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, Peiying Liu, Deng Mao, Dorothy I. Kelly, Ana Hernandez, Min Sheng, Levi B. Good, Qian Ma, Isaac Marin-Valencia, Xuchen Zhang, Jason Y. Park, Linda S. Hynan, Peter Stavinoha, Charles R. Roe, Hanzhang Lu

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 showthat, 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 intermediarymetabolism.

Original languageEnglish (US)
Pages (from-to)1255-1265
Number of pages11
JournalJAMA Neurology
Volume71
Issue number10
DOIs
StatePublished - Oct 1 2014

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Facilitative Glucose Transport Proteins
Dietary Supplements
Ketogenic Diet
Citric Acid Cycle
Brain Diseases
Blood Glucose
Seizures
Tricarboxylic Acids
Outcome Assessment (Health Care)
Food Chain
triheptanoin
Food
Supplements
Modulation
Triglycerides
Adenosine Triphosphate
Magnetic Resonance Imaging
Waves
Diet
Glucose

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology
  • Medicine(all)

Cite this

Triheptanoin for glucose transporter type i deficiency (G1D) : Modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement. / Pascual, Juan M.; Liu, Peiying; Mao, Deng; Kelly, Dorothy I.; Hernandez, Ana; Sheng, Min; Good, Levi B.; Ma, Qian; Marin-Valencia, Isaac; Zhang, Xuchen; Park, Jason Y.; Hynan, Linda S.; Stavinoha, Peter; Roe, Charles R.; Lu, Hanzhang.

In: JAMA Neurology, Vol. 71, No. 10, 01.10.2014, p. 1255-1265.

Research output: Contribution to journalArticle

Pascual, JM, Liu, P, Mao, D, Kelly, DI, Hernandez, A, Sheng, M, Good, LB, Ma, Q, Marin-Valencia, I, Zhang, X, Park, JY, Hynan, LS, Stavinoha, P, Roe, CR & Lu, H 2014, 'Triheptanoin for glucose transporter type i deficiency (G1D): Modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement', JAMA Neurology, vol. 71, no. 10, pp. 1255-1265. https://doi.org/10.1001/jamaneurol.2014.1584
Pascual, Juan M. ; Liu, Peiying ; Mao, Deng ; Kelly, Dorothy I. ; Hernandez, Ana ; Sheng, Min ; Good, Levi B. ; Ma, Qian ; Marin-Valencia, Isaac ; Zhang, Xuchen ; Park, Jason Y. ; Hynan, Linda S. ; Stavinoha, Peter ; Roe, Charles R. ; Lu, Hanzhang. / Triheptanoin for glucose transporter type i deficiency (G1D) : Modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement. In: JAMA Neurology. 2014 ; Vol. 71, No. 10. pp. 1255-1265.
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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 showthat, 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 intermediarymetabolism.",
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T2 - Modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement

AU - Pascual, Juan M.

AU - Liu, Peiying

AU - Mao, Deng

AU - Kelly, Dorothy I.

AU - Hernandez, Ana

AU - Sheng, Min

AU - Good, Levi B.

AU - Ma, Qian

AU - Marin-Valencia, Isaac

AU - Zhang, Xuchen

AU - Park, Jason Y.

AU - Hynan, Linda S.

AU - Stavinoha, Peter

AU - Roe, Charles R.

AU - Lu, Hanzhang

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N2 - 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 showthat, 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 intermediarymetabolism.

AB - 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 showthat, 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 intermediarymetabolism.

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