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Biomedical subjects

J P Colombo

Publications and source records attributed to J P Colombo.

At least 37 records · Page 2Linked to original sources
PubMed1995

A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate.

N-Acetylglutamate synthase (NAGS) deficiency is a rare, autosomal recessive urea-cycle disease. Its clinical presentation is not different from the other hereditary hyperammonaemias. We report a new neonatal case with hyperammonaemic coma. A test by carbamylglutamate was performed at 25 days of life. Since then, the child was treated by carbamylglutamate three or four times a day with a total dose of 80-100 mg/kg per day. Today, the boy is 1 year old. He receives carbamylglutamate 200 mg four times a day. He has normal somatic and neurological development and good metabolic balance.

Acetyltransferases↗
PubMed1995

Bone mass at lumbar spine and tibia in young males--impact of physical fitness, exercise, and anthropometric parameters: a prospective study in a cohort of military recruits.

Bone mineral density (BMD) and bone mineral content (BMC) were measured using DXA at lumbar spine and tibial diaphyses at the beginning and at the end of a 15-week training period in 151 military recruits of the Swiss army belonging to 5 different troop categories (infantry grenadiers, tank drivers, tank gunners, signalmen, and privates) who each were exposed to physical training of various intensity. At baseline, height, body mass index, and degree of physical fitness independently correlated with vertebral and tibial BMD. Over the 15 weeks of physical training BMD at tibial diaphyses increased by 2.2 +/- 0.3% at the left leg (p = 0.0001) and by 1.1% at the right leg (p = 0.002) with differences between troop categories. At lumbar spine, BMD decreased significantly in tank drivers (-1.2 +/- 0.4%, p = 0.001) and particularly in infantry grenadiers (-2.1 +/- 0.4%) who had the most strenuous weight-bearing training, but not in other troop categories. This decrease was twice as large at the center of the vertebra than for the whole vertebra. These BMD changes were associated with increments in serum levels of osteocalcin and alkaline phosphatase activity. From the initial cohort, 48 subjects volunteered for a third investigation carried out 2 years after the end of the military training period. At this time, lumbar BMD and BMC had risen back to baseline, whereas at tibial diaphyses bone width and BMC but not BMD increased by 5.8 +/- 1.1% and 6.2 +/- 0.9%, respectively, vs. baseline (p = 0.0001 for both).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1995

Ultrastructural, immunocytochemical and stereological investigation of hepatocytes in a patient with the mutation of the ornithine transcarbamylase gene.

We studied a male newborn suffering from deficiency of ornithine transcarbamylase (OTC) that is due to a G-to-A substitution in codon 269 of the OTC gene. This study intends to define the cell biological mechanisms in this naturally occurring OTC mutation which may explain the mild clinical course in spite of the very low residual enzyme activity. Using immunogold labeling of thawed thin frozen sections of liver from this patient and a control liver, we analyzed the quantitative distribution of several mitochondrial proteins in the cytosol and the mitochondria of hepatocytes. In addition, the absolute volumes and surface densities of mitochondria and peroxisomes were determined. Our results show that the absolute volume of mitochondria in the patient's hepatocytes was increased to 141% (P < 0.001) without any change in the surface density indicating an increased number of mitochondria. In the patient's hepatocytes the peroxisomes were increased in size but not in number. The concentration of OTC was elevated in the cytosol (P < 0.001) and to a lesser extent in mitochondria (P < 0.01) of the patient's hepatocytes thus indicating a doubling of OTC relative to control liver cells. The quantity of OTC in mitochondria was 63% higher in diseased liver cells. By conventional thin section electron microscopy, mitochondria-like structures with poorly defined cristae and an electron-dense matrix were observed in the cytoplasm of the diseased hepatocytes. By immunoelectron microscopy, they contained the cytochrome c oxidase II subunit as well as DNA but lacked OTC, carbamylphosphate synthetase, F1-ATPase beta subunit and catalase. Thus it appears that these structures represent defective and probably degenerating mitochondria. Our data indicate that the reduced enzyme activity of the mutant OTC is partly compensated by an increased amount of enzyme molecules in the cytosol as well as mitochondria combined with an increase in the biogenesis of mitochondria.

Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzin↗
PubMed1994

Medium-chain acyl-CoA dehydrogenase deficiency does not correlate with apparent life-threatening events and the sudden infant death syndrome: results from phenylpropionate loading tests and DNA analysis.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of fatty acid metabolism and typically presents in early childhood as potentially fatal hypoketotic, hypoglycaemic crisis often associated with Reye-like symptoms. Re-investigations of cases of sudden infant death syndrome (SIDS) have revealed in some instances a deficiency of MCAD, suggesting that this metabolic disorder may lead to sudden infant death without prior clinical symptoms. In the present study, we examined 142 infants who had suffered from an apparent life-threatening event (ALTE) or were otherwise considered at risk for SIDS for MCAD deficiency by phenylpropionate loading. In no case excretion of phenylpropionylglycine, the hallmark of MCAD deficiency, was increased. In contrast, 3 out of 55 children with symptoms of metabolic disorders showed increased phenylpropionylglycine excretion, and in all three cases MCAD deficiency was confirmed by DNA analysis. In addition, we investigated 142 cases of sudden unexplained child death and 100 control subjects for the A985G mutation in the MCAD gene which is associated with about 98% of enzyme deficiencies. We found one case of heterozygosity each in the patient and control group. Our data indicate that MCAD deficiency is not a major cause of ALTE and, in agreement with results from similar studies in other countries, its frequency is not increased in children who died of SIDS.

Acyl-CoA Dehydrogenase↗
PubMed1994

Pitfalls in aminoacid and organic acid analysis: 3-hydroxypropionic aciduria.

Pitfalls in organic acid analysis can originate from inadequate methodology, analytical interferences, in vivo interactions and from pre-analytical conditions which often are unknown to the specialized analytical laboratory. Among the latter, ingested food and additives, metabolites of food processing or medications have to be considered. Bacterial metabolites from the gastrointestinal or urogenital system or formed after sample collection can lead to pitfalls as well. An example of such a patient whose urinary metabolites mimic at first glance inherited propionic aciduria is described.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Ornithine transcarbamylase (OTC) deficiency in a female patient with a de nova deletion of the paternal X chromosome.

A girl with ornithine transcarbamylase (OTC) deficiency was investigated for molecular and cytogenetic abnormalities that might explain this phenotype. Analysis with polymorphic DNA markers indicated that the patient did not inherit paternal alleles of the OTC locus, but that she did inherit the proximal locus DXS7 and the long arm of chromosome X. High-resolution cytogenetic analysis of the patient indicated a deletion of Xp11.4-p21, whereas both parents had normal karyotypes. Since the mother might be heterozygous according to biochemical tests, a second mutation within the maternal OTC gene cannot be excluded.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Carbamyl phosphate synthetase-1 deficiency discovered after valproic acid-induced coma.

Valproic acid induced coma is presented in an adult patient without a history of metabolic disease. Liver biopsy revealed a reduction in activity of carbamyl phosphate synthetase-I, an enzyme obligated for transformation of ammonia to urea in the urea cycle. After recovery CT scan follow-up showed marked cerebral atrophy which did not exist prior to the state of coma. Risk factors are discussed.

Adult↗
PubMed1992

Effect of different protein diets on the distribution of amino acids in plasma, liver and brain in the rat.

The distribution of amino acids between plasma, liver and brain was studied in adult male rats, fed a diet containing 8.7, 17 (control animals), 32 and 51% of protein during 15 days. The caloric intake was nearly equal in all groups. The highest food intake was observed in the animals on the low protein diet. Changes in plasma amino acids were variable. In contrast to the behavior of most amino acids in plasma, the branched chain amino acids were highest in the animals fed the 51% protein diet. Despite the low protein intake in the animals fed a 8.7% protein diet, the concentration of serine, glutamic acid, glutamine, glycine, alanine, methionine, isoleucine, leucine, phenylalanine and ornithine were significantly higher compared to control animals, whereas in those receiving a high protein diet, valine, leucine, tyrosine, tryptophan and histidine increased in relation to the increased protein and amino acid intake. The plasma amino acid patterns are not greatly influenced by the amino acid distribution in the food and the amount ingested. Alanine aminotransferase, aspartate aminotransferase, glutamate dehydrogenase and cholinesterase showed a two- to fivefold increased activity in the liver of animals consuming a high protein diet. In the brain, the concentration of valine, leucine, isoleucine, phenylalanine and tyrosine in animals receiving the low protein diet was higher than in controls and increased further with increasing protein content of the diet. Glutamine was increased in all dietary groups. The predicted influx of amino acids showed increasing influx rates in dependence of the plasma amino acid concentration. The entry of tyrosine and tryptophan and their brain concentration was inversely proportional to the protein content of the diet. In the present study which considers long-term adaptation to an increasing protein and amino acid intake in comparison to a balanced control protein diet, the levels of the indispensable amino acids were maintained within narrow limits in the brain and liver. The results indicate that inspite of a variable protein intake, the body tends to keep organ amino acids in relatively narrow limits favoring in this way amino acid homeostasis.

