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Original Investigation
October 2014

Triheptanoin for Glucose Transporter Type I Deficiency (G1D): Modulation of Human Ictogenesis, Cerebral Metabolic Rate, and Cognitive Indices by a Food Supplement

Author Affiliations
  • 1Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas
  • 2Department of Physiology, The University of Texas Southwestern Medical Center, Dallas
  • 3Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas
  • 4Eugene McDermott Center for Human Growth and Development/Center for Human Genetics, The University of Texas Southwestern Medical Center, Dallas
  • 5Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas
  • 6Department of Psychology, Children’s Medical Center Dallas, Dallas, Texas
  • 7Advanced Diagnostics Laboratory, Children’s Medical Center, Dallas, Texas
  • 8Department of Pathology, The University of Texas Southwestern Medical Center, Dallas
  • 9Department of Clinical Sciences (Biostatistics), The University of Texas Southwestern Medical Center, Dallas
  • 10Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas
JAMA Neurol. 2014;71(10):1255-1265. doi:10.1001/jamaneurol.2014.1584

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 Participants  Unsponsored, 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 Measures  First, 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 Relevance  Triheptanoin 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.