Send to

Choose Destination
Epilepsia. 2015 Nov;56(11):e176-81. doi: 10.1111/epi.13193. Epub 2015 Sep 24.

The ketogenic diet compensates for AGC1 deficiency and improves myelination.

Author information

Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
Department of Neuropediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
Department of Nutrition, Karolinska University Hospital, Stockholm, Sweden.
Center of Child Neurology and Habilitation, Östersund Hospital, Östersund, Sweden.
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Center for Inherited Metabolic Diseases (CMMS), Karolinska University Hospital, Stockholm, Sweden.
Department of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.


The brain aspartate-glutamate carrier (AGC1) is specifically expressed in neurons, where it transports aspartate from the mitochondria to the cytosol, and plays a role in transfer of nicotinamide adenine dinucleotide (NADH)-reducing equivalents into the mitochondria as a part of the malate-aspartate shuttle. Deficient function of AGC1 underlies an inborn error of metabolism that presents with severe hypotonia, arrested psychomotor development, and seizures from a few months of age. In AGC1 deficiency, there is secondary hypomyelination due to lack of N-acetylaspartate (NAA), which is normally generated by acetylation of aspartate in the neuron and required for fatty acid synthesis by the adjacent oligodendrocyte. Based on experiences from AGC2 deficiency, we predicted that reduced glycolysis should compensate for the metabolic defect and allow resumed myelination in AGC1 deficiency. Carbohydrate restriction was therefore initiated in a patient with AGC1 deficiency at 6 years of age by introducing a ketogenic diet. The response was dramatic, clinically as well as radiologically. Psychomotor development showed clear improvement, and magnetic resonance imaging (MRI) indicated resumed myelination. This is the first successful treatment of secondary hypomyelination reported. Because AGC1 is driven by the proton gradient generated by the neuronal mitochondrial respiratory chain, the results have potential relevance for secondary hypomyelination in general.


Aspartate-glutamate carrier; Inborn error of metabolism; Ketogenic diet; Malate-aspartate shuttle; Redox status; Secondary hypomyelination

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center