Amino Acids↗
PubMed1992

Increased plasma amylase in the family of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.

A patient with 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase, EC 4.1.3.4) deficiency presented consistently above-normal values of plasma amylase (EC 3.2.1.1). Activities measured were in the lower normal range in family members not proven heterozygotes and in the upper normal range in the proven heterozygotes. Heterozygosity was proven by intermediate HMG-CoA lyase activities determined in cultured fibroblasts and in lymphocytes in the parents and the paternal grandmother. Because all of the family members had diseases of the pancreas, colon, and liver, we question whether the heterozygote state contributes to the impaired function of these organs. Our findings of significantly increased amylase activities in the heterozygotes and the patient, in comparison with the other family members, support this hypothesis.

Amylases↗
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↗
PubMed1991

N-acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxication.

We report the 9-year follow-up of a patient suffering from N-acetylglutamate synthetase deficiency, an urea cycle disorder leading to severe neonatal hyperammonaemia. Hitherto two patients from two families with this inborn error of metabolism had been observed. Our management consisted mainly of a protein-restricted diet and oral treatment with N-carbamylglutamate, an activator of carbamylphosphate synthetase, together with arginine or citrulline. The somatic development was normal whereas a moderate psychomotor retardation was diagnosed. The patient died after an episode of coma and prolonged generalized convulsions at the age of 9.5 years.

Acetyltransferases↗
PubMed1991

Direct and indirect mutation analyses in patients with ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) is one of 5 enzymes in the detoxification of ammonia to urea, and its deficiency, an X-linked disease, is the most common inborn error of urea genesis in humans. Because of the devastating nature of the disease there is a strong demand for reliable and rapid molecular analyses in OTC families in order to offer carrier detection and prenatal diagnosis. This paper presents the efficiency of direct and indirect mutation analyses in 22 OTC families using Southern blotting and polymerase chain reaction (PCR) amplification. For 89% of the mothers with an affected child, at least 1 RFLP of the OTC locus was informative concerning prenatal diagnosis. 100% informativity was reached by using the additional flanking markers 754 and LI.28. In total, 3 deletions (14%) and 1 TaqI site mutation (4.5%) in exon 3 were detected. 13 (60%) of our 22 mothers were found to be carriers, 9 of them being obligate carriers and 4 detected by biochemical testing. 4 mothers were excluded as carriers by DNA analyses, and in 5 mothers the carrier status could not be assessed positively. DNA analyses permitted carrier detection in 32% and carrier exclusion in 55% of 22 female relatives. Prenatal diagnosis was performed in 4 families: in 1 family by direct mutation detection and in 3 families by linkage analyses. It was possible to determine the mutation origin in 6 families, all of them with male probands. In 4 families the mutation had occurred during grandpaternal spermiogenesis, suggesting higher mutation rates in males, but in 2 cases it was the result of an event during maternal oogenesis, proving that new mutations in the OTC gene do also occur in eggs. Our recommended strategy for carrier detection and prenatal diagnosis in OTC deficiency is to examine routinely Southern blots of BamHI, EcoRI, HindIII, MspI, PstI and TaqI digestions using the OTCcDNA probe pH0731 and the flanking markers 754 and LI.28, as well as the TaqI-digested PCR products of exons 3, 5 and 9.

Base Sequence↗
PubMed1991

Intralysosomal generation of ammonia from urea by endocytosed urease results in secretion of free lysosomal arylsulfatase-A and increased activity of membrane-bound beta-glucosidase in cultured brain cells.

Hyperammonemia interferes with normal brain function. The effect of ammonia on free and membrane-bound lysosomal enzymes and on mucopolysaccharide metabolism was studied in cultured rat brain cells (ROC-1, hybridoma between C6-astrocytoma and oligodendrocytes). Intralysosomal ammoniagenesis was achieved from urea by endocytosed Jackbean urease followed by incubation of the cultures with urea. The intralysosomal location of urease was evidenced by the protective effects of leupeptin and urea on the stability of intracellular urease. Ammonia formed from urea resulted in an increased secretion of lysosomal arylsulfatase-A (AS-A), but not of the membrane-bound lysosomal beta-glucosidase into the culture medium, thus intralysosomal AS-A activity decreased. Lysosomal, membrane-bound beta-glucosidase activity increased, presumably due to intralysosomal proteolytic protection following an increased lysosomal pH. Intralysosomal ammoniagenesis temporarily impaired 35SO4-glycosaminoglycan degradation of prelabeled cells. The results support the hypothesis that hyperammonemic states may interfere with lysosomal functions in vivo as well in cultured cells.

Ammonia↗