Maple syrup urine disease (MSUD) is an inherited disorder caused by severe deficient activity of the branched-chain α-keto acid dehydrogenase complex involved in the degradation pathway of branched-chain amino acids (BCAAs) and their α-ketoacid derivatives. MSUD patients generally present ketoacidosis, poor feeding, ataxia, coma, psychomotor delay, mental retardation and brain abnormalites. Treatment consists of dietary restriction of the BCAA (low protein intake) supplemented by a BCAA-free amino acid mixture. Although the mechanisms of brain damage in MSUD are poorly known, previous studies have shown that oxidative stress may be involved in the neuropathology of this disorder. In this regard, it was recently reported that MSUD patients have deficiency of l-carnitine (l-car), a compound with antioxidant properties that is used as adjuvant therapy in various inborn errors of metabolism. In this work, we investigated DNA damage determined by the alkaline comet assay in peripheral whole blood leukocytes of MSUD patients submitted to a BCAA-restricted diet supplemented or not with l-car. We observed a significant increase of DNA damage index (DI) in leukocytes from MSUD patients under BCAA-restricted diet as compared to controls and that l-car supplementation significantly decreased DNA DI levels. It was also found a positive correlation between DI and MDA content, a marker of lipid peroxidation, and an inverse correlation between DI and l-car levels. Taken together, our present results suggest a role for reactive species and the involvement of oxidative stress in DNA damage in this disorder. Since l-car reduced DNA damage, it is presumed that dietary supplementation of this compound may serve as an adjuvant therapeutic strategy for MSUD patients in addition to other therapies.

Maple syrup urine disease (MSUD) is a disorder of branched‐chain amino acids (BCAA). The defect in the branched‐chain α‐keto acid dehydrogenase complex activity leads to an accumulation of these compounds and their corresponding α‐keto‐acids and α‐hydroxy‐acids. Studies have shown that oxidative stress may be involved in neuropathology of MSUD. l‐carnitine (l‐car), which has demonstrated an important role as antioxidant by reducing and scavenging free radicals formation and by enhancing the activity of antioxidant enzymes, have been used in the treatment of some metabolic rare disorders. This study evaluated the oxidative stress parameters, di‐tyrosine, isoprostanes and antioxidant capacity, in urine of MSUD patients under protein‐restricted diet supplemented or not with l‐car capsules at a dose of 50 mg kg⁻¹ day⁻¹. It was also determined urinary α‐keto isocaproic acid levels as well as blood free l‐car concentrations in blood. It was found a deficiency of carnitine in patients before the l‐car supplementation. Significant increases of di‐tyrosine and isoprostanes, as well as reduced antioxidant capacity, were observed before the treatment with l‐car. The l‐car supplementation induced beneficial effects on these parameters reducing the di‐tyrosine and isoprostanes levels and increasing the antioxidant capacity. It was also showed a significant increase in urinary of α‐ketoisocaproic acid after 2 months of l‐car treatment, compared to control group. In conclusion, our results suggest that l‐car may have beneficial effects in the treatment of MSUD by preventing oxidative damage to the cells and that urine can be used to monitorize oxidative damage in patients affected by this disease.