title: The ketogenic diet compensates for AGC1 deficiency and improves myelination.
abstract: 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.
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Dahlin
authors.affiliation: Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Martin
authors.affiliation: Department of Nutrition, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Zandra
authors.initials: Z
authors.lastname: Hedlund
authors.affiliation: Center of Child Neurology and Habilitation, Östersund Hospital, Östersund, Sweden.
authors.forename: Monica
authors.initials: M
authors.lastname: Jonsson
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.|Center for Inherited Metabolic Diseases (CMMS), Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: von Döbeln
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Wedell
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000172:deficiency*; D017920:Antiporters / Q000172:deficiency*; D002648:Child; D055423:Diet, Ketogenic / Q000379:methods*; D005260:Female; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis* / Q000178:diet therapy*; D006801:Humans; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000178:diet therapy*; D011596:Psychomotor Disorders / Q000175:diagnosis* / Q000178:diet therapy*
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D017920:Antiporters
keywords: Aspartate-glutamate carrier; Inborn error of metabolism; Ketogenic diet; Malate-aspartate shuttle; Redox status; Secondary hypomyelination