title: Increased oxidative stress in patients with 3-hydroxy-3-methylglutaric aciduria.
abstract: 3-hydroxy-3-methylglutaric aciduria (HMGA; OMIM 246450) is a rare autosomal recessive disorder, caused by the deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (4.1.3.4), which results in the accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in tissues and biological fluids of affected individuals. Recent in vivo and in vitro animal studies have demonstrated that the accumulation of these metabolites can disturb the cellular redox homeostasis, which can contribute to the neurological manifestations presented by the patients. So, in the present work, we investigated oxidative stress parameters in plasma and urine samples from HMGA patients, obtained at the moment of diagnosis of this disorder and during therapy with low-protein diet and L-carnitine supplementation. It was verified that untreated HMGA patients presented higher levels of urinary di-tyrosine and plasma thiobarbituric acid-reactive substances (TBA-RS), which are markers of protein and lipid oxidative damage, respectively, as well as a reduction of the urinary antioxidant capacity. Treated HMGA patients also presented an increased protein oxidative damage, as demonstrated by their higher concentrations of plasma protein carbonyl groups and urinary di-tyrosine, as well as by the reduction of total sulfhydryl groups in plasma, in relation to controls. On the other hand, HMGA patients under therapy presented normal levels of TBA-RS and urinary antioxidant capacity, which can be related, at least in part, to the antioxidant and antiperoxidative effects exerted by L-carnitine. The results of this work are the first report showing that a redox imbalance occurs in patients with HMGA what reinforces the importance of the antioxidant therapy in this disorder.
authors.affiliation: Programa de Pós-Graduação Ciências Farmacêuticas da Universidade Federal do Rio Grande do Sul (UFRGS), Ipiranga 2752, Porto Alegre, RS, 90610-000, Brazil, msmello2508@gmail.com.
authors.forename: Mariana
authors.initials: M
authors.lastname: Dos Santos Mello
authors.forename: Graziela Schmitt
authors.initials: GS
authors.lastname: Ribas
authors.forename: Carlos Alberto Yasin
authors.initials: CA
authors.lastname: Wayhs
authors.forename: Tatiane
authors.initials: T
authors.lastname: Hammerschmidt
authors.forename: Gilian Batista Balbueno
authors.initials: GB
authors.lastname: Guerreiro
authors.forename: Jéssica Lamberty
authors.initials: JL
authors.lastname: Favenzani
authors.forename: Ângela
authors.initials: Â
authors.lastname: Sitta
authors.forename: Daniella
authors.initials: D
authors.lastname: de Moura Coelho
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.forename: Carmen Regla
authors.initials: CR
authors.lastname: Vargas
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency* / Q000652:urine; D000293:Adolescent; D000592:Amino Acid Metabolism, Inborn Errors / Q000652:urine*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D015093:Meglutol / Q000652:urine*; D018384:Oxidative Stress; D050050:Protein Carbonylation
chemical_list: D015093:Meglutol; D000101:Acetyl-CoA C-Acetyltransferase