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C Jakobs

Publications and source records attributed to C Jakobs.

At least 199 records · Page 11Linked to original sources
PubMed1996

Amniotic fluid odd-chain fatty acids are increased in propionic acidaemia.

Odd-chain (C15 and C17) fatty acids have been reported to accumulate in tissues and body fluids of patients with propionic and methylmalonic acidaemia. We investigated the occurrence of these substances in amniotic fluid samples. The odd-chain fatty acid levels (expressed as the percentage of total C12-C20 fatty acids) in eight control samples ranged from 3.7 to 12.5 per cent. Three samples from affected propionic acidaemia pregnancies had values of 15.3-22.9 per cent; one methylmalonic acidaemia sample had a normal level of 9.3 per cent. These results supply further evidence of the prenatal accumulation of odd-chain fatty acids in propionic acidaemia.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Magnetic resonance imaging in lactic acidosis.

Mitochondrial defects, defects in gluconeogenesis, and biotin-responsive multiple carboxylase deficiency are disorders characterized by primary lactic acidosis. In this review, characteristic findings in magnetic resonance imaging (MRI) of the brain, as related to histopathological abnormalities, are described for the different disorders and the diagnostic value of the MRI findings is discussed. Inborn errors of metabolism with primary lactic acidosis should be considered in particular when MRI shows lesions similar to or reminiscent of effects of focal or generalized hypoxia-ischaemia, or when MRI shows signs of chronic neurodegeneration, but rarely in cases with predominantly white-matter changes.

Acidosis, Lactic↗
PubMed1996

Congenital nephrotic syndrome: a novel phenotype of type I carbohydrate-deficient glycoprotein syndrome.

Type I carbohydrate-deficient glycoprotein (CDG) syndrome is a genetic multisystem disorder generally without overt renal problems. We report a neonate with neurological abnormalities and congenital nephrotic syndrome of diffuse mesangial sclerosis type. Serum transferrin isoelectric focusing showed the typical abnormalities of type I CDG syndrome. Normal transferrin focusing findings in other patients with similar renal problems excluded the possibility of a secondary biochemical phenomenon. The diagnosis of type I CDG syndrome was confirmed by demonstration of a deficiency of phosphomannomutase. No evidence of pontocerebellar atrophy was found in imaging or at autopsy. We conclude that congenital nephrotic syndrome may occur in type I CDG syndrome, and that this diagnosis should be considered in patients with congenital nephrotic syndrome. Absence of pontocerebellar atrophy does not exclude the diagnosis of type I CDG syndrome.

Congenital Disorders of Glycosylation↗
PubMed1996

L-2-Hydroxyglutaric aciduria: neuropathological correlations and first report of severe neurodegenerative disease and neonatal death.

L-2-Hydroxyglutaric aciduria is a rare organic aciduria associated with neurological and particularly cerebellar abnormalities. These abnormalities developed in childhood or later in all previously described patients. We report a more severe form of L-2-hydroxyglutaric aciduria in which an infant presented shortly after birth with hypotonia, apnoea, and seizures, leading to death in the perinatal period. Computerized tomography scans of the brain at 1 day and 2 weeks of age showed abnormal low density of the cerebellum. Examination of the brain showed brainstem and cerebellar atrophy with neuronal loss and gliosis in an olivopontocerebellar distribution. The diagnosis of L-2-hydroxyglutaric aciduria should be considered in any non-dysmorphic newborn with progressive neurological abnormalities and CNS imaging suggesting low density and size of the cerebellum. The diagnostic consideration is based initially on clinical findings. Conventional urine organic acid analysis reveals the presence of 2-hydroxyglutaric aciduria. Specific diagnosis requires methodologies which distinguish the L- from the D-isomer.

Brain↗
PubMed1996

Major hyperpipecolataemia in a normal adult.

We describe the fortuitous discovery of a 44-year-old man with a very high hyperpipecolataemia (250 mumol/L; normal < 2.5). This patient has none of the clinical features seen in peroxisomal diseases, he is a strictly normal intelligent adult. A stereochemical study of this pipecolic acid was performed using D-amino acid oxidase, and identified it as L-pipecolic acid. We suggest that isolated L-hyperpipecolataemia may be a benign trait.

