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Cornelis Jakobs

Publications and source records attributed to Cornelis Jakobs.

At least 55 records · Page 3Linked to original sources
PubMed2004

Age related reference values for urine creatine and guanidinoacetic acid concentration in children and adolescents by gas chromatography-mass spectrometry.

A new gas chromatography-mass spectrometry method for routine quantification of urine creatine and guanidinoacetic acid (GAA) has been developed to provide a fast, reliable and inexpensive metabolic screening. Our method uses a two-step derivatization procedure which involves a reaction with hexafluoroacetylacetone followed by a reaction with mono-trimethylsilyltrifluoroacetamide. The standard curves showed linearity over a range of 43-4269 micromol/l for GAA and 38-7325 micromol/l for creatine, which covers the range of GAA and creatine normally found in urine. The lower detection limit is 1.54 micromol/l for GAA and 1.22 micromol/l for creatine, whereas the lower quantification limit is 5.04 micromol/l for GAA and 4.19 micromol/l for creatine. This method was also employed to establish reference values for GAA and creatine in healthy infants, children and adolescents based on the analysis of 169 urine samples. Although no sex differences were observed, normal GAA urinary levels and creatine excretion are distinct in age-related subgroups. We identified a statistically significant age difference in two major groups for GAA (children under 4 years, 18-159 micromol/mmol creatinine; and subjects of 5-16 years, 18-130 micromol/mmol creatinine) whereas three groups were discriminated for creatine (children under 4 years, 0.04-1.51 mmol/mmol creatinine; subjects of 5-11 years, 0.04-1.07 mmol/mmol creatinine; and subjects of 12-16 years, 0.04-0.56 mmol/mmol creatinine).

Adolescent↗
PubMed2004

Hyperpipecolic acidaemia: a diagnostic tool for peroxisomal disorders.

Peroxisomal disorders include a complex spectrum of diseases, characterized by a high heterogeneity from both the clinical and the biochemical points of view. Specific assays are required for the study of peroxisome metabolism. Among these, pipecolic acid evaluation is considered as a supplementary test. We have established the diagnostic role of pipecolic acid in 30 patients affected by a peroxisomal defect (5 Zellweger syndromes, 10 Infantile Refsum diseases, 1 neonatal adrenoleukodystrophy, 6 patients affected by a peroxisomal biogenesis disorder with unclassified phenotype, 1 case of rhizomelic chondrodysplasia punctata (RCDP), 2 acyl-CoA oxidase deficiencies, 2 bifunctional enzyme deficiencies, 2 Refsum diseases, and 1 beta-oxidation deficiency). Pipecolic acid was increased in all generalized peroxisomal disorders, while normal pipecolic acid with abnormal very long chain fatty acid concentrations was strong evidence for a single peroxisomal enzyme deficiency. Unexpectedly, hyperpipecolic acidaemia was found also in a child affected by RCDP and in two patients with Refsum disease. In six patients the suggestion of a peroxisomal disorder was raised by the fortuitous finding of a pipecolic acid peak in amino acid chromatography, routinely performed as a general metabolic screening. For all patients, pipecolic acid proved to be a useful parameter in the biochemical classification of peroxisomal disorders.

Adolescent↗
PubMed2004

Creatine and guanidinoacetate: diagnostic markers for inborn errors in creatine biosynthesis and transport.

In this study, measurements of guanidinoacetate (GAA) and creatine (Cr) in urine, plasma, and cerebrospinal fluid (CSF) were performed using stable isotope dilution gas chromatography-mass spectrometry. Both compounds were analyzed in a single analysis. Reference values were established for GAA and Cr. These values were age dependent. No differences with gender were observed. Eight guanidinoacetate methyltransferase (GAMT) deficient patients and eight creatine transporter SLC6A8 deficient patients were investigated. In urine, plasma, and CSF of GAMT deficient patients increased levels of GAA are present. The SLC6A8 deficient patients all show increased creatine/creatinine (Cr/Crn) ratio in urine demonstrating the importance of the Cr/Crn ratio as a pathognomonic marker of the SLC6A8 deficiency.

Adolescent↗
PubMed2004

Evaluation of pentitol metabolism in mammalian tissues provides new insight into disorders of human sugar metabolism.

