TY - JOUR
T1 - Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington's disease
AU - Mochel, Fanny
AU - Duteil, Sandrine
AU - Marelli, Cécilia
AU - Jauffret, Céline
AU - Barles, Agnès
AU - Holm, Janette
AU - Sweetman, Lawrence
AU - Benoist, Jean François
AU - Rabier, Daniel
AU - Carlier, Pierre G.
AU - Durr, Alexandra
PY - 2010/9
Y1 - 2010/9
N2 - We previously identified a systemic metabolic defect associated with early weight loss in patients with Huntington's disease (HD), suggesting a lack of substrates for the Krebs cycle. Dietary anaplerotic therapy with triheptanoin is used in clinical trials to promote energy production in patients with peripheral and brain Krebs cycle deficit, as its metabolites-C5 ketone bodies-cross the blood-brain barrier. We conducted a short-term clinical trial in six HD patients (UHDRS (Unified Huntington Disease Rating Scale)=33±13, 15-49) to monitor the tolerability of triheptanoin. We also assessed peripheral markers of short-term efficacy that were shown to be altered in the early stages of HD, that is, low serum IGF1 and 31P-NMR spectroscopy (NMRS) in muscle. At baseline, 31P-NMRS displayed two patients with end-exercise muscle acidosis despite a low work output. On day 2, the introduction of triheptanoin was well tolerated in all patients, and in particular, there was no evidence of mitochondrial overload from triheptanoin-derived metabolites. After 4 days of triheptanoin-enriched diet, muscle pH regulation was normalized in the two patients with pretreatment metabolic abnormalities. A significant increase in serum IGF1 was also observed in all patients (205±60 ng/ml versus 246±68 ng/ml, P=0.010). This study provides a rationale for extending our anaplerotic approach with triheptanoin in HD.
AB - We previously identified a systemic metabolic defect associated with early weight loss in patients with Huntington's disease (HD), suggesting a lack of substrates for the Krebs cycle. Dietary anaplerotic therapy with triheptanoin is used in clinical trials to promote energy production in patients with peripheral and brain Krebs cycle deficit, as its metabolites-C5 ketone bodies-cross the blood-brain barrier. We conducted a short-term clinical trial in six HD patients (UHDRS (Unified Huntington Disease Rating Scale)=33±13, 15-49) to monitor the tolerability of triheptanoin. We also assessed peripheral markers of short-term efficacy that were shown to be altered in the early stages of HD, that is, low serum IGF1 and 31P-NMR spectroscopy (NMRS) in muscle. At baseline, 31P-NMRS displayed two patients with end-exercise muscle acidosis despite a low work output. On day 2, the introduction of triheptanoin was well tolerated in all patients, and in particular, there was no evidence of mitochondrial overload from triheptanoin-derived metabolites. After 4 days of triheptanoin-enriched diet, muscle pH regulation was normalized in the two patients with pretreatment metabolic abnormalities. A significant increase in serum IGF1 was also observed in all patients (205±60 ng/ml versus 246±68 ng/ml, P=0.010). This study provides a rationale for extending our anaplerotic approach with triheptanoin in HD.
KW - Huntington's disease
KW - Krebs cycle
KW - clinical trial
KW - magnetic resonance spectroscopy
KW - triheptanoin
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U2 - 10.1038/ejhg.2010.72
DO - 10.1038/ejhg.2010.72
M3 - Article
C2 - 20512158
AN - SCOPUS:77955984220
SN - 1018-4813
VL - 18
SP - 1057
EP - 1060
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 9
ER -