Clinical phenotype,biochemical profile,and treatment in 19 patients with arginase 1 deficiency |
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| Authors: | Martina Huemer Daniel R. Carvalho Jaime M. Brum Özlem Ünal Turgay Coskun James D. Weisfeld-Adams Nina L. Schrager Sabine Scholl-Bürgi Andrea Schlune Markus G. Donner Martin Hersberger Claudio Gemperle Brunhilde Riesner Hanno Ulmer Johannes Häberle Daniela Karall |
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| Affiliation: | 1.Division of Metabolic Diseases and Children’s Research Center,University Children’s Hospital Zurich,Zurich,Switzerland;2.Radiz – Rare Disease Initiative Zurich,University Zurich,Zurich,Switzerland;3.Department of Paediatrics,Landeskrankenhaus Bregenz,Bregenz,Austria;4.Genetic Unit, SARAH Network of Rehabilitation Hospital,Brasilia,Brazil;5.Molecular Pathology Department,Rede Sarah de Hospitais de Reabilita??o,Brasilia,Brazil;6.Department of Paediatrics, Division of Paediatric Nutrition and Metabolism,Hacettepe University Faculty of Medicine,Ankara,Turkey;7.Ankara Children’s Hospital, Haematology-Oncology Research and Education Hospital,Ankara,Turkey;8.Program for Inherited Metabolic Diseases, Icahn School of Medicine at Mount Sinai,New York,USA;9.Section of Clinical Genetics and Metabolism, Department of Pediatrics,University of Colorado School of Medicine,Aurora,USA;10.Clinic for Pediatrics I, Inherited Metabolic Disorders,Medical University of Innsbruck,Innsbruck,Austria;11.Department of General Pediatrics, Neonatology and Pediatric Cardiology,University Children’s Hospital, Heinrich Heine University,Düsseldorf,Germany;12.Department of Gastroenterology, Hepatology and Infectious diseases,Heinrich Heine University,Düsseldorf,Germany;13.Division of Clinical Chemistry and Biochemistry,University Children’s Hospital Zurich,Zurich,Switzerland;14.Department of Medical Statistics, Informatics and Health Economics,Medical University of Innsbruck,Innsbruck,Austria |
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| Abstract: | BackgroundArginase 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.MethodsClinical 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.ResultsNineteen 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.ConclusionThree 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. |
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