To more completely elucidate the pathways of sugar metabolism in human, we have evaluated the formation and degradation of pentitols in human fibroblasts and erythrocytes. Cultured human fibroblasts were incubated with d-arabinose, d-ribose, d-ribulose, and d-xylulose. Formation of arabitol and ribitol was analyzed by gas chromatography of the incubation medium and cell homogenate. We found that the pentoses d-arabinose and d-ribose could cross cell membranes, which indicate possible pentitol formation from extracellular pentoses. Fibroblasts formed 17+/-4 nmol arabitol/4 days/mg protein from d-arabinose and ribitol production rates of 70+/-15 nmol/4 days/mg protein were found after d-ribose incubation. Following d-ribulose incubation 13 nmol ribitol/4 days/mg protein was found. Human cultured fibroblasts were also incubated with d-arabitol, ribitol, and xylitol. Analyzing the incubation medium and cell homogenate revealed an absence of pentose formation. However, export of the pentitols arabitol and ribitol across the cell membrane was demonstrated, indicating that pentitols can be cleared from the body without metabolic conversion. Finally, human erythrocytes were incubated with d-/l-arabitol, ribitol, sorbitol, and xylitol. Activities of potential pentitol dehydrogenases were evaluated by a fluorometric assay. No evidence for ribitol and arabitol degradation was observed in human erythrocytes, as compared to polyol dehydrogenase activities ranging from 1.3 to 6.1 pmol NADH/min/microl erythrocytes observed using sorbitol and xylitol. Our results indicate that ribitol and arabitol are metabolic end products in humans.

Cell Membrane↗
PubMed2004

Liver-directed adenoviral gene transfer in murine succinate semialdehyde dehydrogenase deficiency.

Murine succinate semialdehyde dehydrogenase (SSADH) deficiency (OMIM 271980; EC 1.2.1.24), a model of the corresponding human disorder, displays 100% mortality at weeks 3-4 of life, associated with lethal tonic-clonic seizures. The biochemical hallmark, gamma-hydroxybutyrate (GHB), accumulates in both human and murine disorders. In the current study we evaluated rescue of the murine model with liver-directed gene therapy using the E1-deleted adenoviral vector AD:pAD-RSV-humanSSADH. Our working hypotheses were: (1) liver expresses considerable SSADH activity and therefore represents a major source of GHB output, (2) correction of liver enzyme deficiency will reduce GHB load both peripherally and in the central nervous system, and (3) SSADH expression will improve survival. SSADH(-/-) and SSADH(+/+) mice were treated under two protocols: (A) intraperitoneal injection of 10(8)-10(11) viral particles by day 10 of life or (B) retro-orbital injection of 10(11) viral particles at day 13 of life. Intravenous administration was prohibited by the small size and fragility of the mice. Maximal survival (39%; P<0.001) was achieved with intraperitoneal administration (10(8) particles) at day 10; intraperitoneal (10(10) and 10(11) particles) and retro-orbital administration (10(11) particles) yielded lower survival of 11-25% (P<0.02). Under both protocols, the maximal hepatic SSADH enzyme activity was approximately 20% of SSADH(+/+) liver activity (retro-orbital > ip). At various time points postinjection, ip-treated animals (10(8) viral particles) demonstrated upward of 80% reduction in liver GHB concentrations, with little impact on brain or serum GHB levels except at 48-72 h posttreatment (approximately 50% reduction for both tissues). Accordingly, we harvested retro-orbitally treated animals at 72 h and observed significant reductions of 60-70% for GHB in liver, kidney, serum, and brain extracts. Histochemical analysis of liver from retro-orbitally treated mutants demonstrated substantial SSADH staining, but with variability both within tissues and between animals. Our studies provide proof-of-principle that liver-mediated gene therapy has efficacy in treating SSADH deficiency and that hepatic tissue contributes significantly to the pool of GHB within the CNS.

Adenoviridae↗
PubMed2004

Distinct glycoforms of human alpha1-acid glycoprotein have comparable synthesis rates: a [13C]valine-labelling study in healthy humans.

Various alpha1-acid glycoprotein (AGP) glycoforms are present in plasma differing in extent of branching and/or fucosylation of their 5 N-linked glycans, as well as in concentration. It is assumed that hepatic synthesis determines the relative occurrence of the AGP-glycoforms in plasma, but experimental evidence is lacking. In this study, we have investigated the contribution of fractional synthesis rates to the plasma concentration of AGP-glycoforms that differed in relative occurrence in healthy human plasma. During a [13C]valine infusion, AGP was isolated from the plasma of healthy volunteers. Four AGP-glycoforms, differing strongly in plasma concentration were obtained by sequential affinity chromatography over concanavalin-A- and Aleuria aurantia -agarose columns. The incorporation of the [13C]valine tracer into the AGP-glycoforms was measured by gas chromatography combustion isotope ratio mass spectrometry. The mean fractional synthesis rates of the four AGP-glycoforms did not differ significantly between each other as well between individuals. The results indicated a renewal of about 15%/day of the plasma pools of each of the AGP-glycoforms. This is in support to the assumption that the differences in plasma concentration of the AGP-glycoforms are a reflection of the state of the hepatic glycosylation process.

