Late-Onset N-Acetylglutamate Synthase Deficiency: Report of a Paradigmatic Adult Case Presenting with Headaches and Review of the Literature

Abstract

N-acetylglutamate synthase deficiency (NAGSD) is an extremely rare urea cycle disorder (UCD) with few adult cases so far described. Diagnosis of late-onset presentations is difficult and delayed treatment may increase the risk of severe hyperammonemia. We describe a 52-year-old woman with recurrent headaches who experienced an acute onset of NAGSD. As very few papers focus on headaches in UCDs, we also report a literature review of types and pathophysiologic mechanisms of UCD-related headaches. In our case, headaches had been present since puberty (3–4 days a week) and were often accompanied by nausea, vomiting, or behavioural changes. Despite three previous episodes of altered consciousness, ammonia was measured for the first time at 52 years and levels were increased. Identification of the new homozygous c.344C>T (p.Ala115Val) NAGS variant allowed the definite diagnosis of NAGSD. Bioinformatic analysis suggested that an order/disorder alteration of the mutated form could affect the arginine-binding site, resulting in poor enzyme activation and late-onset presentation. After optimized treatment for NAGSD, ammonia and amino acid levels were constantly normal and prevented other headache bouts. The manuscript underlies that headache may be the presenting symptom of UCDs and provides clues for the rapid diagnosis and treatment of late-onset NAGSD.

Noncoding sequence variants define a novel regulatory element in the first intron of the N ‐acetylglutamate synthase gene

“…Two sequence variants found in the first intron define a new NAGS regulatory element that binds and implicates transcription factors HNF4α and RXRα in the regulation of NAGS expression and ureagenesis. The four noncoding sequence variants that cause NAGSD reported here bring the total number of noncoding, disease‐causing NAGS variants to seven, which is almost 14% of deleterious NAGS sequence variants (Al Kaabi & El‐Hattab, 2016; Bijarnia‐Mahay et al, 2018; Cartagena et al, 2013; Cavicchi et al, 2018; Heibel et al, 2011; van de Logt et al, 2017; Williams et al, 2018). This underscores the importance of analyzing both coding and noncoding regions of the NAGS gene, which is amenable to both Sanger and next‐generation sequencing, for the presence of disease‐causing sequence variants.…”

Gene delivery corrects N-acetylglutamate synthase deficiency and enables insights in the physiological impact of L-arginine activation of N-acetylglutamate synthase

“…The two groups of Nags −/− mice expressing E354A mutant mNAGS had 1.3 and 1.6-fold higher concentration of plasma ammonia than the Nags −/− mice expressing wild type mNAGS. Although these increases in the concentration of plasma ammonia may seem small they are comparable increases in plasma ammonia concentrations that trigger symptoms of hyperammonemia in patients with NAGS deficiency 35,36 . www.nature.com/scientificreports/ Although doubling of human and mouse NAGS enzymatic activities in the presence of L-arginine 37 may appear insufficient to accommodate the need for increased ureagenesis in situations of increased ammonia load, increased production of NAG is amplified through continuous activation of additional CPS1 molecules.…”

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

“…In later onset cases, vomiting, behavioral changes, ataxia, lethargy, decreased level of consciousness, seizures, and hypotonia were common. A variety of physical stressors have been implicated as triggers in post-neonatal cases, and the symptoms can be episodic, especially if the patient normalizes ammonia levels by self-restricting protein intake [2,11,13]. Given that the presentation is non-specific, ammonia level assessment in individuals with depressed consciousness or unexplained encephalopathy has been suggested [20,40].…”

“…Common presenting symptoms in later onset cases included vomiting, confusion or disorientation, ataxia, lethargy, decreased level of consciousness, seizures, and hypotonia. In some cases of later onset NAGS deficiency, there was a history of avoidance of highprotein foods [11][12][13][14]. In addition to elevated ammonia, the most commonly-reported biomarkers in blood were elevated glutamine and alanine, decreased citrulline, and respiratory alkalosis.…”

“…Suspected triggers in post-neonatal cases that were reported in the literature included febrile illness [14][15][16], pregnancy and delivery [17][18][19], a high-protein meal [11,20], the introduction of cow milk [21], low caloric intake and dehydration [13], an upper respiratory illness [22], a vehicle accident [23], and a fractured pelvis [24].…”