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.