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Cornelis Jakobs

Publications and source records attributed to Cornelis Jakobs.

At least 19 recordsLinked to original sources
PubMed2007

Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene.

Patients with pyridoxine dependent epilepsy (PDE) present with early-onset seizures resistant to common anticonvulsants. According to the benefit of pyridoxine (vitamin B(6)) and recurrence of seizures on pyridoxine withdrawal, patients so far have been classified as having definite, probable, or possible PDE. Recently, PDE has been shown to be caused by a defect of alpha-amino adipic semialdehyde (AASA) dehydrogenase (antiquitin) in the cerebral lysine degradation pathway. The accumulating compound piperideine-6-carboxylic acid (P6C) was shown to inactivate pyridoxalphosphate (PLP) by a Knoevenagel condensation. Pipecolic acid (PA) and AASA are markedly elevated in urine, plasma, and cerebrospinal fluid (CSF) and thus can be used as biomarkers of the disease. We have investigated 18 patients with neonatal seizure onset, who have been classified as having definite (11), probable (four), or possible (three) PDE. All patients had elevated PA and AASA in plasma (and urine) while on treatment with individual dosages of pyridoxine. Within this cohort, molecular analysis identified 10 novel mutations (six missense mutations, one nonsense mutation, two splice site mutations) within highly conserved regions of the antiquitin gene. Seven mutations were located in exonic sequences and two in introns 7 and 17. Furthermore, a novel deletion of exon 7 was identified. Two of the 36 alleles investigated require further investigation. A known mutation (p.Glu399Gln) was found with marked prevalence, accounting for 12 out of 36 alleles (33%) within our cohort. Pyridoxine withdrawal is no longer needed to establish the diagnosis of "definite" PDE. Administration of pyridoxine in PDE may not only correct secondary PLP deficiency, but may also lead to a reduction of AASA (and P6C) as presumably toxic compounds.

Aldehyde Dehydrogenase↗
PubMed2006

Glutaric aciduria type 1: clinical, biochemical and molecular findings in patients from Israel.

Glutaric aciduria type 1 (GA1) is a rare cerebral organic aciduria which typically manifests as an acute encephalopathic crisis followed by profound long-term neurological handicap. We report the diagnosis of 12 new patients from a single laboratory in Israel during a 5-year period. Eleven of the 12 were of Palestinian origin, and only two were related. One patient was asymptomatic whilst one was mildly, one moderately and nine severely affected, two of whom had unusual MRI findings. Two patients had normal glutaric acid excretion and normal blood glutarylcarnitine levels yet glutarylcarnitine excretion was increased, indicating its utility as a diagnostic marker. Four novel GCDH mutations (Thr193_Arg194insHis, Asn329Ser, Thr341Pro, Met405Val) and five previously reported mutations (Ser119Leu, Leu283Pro, Ala293Thr, Gly390Arg and Thr416Ile) were identified. Severely and mildly affected or even asymptomatic patients shared the same genotypes (Thr416Ile/Thre416Ile and Aal293Thr/Thr193_Arg194insHis). Knowledge of the responsible mutation enabled successful prenatal diagnosis on chorionic villous DNA in three families. In conclusion, GA1 is genetically heterogeneous and has a relatively high incidence in the Palestinian population, reflecting the historical tradition of marriages within extended kindreds, particularly in isolated villages. Additional genetic and/or environmental factors must account for the phenotypic heterogeneity in patients with the same genotype. The diagnosis was not suspected in the majority of cases despite typical clinical and/or neuroimaging features, suggesting that glutaric aciduria may be under-diagnosed. Greater awareness of glutaric aciduria amongst pediatricians, neonatologists and radiologists is the key to identifying the disorder in the presymptomatic phase and preventing its catastrophic consequences.

Adolescent↗
PubMed2006

Pyridoxine-dependent seizures in Dutch patients: diagnosis by elevated urinary alpha-aminoadipic semialdehyde levels.

BACKGROUND: Pyridoxine-dependent seizures (PDS) is a rare, autosomal recessively inherited disorder. Recently alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency was identified as a major cause of PDS, which causes accumulation of both alpha-AASA and pipecolic acid (PA) in body fluids. METHODS: We studied urinary and plasma alpha-AASA and PA levels in 12 Dutch clinically diagnosed patients with PDS. RESULTS: Alpha-AASA was elevated in both urine and plasma in 10 patients. In these patients plasma PA levels were also elevated but urinary PA levels were normal. DISCUSSION: In all patients with clinically definite PDS, and in most patients with probable or possible PDS, the clinical diagnosis of PDS could be confirmed at the metabolite level. Non-invasive urinary screening for alpha-AASA accumulation provides a reliable tool to diagnose PDS and can save these patients from the classical and potentially dangerous pyridoxine withdrawal test to prove PDS.

