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Open AccessCase Report
Int. J. Mol. Sci. 2018, 19(2), 345; doi:10.3390/ijms19020345

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

1
Molecular and Cell Biology Laboratory of Neurometabolic Diseases, Neuroscience Department, Meyer Children’s Hospital, 50139 Florence, Italy
2
Structural Biology Researcher Center, VIB, Vrije Universiteit Brussel, 1050 Brussels, Belgium
3
Neurology Unit, Santa Maria della Misericordia Hospital, 06123 Perugia, Italy
4
Medical Genetics Unit, Santa Maria della Misericordia Hospital, 06123 Perugia, Italy
5
Metabolic and Muscular Unit, Neuroscience Department, Meyer Children’s Hospital, 50139 Florence, Italy
6
Newborn Screening, Biochemistry and Pharmacology Laboratory, Neuroscience Department, Meyer Children’s Hospital, 50139 Florence, Italy
7
Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy
8
Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139 Florence, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 4 January 2018 / Revised: 17 January 2018 / Accepted: 18 January 2018 / Published: 24 January 2018
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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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. View Full-Text
Keywords: N-acetylglutamate synthase deficiency (NAGSD); NAGS gene mutations; N-carbamylglutamate (NCG); urea cycle disorders (UCDs); late-onset UCDs; hyperammonemic encephalopathy; headaches N-acetylglutamate synthase deficiency (NAGSD); NAGS gene mutations; N-carbamylglutamate (NCG); urea cycle disorders (UCDs); late-onset UCDs; hyperammonemic encephalopathy; headaches
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Cavicchi, C.; Chilleri, C.; Fioravanti, A.; Ferri, L.; Ripandelli, F.; Costa, C.; Calabresi, P.; Prontera, P.; Pochiero, F.; Pasquini, E.; Funghini, S.; la Marca, G.; Donati, M.A.; Morrone, A. Late-Onset N-Acetylglutamate Synthase Deficiency: Report of a Paradigmatic Adult Case Presenting with Headaches and Review of the Literature. Int. J. Mol. Sci. 2018, 19, 345.

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