Adult↗
PubMed1996

Atypical vitamin B12-unresponsive methylmalonic aciduria in sibship with severe progressive encephalomyelopathy: a new genetic disease?

UNLABELLED: We report on two siblings, a girl of 7 years and a boy of 2 years, who presented in infancy with hypotonia, athetoid movements, myopathy and severe developmental delay. The progressive clinical course was characterized by ophthalmoplegia, pyramidal tract signs, loss of visual contact and failure to thrive. The older sister died at the age of 7 years. The younger brother followed an almost identical clinical course. MRI of the brain revealed bilateral hypodensities and atrophy of the putamen. Neurophysiological investigations were consistent with peripheral neuropathy. Investigations for neurometabolic disorders in urine, plasma and CSF of both patients revealed a consistent increase of methylmalonic acid in urine, plasma and CSF as well as borderline low free GABA in CSF. Except for an inconstant elevation of lactate in the boy, metabolic acidosis, hypoglycaemia, episodic ketoacidosis, or hyperammonaemia, the usual concomitants of organoacidopathies, were absent in both children. Homocystinuria was excluded. Methylmalonic aciduria did not respond to antibiotic treatment, vitamin B12 therapy nor dietary protein restriction. Incorporation of [14C]propionate into protein in cultured fibroblasts was pathologically but inconsistently decreased. Both patients' cell lines showed only minimal response to hydroxocobalamin and normal methylmalonyl-CoA mutase activity. CONCLUSION: Even though the definitive underlying enzymatic defect in this sibship remains obscure our results suggest a new genetic disorder. This report illustrates that hitherto undescribed metabolic disorders remain to be elucidated even in long investigated areas of intermediary metabolism such as methylmalonic aciduria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Leucine and glucose kinetics during growth hormone treatment in intrauterine growth-retarded preterm infants.

The present study was performed with the objective to investigate the possible effects of recombinant human growth hormone (rhGH) supplementation on protein and glucose metabolism during the early postnatal period in seven intrauterine growth-retarded (IUGR) preterm infants. Eight infants were studied as controls. The metabolic rate was measured by indirect calorimetry, and whole body protein and glucose kinetics were measured using constant-rate infusions of [1-13C] leucine and [U-13C]glucose during continuous adequate oral feeding. Energy expenditure was similar in both groups. In the rhGH-treated group of infants, leucine turnover (470 +/- 76 vs. 409 +/- micromol/ kg/day), leucine used for protein synthesis (402 +/- 72 vs. 337 +/- 36 micromol /kg/day), and leucine derived from protein breakdown (365 +/- 71 vs. 304 +/- 41 micromol/kg/day) were increased. However, net leucine balance was not increased (37 +/- 17 vs. 34 +/- 13 micromol/kg/day). The total rate of appearance of glucose was 10.1 +/- 1.2 vs. 10.0 +/- 1.3 mg/kg/min. We suggest that immediate postnatal treatment with rhGH is not effective in stimulating protein gain and has no effect on glucose kinetics in IUGR preterm infants.

Birth Weight↗
PubMed1996

Prenatal diagnosis of organic acidemias based on amniotic fluid levels of acylcarnitines.

Acylcarnitines in amniotic fluid samples were analyzed for the prenatal diagnosis of propionic acidemia, methylmalonic aciduria, isovaleric acidemia, and glutaric aciduria by electrospray tandem mass spectrometry. Although the levels of the specific acylcarnitine between affected and unaffected cases showed an overlap, the ratios of propionylcarnitine to 4-carbon acylcarnitine levels for propionic acidemia and methylmalonic aciduria, those of isovalerylcarnitine to propionylcarnitine for isovaleric acidemia, and those of glutarylcarnitine to propionylcarnitine for glutaric aciduria type I were shown to be reliable indicators in the prenatal diagnosis. In addition, it is suggested that the combination of the ratios of glutarylcarnitine, isovaleryl-carnitine, and hexanoylcarnitine to propionylcarnitine may be useful for the prenatal diagnosis of glutaric aciduria type II.

