Ketone Bodies as a Possible Adjuvant to Ketogenic Diet in PDHc Deficiency but Not in GLUT1 Deficiency

Abstract

Objective: Ketogenic diet is the first line therapy for neurological symptoms associated with pyruvate dehydrogenase deficiency (PDHD) and intractable seizures in a number of disorders, including GLUT1 deficiency syndrome (GLUT1-DS). Because high-fat diet raises serious compliance issues, we investigated if oral l,d-3-hydroxybutyrate administration could be as effective as ketogenic diet in PDHD and GLUT1-DS.

Methods: We designed a partial or total progressive substitution of KD with l,d-3-hydroxybutyrate in three GLUT1-DS and two PDHD patients.

Results: In GLUT1-DS patients, we observed clinical deterioration including increased frequency of seizures and myoclonus. In parallel, ketone bodies in CSF decreased after introducing 3-hydroxybutyrate. By contrast, two patients with PDHD showed clinical improvement as dystonic crises and fatigability decreased under basal metabolic conditions. In one of the two PDHD children, 3-hydroxybutyrate has largely replaced the ketogenic diet, with the latter that is mostly resumed only during febrile illness. Positive direct effects on energy metabolism in PDHD patients were suggested by negative correlation between ketonemia and lactatemia (r ² = 0.59). Moreover, in cultured PDHc-deficient fibroblasts, the increase of CO₂ production after ¹⁴C-labeled 3-hydroxybutyrate supplementation was consistent with improved Krebs cycle activity. However, except in one patient, ketonemia tended to be lower with 3-hydroxybutyrate administration compared to ketogenic diet.

Conclusion: 3-hydroxybutyrate may be an adjuvant treatment to ketogenic diet in PDHD but not in GLUT1-DS under basal metabolic conditions. Nevertheless, ketogenic diet is still necessary in PDHD patients during febrile illness.

Appendices

Take-Home Message

3-Hydroxybutyrate may be used as an adjuvant to ketogenic diet in PDHD, not in GLUT1-DS, and only under basal metabolic conditions.

Contribution of Individual Authors

Acquisition, analysis, interpretation of data: F. Habarou, E. Lebigot, A. Boutron, S. Vuillaumier-Barrot, C. Pontoizeau, C. Ottolenghi, P. de Lonlay.

Clinical work and treatment supervision: N. Bahi-Buisson, M.T. Abi-Warde, A. Brassier, A. Roubertie, K.H. Le Quan Sang, C. Broissand, P. de Lonlay.

Drafting of the manuscript: F. Habarou, C. Ottolenghi, P. de Lonlay.

Critical revision of the manuscript: all authors.

Corresponding Author

Pr Pascale de Lonlay, Reference Center of Inherited Metabolic Diseases, Necker Enfants Malades Hospital, AP-HP, 149 rue de Sèvres, 75015 Paris, France; pascale.delonlay@aphp.fr.

Competing Interest Statement

F. Habarou, N. Bahi-Buisson, E. Lebigot, C. Pontoizeau_, M.T. Abi-Warde, A. Brassier, K.H. Le Quan Sang, C. Broissand, S. Vuillaumier-Barrot, A. Roubertie, A. Boutron, C. Ottolenghi, and P. de Lonlay declare that they have no conflict of interest.

This work is academic. It was carried out by clinicians and biologists independent of any pharmaceutical company.

Funding

The authors did not receive any specific private financial support for the research, authorship, and/or publication of this article. We thank the “Jérôme Lejeune” foundation (2014), and Associations of Families (Nos Anges, AMMI, Noa Luu, Hyperinsulinisme).

Ethics Approval and Patient Consent

This work was approved by our institutional ethical committee after declaration to the Département de la Recherche Clinique et du Développement, and informed consent was obtained from the parents.