1.Current issues regarding treatment of mitochondrial fatty acid oxidation disorders
Ute Spiekerkoetter & Jean Bastin & Melanie Gillingham. J Inherit Metab Dis (2010) 33:555–561
Treatment with triheptanoin has been recommended by Roe and colleagues in patients with long-chain FAOD who have persistent myopathy or cardiomyopathy despite treatment with conventional MCT preparations (Roe et al. 2002). According to this study, it is suggested that the poor response to even-chain MCT may be due to citric acid cycle intermediates leaking out of muscle and heart mitochondria in these patients. The resulting oxaloacetate depletion would limit the oxidation of acetyl-CoA derived from MCT. Anaplerosis from pyruvate is slow because the pyruvate carboxylase has a high Km relative to physiological pyruvate concentrations. Triheptanoin is a glycerol ester of three C7 fatty acids (heptanoate). β-oxidation of heptanoate in the liver generates propionyl-CoA as well as acetyl-CoA. C5 ketone bodies (β-hydroxypentanoate and β-ketopentanoate) are exported to other tissues as well as conventional ketone bodies. Again, oxidation of C5 ketone bodies generates propionyl-CoA as well as acetyl-CoA. Propionyl-CoA can be converted via succinyl-CoA to oxaloacetate. If the oxidation of conventional MCT is limited by the availability of oxaloacetate, then triheptanoin might be a more effective fuel. As yet, there is little published evidence concerning the effectiveness of triheptanoin. Its use in three children with VLCADD was reported in 2002 (Roe et al. 2002).
2.Unsuccessful treatment of severe pyruvate carboxylase deficiency with triheptanoin
C. Breen & F. J. White & C. A. B. Scott & L. Heptinstall.Eur J Pediatr (2014) 173:361–366
Triheptanoin is a triglyceride of C7 fatty acids. The oxidation of odd chain fatty acids leads to the production not only of acetyl-CoA but also of propionyl-CoA. The latter can be converted to succinyl-CoA, which is an anaplerotic substrate for the Krebs cycle. Triheptanoin is a particularly good anaplerotic agent as it can be given in large quantities without accompanying electrolytes. Moreover, on first pass through the liver, triheptanoin is largely converted to C5 ketone bodies, which can cross the blood–brain barrier and might, potentially, correct the metabolic disorder in the brain. One infant with the ‘French’ form of PC deficiency has previously been treated with triheptanoin as well as citrate and 2-chloropropionate. Treatment led to an improvement in liver function and other biochemical parameters, including the CSF glutamine concentration, but she died at the age of 6 months.
3.Anaplerotic diet therapy in inherited metabolic disease: Therapeutic potential
Charles R. Roe, Fanny Mochel. J Inherit Metab Dis (2006) 29:332–340
When ingested, one mole of triheptanoin is split into one mole of glycerol and 3 moles of heptanoic acid that are metabolized mainly in liver. Figure 1 summarizes the oxidation of heptanoate (C7) and the export of 5-carbon ketone bodies that are also produced in the liver. C7 can enter the mitochondrion largely as a carboxylate, but it is possible that it may also undergo cytosolic activation and then be exchanged for carnitine, as occurs with other longer chain-length fatty acids. The fact that C7 does not require CPT I, carnitine-acylcarnitine translocase or CPT II for entry and oxidation, suggests that it largely enters the mitochondrion as a carboxylate. Presumably, it is converted to C7-CoA by a medium-chain acyl-CoA synthetase and undergoes a cycle of β-oxidation to pentanoyl-CoA (C5-CoA), which requires the medium-chain acyl-CoA dehydrogenase (MCAD). Pentanoyl-CoA (N-valeryl-CoA) can be used as substrate by isovaleryl-CoA dehydrogenase, which permits oxidation even in the absence of the short-chain acyl-CoA dehydrogenase (SCAD). The partial cycle of β-oxidation produces β-ketopentanoyl-CoA (BKP-CoA), which can be cleaved by thiolase to provide acetyl-CoA and propionylCoA to fuel the hepatic CAC.
4.Dietary triheptanoin rescues oligodendrocyte loss, dysmyelination and motor function in the nur7 mouse model of Canavan disease
Jeremy S. Francis & Vladimir Markov & Paola Leone. J Inherit Metab Dis (2014) 37:369–381
The odd-carbon triglyceride triheptanoin is a dietary anaplerotic substrate that provides ketone bodies capable of traversing the blood brain barrier (BBB) and increasing the mass of tricarboxylic acid (TCA) cycle intermediates to support the brains synthetic needs. Triheptanoin has shown efficacy in the treatment of disorders of mitochondrial oxidation
and pyruvate metabolism (Roe and Mochel 2006; MarinValencia et al 2010), and the ability to provide AcCoA via the ß-oxidation of carbons 1–4 is believed to be the basis of reported anti-convulsant effects in models of epilepsy (Willis et al 2010; Thomas et al 2012). Because AcCoA is a key intermediate for both fatty acid synthesis and the TCA cycle, we hypothesized that triheptanoin may compensate for the loss of the ASPA function by uncoupling a portion of fatty acid synthesis from energetic metabolism through the provision of AcCoA while simultaneously providing anaplerotic support for the TCA cycle via the propionyl moiety of heptanoate.