Triheptanoin in Epilepsy and Beyond

Abstract

AbstractTriheptanoin, the triglyceride of heptanoate (C7 fatty acid), is a novel treatment that is being used to treat patients with rare genetic metabolic disorders. In the gastrointestinal tract, triheptanoin is hydrolyzed to heptanoate, which diffuses into the blood and the rest of the body. Within mitochondria, heptanoate and its liver ketone metabolites are then metabolized to acetyl-CoA and propionyl-CoA. After carboxylation, the latter becomes succinyl-CoA, which can be anaplerotic—refilling a deficient tricarboxylic acid (TCA) cycle. Here, data are summarized and discussed in relation to triheptanoin’s anticonvulsant effects in rodent seizure models and clinical trials. Clinical improvements in people with long-chain fatty acid oxidation deficiencies were mostly reported with regard to cardiac dysfunction and are summarized. Moreover, there are increasing preclinical and clinical studies indicating that triheptanoin can be antioxidant and sometimes beneficial in other neurologic and neuromuscular disorders, which are also summarized here. In general, triheptanoin treatment appears to be safe. Tolerability can be an issue due to gastrointestinal side effects, such as diarrhea, bloating, and nausea, which often can be managed with smaller, more frequent doses of triheptanoin and mixing it with food. However, despite its efficacy in long-chain fatty acid oxidation deficiencies, beneficial effects of triheptanoin in neurologic conditions appear to be limited. In summary, triheptanoin is safe and promising for a variety of conditions, and it is now important to identify the disorders that respond to this anaplerotic treatment.