Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of metabolism caused by deficiency of the activity of the mitochondrial enzyme complex branched-chain α-keto acid dehydrogenase (BCKAD) leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine and their corresponding branched-chain α-keto acids. Affected patients present severe brain dysfunction manifested such as ataxia, seizures, coma, psychomotor delay and mental retardation. The mechanisms of brain damage in this disease remain poorly understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. L-Carnitine (L-Car) is considered a potential antioxidant through its action against peroxidation as a scavenger of reactive oxygen species and by its stabilizing effect of damage to cell membranes. In this study we evaluate the possible neuroprotective in vivo effects of L-Car against pro-oxidative effects of BCAA in cerebral cortex of rats. L-Car prevented lipoperoxidation, measured by thiobarbituric acid-reactive substances, protein damage, measured by sulfhydryl and protein carbonyl content and alteration on catalase and glutathione peroxidase activity in rat cortex from a chemically-induced model of MSUD. Our data clearly show that L-Car may be an efficient antioxidant, protecting against the oxidative stress promoted by BCAA. If the present results are confirmed in MSUD patients, this could represent an additional therapeutic approach to the patients affected by this disease.

d-2-hydroxyglutaric (D-2-HGA) and l-2-hydroxyglutaric (L-2-HGA) acidurias are rare neurometabolic disorders biochemically characterized by increased levels of d-2-hydroxyglutaric acid (D-2-HG) and l-2-hydroxyglutaric acid (L-2-HG) respectively, in biological fluids and tissues. These diseases are caused by mutations in the specific enzymes involved in the metabolic pathways of these organic acids. In the present work, we first investigated whether D-2-HG and L-2-HGA could provoke DNA oxidative damage in blood leukocytes and whether l-carnitine (LC) could prevent the in vitro DNA damage induced by these organic acids. It was verified that 50μM of D-2-HG and 30μM of L-2-HG significantly induced DNA damage that was prevented by 30 and 150μM of LC. We also evaluated oxidative stress parameters in urine of L-2-HGA patients and observed a significant increase of oxidized guanine species and di-tyrosine, biomarkers of oxidative DNA and protein damage, respectively. In contrast, no significant changes of urinary isoprostanes and reactive nitrogen species levels were observed in these patients. Taken together, our data indicate the involvement of oxidative damage, especially on DNA, in patients affected by these diseases and the protective effect of LC.

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X-linked adrenoleukodystrophy (X-ALD) is an inherited disease characterized by progressive inflammatory demyelization in the brain, adrenal insufficiency, and an abnormal accumulation of very long chain fatty acids (VLCFA) in tissue and body fluids. Considering that inflammation might be involved in pathophysiology of X-ALD, we aimed to investigate pro-and anti-inflammatory cytokines in plasma from three different male phenotypes (CCER, AMN, and asymptomatic individuals). Our results showed that asymptomatic patients presented increased levels of proinflammatory cytokines IL-1β, IL-2, IL-8, and TNF-α and the last one was also higher in AMN phenotype. Besides, asymptomatic patients presented higher levels of antiinflammatory cytokines IL-4 and IL-10. AMN patients presented higher levels of IL-2, IL-5, and IL-4. We might hypothesize that inflammation in X-ALD is related to plasmatic VLCFA concentration, since there were positive correlations between C26:0 plasmatic levels and pro-inflammatory cytokines in asymptomatic and AMN patients and negative correlation between anti-inflammatory cytokine and C24:0/ C22:0 ratio in AMN patients. The present work yields experimental evidence that there is an inflammatory imbalance associated Th1, (IL-2, IL-6, and IFN-γ), Th2 (IL-4 and IL-10), and macrophages response (TNF-α and IL-1β) in the periphery of asymptomatic and AMN patients, and there is correlation between VLCFA plasmatic levels and inflammatory mediators in X-ALD. Furthermore, we might also speculate that the increase of plasmatic cytokines in asymptomatic patients could be considered an early biomarker of brain damage and maybe also a predictor of disease progression.