Presentation and management of N-acetylglutamate synthase deficiency: a review of the literature

Abstract

Background N-Acetylglutamate synthase (NAGS) deficiency is an extremely rare autosomal recessive metabolic disorder affecting the urea cycle, leading to episodes of hyperammonemia which can cause significant morbidity and mortality. Since its recognition in 1981, NAGS deficiency has been treated with carbamylglutamate with or without other measures (nutritional, ammonia scavengers, dialytic, etc.). We conducted a systematic literature review of NAGS deficiency to summarize current knowledge around presentation and management. Methods Case reports and case series were identified using the Medline database, as well as references from other articles and a general internet search. Clinical data related to presentation and management were abstracted by two reviewers. Results In total, 98 cases of NAGS deficiency from 79 families, in 48 articles or abstracts were identified. Of these, 1 was diagnosed prenatally, 57 were neonatal cases, 34 were post-neonatal, and 6 did not specify age at presentation or were asymptomatic at diagnosis. Twenty-one cases had relevant family history. We summarize triggers of hyperammonemic episodes, diagnosis, clinical signs and symptoms, and management strategies. DNA testing is the preferred method of diagnosis, although therapeutic trials to assess response of ammonia levels to carbamylglutamate may also be helpful. Management usually consists of treatment with carbamylglutamate, although the reported maintenance dose varied across case reports. Protein restriction was sometimes used in conjunction with carbamylglutamate. Supplementation with citrulline, arginine, and sodium benzoate also were reported. Conclusions Presentation of NAGS deficiency varies by age and symptoms. In addition, both diagnosis and management have evolved over time and vary across clinics. Prompt recognition and appropriate treatment of NAGS deficiency with carbamylglutamate may improve outcomes of affected individuals. Further research is needed to assess the roles of protein restriction and supplements in the treatment of NAGS deficiency, especially during times of illness or lack of access to carbamylglutamate.

N‐acetylglutamate synthase deficiency with associated 3‐methylglutaconic aciduria: A case report

“…NAGS deficiency is the rarest of the urea cycle disorders, with only approximately 100 cases reported to‐date. 2 The majority of diagnosed patients have presented with neonatal‐onset disease, manifesting with poor feeding, vomiting, lethargy, tone abnormalities, tachypnoea and seizures. 7 Similar to the other urea cycle disorders, late‐onset forms have also been reported.…”

“…NAGS deficiency can be amenable to treatment with carglumic acid, and so the distinction also carries therapeutic significance. 2 …”

“…NAGS deficiency can be amenable to treatment with carglumic acid, and so the distinction also carries therapeutic significance. 2 Previously 3-methylglutaconic aciduria (3-MGA) had been reported in many cases of neonatal-onset CPS1 deficiency, 3,4 as well as patients with ornithine transcarbamylase (OTC) deficiency and argininosuccinate lyase (ASL) deficiency, 5 but not in NAGS deficiency. 4 The 3-MGA is often a marker of mitochondrial dysfunction, either primary or secondary, 6 and occurred in these cases with concomitant elevations in serum lactate.…”

“…Distinguishing between NAGS deficiency and CPS1 deficiency (OMIM #237300) is difficult from a biochemical perspective, as both have hyperammonaemia, low citrulline, and normal orotate: hence, molecular testing is often required. NAGS deficiency can be amenable to treatment with carglumic acid, and so the distinction also carries therapeutic significance 2 …”

Application of Next Generation Sequencing Genetic Studies of Urea Cycle Disorders

“…Năm 2016, số liệu ghi nhận 59 bệnh nhân mắc bệnh thiếu hụt NAGS, ở 45 gia đình, đã được xác nhận ở mức độ di truyền phân tử [25]. Năm 2020, từ 48 bài báo được công bố, Kennenson và Singh (2020) đã thống kê được 98 trường hợp mắc bệnh ở 79 gia đình [26]. Đến nay, 83 đột biến gây bệnh trên gen NAGS1 được cơ sở dữ liệu ClinVar ghi nhận.…”