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Four L-glutamate neurotransmitter transporters, the three Na(+)-dependent GLAST-1, GLT-1 and EAAC-1, and the Cl(-)-dependent EAAT-4, form a new family of structurally related integral plasma membrane proteins with different distribution in the central nervous system. They may have pivotal functions in the regulation of synaptic L-glutamate concentration during neurotransmission and are believed to prevent glutamate neurotoxicity. To investigate the specific physiological and pathophysiological role of the neuronal EAAC-1, which is also expressed in kidney and small intestine, we have generated two independent mouse lines lacking EAAC-1. eaac-1(-/-) mice develop dicarboxylic aminoaciduria. No neurodegeneration has been observed during a period of >12 months, but homozygous mutants display a significantly reduced spontaneous locomotor activity.

A patient with deficient activity of cytochrome c oxidase in muscle presented at 1 year of age with extreme failure to thrive. He was found to have dicarboxylic aciduria, renal tubular acidosis, and deficiency of carnitine. Treatment with sodium bicarbonate, riboflavin, and carnitine led to considerable improvement in growth and a significant reduction in the dicarboxylic aciduria.

A 38-month-old apparently healthy male has been followed for three years because of a massive glutamic and aspartic aminoaciduria detected shortly after birth in a neonatal screening program. Amino acid clearance studies revealed the presence of renal wastage of dicarboxylic amino acids. Intestinal transport and in vitro oxidation of dicarboxylic amino acids were found to be intact. Clinical and metabolic data obtained on a previously described patient and the present case suggest that some patients with dicarboxylic aminoaciduria might have a selective renal conservation defect without clinical abnormalities, whereas others might demonstrate an additional defect in intestinal transport associated with fasting hypoglycemia.

Administration of maleic acid to rats caused increased urinary excretion of S-(1,2-dicarboxyethyl)cysteine [DCEC] and increased binding of maleic acid to tissue proteins. The trichloroacetic acid precipitate from a combined fraction of supernatant and microsome gave the maximum amount of DCEC after hydrolysis. It would appear that aminoaciduria produced by maleate was partially due to increased destruction of some succinylated tissue proteins.

The case of a mentally retarded girl with a number of dysmorphic features, Raynaud's phenomenon, hypotonia and petit mal seizures is presented. Laboratory investigations showed alpha-aminoadipic aciduria and a high level of fetal haemoglobin. Oral L-lysine loading resulted in a marked increase of alpha-aminoadipic acid in blood and urine. After 3 months of pyridoxine medication the increase of alpha-aminoadipic acid in blood and urine during the oral L-lysine loading test was less than in the test before treatment. A normal degradation rate of DL-alpha-amino [1-14C] adipic acid in fibroblasts of the patient, as measured by 14CO2 production, did not indicate a primary enzyme defect in the alpha-aminoadipic acid transamination or decarboxylation steps. The persistent HbF could be the result of stress on the erythropoiesis by a secondary induced defect in an early stage of haemoglobin synthesis in which alpha-amino-beta-ketoadipic acid, a structural analogue of alpha-amino-adipic acid, is an intermediate.

A new case of alpha-aminoadipic aciduria had an apparent immunodeficiency and died at the age of 4 months. The urine contained large amounts of alpha-aminoadipate and smaller quantities of alpha-keto- and alpha-hydroxyadipate. Post mortem, the highest concentrations of alpha-aminoadipate were found in liver and kidney. Enzymatic studies on liver and cultured fibroblasts failed to demonstrate the expected deficiency of alpha-amino-adipate aminotransferase, a result perhaps explicable by the presence of cytoplasmic aminotransferase activity.

The cerebrohepatorenal syndrome of Zellweger (CHRS) is remarkable not only for a distinctive combination of congenital anomalies, but also for an unusual variety of profound metabolic disturbances. After a discussion of the clinical diagnosis of CHRS, abnormalities in the metabolism of peroxisomes, mitochondria, iron, pipecolic acid, glycogen, bile acids, and organic acids are discussed and related to the clinical and other biochemical findings in the syndrome. Attention is also drawn to syndromes with biochemical or clinical abnormalities similar to those of CHRS. Although the biochemical findings indicate major abnormalities in oxidative metabolism, the primary defect remains obscure.

Five hundred mentally retarded children (of both sexes and under 15 years of age) referred to our institute were screened for aminoacid disorders. One case of dicarboxylic aminoaciduria was found in a girl.