Aldehyde Dehydrogenase↗
PubMed2006

Chronic intragastric administration of gamma-butyrolactone produces physical dependence in baboons.

RATIONALE: Abuse of gamma-hydroxybutyrate (GHB) and its precursors is a public health concern. Gamma-butyrolactone (GBL) is found in commercially available products and, when ingested, is metabolized to GHB. OBJECTIVE: The goal was to evaluate the physical dependence potential and behavioral effects of GBL. METHODS: Vehicle and then GBL were administered continuously (24 h per da y) in baboons (Papio anubis, n=5) via intragastric catheters. GBL dosing was initiated at 100 mg/kg/day and then progressively increased stepwise by increments of 100 mg/kg to a final dose of 600 mg/kg. The number of food pellets earned, fine-motor task performance, and observed behaviors were used as dependent measures. Precipitated withdrawal was evaluated after administration of GABA-B and benzodiazepine receptor antagonists during chronic GBL dosing (400-600 mg/kg). Spontaneous withdrawal was evaluated after discontinuation of chronic GBL 600 mg/kg. Blood GHB levels were determined during chronic dosing of each GBL dose by isotope dilution assay. RESULTS: Chronic GBL dose-dependently decreased food-maintained behavior, disrupted performance on the fine-motor task, and produced signs of sedation and muscle relaxation. The GABA-B antagonist SGS742 [56 mg/kg, intramuscular (IM)] precipitated a withdrawal syndrome, whereas the benzodiazepine antagonist flumazenil (5 mg/kg, IM) produced little or no effect. Signs of physical dependence were also demonstrated when chronic GBL dosing was discontinued. Analysis of plasma indicated GBL was metabolized to GHB; levels were 825 to 1,690 micromol l(-1) GHB and 2,430 to 3,785 micromol l(-1) GHB after week 1 of 400 and 600 mg/kg/day, respectively. CONCLUSIONS: These data indicate that, like GHB, chronic GBL dosing produced physical dependence that likely involved the GABA-B receptor.

4-Butyrolactone↗
PubMed2006

Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells.

Children with hereditary severe hyperhomocysteinemia present with a variety of neurological impairment, and mild hyperhomocysteinemia has been associated with neurodegeneration in the elderly. The link of hyperhomocysteinemia to neurological dysfunction is unknown. We investigated mitochondrial mechanisms of homocysteine (HCys) neurotoxicity in rat dopaminergic pheochromocytoma cells, human neuroblastoma cells and primary rat cerebellar granule neurons. HCys dose dependently impaired cytochrome c oxidase (COX) activity as well as stability and induced reactive oxygen species and apoptotic cell death. We found that HCys binds the COX cofactor Cu(2+), and Cu(2+) supplementation prior to HCys treatment preserved COX activity and prevented cell death. The Cu(2+) chelating action of HCys and impairement of COX activity represent novel mechanisms of HCys neurotoxicity, which might be preventable by supplementation of Cu(2+).

Animals↗
PubMed2006

X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology.

Mutations in the creatine transporter gene, SLC6A8 (MIM 30036), located in Xq28, have been found in families with X-linked mental retardation (XLMR) as well as in males with idiopathic mental retardation (MR). In order to estimate the frequency of such mutations in the MR population, a screening of 478 males with MR of unknown cause was undertaken. All 13 exons of SLC6A8 were sequenced using genomic DNA. Six novel potentially pathogenic mutations were identified that were not encountered in at least 588 male control chromosomes: two deletions (p.Asn336del, p.Ile347del) and a splice site alteration (c.1016+2C>T) are considered pathogenic based on the nature of the variant. A mutation (p.Arg391Trp) should be considered pathogenic owing to its localization in a highly conserved region. Two other missense variants (p.Lys4Arg, p.Gly26Arg) are not conserved but were not observed in over 300 male control chromosomes. Their pathogenicity is uncertain. A missense variant (p.Val182Met), was classified as a polymorphism based on a normal creatine/creatinine (Cr:Crn) ratio and cerebral creatine signal in proton magnetic resonance spectroscopy (H-MRS) in the patient. Furthermore, we found 14 novel intronic and neutral variants that were not encountered in at least 280 male control chromosomes and should be considered as unclassified variants. Our findings of a minimum of four pathogenic mutations and two potentially pathogenic mutations indicate that about 1% of males with MR of unknown etiology might have a SLC6A8 mutation. Thus, DNA sequence analysis and/or a Cr:Crn urine screen is warranted in any male with MR of unknown cause.

