Protein and lipid damage in maple syrup urine disease patients: l‐carnitine effect

Abstract

Maple syrup urine disease (MSUD) is an inborn error of metabolism biochemically characterized by elevated levels of the branched chain amino acids (BCAA) leucine, isoleucine, valine and the corresponding branched-chain α-keto acids. This disorder is clinically characterized by ketoacidosis, seizures, coma, psychomotor delay and mental retardation whose pathophysiology is not completely understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. l-Carnitine (l-Car) plays a central role in the cellular energy metabolism because it transports long-chain fatty acids for oxidation and ATP generation. In recent years many studies have demonstrated the antioxidant role of this compound. In this work, we investigated the effect of BCAA-restricted diet supplemented or not with l-Car on lipid peroxidation and in protein oxidation in MSUD patients. We found a significant increase of malondialdehyde and of carbonyl content in plasma of MSUD patients under BCAA-restricted diet compared to controls. Furthermore, patients under BCAA-restricted diet plus l-Car supplementation presented a marked reduction of malondialdehyde content in relation to controls, reducing the lipid peroxidation. In addition, free l-Car concentrations were negatively correlated with malondialdehyde levels. Our data show that l-Car may have an antioxidant effect, protecting against the lipid peroxidation and this could represent an additional therapeutic approach to the patients affected by MSUD.

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

“…The reported mechanisms for the L-carnitine antiperoxidative role include inhibition of xanthine oxidase activity, scavenger action of free radicals, and chelation of the iron required for the generation of hydroxyl radicals [45,46] or by facilitating the fatty acids transport, thereby lowering the availability of lipids for peroxidation [47]. Reinforcing the hypothesis that L-carnitine could prevent lipid peroxidation in HMGA, this same protective effect was observed in other inborn errors of metabolism, such as in phenylketonuria [48], in maple syrup urine disease [24,31], and in disorders of propionate metabolism [28,33].…”

“…In addition to its role in the energy metabolism, L-carnitine has been used as an important adjuvant for the therapy of patients with some organic acidurias, including HMGA, in an attempt to facilitate the elimination of toxic acyl groups and presumably to replenish the decreased stores of free carnitine, as well as to release CoASH for essential oxidative pathways. Furthermore, antioxidant properties have been demonstrated for L-carnitine in several pathologies, including in some inborn errors of metabolism [22][23][24].…”

Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency

“…The investigation of redox status in cell cultures exposed to the metabolites and in the liver-specific HL-deficient mice model developed by Gauthier et al (2013) would also be of great importance for this purpose. As regards to L-carnitine, it was shown that supplementation of this compound normalized various parameters of oxidative stress in patients with HL deficiency and other inborn errors (Sitta et al 2009;Mescka et al 2013;dos Santos et al 2015;Guerreiro et al 2015). This beneficial effect could be due to its capacity to remove toxic metabolites and/or its antioxidant properties, signalizing the potential use of this compound as an adjuvant therapy for these inherited metabolic conditions.…”

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

“…There are reports showing improvement after L-carnitine therapy in patients with some organic acidemias, including propionic acidemia, methylmalonic acidemia, and glutaric acidemia type I [71–75]. More recent reports have demonstrated that L-carnitine supplementation as adjuvant therapy contributes to the amelioration of blood markers of oxidative damage in patients affected by phenylketonuria [76], maple syrup urine disease [77], and disorders of propionate metabolism [78]. …”