Physiological Perspectives on the Use of Triheptanoin as Anaplerotic Therapy for Long Chain Fatty Acid Oxidation Disorders

Abstract

Inborn errors of mitochondrial fatty acid oxidation (FAO) comprise the most common group of disorders identified through expanded newborn screening mandated in all 50 states in the United States, affecting 1:10,000 newborns. While some of the morbidity in FAO disorders (FAODs) can be reduced if identified through screening, a significant gap remains between the ability to diagnose these disorders and the ability to treat them. At least 25 enzymes and specific transport proteins are responsible for carrying out the steps of mitochondrial fatty acid metabolism, with at least 22 associated genetic disorders. Common symptoms in long chain FAODs (LC-FAODs) in the first week of life include cardiac arrhythmias, hypoglycemia, and sudden death. Symptoms later in infancy and early childhood may relate to the liver or cardiac or skeletal muscle dysfunction, and include fasting or stress-related hypoketotic hypoglycemia or Reye-like syndrome, conduction abnormalities, arrhythmias, dilated or hypertrophic cardiomyopathy, and muscle weakness or fasting- and exercise-induced rhabdomyolysis. In adolescent or adult-onset disease, muscular symptoms, including rhabdomyolysis, and cardiomyopathy predominate. Unfortunately, progress in developing better therapeutic strategies has been slow and incremental. Supplementation with medium chain triglyceride (MCT; most often a mixture of C8–12 fatty acids containing triglycerides) oil provides a fat source that can be utilized by patients with long chain defects, but does not eliminate symptoms. Three mitochondrial metabolic pathways are required for efficient energy production in eukaryotic cells: oxidative phosphorylation (OXPHOS), FAO, and the tricarboxylic (TCA) cycle, also called the Krebs cycle. Cell and mouse studies have identified a deficiency in TCA cycle intermediates in LC-FAODs, thought to be due to a depletion of odd chain carbon compounds in patients treated with a predominantly MCT fat source. Triheptanoin (triheptanoyl glycerol; UX007, Ultragenyx Pharmaceuticals) is chemically composed of three heptanoate (seven carbon fatty acid) molecules linked to glycerol through ester bonds that has the potential to replete TCA cycle intermediates through production of both acetyl-CoA and propionyl-CoA through medium chain FAO. Compassionate use, retrospective, and recently completed prospective studies demonstrate significant reduction of hypoglycemic events and improved cardiac function in LC-FAOD patients, but a less dramatic effect on muscle symptoms.

Metabolic Outcomes of Anaplerotic Dodecanedioic Acid Supplementation in Very Long Chain Acyl-CoA Dehydrogenase (VLCAD) Deficient Fibroblasts

“…At the baseline, VLCAD deficient cells demonstrated decreased levels of succinate, α-KG, and citrate ( Figure 3 ). A depletion of Krebs cycle intermediates that was recently also reported in VLCAD (−/−) mice [ 40 ] and eight VLCAD patients [ 18 ] contributes further to energy-related impairments associated with the VLCAD phenotype.…”

“…Effect on Krebs cycle intermediates: increase plasma citrate, aconitate, fumarate, and malate in VLCAD affected individuals [ 18 ]…”

“…Effect on lipids profile: increase in odd chain sphingomyelins, phosphatidylcholines, and phosphatidylethanolamines in VLCAD affected individuals [ 18 ]…”

“…This therapeutic approach is directed towards the restoration of energy production by replenishing pools of Krebs cycle intermediates [ 14 ] while bypassing defective β-oxidation of long-chain fatty acids (LCFA). Nutritional therapy with a recently FDA-approved anaplerotic triglyceride triheptanoin in VLCADD demonstrated long-term positive effects, such as improvement of some clinical symptoms and hospitalization frequency [ 15 , 16 , 17 , 18 ]. Nevertheless, VLCADD presents with a very heterogenic phenotype and clinical outcomes under triheptanoin supplementation are also heterogenic [ 16 , 17 ].…”

“…Metabolites 2021, 11, x FOR PEER REVIEW 2 of 13 acids (LCFA). Nutritional therapy with a recently FDA-approved anaplerotic triglyceride triheptanoin in VLCADD demonstrated long-term positive effects, such as improvement of some clinical symptoms and hospitalization frequency [15][16][17][18]. Nevertheless, VLCADD presents with a very heterogenic phenotype and clinical outcomes under triheptanoin supplementation are also heterogenic [16,17].…”