Amino Acid Sequence↗
PubMed2006

Clinical, cytogenetic and molecular characterization of a patient with combined succinic semialdehyde dehydrogenase deficiency and incomplete WAGR syndrome with obesity.

We describe the clinical course, as well as cytogenetic and molecular findings, of a 3-year-old obese boy with psychomotor retardation who exhibited two rare conditions: succinic semialdehyde dehydrogenase deficiency (SSADH deficiency, MIM 271980), a disorder of gamma-aminobutyric acid metabolism with a heterogeneous clinical spectrum, and partial Wilms' tumor, aniridia, genital abnormalities, and mental retardation (WAGR) syndrome, an association between Wilms' tumor, aniridia, genitourinary malformations, and mental retardation due to mutations involving the short arm of chromosome 11, particularly deletions at the chromosomal region 11p13 (MIM 194072). Diagnosis of SSADH deficiency in our patient was established by demonstration of absent enzyme activity in isolated leucocytes, and was associated with a novel missense mutation (c.587G>A; p.Gly196Asp) in the SSADH coding sequence. We further confirmed an incomplete WAGR syndrome in this boy [karyotype 46, XY, del (11) (p13p14.2)] with a normal WT1 (Wilms' tumor) gene and an absence of pathology in the genitourinary tract, but with obesity (WAGR syndrome with obesity, WAGRO syndrome). The patient also exhibited distinctive cerebral anomalies such as increased signals of the globi pallidi, internal hydrocephalus and cerebellar vermian atrophy. However, treatment options for this patient are limited, including supportive treatment, physiotherapy, special educational training, and vigabatrin. In summary, we report the first patient with the exceptional rare findings of both SSADH deficiency and partial WAGR/WAGRO syndrome.

Cerebellum↗
PubMed2006

Mutations in antiquitin in individuals with pyridoxine-dependent seizures.

We show here that children with pyridoxine-dependent seizures (PDS) have mutations in the ALDH7A1 gene, which encodes antiquitin; these mutations abolish the activity of antiquitin as a delta1-piperideine-6-carboxylate (P6C)-alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase. The accumulating P6C inactivates pyridoxal 5'-phosphate (PLP) by forming a Knoevenagel condensation product. Measurement of urinary alpha-AASA provides a simple way of confirming the diagnosis of PDS and ALDH7A1 gene analysis provides a means for prenatal diagnosis.

Aldehyde Dehydrogenase↗
PubMed2006

Increased guanidino species in murine and human succinate semialdehyde dehydrogenase (SSADH) deficiency.

Mice with targeted deletion of the GABA-degradative enzyme succinate semialdehyde dehydrogenase (SSADH; Aldh5a1; OMIM 271,980) manifest globally elevated GABA and regionally decreased arginine in brain extracts. We examined the hypothesis that arginine-glycine amidinotransferase catalyzed the formation of guanidinobutyrate (GB) from increased GABA by quantifying guanidinoacetate (GA), guanidinopropionate (GP) and GB in brain extracts employing stable isotope dilution gas chromatographic-mass spectrometry. GA and GB were up to 4- and 22-fold elevated, respectively, in total and regional (cerebellum, hippocampus, cortex) brain extracts derived from SSADH(-/-) mice. Corresponding analyses of urine and cerebrospinal fluid derived from SSADH-deficient patients revealed significant (P<0.05) elevations of GA and GB in urine, as well as GB levels in CSF. These data suggest that GB may be an additional marker of SSADH deficiency, implicate additional pathways of pathophysiology, and identify the second instance of elevated GB in a human inborn error of metabolism.

Animals↗
PubMed2006

Exocytotic release of creatine in rat brain.

The guanidino compound creatine has been shown to occur throughout the brain affecting energy metabolism and mental performance and to act at central GABAA receptors as a partial agonist. Therefore, we examined the possibility that creatine may in fact represent a neuromodulator that is released in the brain in an action-potential dependent manner. To that end, we studied the uptake of [3H]creatine and its electrically evoked release from superfused rat brain slices as well as the evoked release of endogenously synthesized creatine. [3H]creatine was accumulated in neocortex slices in a Na+-dependent manner, consistent with the involvement of the Na+-dependent SLC6A8 creatine transporter. Most importantly, the electrically evoked release of [3H]creatine from neocortex slices (like that from caudate putamen and hippocampus slices) as well as the evoked release of endogenous (unlabeled) creatine was abolished when Ca2+ was omitted from the superfusion medium or in the presence of the Na+-channel blocker tetrodotoxin (TTX). Moreover, blockade of K+-channels by 4-aminopyridine (4-AP) strongly enhanced the electrically evoked release of [3H]creatine as well as that of endogenous creatine. These in vitro data indicate that creatine is not only synthesized and taken up by central neurons, but also released in an action-potential dependent (exocytotic) manner, providing strong evidence for its role as a neuromodulator in the brain.