Adult↗
PubMed2004

Valproyl-dephosphoCoA: a novel metabolite of valproate formed in vitro in rat liver mitochondria.

The mitochondrial metabolism of valproic acid (VPA) was investigated in vitro to elucidate its beta-oxidation pathway since the characterization of VPA intermediates in the acyl-CoA thioester form, and not just in their free acid form, has not been fully achieved. Intact rat liver mitochondria were incubated with [4,5-3H2]VPA and [2-3H]VPA. The respective intermediates, valproyl-CoA, Delta2(E)-valproyl-CoA, 3-hydroxyvalproyl-CoA, and 3-oxovalproyl-CoA were analyzed by reverse phase high performance liquid chromatography (HPLC) with radioisotope and UV detection. An unknown metabolite, originating from both labeled substrates, was detected. It was identified as valproyl-dephosphoCoA (valproyl-dephCoA) by fast atom bombardment mass spectrometry (FAB-MS) analysis of the corresponding HPLC peak fraction. The FAB-MS spectrum of the authentic chemically synthesized valproyl-dephCoA proved to be consistent with that of the unknown compound. Valproyl-dephCoA is produced from valproyl-CoA in mitochondria, probably via a phosphatase-catalyzed reaction. This conversion was shown to be more dependent on the energy state involving [AXP] ([AXP] = [ATP] + [ADP] + [AMP]) and [phosphate] concentrations rather than the strict mitochondrial [ATP]/[ADP] ratio. The results indicate that higher concentrations of AXP and phosphate inhibit the dephosphorylation of valproyl-CoA. A complete understanding of the toxic significance of valproyl-dephCoA formation in vivo as a potential inhibitor of fatty acid beta-oxidation is important to clarify the pathogenesis of VPA-associated hepatotoxicity.

Acyl Coenzyme A↗
PubMed2004

Homocysteine clearance and methylation flux rates in health and end-stage renal disease: association with S-adenosylhomocysteine.

Hyperhomocysteinemia is a risk factor for cardiovascular disease and occurs frequently in end-stage renal disease (ESRD), but its pathogenesis is poorly understood. We aimed to evaluate one-carbon flux rates of methionine and homocysteine (Hcy) in ESRD patients and healthy controls. Transmethylation (TM), remethylation (RM), and transsulfuration (TS), as well as Hcy clearance by TS (i.e., TS/plasma total Hcy concentration) and by RM (i.e., RM/plasma total Hcy concentration) were evaluated in relation to body composition, vitamins, and S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) levels. After a fixed protein diet for 3 days, primed-continuous infusion of [(2)H(3)-methyl-1-(13)C]methionine was performed in the postabsorptive state in 12 hemodialysis patients and 16 healthy volunteers. Hcy clearance by TS (-80%, P < 0.001) and by RM (-77%, P < 0.001) in ESRD patients was decreased compared with healthy controls. The absolute flux rates of TM (-27%, P < 0.01) and RM (-28%, P = 0.02) were lower in the ESRD patients. After adjustment for age, TS was not significantly reduced. Whole blood AdoHcy was significantly elevated in ESRD and was a significant determinant of TM (standardized beta = -1.24, P = 0.01) and RM (standardized beta = -1.43, P = 0.03). In conclusion, patients with ESRD have impaired Hcy clearance by TS and RM. Elevated whole blood AdoHcy levels are associated with impaired RM and TM flux rates in these patients, and AdoHcy may be a key regulatory compound in one-carbon flux.

Adult↗
PubMed2003

Significant behavioral disturbances in succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria).

