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Summary: The main substrates for brain energy metabolism were measured in blood samples taken from the carotid artery and the internal jugular bulb of four children with glycogen storage disease caused by deficiency of glucose-6-phosphatase. Multiple paired arterial and venous blood samples were analyzed for glucose, lactate, pyruvate, D-ß-hydroxybutyrate, acetoacetate, glycerol and O2, and the arteriovenous differences of the concentrations were calculated. In the first three patients the substrates were measured in two successive conditions with lower and higher glucose-intake, respectively, inducing reciprocally higher and lower concentrations of blood lactate. In the fourth patient medium chain triglycerides were administered simultaneously with the glucose-containing gastric drip feeding.Lactate appeared to be taken up significantly. It consumed, if completely oxidized, between 40-50% of the total O2uptake in most cases. Only once in one patient the uptake of lactate switched to its release, when the blood lactate level decreased to normal. D-ß-hydroxybutyrate and acetoacetate arteriovenous (AV) differences were small to negligible and these ketone bodies, therefore, did not contribute substantially to the brain's energy expenditure. Glycerol was not metabolized by the brain. Lactate thus appeared to be the second brain fuel next to glucose. It may protect the brain against fuel depletion in case of hypoglycemia.

We found evidence for an increased oxidation of fatty acids in two Silver-Russell patients (dwarfism of prenatal onset, typical craniofacial appearance and dystrophy).Fasting studies showed elevated blood and urine levels of ß-hydroxybutyrate (BHB) and aceto-acetate (AA) and a massive urinary excretion of C6-C12dicarboxylic acids. After 20 hrs of fasting BHB in blood was 3.50 and 3.50 mmol/1 while AA was 1.02 and 1.12 mmol/1 in the two Silver-Russell dwarfs, respectively. Seven controls of comparable age (1-2½ yr) had significanly lower blood levels of BHB (mean: 1.68 mmol/l) and AA (mean: 0.63 mmol/1). GC-MS analysis of urine organic acids of both Silver-Russell patients showed a very similar pattern with a massive excretion of BHB (<10 mmol/1) and C6-C12dicarboxylic acids (adipic acid, suberic acid, sebacic acid, C12-dicarboxylic acid, cis/trans unsaturated suberic acid and sebacic acid, cis unsaturated 3-OH-derivates of sebacic acid and C12dicarboxylic acid). In contrast controls had a low excretion of BHB (<1 mmol/l), while C6-C12dicarboxylic acids were present in very small amounts or not detectable. The combination of both an activated ß-oxidation resulting in high blood and urine levels of BHB and AA, and an activated ?-oxidation resulting in a massive urinary excretion of dicarboxylic acids is very typical.We suggest that this increased oxidation of fatty acids is a distinct feature in the Silver-Russell syndrome and might provide an explanation for the dystrophy which is so characteristic.