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Int J Mol Sci. 2018 Jan 24;19(2). pii: E345. doi: 10.3390/ijms19020345.

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

Author information

1
Molecular and Cell Biology Laboratory of Neurometabolic Diseases, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy. catia.cavicchi@meyer.it.
2
Molecular and Cell Biology Laboratory of Neurometabolic Diseases, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy. chiara.chilleri@meyer.it.
3
Structural Biology Researcher Center, VIB, Vrije Universiteit Brussel, 1050 Brussels, Belgium. Antonella.Fioravanti@vub.be.
4
Molecular and Cell Biology Laboratory of Neurometabolic Diseases, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy. lorenzo.ferri@meyer.it.
5
Neurology Unit, Santa Maria della Misericordia Hospital, 06123 Perugia, Italy. fra.ripandelli@gmail.com.
6
Neurology Unit, Santa Maria della Misericordia Hospital, 06123 Perugia, Italy. cinzia.costa@unipg.it.
7
Neurology Unit, Santa Maria della Misericordia Hospital, 06123 Perugia, Italy. paolo.calabresi@unipg.it.
8
Medical Genetics Unit, Santa Maria della Misericordia Hospital, 06123 Perugia, Italy. pprontera@hotmail.com.
9
Metabolic and Muscular Unit, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy. francesca.pochiero@meyer.it.
10
Metabolic and Muscular Unit, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy. elisabetta.pasquini@meyer.it.
11
Newborn Screening, Biochemistry and Pharmacology Laboratory, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy. silvia.funghini@meyer.it.
12
Newborn Screening, Biochemistry and Pharmacology Laboratory, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy. g.lamarca@meyer.it.
13
Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy. g.lamarca@meyer.it.
14
Metabolic and Muscular Unit, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy. m.donati@meyer.it.
15
Molecular and Cell Biology Laboratory of Neurometabolic Diseases, Neuroscience Department, Meyer Children's Hospital, 50139 Florence, Italy. amelia.morrone@meyer.it.
16
Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139 Florence, Italy. amelia.morrone@meyer.it.

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.

KEYWORDS:

N-acetylglutamate synthase deficiency (NAGSD); N-carbamylglutamate (NCG); NAGS gene mutations; headaches; hyperammonemic encephalopathy; late-onset UCDs; urea cycle disorders (UCDs)

PMID:
29364180
PMCID:
PMC5855567
DOI:
10.3390/ijms19020345
[Indexed for MEDLINE]
Free PMC Article

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