Med. 304: 543 only, 1981. [PubMed: 7453791] [Full Text: https://doi.org/10.1056/NEJM198102263040918]
Batshaw, M. L., Tuchman, M., Summar, M., Seminara, J., Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Molec. Genet. Metab. 113: 127-130, 2014. [PubMed: 25135652] [Full Text: https://doi.org/10.1016/j.ymgme.2014.08.001]
Burlina, A. B., Bachmann, C., Wermuth, B., Bordugo, A., Ferrari, V., Colombo, J. P., Zacchello, F. Partial N-acetylglutamate synthetase deficiency: a new case with uncontrollable movement disorders. J. Inherit. Metab. Dis. 15: 395-398, 1992. [PubMed: 1405478] [Full Text: https://doi.org/10.1007/BF02435986]
Caldovic, L., Morizono, H., Pangiao, M. G., Cheng, S. F., Packman, S., Tuchman, M. Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum. Genet. 112: 364-368, 2003. [PubMed: 12594532] [Full Text: https://doi.org/10.1007/s00439-003-0909-5]
Caldovic, L., Morizono, H., Tuchman, M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum. Mutat. 28: 754-759, 2007. [PubMed: 17421020] [Full Text: https://doi.org/10.1002/humu.20518]
Elpeleg, O. N., Colombo, J. P., Amir, N., Bachmann, C., Hurvitz, H. Late-onset form of partial N-acetylglutamate synthetase deficiency. Europ. J. Pediat. 149: 634-636, 1990. [PubMed: 2373115] [Full Text: https://doi.org/10.1007/BF02034751]
Forget, P. P., van Oosterhout, M., Bakker, J. A., Wermuth, B., Vles, J. S. H., Spaapen, L. J. M. Partial N-acetyl-glutamate synthetase deficiency masquerading as a valproic acid-induced Reye-like syndrome. Acta Paediat. 88: 1409-1411, 1999. [PubMed: 10626533] [Full Text: https://doi.org/10.1080/080352599750030194]
Guffon, N., Vianey-Saban, C., Bourgeois, J., Rabier, D., Colombo, J. P., Guibaud, P. A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate. J. Inherit. Metab. Dis. 18: 61-65, 1995. [PubMed: 7623444] [Full Text: https://doi.org/10.1007/BF00711374]
Haberle, J., Schmidt, E., Pauli, S., Kreuder, J. G., Plecko, B., Galler, A., Wermuth, B., Harms, E., Koch, H. G. Mutation analysis in patients with N-acetylglutamate synthase deficiency. Hum. Mutat. 21: 593-597, 2003. [PubMed: 12754705] [Full Text: https://doi.org/10.1002/humu.10216]
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. Europ. J. Pediat. 157: 996-998, 1998. [PubMed: 9877039] [Full Text: https://doi.org/10.1007/s004310050985]
Schubiger, G., Bachmann, C., Barben, P., Colombo, J. P., Tonz, O., Schupbach, D. N-acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxication. Europ. J. Pediat. 150: 353-356, 1991. [PubMed: 2044610] [Full Text: https://doi.org/10.1007/BF01955939]