We report two adult patients with succinic semialdehyde dehydrogenase deficiency, manifesting as gamma-hydroxybutyric aciduria. For both, the clinical presentation included significant behavioral disturbances and psychosis (hallucinations, disabling anxiety, aggressive behavior, and sleep disorder), leading to multiple therapeutic attempts. Intervention with benzodiazepines appeared most efficacious, resulting in decreased aggression and agitation and improvement in anxiety. A review of 56 published and unpublished studies of SSADH-deficient patients revealed that 42% manifested behavioral disturbances, whereas 13% (predominantly adults) displayed psychotic symptomatology. To explore the potential biochemical basis of these behavioral abnormalities, we studied cerebrospinal fluid derived from 13 patients, which revealed significantly elevated GHB (65- to 230-fold), high free and total GABA (up to threefold), and low glutamine. Although within the control range, homovanillic and 5-hydroxyindoleacetic acids (end products of dopamine and serotonin metabolism, respectively) showed a significant linear correlation with increasing GHB concentration, suggesting enhanced dopamine and serotonin turnover. We conclude that elevated GABA combined with low glutamine suggest disruption of the glial-neuronal glutamine/GABA/glutamate shuttle necessary for replenishment of neuronal neurotransmitters, whereas altered dopamine and serotonin metabolism may be causally linked to the hyperkinetic movement disorders and behavioral disturbances seen in SSADH-deficient patients.

Adult↗
PubMed2003

D-2-hydroxyglutaric aciduria: a case with an intermediate phenotype and prenatal diagnosis of two affected fetuses.

D-2-hydroxyglutaric aciduria (D2HGA) is a rare autosomal recessive disorder with variable clinical expression. The biochemical defect is unknown at present. Previously reported cases have either followed a severe clinical course characterized by neonatal epileptic encephalopathy, cortical blindness, and profound developmental delay, or a mild course characterized by mild developmental delay, manageable epilepsy, and mild hypotonia. To date there has been a clear distinction between these two groups. We report the second case of a child with D2HGA who has followed an intermediate course. She presented in infancy with hypotonia, manageable epilepsy and developed moderate to severe developmental delay, and cortical visual impairment. The proposita had a coarse facial appearance, flat face, broad nasal bridge, up-turned nose, and simple, anteverted ears. These facial anomalies have been noted in other children with D2HGA and this case strengthens the proposed association between this facial phenotype and D2HGA. We also report the third and fourth instances of prenatal diagnosis for D2HGA. At each prenatal diagnosis, an affected fetus was diagnosed on the basis of markedly increased levels of D-2-hydroxyglutaric acid in amniotic fluid.

Adult↗
PubMed2003

A novel gamma-hydroxybutyrate dehydrogenase: identification and expression of an Arabidopsis cDNA and potential role under oxygen deficiency.

In plants, gamma-aminobutyrate (GABA), a non-protein amino acid, accumulates rapidly in response to a variety of abiotic stresses such as oxygen deficiency. Under normoxia, GABA is catabolized to succinic semialdehyde and then to succinate with the latter reaction being catalyzed by succinic semialdehyde dehydrogenase (SSADH). Complementation of an SSADH-deficient yeast mutant with an Arabidopsis cDNA library enabled the identification of a novel cDNA (designated as AtGH-BDH for Arabidopsis thaliana gamma-hydroxybutyrate dehydrogenase), which encodes a 289-amino acid polypeptide containing an NADP-binding domain. Constitutive expression of AtGHBDH in the mutant yeast enabled growth on 20 mm GABA and significantly enhanced the cellular concentrations of gamma-hydroxybutyrate, the product of the GHDBH reaction. These data confirm that the cDNA encodes a polypeptide with GHBDH activity. Arabidopsis plants subjected to flooding-induced oxygen deficiency for up to 4 h possessed elevated concentrations of gamma-hydroxybutyrate as well as GABA and alanine. RNA expression analysis revealed that GHBDH transcription was not up-regulated by oxygen deficiency. These findings suggest that GHBDH activity is regulated by the supply of succinic semialdehyde or by redox balance. It is proposed that GHBDH and SSADH activities in plants are regulated in a complementary fashion and that GHBDH and gamma-hydroxybutyrate function in oxidative stress tolerance.

Alanine↗
PubMed2003

Lack of creatine in muscle and brain in an adult with GAMT deficiency.

Guanidinoacetate methyltransferase deficiency, which so far has been exclusively detected in children, was diagnosed in a 26-year-old man. The full-blown spectrum of clinical symptoms already had been present since infancy without progression of symptoms during adolescence. Cranial magnetic resonance imaging showed normal findings. Ophthalmological examination showed no retinal changes. Besides creatine deficiency in the brain, a distinct lack of phosphocreatine in skeletal muscle was proved by (31)P magnetic resonance spectroscopy. Creatine substitution combined with a guanidinoacetate-lowering diet introduced first at the age of 26 years was shown to be effective by an impressive improvement of epileptic seizures, mental capabilities, and general behavior and by normalization of the (31)P spectrum in the skeletal muscle.

