title: Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency.
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.
authors.affiliation: Division of Metabolic Diseases and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland. martina.huemer@lkhb.at.|Radiz - Rare Disease Initiative Zurich, University Zurich, Zurich, Switzerland. martina.huemer@lkhb.at.|Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria. martina.huemer@lkhb.at.
authors.forename: Martina
authors.initials: M
authors.lastname: Huemer
authors.affiliation: Genetic Unit, SARAH Network of Rehabilitation Hospital, Brasilia, Brazil.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carvalho
authors.affiliation: Molecular Pathology Department, Rede Sarah de Hospitais de Reabilitação, Brasilia, Brazil.
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Brum
authors.affiliation: Department of Paediatrics, Division of Paediatric Nutrition and Metabolism, Hacettepe University Faculty of Medicine, Ankara, Turkey.|Ankara Children's Hospital, Haematology-Oncology Research and Education Hospital, Ankara, Turkey.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Ünal
authors.affiliation: Department of Paediatrics, Division of Paediatric Nutrition and Metabolism, Hacettepe University Faculty of Medicine, Ankara, Turkey.
authors.forename: Turgay
authors.initials: T
authors.lastname: Coskun
authors.affiliation: Program for Inherited Metabolic Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Weisfeld-Adams
authors.affiliation: Program for Inherited Metabolic Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Nina L
authors.initials: NL
authors.lastname: Schrager
authors.affiliation: Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Scholl-Bürgi
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schlune
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious diseases, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Donner
authors.affiliation: Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
authors.affiliation: Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Gemperle
authors.affiliation: Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria.
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Riesner
authors.affiliation: Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Hanno
authors.initials: H
authors.lastname: Ulmer
authors.affiliation: Division of Metabolic Diseases and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.|Radiz - Rare Disease Initiative Zurich, University Zurich, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
authors.affiliation: Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Karall
mesh_terms: D000293:Adolescent; D000328:Adult; D000596:Amino Acids / Q000097:blood; D001119:Arginase / Q000235:genetics* / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000097:blood; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype; D012189:Retrospective Studies; D056806:Urea Cycle Disorders, Inborn / Q000097:blood* / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000596:Amino Acids; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C574619:ARG1 protein, human; D001119:Arginase; C004946:glycocyamine; D005998:Glycine