Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist.

Methylmalonic acidurias are a heterogeneous group of inborn errors of branched-chain amino acid metabolism. Depending on the underlying etiology, acute or chronic renal disease constitutes major (long-term) complications. In recent decades, overall survival has improved due to optimized treatment strategies based on the use of standardized emergency protocols and dialysis techniques. The majority of these patients, especially those having mut°, cblB, and cblA deficiency, are at increased risk of developing chronic kidney disease secondary to tubulointerstitial nephritis to require hemo- or peritoneal dialysis. Kidney and/or liver transplantation, as organ replacement, or even gene therapy on a limited scale, are controversially discussed treatment options in methylmalonic acidurias. The pathophysiological basis of renal disease has not been clarified in detail until now, but a severe mitochondrial dysfunction and an impairment of tubular dicarboxylic acid transport due to accumulated toxic metabolic compounds has been recently proposed. Another severe renal complication of methylmalonic acidurias is the occurrence of cblC-associated infantile atypical hemolytic syndrome, which can result in acute kidney injury. Close collaboration between (pediatric) nephrologists and metabolic specialists is required for the long-term management of these patients.

Therapeutic modulation of cerebral L-lysine metabolism in a mouse model for glutaric aciduria type I.

Glutaric aciduria type I, an inherited deficiency of glutaryl-coenzyme A dehydrogenase localized in the final common catabolic pathway of L-lysine, L-hydroxylysine and L-tryptophan, leads to accumulation of neurotoxic glutaric and 3-hydroxyglutaric acid, as well as non-toxic glutarylcarnitine. Most untreated patients develop irreversible brain damage during infancy that can be prevented in the majority of cases if metabolic treatment with a low L-lysine diet and L-carnitine supplementation is started in the newborn period. The biochemical effect of this treatment remains uncertain, since cerebral concentrations of neurotoxic metabolites can only be determined by invasive techniques. Therefore, we studied the biochemical effect and mechanism of metabolic treatment in glutaryl-coenzyme A dehydrogenase-deficient mice, an animal model with complete loss of glutaryl-coenzyme A dehydrogenase activity, focusing on the tissue-specific changes of neurotoxic metabolites and key enzymes of L-lysine metabolism. Here, we demonstrate that low L-lysine diet, but not L-carnitine supplementation, lowered the concentration of glutaric acid in brain, liver, kidney and serum. L-carnitine supplementation restored the free L-carnitine pool and enhanced the formation of glutarylcarnitine. The effect of low L-lysine diet was amplified by add-on therapy with L-arginine, which we propose to result from competition with L-lysine at system y(+) of the blood-brain barrier and the mitochondrial L-ornithine carriers. L-lysine can be catabolized in the mitochondrial saccharopine or the peroxisomal pipecolate pathway. We detected high activity of mitochondrial 2-aminoadipate semialdehyde synthase, the rate-limiting enzyme of the saccharopine pathway, in the liver, whereas it was absent in the brain. Since we found activity of the subsequent enzymes of L-lysine oxidation, 2-aminoadipate semialdehyde dehydrogenase, 2-aminoadipate aminotransferase and 2-oxoglutarate dehydrogenase complex as well as peroxisomal pipecolic acid oxidase in brain tissue, we postulate that the pipecolate pathway is the major route of L-lysine degradation in the brain and the saccharopine pathway is the major route in the liver. Interestingly, treatment with clofibrate decreased cerebral and hepatic concentrations of glutaric acid in glutaryl-coenzyme A dehydrogenase-deficient mice. This finding opens new therapeutic perspectives such as pharmacological stimulation of alternative L-lysine oxidation in peroxisomes. In conclusion, this study gives insight into the discrepancies between cerebral and hepatic L-lysine metabolism, provides for the first time a biochemical proof of principle for metabolic treatment in glutaric aciduria type I and suggests that further optimization of treatment could be achieved by exploitation of competition between L-lysine and L-arginine at physiological barriers and enhancement of peroxisomal L-lysine oxidation and glutaric acid breakdown.

Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins.

Mitochondrial dysfunction during acute metabolic crises is considered an important pathomechanism in inherited disorders of propionate metabolism, i.e. propionic and methylmalonic acidurias. Biochemically, these disorders are characterized by accumulation of propionyl-CoA and metabolites of alternative propionate oxidation. In the present study, we demonstrate uncompetitive inhibition of PDHc (pyruvate dehydrogenase complex) by propionyl-CoA in purified porcine enzyme and in submitochondrial particles from bovine heart being in the same range as the inhibition induced by acetyl-CoA, the physiological product and known inhibitor of PDHc. Evaluation of similar monocarboxylic CoA esters showed a chain-length specificity for PDHc inhibition. In contrast with CoA esters, non-esterified fatty acids did not inhibit PDHc activity. In addition to PDHc inhibition, analysis of respiratory chain and tricarboxylic acid cycle enzymes also revealed an inhibition by propionyl-CoA on respiratory chain complex III and alpha-ketoglutarate dehydrogenase complex. To test whether impairment of mitochondrial energy metabolism is involved in the pathogenesis of propionic aciduria, we performed a thorough bioenergetic analysis in muscle biopsy specimens of two patients. In line with the in vitro results, oxidative phosphorylation was severely compromised in both patients. Furthermore, expression of respiratory chain complexes I-IV and the amount of mitochondrial DNA were strongly decreased, and ultrastructural mitochondrial abnormalities were found, highlighting severe mitochondrial dysfunction. In conclusion, our results favour the hypothesis that toxic metabolites, in particular propionyl-CoA, are involved in the pathogenesis of inherited disorders of propionate metabolism, sharing mechanistic similarities with propionate toxicity in micro-organisms.