1. Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency
- Author
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Nina L. Schrager, Brunhilde Riesner, Markus G. Donner, Hanno Ulmer, Jaime M. Brum, Turgay Coşkun, Özlem Ünal, Andrea Schlune, Johannes Häberle, James D. Weisfeld-Adams, Sabine Scholl-Bürgi, Martina Huemer, Daniel R. Carvalho, Claudio Gemperle, Daniela Karall, Martin Hersberger, University of Zurich, and Huemer, Martina
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Pathology ,2716 Genetics (clinical) ,Adolescent ,Nitric Oxide Synthase Type III ,Urea cycle disorder ,Glycine ,Nitric Oxide Synthase Type II ,Hyperargininemia ,610 Medicine & health ,Biology ,Arginine ,Nitric Oxide ,complex mixtures ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,1311 Genetics ,Molecular genetics ,Genetics ,medicine ,Humans ,Amino Acids ,Child ,ARG1 ,Urea Cycle Disorders, Inborn ,Genetics (clinical) ,Retrospective Studies ,Arginase ,Case-control study ,Infant ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Human genetics ,3. Good health ,Oxidative Stress ,Phenotype ,030104 developmental biology ,10036 Medical Clinic ,Case-Control Studies ,Child, Preschool ,Immunology ,Female ,030217 neurology & neurosurgery - Abstract
Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology.Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site.Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome.Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.
- Published
- 2016
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