Hyperammonemia via the NAGS Gene

Urea cycle defects are characterized by (1) hyperammonemia, (2) encephalopathy, and (3) respiratory alkalosis. Five clinical disorders have been described involving defective urea cycle enzymes: ornithine transcarbamolase deficiency (OMIM 311250), carbamoyl phosphate synthetase I deficiency (OMIM 237300), argininosuccinate synthetase deficiency (OMIM 215700), argininosuccinate lyase deficiency (OMIM 207900), and arginase deficiency (OMIM 207800). A sixth cause of hyperammonemia is N-acetlyglutamate synthase (NAGS) deficiency (OMIM 237310; Bachmann et al. N Eng J Med 304:543, 1981). N-acetylglutamate is an essential activating cofactor for Carbamoyl Phosphate Synthetase I (CPS1) and, therefore, clinical signs of CPS1 and NAGS deficiencies are indistinguishable. Like CPS1 deficiency, two clinical presentations of NAGS deficiency are recognized: an acute neonatal hyperammonemia form and a delayed onset form (Haberle et al. Hum Mut 21:593-597, 2003). NAGS deficiency also presents with irritability and hyperammonemia leading to coma and death if untreated. Successful treatment with N-carbamylglutamate (NCG) has been reported (Bachmann et al. 1981).

Hyperammonemia due to N-Acetylglutamate Synthase (NAGS) deficiency is an autosomal recessive disorder. NAGS mutations are distributed throughout the entire coding region except for the mitochondrial targeting signal encoded by exon 1 (Caldovic et al. Hum Mut 28:754-759, 2007). The majority of mutations are missense, however nonsense and splice site mutations are known as well. A regulatory mutation (c.-3064C>A) in an enhancer region 3kb upstream of the NAGS coding sequence has also been identified, and patients homozygous for c.-3064C>A responded well to NCG treatment, showing enhanced ureagenesis (Heibel et al, Hum Mutat. 32:1153-60, 2011).

Deficiency of N-Acetylglutamate Synthase is a rare cause of hyperammonemia. Approximately 20 causative mutations have been reported worldwide (Caldovic et al. Hum Mutat 28:754-759, 2007). Mutations in NAGS should be considered in patients with a high index of suspicion who have normal CPS1 enzyme activity and/or normal CPS1 gene sequencing results.

No gross deletions or duplications in NAGS have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the NAGS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Testing also includes the regulatory region surrounding the c.-3064C>A variant.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).