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Summary: A mentally retarded boy exhibiting both hyper-D-glyceric acidemia and hyperglycinemia and in whom a deficiency of D-glycerate dehydrogenase had previously been demonstrated was investigated to elucidate the ethiology of the glycine accumulation and its relationship to the D-glyceric acid accumulation. It was found that a positive correlation existed between excretion of D-glyceric acid and glycine (coefficient of correlation: r = 0.62, P < 0.001), that part of the IV injected [14C]glycine was metabolized to D-glyceric acid whereas no [14C]glyceric acid was metabolized to glycine, and that the in vivo degradation of IV injected [14C]glycine to 14CO2was diminished. Measurement of glycine cleavage activity in autoptic liver tissue from the patient showed only 10% of normal activity. It is argued that this diminished activity could be caused by an endogenous inhibitor, D-glyceric acid is demonstrated not to possess such an inhibitory effect. Based on the finding of increased urinary excretion of both free and conjugated isobutyric acid, 2-methylbutyric acid, and isovaleric acid, it is hypothesized that the diminished glycine cleavage activity might be due, at least partially, to inhibition by 2-methylbutyryl-CoA and isobutyryl-CoA, two compounds that are known to inhibit the glycine cleavage system.Speculation: The deranged branched-chain amino acid metabolism demonstrated in this patient is. like the hyperglycinemia, considered to be a secondary phenomenon, possibly caused by the D-glyceric acidemia.

Extract: Studies of a mentally retarded boy, clinically suffering from nonketotic hyperglycinemia, are reported. Using combined gas chromatography-mass spectrometry, enzyme specificity studies, and spectropolariometry D-glyceric acid in extremely elevated concentrations was demonstrated in both serum and urine (serum: 1.0–1.3 mmol/liter, urine: 33–187 mmol/liter). Hydroxypyruvic acid was not detectable in urine from this boy using a gas chromatographic method with a limit of detection of 0.3 mmol/liter. Enzyme assays of D-glyceric dehydrogenase on blood leukocytes demonstrated significantly lower activity in the patient compared with five normal children.Speculation: The accumulation of glycine in this new metabolic defect may result from a secondary inhibition of the glycine cleavage system, an explanation that would correspond well with the current concept on the genesis of the glycine accumulation found in ketotic hyperglycinemia.

Summary: The abnormal metabolites-adipic, suberic, and sebacic acids-were detected in large amounts in the urine of a boy during a Reye's syndrome-like crisis. Substantial amounts of 5-OH-caproic acid, caproylglycine, glutaric acid, and 3-OH-butyric acid and moderately elevated amounts of ethylmalonic acid, methylsuccinic acid, 3-OH-isovaleric acid, and isovalerylglycine were also found. These metabolites were consistently present in urine samples collected in the boy's habitual condition after the attack. 1-[14C]-Palmitic acid was oxidized at a normal rate, whereas U-[14C]-Palmitic acid was oxidized at a reduced rate in cultured skin fibroblasts from the patient, thus indicating a defect at the level of medium- and/or short-chain fatty acid oxidation. Riboflavin medication (100 mg three times a day) significantly reduced the excreted amounts of pathologic metabolites, suggesting a flavineadeninedinucleotide-related acyl-CoA dehydrogenation defect as the cause of the disease.Carnitine in plasma was low in the patient (6 µmole/liter, controls 26–74 µmole/liter), suggesting carnitine deficiency as a secondary effect of the acyl-CoA dehydrogenation deficiency.Speculation: The present patient, who presented with a Reye's syndrome-like attack, suffers from impaired dehydrogenation of acyl-CoA resulting in accumulation of acyl-CoA in the cells. Attacks with similar symptoms are seen in other acyl-CoA dehydrogenation deficiencies, such as glutaric aciduria types I and II, other types of C6—C10-dicarboxylic acidurias and isovaleric acidemia. Reduced flow through the acyl-CoA dehydrogenation steps may therefore be an ethiologic factor in Reye's syndrome. Several of the accumulated acyl-CoA's are toxic and may be responsible for some of the symptoms. The low carnitine level in plasma and the elevated esterified carnitine excretion in the present patient indicate that acyl-CoA accumulation may cause a functional carnitine deficiency by sequestration of carnitine as acyl-carnitines. As the inborn defect, systemic carnitine deficiency may exhibit symptoms like those of Reye's syndrome, it may be speculated whether functional carnitine deficiency in patients with accumulated acyl-CoA is another causal factor in the development of the symptoms during attacks.