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PubMed1992

Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy.

To date, two variants of argininosuccinic acid lyase deficiency, the second most common enzymatic defect of the urea cycle, have been described. Most of the previous studies reported on outcomes involving neurological and intellectual impairment in affected children. This study is the first to demonstrate that the physical and mental development of such children can be normal and adequate for their age if they are treated with a low-protein diet and/or arginine supplements. Since 1973, 12 Austrian children suffering from argininosuccinic acid lyase deficiency have been detected in the Austrian Neonates Screening Program and could have been followed up. After confirmation of diagnosis, all the children were administered a daily arginine supplement (3 to 4 mmol/kg per day) in conjunction with either a normal diet or a special diet in which protein intake was restricted to 1.2 to 1.5 g/kg per day. Routine checks, including physical examination, determination of biochemical parameters, and IQ tests, were performed so the further development of these 12 patients with respect to treatment could be observed. It can be concluded that early treatment of partial argininosuccinic acid lyase deficiency results in normal intellectual and psychomotor development.

Amino Acid Metabolism, Inborn Errors↗
PubMed1979

Familial hyperlysinemia: enzyme studies, diagnostic methods, comments on terminology.

Enzyme assays of skin fibroblasts from five children with familial hyperlysinemia from unrelated families are added to the previous report of three children from two unrelated families. In all instances there was a deficiency in lysine-ketoglutarate reductase, saccharopine dehydrogenase, and saccharopine oxidoreductase activities. To complete the studies on the enzymes associated with familial hyperlysinemia, saccharopine oxidoreductase was partially purified from human liver and characterized. The activity did not separate from that of lysine-ketoglutarate reductase or saccharopine dehydrogenase. A simple screening test for familial hyperlysinemia is described based on the evolution of 14CO2 from lysine-14C by skin fibroblasts. The test differentiated, without overlap, seven patients with familial hyperlysinemia from control subjects. The relation of the two genetic entities involving lysine degradation, familial hyperlysinemia and saccharopinuria, is discussed. It is suggested that familial hyperlysinemia, type I, be applied to patients with major defects in lysine-ketoglutarate reductase and saccharopine dehydrogenase, and that familial hyperlysinemia, type II, to be used to designate patients in whom significant amounts of lysine-ketoglutarate reductase are retained. The nomenclature would be consistent with that of an analogous disease, orotic aciduria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1977

[Screening of newborns for argininosuccinase deficiency. First experiences in Austria (author's transl)].

In 1973, the screening for argininosuccinase deficiency was taken up by the Austrian Metabolic Disorder Screening Program using Murphey's enzyme auxotroph test. Amongst 293802 tested newborn infants, two cases of this disorder could be identified, which under protein restricted diet had a normal development until now. Inhibition zones due to antibiotic or desinfectant contamination do not disturb test evaluation in contrast to the bacterial inhibition assay (Guthrie test). The frequency of "false positive" results is small (0.05%) as well as additional work for this test procedure. So screening for argininosuccinase deficiency seems to be a useful completion of a neonatal blood screening program.

Amino Acid Metabolism, Inborn Errors↗
PubMed1991

Metabolic consequences of methylenecyclopropylglycine poisoning in rats.

We describe the effects of methylenecyclopropylglycine in fasted rats. A 75% decrease in the blood glucose concentration and an increase of lactate and pyruvate were observed 6 h after administration of 100 mg of this amino acid/kg. By contrast with the effects reported for hypoglycin [Williamson & Wilson (1965) Biochem. J. 94, 19c-21c], the plasma concentrations of ketone bodies decreased after administration of methylenecyclopropylglycine and the concentrations of branched-chain amino acids in the plasma were increased 6-fold. The oxidation of decanoylcarnitine or of palmitate was nearly completely inhibited in rat liver mitochondria from methylenecyclopropylglycine-poisoned rats. The activities of acetoacetyl-CoA and of 3-oxoacyl-CoA thiolase were decreased to 25% and less than 10% of the controls. There was a pronounced aciduria, due to the excretion of dicarboxylic acids and of oxidation products of branched-chain amino acids. The accumulation of the toxic metabolite methylenecyclopropylformyl-CoA in the mitochondrial matrix was detected after administration of methylenecyclopropylglycine. Similarly we confirmed experimentally that methylenecyclopropylacetyl-CoA accumulates in mitochondria incubated with methylenecyclopropylpyruvate.

Acyl Coenzyme A↗
PubMed1991

[Macrocephaly and dystonic cerebral palsy in a child with type I glutaric aciduria].