A mentally retarded, 10-year-old female with obesity, hypotonia, clumsiness and mild ocular abnormalities excreted in her urine large amounts of alpha-aminoadipic acid. Amino acid analyser studies and gas-liquid chromatography--mass spectrometry (GC--MS) confirmed the presence of alpha-aminoadipic acid in both urine and plasma but, in contrast to most other patients with this disorder, failed to demonstrate significant levels of alpha-ketoadipic acid in urine. Other known causes of alpha-aminoadipic aciduria were eliminated by showing that levels of lysine, saccharopine and pipecolic acid in plasma and urine were normal and that the activity of glutaryl-CoA dehydrogenase was also normal. Loading with L-lysine and L-tryptophan both increased the concentration of alpha-aminoadipic acid in blood and urine compatible with the primary deficiency of alpha-ketoadipate dehydrogenase, in spite of the absence of alpha-ketoadipic aciduria. Dietary restriction of lysine and administration of vitamins B1 and B6 were unsuccessful in correcting the biochemical abnormality.

A new acidic amino acid has been isolated from the hydrolysate of normal human urine. The chemical structure of the amino acid was determined to be alpha-amino-gamma, delta-dihydroxyadipic acid, based on its physical properties involving nuclear magnetic resonance, infrared and mass spectrometry as well as chemical degradation and chemical synthesis.

Urine samples from 18 individuals with various types of dicarboxylic acidurias have been investigated by mass fragmentography for N-dicarboxyl-mono-glycines (dicarboxylglycines). One patient with methylmalonic acidemia excreted 14-20 microgram methylmalonylglycine/mg creatinine, three patients with glutaric aciduria excreted 20-60 microgram glutarylglycine/creatinine, and one patient with C6-C10-dicarboxylic aciduria excreted 120-365 microgram succinylglycine/mg creatinine. Excretion of C6-C10-dicarboxylic acids in patients with ketosis and glycogenosis and in neonates were not accompanied by excretion of C8-C10-dicarboxylglycines in measurable amounts (greater than 1 microgram/mg creatinine). Nor did patients with succinic aciduria excrete succinylglycine in amounts larger than 1 microgram/mg creatinine. On the basis of these data it is argued that production of short- and medium-chain dicarboxylglycines is not a metabolic pathway of biological significance for the elimination of short- and medium-chain dicarboxylic acids from individuals with dicarboxylic acidurias.

Oxo- and hydroxycarboxylic acids in serum and urine are metabolites of valine, leucine and isoleucine and products of ketogenesis. They are simultaneously determined in the form of their methyl esters and methyl esters-O-methyloximes by gas chromatography, using internal and external standards. Normal values for the urinary excretion of these amino acid metabolites are between 3 +/- 2 mumole per 24 h (mean +/- standard deviation) for 2-oxoisocaproic acid and 122 +/- 58 mumole per 24 h for 3-hydroxyisobutyric acid. In diabetic ketoacidosis the values are increased by a factor of 2-10. In the urine of diabetic patients under fasting conditions all metabolites are elevated and reach a maximum on about the seventh day of fasting. In the serum only 2-oxoisocaproic acid, 3-oxobutyric acid and 3-hydroxybutyric acid reach elevated levels under fasting conditions.

Two brothers previously diagnosed as having alpha-aminoadipic aciduria (alpha-AA) were subjected to a tryptophan loading test to determine if their condition resulted from a defect in the alpha-aminoadipate aminotransferase (kynurenine aminotransferase) system. Normal increases in kynurenic and xanthurenic acids eliminated this possibility. Further analyses of their urines revealed that both boys had measurable amounts of previously undetected alpha-ketoadipic acid (alpha-KA) before and after the loading test. A reexamination of speciments from a prelysine and postlysine loading test reconfirmed the existence of alpha-KA in their urines at the time the original observation of alpha-AA was made. The response to the lysine load was a predictable increase in both alpha-AA and alpha-KA. The boy who had been referred to this institution with a learning defect responded to the tryptophan load with a slight decrease in alpha-AA and an unpredicted decrease in alpha-KA and 3-hydroxykynurenine. His mentally normal brother showed a significant decrease in alpha-AA and major increases in all other measured metabolites including alpha-KA. The latter results were compatible with a defect in the oxidative decarobxylation of alpha-KA. A comparison of the urinary alpha-AA and alpha-KA concentrations in our subjects with comparable data in mentally normal and mentally retarded patients with this condition suggested that the retardation may result from other causes.

Glutamic and aspartic acid uptake was measured in skin fibroblasts from patients with Friedreich's Ataxia, dicarboxylic aminoaciduria, and normal individuals. The results showed no difference in uptake kinetics of either dicarboxylic amino acids between Friedreich's Ataxia and normal cells, but reduced uptake velocities in dicarboxylic aminoaciduria fibroblasts. Friedreich's Ataxia fibroblasts were, however, less calcium-dependent and more magnesium and phosphate-dependent than controls in glucose-free incubation mixture. This difference might be related to some degree of glucose intolerance by Friedreich's Ataxia fibroblasts in culture.