Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency

Abstract

Objective: On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets.

Methods: We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7-47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional (31)P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus.

Results: Patients with GLUT1-DS experienced a mean of 30.8 (± 27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (± 2.9, 76% motor events) during the treatment phase (p = 0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (± 21.9, 52% motor events; p = 0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p = 0.021), and deteriorated when triheptanoin was withdrawn.

Conclusions: Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS.

Trial registration number: NCT02014883.

Keywords: METABOLIC DISEASE; MOVEMENT DISORDERS.

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Figures

Figure 1

(A) Number of total paroxysmal manifestations in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) during the three phases of the study (baseline, treatment and withdrawal) of 2 months each. A significant reduction of non-epileptic paroxysmal manifestations was observed when patients were treated with triheptanoin for 2 months (*p31P-NMR spectroscopy (f-MRS) studies during the three phases of the study (baseline, treatment and withdrawal). During baseline, f-MRS showed an abnormal brain energy profile in patients with GLUT1-DS with no change in the Pi/PCr ratio during visual stimulation. After 2 months of treatment with triheptanoin, the profile was corrected and we observed an increase in the Pi/PCr ratio during visual stimulation followed by a decrease during recovery (*p=0.021). Error bars represent SEM of within-subject differences using the method of Morey.