title: Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria.
abstract: Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea-cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sandesh C S
authors.initials: SC
authors.lastname: Nagamani
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Campeau
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Shchelochkov
authors.forename: Muralidhar H
authors.initials: MH
authors.lastname: Premkumar
authors.forename: Kilian
authors.initials: K
authors.lastname: Guse
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Qin
authors.initials: Q
authors.lastname: Sun
authors.forename: Yaoping
authors.initials: Y
authors.lastname: Tang
authors.forename: Donna
authors.initials: D
authors.lastname: Palmer
authors.forename: Anilkumar K
authors.initials: AK
authors.lastname: Reddy
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Slesnick
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Feig
authors.forename: Susan
authors.initials: S
authors.lastname: Caudle
authors.forename: David
authors.initials: D
authors.lastname: Harrison
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.forename: Juan C
authors.initials: JC
authors.lastname: Marini
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Bryan
authors.forename: Ayelet
authors.initials: A
authors.lastname: Erez
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000818:Animals; D001120:Arginine / Q000097:blood; D001123:Argininosuccinate Lyase / Q000235:genetics; D056807:Argininosuccinic Aciduria / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis / Q000172:deficiency* / Q000494:pharmacology*
chemical_list: D009569:Nitric Oxide; D001120:Arginine; D001123:Argininosuccinate Lyase