Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency
- 852 Downloads
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.
We gratefully acknowledge the contribution of Veronique Rüfenacht and Martin Volleberg, University Children’s Hospital Zürich, Switzerland; Andreas Kurringer, Christian Kerle, Fulya Zimmerer, Martin Fleger, Maximilian Obwegeser, Evelyn Gamper and Klaus Ludescher, LKH Bregenz, Austria and Luca Fierro and George A. Diaz, Icahn School of Medicine at Mount Sinai, New York, USA. The Government of Vorarlberg, Austria and Nutricia Metabolics, Friedrichsdorf, Germany have financially supported the study.
Compliance with ethical standards
All procedures followed were in accordance with the ethical standards of the responsible local committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained by the physicians from their patients or their caregivers for being included in the study.
Conflict of interest
- Grioni D, Furlan F, Canonico F, Parini R (2014) Epilepsia partialis continua and generalized nonconvulsive status epilepticus during the course of argininemia: a report on two cases. Neuropediatr 45:123–128Google Scholar
- Olsen RK, Cornelius N, Gregersen N (2015) Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism. J Inherit Metab Dis doi: 10.1007/s10545-015-9861-5Google Scholar
- Schulze A, Battini R (2008) Pre-symptomatic treatment of creatine biosynthesis defects. In: Salomons GS, Wyss M (eds) Creatine and creatine kinase in health and disease, Subcellular Biochemistry 46:167–181Google Scholar
- Schulze F, Lenzen H, Hanefeld C et al (2006) Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter coronary artery risk determination investigating the influence of ADMA concentration (CARDIAC) study. Am Heart J 152:e1–e8Google Scholar
- Wijnands KA, Hoeksema MA, Meesters DM et al (2014) Arginase-1 deficiency regulates arginine concentrations and NOS2-mediated NO production during endotoxemia. PLoS One 9:e86135Google Scholar