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JAMA Neurol. 2014 Oct;71(10):1255-65. doi: 10.1001/jamaneurol.2014.1584.

Triheptanoin for glucose transporter type I deficiency (G1D): modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement.

Author information

1
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.
2
Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas.
3
Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas.
4
Department of Psychology, Children's Medical Center Dallas, Dallas, Texas.
5
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.
6
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.
7
Department of Clinical Sciences (Biostatistics), The University of Texas Southwestern Medical Center, Dallas10Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas.
8
Department of Psychology, Children's Medical Center Dallas, Dallas, Texas10Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas.
9
Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas10Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas.

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 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.

PMID:
25110966
PMCID:
PMC4376124
DOI:
10.1001/jamaneurol.2014.1584
[Indexed for MEDLINE]
Free PMC Article

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