JIMD Reports, Volume 38

Habarou, F., Bahi-Buisson, N., Lebigot, E., Pontoizeau, C., Abi-Warde, M. T., Brassier, A., Le Quan Sang, K. H., Broissand, C., Vuillaumier-Barrot, S., Roubertie, A., Boutron, A., Ottolenghi, C., de Lonlay, P., 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, P. de Lonlay

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. We designed a partial or total progressive substitution of KD with L,D-3-hydroxybutyrate in three GLUT1-DS and two PDHD patients. 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 (14)C-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. 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.