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Original Investigation |

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

Juan M. Pascual, MD, PhD1,2,3,4; Peiying Liu, PhD5; Deng Mao, BS5; Dorothy I. Kelly, MA1; Ana Hernandez, MS6; Min Sheng, PhD5; Levi B. Good, PhD1; Qian Ma, MD, PhD1; Isaac Marin-Valencia, MD, MS1,3; Xuchen Zhang, MD1; Jason Y. Park, MD, PhD4,7,8; Linda S. Hynan, PhD9,10; Peter Stavinoha, PhD6,10; Charles R. Roe, MD1; Hanzhang Lu, PhD5,10
[+] 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.
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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.

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Figures

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Figure 1.
Flow Diagram of Study Visits and Procedures

Each patient participated in 3 visits. A limited number of patients underwent electroencephalogram (EEG) and magnetic resonance imaging (MRI) at the 3-month follow-up visit.

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Figure 2.
Electroencephalogram (EEG)-Captured Spike-Wave Seizures in Patients With Glucose Transporter Type 1 Deficiency

A, An example segment of an EEG recording containing 3 spike-wave seizure periods. Electrode positioning followed standard abbreviated nomenclature. Vertical bars indicate 1 second. B, Illustration of the identification of seizure duration. C, The seizure-nonseizure binarized time course of a representative participant. Spike-wave periods are represented as bar plots against an EEG time course in the setting of a nonseizure baseline state. The pink bar indicates triheptanoin (oil) administration.

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Figure 3.
Seizure Rate Reduction After Acute Triheptanoin Oil Consumption

A, Seizure rate of all participants before and after triheptanoin oil consumption. B, Data representing the seizure rate of all participants except GD002 (who exhibited the largest seizure rate) before and after triheptanoin oil consumption. The vertical axis (note the different ranges) represents the fractional seizure rate in both panels. Participant GD007 manifested no seizure or other EEG abnormalities, and triheptanoin had no effect on his EEG.

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Figure 4.
Neuropsychological Indices in Patients With Glucose Transporter Type I Deficiency (G1D) After Triheptanoin Food Supplementation

Vocabulary performance improved acutely and over long-term follow-up with triheptanoin supplementation. The neuropsychological scores of all 8 participants before and after triheptanoin use are represented. Standardized Peabody Picture Vocabulary Test, Fourth Edition (PPVT-4), and Expressive Vocabulary Test, Second Edition (EVT-2), ratings were obtained in the fasting state (baseline) at time 0 minutes (PPVT-4 1A) and 60 minutes (PPVT-4 1B) following triheptanoin ingestion and then after 3 months of daily triheptanoin supplementation (PPVT-4 2). PPVT-4 and EVT-2 scores were below normal for the age ranges and increased at subsequent time points in rigorously statistically significant fashion. The interquartile ranges (IQRs) for the PPVT-4 scaled scores at each of the 3 time points were 59-75, 62-86, and 61-84, respectively. PPVT-4 scores improved significantly over time (Friedman test; P = .03). The IQRs for the EVT-2 scaled scores at each of the 3 time points were 60-80, 57-84, and 65-89, respectively. EVT-2 scores improved significantly over time (Friedman test, P = .02).

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Figure 5.
Magnetic Resonance Imaging–Measured Cerebral Metabolic Rate (CMRO2) in Patients Before and After Acute Triheptanoin Oil (C7) Consumption

In participants GD009 and GD007, CMRO2 was measured again 5 to 6 months after triheptanoin oil consumption. The reference values for CMRO2 have been measured by us in a broad adult age range and are sex dependent (ie, females exhibit higher CMRO2 than males). At ages 21 and 28 years, the CMRO2 reference values for men are 149 and 154 µmol/100 g/min, respectively. The SD for none of our normal CMRO2 measurements exceeded 12.5 µmol/100 g/min (unpublished findings).

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