Anaplerotic diet therapy in inherited metabolic disease: Therapeutic potential

Abstract

Beginning with phenylketonuria, dietary therapy for inborn errors has focused primarily on the restriction of the precursor to an affected catabolic pathway in an attempt to limit the production of potential toxins. Anaplerotic therapy is based on the concept that there may exist an energy deficit in these diseases that might be improved by providing alternative substrate for both the citric acid cycle (CAC) and the electron transport chain for enhanced ATP production. This article focuses on this basic problem, as it may relate to most catabolic disorders, and provides our current experience involving inherited diseases of mitochondrial fat oxidation, glycogen storage, and pyruvate metabolism using the anaplerotic compound triheptanoin. The observations have led to a realization that 'inter-organ' signalling and 'nutrient sensors' such as adenylate monophosphate mediated-protein kinase (AMPK) and mTOR (mammalian target of rapamycin) appear to play a significant role in the intermediary metabolism of these diseases. Activated AMPK turns on catabolic pathways to augment ATP production while turning off synthetic pathways that consume ATP. Information is provided regarding the inter-organ requirements for more normal metabolic function during crisis and how anaplerotic therapy using triheptanoin, as a direct source of substrate to the CAC for energy production, appears to be a more successful approach to an improved quality of life for these patients.

Carnitine-Acylcarnitine Translocase Deficiency: Experience with Four Cases in Spain and Review of the Literature

“…Low C10 MCT is recommended due to the evidence that C10 fats require CACT for oxidation (Rubio-Gozalbo et al 2004). Some cases with long-chain FAO disorders (LCHAD, VLCAD, CPT1, CPT2, and CACT) have been treated with triheptanoin, a fatty acid with seven carbon acids, with good results, especially with respect to myocardiopathy and hypoglycemia (Roe and Mochel 2006). The essential fatty acids linoleic acid (3-4%) and linolenic acid (0.5-1%) should be provided, in a ratio from 5:1 to 10:1, with walnut, canola, linseed, sunflower, wheat germ, or soy oil; this has been used with our patients (Spiekerkoetter et al 2009).…”

Heptanoate as a Neural Fuel: Energetic and Neurotransmitter Precursors in Normal and Glucose Transporter I-Deficient (G1D) Brain

“…Mass isotopomers of 13 C-glucose in plasma. Plasma 13 Cglucose was enriched from [5,6,[7][8][9][10][11][12][13] C 3 ]heptanoate in both normal and mutant (glucose transporter type I deficiency, G1D) animal groups. Data were corrected for the natural abundance of 13 C. Glucose was mostly enriched in M þ 2 (Control: 4.63%±1.5%; G1D: 5.28%±1.22%) and M þ 3 (Control: 3.65%±0.86%; G1D: 3.45%±0.69%).…”

“…[9][10][11] Triheptanoin has been previously used in disorders of mitochondrial fat oxidation, glycogen storage, and pyruvate metabolism. 10,12 Additionally, it has been reported that heptanoate derived from triheptanoic diet may exert anticonvulsant effects in epileptic animal models while refilling depleted brain TCA cycle intermediates. 11 As illustrated in Figure 1, the standard, whole-organ notion that explains these findings is that dietary triheptanoin is metabolized to plasma heptanoate and C5 ketones (b-ketopentanoate and b-hydroxypentanoate), 10 both of which can enter the TCA cycle at the level of acetyl-CoA and propionyl-CoA.…”

“…In this work, we sought to characterize the metabolism of [5,6,7-13 C 3 ]heptanoate in the brain of normal conscious mice and of a transgenic antisense mouse model of G1D that exhibits the common epileptic phenotype typical of the human glucose transporter defect. 14 Administration of heptanoate labeled in this fashion is followed by oxidation of [5,6,7-13 C 3 ]heptanoate or [3,4,[5][6][7][8][9][10][11][12][13] C 3 ]C5-ketone derivatives in the brain without generation of [1,2-13 C 2 ]acetyl-CoA, and, consequently, without enrichment of carbons 4 or 5 of glutamine or glutamate. Using this approach, we demonstrate that plasma glucose becomes enriched with 13 C in the presence of intravenously infused [5,6,7-13 C 3 ]heptanoate as expected, indicating that the understanding of any effects of heptanoate therapy must consider its effects on glucose production.…”

“…In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,[7][8][9][10][11][12][13] C 3 ]heptanoate was examined in the normal mouse brain and in G1D by 13 C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in 13 C, confirming gluconeogenesis from heptanoate.…”