title: Triheptanoin for glucose transporter type I deficiency (G1D): modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Supplementation of the regular diet with food-grade triheptanoin.
  
  
  METHODS
  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
  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.
authors.affiliation: Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas2Department of Physiology, The University of Texas Southwestern Medical Center, Dallas3Department of Pediatrics, The Un.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Pascual
authors.affiliation: Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Peiying
authors.initials: P
authors.lastname: Liu
authors.affiliation: Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Deng
authors.initials: D
authors.lastname: Mao
authors.affiliation: Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Dorothy I
authors.initials: DI
authors.lastname: Kelly
authors.affiliation: Department of Psychology, Children's Medical Center Dallas, Dallas, Texas.
authors.forename: Ana
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Min
authors.initials: M
authors.lastname: Sheng
authors.affiliation: Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Levi B
authors.initials: LB
authors.lastname: Good
authors.affiliation: Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas3Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Isaac
authors.initials: I
authors.lastname: Marin-Valencia
authors.affiliation: Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Xuchen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Eugene McDermott Center for Human Growth and Development/Center for Human Genetics, The University of Texas Southwestern Medical Center, Dallas7Advanced Diagnostics Laboratory, Children's Medical Center, Dallas, Texas8Department of Pathology, The Universi.
authors.forename: Jason Y
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Clinical Sciences (Biostatistics), The University of Texas Southwestern Medical Center, Dallas10Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Hynan
authors.affiliation: Department of Psychology, Children's Medical Center Dallas, Dallas, Texas10Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Peter
authors.initials: P
authors.lastname: Stavinoha
authors.affiliation: Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Roe
authors.affiliation: Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas10Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas.
authors.forename: Hanzhang
authors.initials: H
authors.lastname: Lu
mesh_terms: D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002239:Carbohydrate Metabolism, Inborn Errors / Q000188:drug therapy* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002952:Citric Acid Cycle; D015331:Cohort Studies; D019587:Dietary Supplements; D004569:Electroencephalography; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000172:deficiency* / Q000378:metabolism; D016896:Treatment Outcome; D014280:Triglycerides / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D009004:Monosaccharide Transport Proteins; D014280:Triglycerides; C531010:triheptanoin; D005947:Glucose
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