Adult↗
PubMed2003

Murine succinate semialdehyde dehydrogenase deficiency.

Inherited succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria) is one of the few neurogenetic disorders of GABA metabolism, and one in which tonic-clonic seizures associate with increased central nervous system GABA and gamma-hydroxybutyrate (GHB). To explore pathomechanisms and develop new preclinical treatment approaches, we developed a murine knockout model of SSADH deficiency. In the absence of intervention, SSADH(-/-) mice suffer 100% mortality at week 3 to 4 of life from generalized tonic-clonic seizures. In this report, we summarize earlier studies indicating disruption of the GABA/glutamine axis in SSADH(-/-) mouse brain, effective pharmacotherapeutic approaches, preliminary gene-therapy results, and electrophysiological analyses of mutant mice. We also present new evidence for oxidative stress in SSADH(-/-) mice, significant alterations of dopamine metabolism, and abnormal neurosteroid levels in brain, potentially implicating the GABA(A) receptor in pathogenesis. In SSADH deficiency, the accumulation of two neuroactive species, GABA and GHB, is significant because GABA is one of the earliest transmitters expressed in mammals, with key roles in synaptogenesis and myelination, whereas GHB displays a vast array of pharmacological actions. The SSADH(-/-) mouse may represent a useful model in which to explore the effect of GABA and GHB accumulation on central nervous system development and function.

Aldehyde Oxidoreductases↗
PubMed2003

Succinic semialdehyde dehydrogenase deficiency in children and adults.

Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the degradation pathway of gamma-aminobutyric acid. The disorder is detected when 4-hydroxybutyric aciduria is present on urine organic acid analysis, and is subsequently confirmed by enzyme measurement on leucocytes. The disorder has been identified in approximately 350 individuals worldwide. We review the clinical features in 60 patients. The most common characteristics are developmental delay maximally involving expressive language, hypotonia, mental retardation, ataxia, and behavioral problems. Seizures occur in approximately half of patients, and include tonic-clonic, absence, and myoclonic seizures, including status epilepticus. Electroencephalographic findings are background slowing and generalized and focal epileptiform discharges. Magnetic resonance imaging typically reveals increased T2-weighted signal of the globus pallidus bilaterally, with variable involvement of white matter and the cerebellar dentate nucleus. Preliminary human cerebrospinal fluid measurements are consistent with neurometabolic aberrations documented in the murine animal model, with elevations in gamma-aminobutyric acid, gamma-hydroxybutyrate, and homocarnosine, and low glutamine. Succinic semialdehyde dehydrogenase deficiency may be an underrecognized neurometabolic disorder with a nonspecific and wide phenotypic spectrum, and carries implications for a comprehensive fundamental understanding of interrelations between multiple neurotransmitter systems.

Adult↗
PubMed2003

Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency.

Succinate semialdehyde dehydrogenase (SSADH; ALDH5A1) deficiency, a rare metabolic disorder that disrupts the normal degradation of GABA, gives rise to a highly heterogeneous neurological phenotype ranging from mild to very severe. The nature of the mutation has so far been reported in patients from six families world wide and eight different mutations were described. Here we report the mutational spectrum in 48 additional unrelated families of different geographic origin. We detected 27 novel mutations at the cDNA level, of which 26 could be attributed to changes at the genomic level. Furthermore, six mutations were detected that did not strongly affect SSADH activity when expressed in HEK 293 cells and are considered nonpathogenic allelic variants. Twenty of the mutations were only found in one family. The spectrum of disease-causing mutations from all patients sequenced thus far consists of 25 point mutations, four small insertions, and five small deletions. Seven of these mutations affect splice junctions, seven are nonsense mutations, and 12 are missense mutations. Although there were no mutational hotspots or prevalent mutations responsible for a significant number of cases, 14 out of 37 (38%) of the missense alleles were present in exon 4 or 5. With one exception, the missense mutations we consider to be causative of SSADH deficiency reduced the SSADH activity to less than 5% of the normal activity in our in vitro expression system. This indicates that residual expression is not likely to be an important factor contributing to the large phenotypic differences observed among different families and even among siblings, suggesting that other modifying factors are of great importance in disease pathology.

Aldehyde Oxidoreductases↗