Acetylcarnitine↗
PubMed1996

Relative kinetics of phenylalanine and leucine in low birth weight infants during nutrient administration.

The effect of the route of nutrient administration on the relative rates of leucine and phenylalanine kinetics was examined in 30 low birth weight (LBW) infants using L-[1-(13)C]leucine, L-[2H5]phenylalanine, and L-[2H2]tyrosine tracers. The infants received special premature formula (PF, n = 10, 117 +/- 8 kcal.kg-1.d-1 and 3.2 +/- 0.2 g protein.kg-1.d-1) or fortified human milk (HM, n = 10, 106 +/- 6 kcal.kg-1.d-1 and 3.0 +/- 0.2 g protein.kg-1.d-1), or parenteral nutrition (PN, n = 10, 80 +/- 25 kcal.kg-1.d-1 and 1.8 +/- 0.3 g protein.kg-1.d-1). The rate of appearance (Ra) of leucine (RaLeu), was significantly higher in group PF as compared with groups HM and PN (434 +/- 51 versus 377 +/- 33 and 359 +/- 50 mumol.kg-1.h-1, p < 0.05). The Ra of phenylalanine (RaPhe) was lower in group HM as compared with group PF (94 +/- 18 versus 115 +/- 16, p < 0.05), RaPhe in group PN (108 +/- 24 mumol.kg-1.h-1) was in between group PF and HM. The relative rate of RaPhe and RaLeu expressed as RaPhe/ RaLeu ratio was lower in all groups than that expected from reported whole body protein composition and from that reported in adults. The ratio of phenylalanine hydroxylation to leucine decarboxylation was 0.202 in group PF, 0.212 in group HM, and 0.161 in group PN, suggesting a higher rate of decarboxylation of leucine relative to hydroxylation of phenylalanine. We conclude that: 1) the higher RaLeu compared with the RaPhe may be the result of either a higher turnover of a body protein enriched in leucine or the consequence of higher leucine intake in infant nutrition and 2) whole body protein kinetics calculated from a single amino acid tracer do not adequately represent whole body protein metabolism.

Food, Fortified↗
PubMed1995

Molecular cloning of the mature NAD(+)-dependent succinic semialdehyde dehydrogenase from rat and human. cDNA isolation, evolutionary homology, and tissue expression.

Three rat brain cDNA clones approximately 3500, 1465, and 1135 base pairs in length encoding succinic semialdehyde dehydrogenase (SSADH; EC 1.2.1.24) were isolated from two cDNA libraries using a polymerase chain reaction derived probe. Restriction mapping and DNA sequencing revealed that the 3.5-kilobase clone contained an 84-base pair (28 amino acid) insert in the coding region. Composite clones encoding mature SSADH predicted proteins with 488 amino acids (M(r) = 52,188) when including the insert and 460 amino acids (M(r) = 48,854) without the insert. The cDNA clones were confirmed by expression of enzyme activity in bacteria and protein sequence data obtained from sequencing purified rat brain SSADH. Two human liver SSADH cDNA clones of 1091 and 899 base pairs were also isolated. Human and rat SSADH share 83 and 91% identity in nucleotide and protein sequence, respectively. Northern blot analysis revealed two differentially expressed SSADH transcripts of approximately 2.0 and 6.0 kilobases in both rat and human tissues. Human genomic Southern blots indicate that the two SSADH transcripts are encoded by a greater than 20-kilobase single copy gene. Mammalian SSADH contains significant homology to bacterial NADP(+)-succinic semialdehyde dehydrogenase (EC 1.2.1.16) and conserved regions of general aldehyde dehydrogenases (EC 1.2.1.3), suggesting it is a member of the aldehyde dehydrogenase superfamily of proteins.

Aldehyde Dehydrogenase↗
PubMed1995

Prenatal diagnosis of isovaleric acidaemia by enzyme and metabolite assay in the first and second trimesters.