In a male infant with macrocephaly and dystonic cerebral palsy glutaric aciduria type I was detected by analysis of urine for organic acids. Glutaric aciduria type I is an inherited metabolic disorder of organic acids due to a defect of glutaryl-CoA-dehydrogenase in the intermediate metabolic step of lysine and tryptophan degradation. In the urine glutaric acid is usually accompanied by 3-hydroxy-glutaric acid in abnormal quantities. The enzyme defect in our patient was proved in cultured fibroblasts. In the cerebral computer tomography marked atrophy of bilateral frontotemporal regions could be demonstrated. The amount of urinary glutarat excretion decreased after protein but especially after lysine and tryptophan restriction in the diet. The administration of carnitine improved carnitine levels in blood and urine. Although the progression of neurological impairment could be stopped, dystonia and dyskinesis remained nearly unaltered. In spite of severe motor retardation, recognition and vocalisation were established. In the two year old patient mental retardation is relatively mild comparing with motor retardation. The administration of 100 or 200 mg Riboflavin/day was stopped, as it did not alter clinical symptoms or excretion of glutarat. Baclofen, an analogue of gamma-amino-butyric acid, was orally given (2 mg/kg/day) and improved dystonia, but did not influence organic aciduria. The neurological manifestations may be due in part to inhibition of neuronal glutamat decarboxylase by glutaric acid with decreased gamma-amino-butyric acid biosynthesis. The characteristic clinical symptoms with macrocephaly and dystonia and the very typical pattern of organic acids in urine are a challenge for rapid diagnosis and therapy.

Amino Acid Metabolism, Inborn Errors↗
PubMedDate not supplied

Role of the laboratory in diagnosis of organic acidurias.

Clinical signs and symptoms of organic acidurias are usually subtle and non-specific. Laboratory evaluation, therefore, is usually the only conclusive way to reach a definitive diagnosis. Defects of amino acid catabolism generally caused by diminished activity or complete absence of specific enzymes usually occurs at the later stages of a pathway and results in organic aciduria. Most of these acids are effectively cleared from the blood by the kidneys, resulting in their concentration in urine to exceed greatly that in serum. Therefore, the detection of increased organic acids is greatly facilitated by a urine assay. The use of dual capillary column gas chromatography should allow the unambiguous determination of all known organic aciduria. Using this method provides a cost-effective alternative to gas chromatography-mass spectrometry.

Carboxylic Acids↗
PubMed2002

Diagnostic value of urinary orotic acid levels: applicable separation methods.

Urinary orotic acid determination is a useful tool for screening hereditary orotic aciduria and for differentiating the hyperammonemia disorders which cannot be readily diagnosed by amino acid chromatography, thus reducing the need for enzyme determination in tissue biopsies. This review provides an overview of metabolic aberrations that may be related to increased orotic acid levels in urine, and summarises published methods for separation, identification and quantitative determination of orotic acid in urine samples. Applications of high-performance liquid chromatography, gas chromatography, and capillary electrophoresis to the analysis of urinary specimens are described. The advantages and limitations of these separation and identification methodologies as well as other less frequently employed techniques are assessed and discussed.

Chromatography↗
PubMed1975

Abnormal organic acidurias in mentally retarded patients.

Urine specimens from 1778 mentally retarded patients and 420 age and sex matched non-retarded controls selected from a general practice have been analysed for non-amino organic acids by a quantitative extraction and gas chromatographic method. The compounds were identified by combined gas chromatography and mass spectrometry. Approximately 5% of the patients had an abnormal organic aciduria. The frequency of abnormalities was slightly higher (about 7%) in a group of 248 severely subnormal children, but not in cases with a family history of mental retardation, retarded sibs, or whose parents were consanguineous. The most frequently observed abnormalities were phenylalanine metabolites in cases of phenylketonuria (about 1%), increased excretion of benzoic acid (about 1%), and increased excretion of 2-oxoglutaric acid with or without raised urinary citric-acid levels (about 1%). The biochemical and clinical significance of these findings is being further investigated.

Acidosis↗
PubMed1998

The human glutaryl-CoA dehydrogenase gene: report of intronic sequences and of 13 novel mutations causing glutaric aciduria type I.

Glutaric acidemia type I (GAI) (McKusick 231670) is an autosomal recessive disease affecting the catabolism of the amino acids lysine, hydroxylysine and tryptophan, caused by a defect in the gene encoding glutaryl-coenzyme A dehydrogenase (GCDH) and associated with severe neurological symptoms. Several pathogenic mutations in GCDH have been reported to cause GAI. One mutation, R402W, is more common than the others, which seem to be private" mutations. Here we report the entire sequences of introns 1, 2, 3, 6, 7, 8 and 9, and part of those of introns 4, 5 and 10 as well as 21 different mutations in 20 patients with GAI, corresponding to 38 out of 40 alleles.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

The contribution of protein catabolism to metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria.

Leucine and protein metabolism were studied using stable isotope techniques in 6-year-old twins with 3-hydroxy-3-methylglutaric aciduria during acute metabolic decompensation. The decompensation was preceded by prolonged fasting in twin 1 and by an upper respiratory infection in twin 2. Twin 2 was also studied when well (control study). During infection, leucine oxidation (36 mumol/kg per hour), protein catabolism (6.0 g/kg per day) and urinary excretion of major leucine metabolites (104 mumol/kg per hour) were all increased compared with the control study (16 mumol/kg per hour, 4.7 g/kg per day and 28 mumol/kg per hour respectively). During fasting, leucine oxidation (18 mumol/kg per hour) was unchanged and protein catabolism (4.1 g/kg per day) was decreased despite substantially increased urinary metabolite excretion (87 mumol/kg per hour) compared with the control study. These results indicate that protein mobilisation and leucine oxidation played important roles in metabolic decompensation during infection but not during fasting. It is likely that the increased metabolite excretion during fasting arose primarily from fatty acid catabolism, indicating the importance of this substrate in metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria.

Amino Acid Metabolism, Inborn Errors↗