Action Potentials↗
PubMed2006

Transaldolase deficiency: a new cause of hydrops fetalis and neonatal multi-organ disease.

Transaldolase (TALDO) deficiency is a newly recognized metabolic disease, which has been reported so far in 2 patients presenting with liver failure and cirrhosis. We report a new sibship of 4 infants born to the same consanguineous parents; all presented at birth or in the antenatal period with dysmorphic features, cutis laxa and hypertrichosis, hepatomegaly, splenomegaly, liver failure, hemolytic anemia, thrombocytopenia, and genitourinary malformations. The clinical courses were variable: the first child died of liver failure at 4 months of age; the second pregnancy was medically terminated at 28 weeks gestation because of hydrops fetalis with oligohydramnios. The third child is doing well at age 7 with liver fibrosis and mild kidney failure. The fourth child is now 21 months old and has hepatosplenomegaly, mild anemia, and thrombocytopenia. Urine assessment of polyols showed elevations of erythritol, arabitol, and ribitol consistent with TALDO deficiency. TALDO activity was undetectable in the patients' tissues, and mutation in the TALDO1 gene was found in the 4 patients.

Biomarkers↗
PubMed2006

Hemiconvulsion-hemiplegia-epilepsy syndrome as a presenting feature of L-2-hydroxyglutaric aciduria.

L-2-hydroxyglutaric aciduria was diagnosed in a 9-month-old female infant after a complex febrile convulsion with subsequent transient left-sided hemiplegia. The symptoms were consistent with acute hemiconvulsion-hemiplegia-epilepsy syndrome. Magnetic resonance imaging (MRI) of the brain revealed distinct white-matter abnormalities in the bifrontal and bioccipital periventricular area and increased signal intensity in the lenticular, caudate, and dentate nuclei, consistent with L-2-hydroxyglutaric aciduria. Increased concentrations of L-2-hydroxyglutaric acid were detected in the urine, plasma, and cerebrospinal fluid. The patient was homozyous for the p.Lys81Glu (c.241A>G) missense mutation in the L-2-HGA gene, confirming the diagnosis of L-2-hydroxyglutaric aciduria. Acute hemiconvulsion-hemiplegia-epilepsy syndrome has not been reported as a presenting feature in L-2-hydroxyglutaric aciduria. In patients with prolonged or complicated febrile seizures such as hemiconvulsion-hemiplegia-epilepsy syndrome, L-2-hydroxyglutaric aciduria should be included in the differential diagnosis, especially in children with concomitant macrocephaly.

Epilepsy↗
PubMed2006

Quantitative determination of erythrocyte folate vitamer distribution by liquid chromatography-tandem mass spectrometry.

BACKGROUND: Given the role of folate in many disorders, intracellular distribution of folate vitamers is of potential clinical importance. In particular, accumulation of non-methyltetrahydrofolates due to altered partitioning of folate metabolism at the level of methylenetetrahydrofolate is of interest. METHODS: We describe a positive-electrospray liquid chromatography tandem mass spectrometry (LC-MS/MS) method that allows determination of erythrocyte folate vitamer distribution by accurately measuring both 5-methyltetrahydrofolate (5-methylTHF) and non-methyl folate vitamers. Whole blood lysates are deconjugated in ascorbic acid solutions, deproteinized, purified using folate-binding protein affinity columns, concentrated by solid-phase extraction (SPE) and evaporation, and separated on a C18 column within 6 min. RESULTS: The limit of quantification for both 5-methylTHF and non-methylTHF was 0.4 nmol/L (signal-to-noise >10). Intra- and inter-assay CVs for 5-methylTHF were 1.2% and 2.8%, respectively. Intra- and inter-assay CVs for non-methylTHF as a group were 1.6% and 1.5%, respectively. Recovery results were 97-107%. We measured 8-72% non-methyl folate vitamers in volunteers (n=5) with the methylenetetrahydrofolate reductase (MTHFR) 677 TT genotype. Concentrations ranged from 117 to 327 nmol/L and 23 to 363 nmol/L for 5-methylTHF and non-methylTHF vitamers, respectively. We measured 0-2% non-methylTHF vitamers in MTHFR 677 CC genotype volunteers. In addition, we found that storage of whole-blood samples in ascorbic acid at low pH resulted in 53-90% loss of the non-methylTHF fraction. CONCLUSION: This LC-MS/MS method accurately determines erythrocyte 5-methylTHF and non-methyl folate vitamers.

