title: Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation.
abstract: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders. The pathogenesis of this syndrome is not fully understood and believed to result from several interacting mechanisms including impaired mitochondrial energy production, microvasculature angiopathy, and nitric oxide (NO) deficiency. NO deficiency in MELAS syndrome is likely to be multifactorial in origin with the decreased availability of the NO precursors, arginine and citrulline, playing a major role. In this study we used stable isotope infusion techniques to assess NO production in children with MELAS syndrome and healthy pediatric controls. We also assessed the effect of oral arginine and citrulline supplementations on NO production in children with MELAS syndrome. When compared to control subjects, children with MELAS syndrome were found to have lower NO production, arginine flux, plasma arginine, and citrulline flux. In children with MELAS syndrome, arginine supplementation resulted in increased NO production, arginine flux, and arginine concentration. Citrulline supplementation resulted in a greater increase of these parameters. Additionally, citrulline supplementation was associated with a robust increase in citrulline concentration and flux and de novo arginine synthesis rate. The greater effect of citrulline in increasing NO production is due to its greater ability to increase arginine availability particularly in the intracellular compartment in which NO synthesis takes place. This study, which is the first one to assess NO metabolism in children with mitochondrial diseases, adds more evidence to the notion that NO deficiency occurs in MELAS syndrome, suggests a better effect for citrulline because of its greater role as NO precursor, and indicates that impaired NO production occurs in children as well as adults with MELAS syndrome. Thus, the initiation of treatment with NO precursors may be beneficial earlier in life. Controlled clinical trials to assess the therapeutic effects of arginine and citrulline on clinical complications of MELAS syndrome are needed.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Division of Clinical Genetics and Metabolic Disorders, Pediatrics Department, Tawam Hospital, Al-Ain, United Arab Emirates.
authors: Ayman W
authors: AW
authors: El-Hattab
authors: Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA.
authors: Lisa T
authors: LT
authors: Emrick
authors: USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
authors: Jean W
authors: JW
authors: Hsu
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
authors: Sirisak
authors: S
authors: Chanprasert
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
authors: Mohammed
authors: M
authors: Almannai
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
authors: William J
authors: WJ
authors: Craigen
authors: USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
authors: Farook
authors: F
authors: Jahoor
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA. Electronic address: fscaglia@bcm.edu.
authors: Fernando
authors: F
authors: Scaglia
mesh_terms: D000293:Adolescent; D001120:Arginine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002956:Citrulline / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D017241:MELAS Syndrome / Q000175:diagnosis / Q000178:diet therapy* / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D016896:Treatment Outcome
chemical_list: D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine
keywords: Lactic acidosis; Mitochondrial diseases; Stable isotope; Stroke-like