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Increased oxidative stress in patients with 3-hydroxy-3-methylglutaric aciduria

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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.

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Acknowledgments

The authors are grateful to the patients, their families, and the physicians of the patients. This work was supported in part by grants from CNPq, FAPERGS, and FIPE/HCPA-Brazil.

Conflict of interest

The authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Programa de Pós-Graduação Ciências Farmacêuticas da Universidade Federal do Rio Grande do Sul (UFRGS), Ipiranga 2752, Porto Alegre, RS, 90610-000, Brazil

    Mariana dos Santos Mello & Carmen Regla Vargas

  2. Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Bairro: Bom Fim, Porto Alegre, RS, 90035-903, Brazil

    Mariana dos Santos Mello, Graziela Schmitt Ribas, Carlos Alberto Yasin Wayhs, Tatiane Hammerschmidt, Gilian Batista Balbueno Guerreiro, Jéssica Lamberty Favenzani, Ângela Sitta, Daniella de Moura Coelho, Moacir Wajner & Carmen Regla Vargas

  3. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica da Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos 2700, Porto Alegre, RS, 90035-000, Brazil

    Moacir Wajner & Carmen Regla Vargas

Authors
  1. Mariana dos Santos Mello
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  2. Graziela Schmitt Ribas
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  3. Carlos Alberto Yasin Wayhs
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Correspondence to Mariana dos Santos Mello or Carmen Regla Vargas.

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dos Santos Mello, M., Ribas, G.S., Wayhs, C.A.Y. et al. Increased oxidative stress in patients with 3-hydroxy-3-methylglutaric aciduria. Mol Cell Biochem 402, 149–155 (2015). https://doi.org/10.1007/s11010-014-2322-x

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