Chromatography, High Pressure Liquid↗
PubMed2005

Determination of succinylacetone in dried blood spots and liquid urine as a dansylhydrazone by liquid chromatography tandem mass spectrometry.

Succinylacetone (SA) is a specific marker for the inherited metabolic disease, hepatorenal tyrosinemia. We developed a stable-isotope dilution liquid chromatography tandem mass spectrometry for the determination of SA in dried blood spots (DBS) and liquid urine using a (13)C(4)-SA as internal standard. SA was extracted, converted to the butyl ester and derivatized with dansylhydrazine (Dns-H). Calibration curves in DBS and urine calibrators were linear up to 100 and 30 microM, respectively. At a signal-to-noise ratio of 3, the limits of detection in DBS and urine were 0.2 and 0.005 microM, respectively. Total run time was 5 min. Intra- and inter-assay precision expressed as coefficient of variation were better than 9.1% with more than 96% recovery. The method was applied retrospectively and prospectively for the diagnosis of hepatorenal tyrosinemia and for follow-up of patients under treatment.

Chromatography, High Pressure Liquid↗
PubMed2005

A novel, quantitative assay for homocarnosine in cerebrospinal fluid using stable-isotope dilution liquid chromatography-tandem mass spectrometry.

We describe a rapid and sensitive method for the quantification of homocarnosine in physiological fluids, with particular emphasis on cerebrospinal fluid (CSF). Homocarnosine was quantified as the butyl derivative, with (2)H(2)-l-homocarnosine as internal standard. Following deproteinization of CSF samples, supernatants were evaporated to dryness and derivatized with 10% 6M HCl in butanol. Samples were chromatographed on a C(18) column and detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) operating in the multiple reaction monitoring mode. The intra- and inter-assay variations were 4.6 and 10.9%, respectively. Mean recovery of homocarnosine at two concentrations was 105%. The limit of detection in CSF approximated 20 nmol/L. CSF homocarnosine is age dependent and ranges from <0.02 to 10 micromol/L. Our method is applicable to the analysis of CSF derived from patients with heritable defects in the GABA pathway, patients with homocarnosinosis or serum carnosinase deficiency, and should be applicable to other model systems in order to further explore the biological role and significance of homocarnosine in mammalian systems.

Adolescent↗
PubMed2005

The transmethylation cycle in the brain of Alzheimer patients.

Homocysteine accumulation, frequently observed in plasma of AD patients, may be a sign of a reduced activity of the brain methionine-homocysteine transmethylation cycle. S-Adenosylmethionine (SAM) is the main methyl donor in several transmethylation reactions. The demethylated product of SAM, S-adenosylhomocysteine (SAH), is hydrolyzed to yield homocysteine, which can be remethylated to methionine by transfer of a methyl group of 5-methyltetrahydrofolate (5-MTHF). A reduced activity of the transmethylation cycle in the brain may result in hypomethylation of the promoter of the presenilin 1 (PS1) gene, which will lead to overexpression of presenilin 1 and, consequently, to increased Abeta(1-42) (Abeta42) formation. Brain transmethylation was studied in 30 patients with 'probable' AD and 28 age-matched non-demented controls by measuring the cerebrospinal fluid (CSF) levels of SAM, SAH and 5-MTHF. 5-MTHF was determined by HPLC with electrochemical detection, while SAM and SAH were assayed by stable isotope dilution tandem mass spectrometry. We found no statistical differences between AD patients and controls for 5-MTHF, SAM and SAH levels, and the SAM/SAH-ratio in CSF. These findings argue against a possible change in methylation of the promoter and expression of PS1.

Aged↗
PubMed2005

X-linked creatine transporter deficiency: clinical description of a patient with a novel SLC6A8 gene mutation.

Creatine transporter deficiency is an X-linked disorder characterized by mental retardation and language delay. The authors report a patient affected by creatine transport deficiency caused by a novel mutation in the SLC6A8 gene. Impairment in social interaction represents a consistent clinical finding in the few cases described to date and may be a diagnostic clue for creatine transporter deficiency in males affected by mental retardation, seizures, and language impairment.

Electroencephalography↗