The ketogenic diet compensates for AGC 1 deficiency and improves myelination
2015; Wiley; Volume: 56; Issue: 11 Linguagem: Inglês
10.1111/epi.13193
ISSN1528-1167
AutoresMaria Dahlin, Daniel Martín Muñoz, Zandra Hedlund, Monica Jönsson, Ulrika von Döbeln, Anna Wedell,
Tópico(s)Amino Acid Enzymes and Metabolism
ResumoSummary The brain aspartate‐glutamate carrier ( AGC 1) 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 AGC 1 underlies an inborn error of metabolism that presents with severe hypotonia, arrested psychomotor development, and seizures from a few months of age. In AGC 1 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 AGC 2 deficiency, we predicted that reduced glycolysis should compensate for the metabolic defect and allow resumed myelination in AGC 1 deficiency. Carbohydrate restriction was therefore initiated in a patient with AGC 1 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 AGC 1 is driven by the proton gradient generated by the neuronal mitochondrial respiratory chain, the results have potential relevance for secondary hypomyelination in general.
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