Isovaleric acidaemia (IVA) is caused by a deficiency of isovaleryl CoA dehydrogenase. The diagnosis can be established biochemically by the demonstration of increased levels of isovalerylglycine (IVG) and 3-hydroxyisovaleric acid in urine and by the deficiency of incorporation of radiolabel from [14C]isovaleric acid in macromolecules in cultured fibroblasts. This paper reports a consecutive series of 24 prenatal diagnoses in pregnancies at high risk, using both methods--metabolite and indirect enzyme assay. Affected fetuses were diagnosed in four pregnancies: three in the second trimester and one recent case in the first trimester. The latter represents the first reported case of a first-trimester diagnosis of IVA by direct analysis of chorionic villi. We also report the first demonstration of strongly accumulated IVG in the amniotic fluid in the 12th week of an affected pregnancy.

Amniocentesis↗
PubMed1995

Molecular prenatal diagnosis of 3-hydroxy-3-methylglutaryl CoA lyase deficiency.

We report the first molecular prenatal diagnosis of 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency. The proband had a classic but severe presentation with hypoketotic hypoglycaemia and acidosis, secondary mental retardation, and epilepsy, and HL deficiency was documented in cultured fibroblasts. We found him to be homozygous for the frameshift mutation N46fs (+1), which yields a distinct pattern on single-strand conformation polymorphism (SSCP) analysis. In two subsequent pregnancies, molecular prenatal diagnosis was performed using SSCP. In the first, chorionic villus biopsy was normal. In the second pregnancy, amniocentesis revealed an affected fetus. In both pregnancies, the diagnosis was confirmed enzymatically. HL activity was less than 7 per cent of control values in amniocytes and fetal liver of the affected pregnancy. In the second pregnancy, amniotic fluid metabolite measurements by stable isotope dilution-selected ion monitoring mass spectrometry showed greater than 100-fold increases of 3-hydroxy-3-methylglutaric acid and of 3-methylglutaconic acid levels compared with controls.

Amniocentesis↗
PubMed1995

Molecular basis of phenotypic variation in patients with argininemia.

Argininemia is an autosomal recessive disorder caused by a deficiency in the liver-type arginase enzyme. Clinical manifestations include progressive spastic diplegia and mental retardation. While the quality of life can severely deteriorate in most such patients, some do show remarkable improvement in neurological symptoms while on controlled diets. We examined the thesis that differences in clinical responses to dietary treatment are based on molecular heterogeneity in mutant arginase alleles. Genomic DNAs from 11 patients with argininemia were examined using the polymerase chain reaction, cloning, and sequencing. Nine mutations representing 21/22 mutant alleles were identified in 11 patients with argininemia, and four of these mutations were expressed in vitro to determine the severity of enzymatic defects. We found that these mutations accounted for 64% of the mutant alleles in our patients. Based on findings in vitro expression tests, the mutations can be considered either severe or moderate. Patients with at least one moderate mutant allele responded well to dietary treatment; concentrations of plasma arginine were controlled within 300 microM. In contrast, patients with two severely mutated alleles did not respond to dietary treatment and plasma arginine was over 400 microM. Argininemia is heterogeneous at the molecular level. The degree of clinical improvement during dietary treatment is reflected in the concentration of arginine in plasma, as a measure of metabolic control. Plasma arginine levels during treatment is reflected in the concentration of arginine in plasma, as a measure of metabolic control. Plasma arginine levels during treatment correlated with types of molecular defects in the arginase genes.

Alleles↗
PubMed1995

Pre- and postnatal diagnosis of peroxisomal disorders using stable-isotope dilution gas chromatography--mass spectrometry.

Quantitative analysis of the following peroxisomal metabolites is reported: very long-chain fatty acids (VLCFA), pipecolic acid, bile acid intermediates, phytanic and pristanic acid, in plasma, urine, cerebrospinal fluid (CSF), blood spots collected at neonatal screening and amniotic fluid. An overview is given of the concentrations of these metabolites in body fluids from control subjects and all patients investigated so far in this laboratory. The method of choice is gas chromatography -- mass spectrometry (GC-MS) with electron capture detection, combined with the use of stable-isotope-labelled internal standards.

Amniotic Fluid↗