Investigation of L-Carnitine Concentrations in Treated Patients with Maple Syrup Urine Disease

Abstract

Maple syrup urine disease (MSUD), also known as branched-chain α ketoaciduria, is a metabolic disorder caused by an inborn deficiency in the activity of the branched-chain α-ketoacid dehydrogenase complex. Severe neurological damage occurs in most patients with MSUD although the exact mechanism of neurotoxicity still remains unknown. Studies have suggested that neuropathology in patients with MSUD may be related to oxidative stress. L-carnitine mediates the transport of fatty acids into the mitochondria that are required for β-oxidation and ATP production. Along with the important roles it plays in lipid metabolism, L-carnitine also protects tissues from oxidative damage through its antioxidant properties. The study included a total of 15 patients with MSUD who attended regular follow-up visits, and 15 age-matched healthy control subjects, and aimed to investigate L-carnitine levels in treated patients with MSUD and healthy control subjects. L-carnitine levels were found to be significantly lower in the patient group than in the healthy controls. No significant correlation was identified between the plasma branched-chain amino acids leucine, isoleucine, valine, and L-carnitine levels. Patients with MSUD can be treated with adjuvant therapy with L-carnitine supplementation.

Keywords

maple syrup urine disease - L-carnitine - oxidative stress

• References

• 1 Knerr I, Weinhold N, Vockley J, Gibson KM. Advances and challenges in the treatment of branched-chain amino/keto acid metabolic defects. J Inherit Metab Dis 2012; 35 (01) 29-40
• 2 Mescka CP, Rosa AP, Schirmbeck G. , et al. L-carnitine prevents oxidative stress in the brains of rats subjected to a chemically induced chronic model of MSUD. Mol Neurobiol 2016; 53 (09) 6007-6017
• 3 Barschak AG, Sitta A, Deon M. , et al. Erythrocyte glutathione peroxidase activity and plasma selenium concentration are reduced in maple syrup urine disease patients during treatment. Int J Dev Neurosci 2007; 25 (05) 335-338
• 4 Barschak AG, Sitta A, Deon M. , et al. Evidence that oxidative stress is increased in plasma from patients with maple syrup urine disease. Metab Brain Dis 2006; 21 (04) 279-286
• 5 Sitta A, Ribas GS, Mescka CP, Barschak AG, Wajner M, Vargas CR. Neurological damage in MSUD: the role of oxidative stress. Cell Mol Neurobiol 2014; 34 (02) 157-165
• 6 Ribas GS, Vargas CR, Wajner M. L-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders. Gene 2014; 533 (02) 469-476
• 7 Derin N, Izgut-Uysal VN, Agac A, Aliciguzel Y, Demir N. L-carnitine protects gastric mucosa by decreasing ischemia-reperfusion induced lipid peroxidation. J Physiol Pharmacol 2004; 55 (03) 595-606
• 8 Abdul HM, Butterfield DA. Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and α-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. Free Radic Biol Med 2007; 42 (03) 371-384
• 9 Beal MF. Bioenergetic approaches for neuroprotection in Parkinson's disease. Ann Neurol 2003; 53 (Suppl. 03) S39-S47 , discussion S47–S48
• 10 Mescka CP, Wayhs CA, Vanzin CS. , et al. Protein and lipid damage in maple syrup urine disease patients: l-carnitine effect. Int J Dev Neurosci 2013; 31 (01) 21-24
• 11 Mescka CP, Wayhs CA, Guerreiro G, Manfredini V, Dutra-Filho CS, Vargas CR. Prevention of DNA damage by L-carnitine induced by metabolites accumulated in maple syrup urine disease in human peripheral leukocytes in vitro. Gene 2014; 548 (02) 294-298
• 12 Barschak AG, Sitta A, Deon M. , et al. Oxidative stress in plasma from maple syrup urine disease patients during treatment. Metab Brain Dis 2008; 23 (01) 71-80
• 13 Mescka CP, Guerreiro G, Donida B. , et al. Investigation of inflammatory profile in MSUD patients: benefit of L-carnitine supplementation. Metab Brain Dis 2015; 30 (05) 1167-1174
• 14 Vaz FM, Wanders RJA. Carnitine biosynthesis in mammals. Biochem J 2002; 361 (Pt 3): 417-429
• 15 Barschak AG, Marchesan C, Sitta A. , et al. Maple syrup urine disease in treated patients: biochemical and oxidative stress profiles. Clin Biochem 2008; 41 (4-5): 317-324
• 16 Mescka C, Moraes T, Rosa A. , et al. In vivo neuroprotective effect of L-carnitine against oxidative stress in maple syrup urine disease. Metab Brain Dis 2011; 26 (01) 21-28
• 17 De Simone R, Vissicchio F, Mingarelli C. , et al. Branched-chain amino acids influence the immune properties of microglial cells and their responsiveness to pro-inflammatory signals. Biochim Biophys Acta 2013; 1832 (05) 650-659
• 18 Guerreiro G, Mescka CP, Sitta A. , et al. Urinary biomarkers of oxidative damage in maple syrup urine disease: the L-carnitine role. Int J Dev Neurosci 2015; 42: 10-14
• 19 Scaini G, Jeremias IC, Morais MO. , et al. DNA damage in an animal model of maple syrup urine disease. Mol Genet Metab 2012; 106 (02) 169-174
• 20 Mescka CP, Guerreiro G, Hammerschmidt T. , et al. L-Carnitine supplementation decreases DNA damage in treated MSUD patients. Mutat Res 2015; 775: 43-47