Triheptanoin for Glucose Transporter Type I Deficiency (G1D)

Abstract

IMPORTANCE Disorders of brain metabolism are multiform in their mechanisms and manifestations, many of which remain insufficiently understood and are thus similarly treated. Glucose transporter type I deficiency (G1D) is commonly associated with seizures and with electrographic spike-waves. The G1D syndrome has long been attributed to energy (ie, adenosine triphosphate synthetic) failure such as that consequent to tricarboxylic acid (TCA) cycle intermediate depletion. Indeed, glucose and other substrates generate TCAs via anaplerosis. However, TCAs are preserved in murine G1D, rendering energy-failure inferences premature and suggesting a different hypothesis, also grounded on our work, that consumption of alternate TCA precursors is stimulated and may be detrimental. Second, common ketogenic diets lead to a therapeutically counterintuitive reduction in blood glucose available to the G1D brain and prove ineffective in one-third of patients.OBJECTIVE To identify the most helpful outcomes for treatment evaluation and to uphold (rather than diminish) blood glucose concentration and stimulate the TCA cycle, including anaplerosis, in G1D using the medium-chain, food-grade triglyceride triheptanoin. DESIGN, SETTING, AND PARTICIPANTSUnsponsored, open-label cases series conducted in an academic setting. Fourteen children and adults with G1D who were not receiving a ketogenic diet were selected on a first-come, first-enrolled basis.INTERVENTION Supplementation of the regular diet with food-grade triheptanoin. MAIN OUTCOMES AND MEASURESFirst, we show that, regardless of electroencephalographic spike-waves, most seizures are rarely visible, such that perceptions by patients or others are inadequate for treatment evaluation. Thus, we used quantitative electroencephalographic, neuropsychological, blood analytical, and magnetic resonance imaging cerebral metabolic rate measurements.RESULTS One participant (7%) did not manifest spike-waves; however, spike-waves promptly decreased by 70% (P = .001) in the other participants after consumption of triheptanoin. In addition, the neuropsychological performance and cerebral metabolic rate increased in most patients. Eleven patients (78%) had no adverse effects after prolonged use of triheptanoin. Three patients (21%) experienced gastrointestinal symptoms, and 1 (7%) discontinued the use of triheptanoin. CONCLUSIONS AND RELEVANCETriheptanoin can favorably influence cardinal aspects of neural function in G1D. In addition, our outcome measures constitute an important framework for the evaluation of therapies for encephalopathies associated with impaired intermediary metabolism.

From splitting GLUT1 deficiency syndromes to overlapping phenotypes

“…Our study provides a comprehensive overview of the variety of symptoms associated with GLUT1DS and their variability with age. Consequently, our data underlines the considerable delay in diagnosing the disease (even considering that mutational analysis was available since 1998 [Seidner et al, 1998] in our cohort only 6 patients exhibited symptoms before 1998, thus the median delay between 1998 and the age at diagnosis, was still 6 years (12 months-11years 7months)), when a potential treatment can be proposed with KD, and maybe in the future other potential treatments [Pascual et al, 2014]. Prior studies have emphasized the wide range of epilepsies associated with GLUT1DS [Arsov et al, 2012a[Arsov et al, , 2012bMullen, 2011;Mullen et al, 2010;Pong et al, 2012;Striano et al, 2012;Suls et al, 2009].…”

New insights into the mechanisms of the ketogenic diet

“…A small scale open-label case series tested the effects of triheptanoin-supplemented diets in 14 patients with inborn glucose transporter type I deficiency. The authors of this study reported a modest improvement in ictal events, but the underlying mechanisms were not further evaluated [20]. Branched octanoic acid compounds have been generated that show promising antiseizure activity in in vitro and in vivo seizure models, without affecting histone deacetylase activity [21].…”

Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments

“…The ability of triheptanoin to provide both acetyl-CoA and propionyl-CoA makes it an ideal metabolic treatment for disorders with deficient levels of TCA cycle intermediates and impairments in energy production. For instance, triheptanoin alleviated metabolic disturbances associated with several neurological and neuromuscular disorders and improved symptoms in models of epilepsy (Willis et al, 2010; Thomas et al, 2012; Hadera et al, 2014), Canavan disease (Francis et al, 2014), autism disorders (Park et al, 2014) and Alzheimer's Disease (Aso et al, 2013) as well as patients and a mouse model of glucose transporter 1 deficiency (Marin-Valencia et al, 2013; Pascual et al, 2014; Mochel et al, 2016), and patients with Huntington's disease (Mochel et al, 2010; Adanyeguh et al, 2015). In chronically “epileptic” mice it was shown that triheptanoin partially restores reduced TCA cycle intermediate and metabolite levels (Willis et al, 2010; Hadera et al, 2014).…”