Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington's disease

Abstract

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 (31)P-NMR spectroscopy (NMRS) in muscle. At baseline, (31)P-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.

Figures

Figure 1

End-exercise pH before (1) and after (2) triheptanoin in six patients with Huntington's disease (P1–P6). We observed normalization of the pH in the two patients (P5 and P6) with pretreatment metabolic abnormalities.

Figure 2

Perfusion kinetics during exercise recovery before and after treatment in patients 5 and 6. The global hyperemic response was improved after treatment: more regular and rapid return to basal level for patient 5 (left panel) and distinction of a peak of hyperemia before reaching basal level of perfusion for patient 6 (right panel).