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Biomedical subjects

C Jakobs

Publications and source records attributed to C Jakobs.

At least 19 recordsLinked to original sources
PubMed1996

Coexistence of hereditary homocystinuria and factor V Leiden--effect on thrombosis.

BACKGROUND: Venous and arterial thromboembolism occurs in only about one third of patients homozygous for homocystinuria, which suggests that other, contributory factors are necessary for the development of thrombosis in these patients. Factor V Leiden, an R506Q mutation in the gene coding for factor V, is the most common cause of familial thrombosis and could be a potentiating factor. METHODS: We determined activated partial-thromboplastin times in the presence and absence of activated protein C and tested for the factor V Leiden mutation in 45 members of seven unrelated consanguineous kindreds in which at least 1 member was homozygous for homocystinuria. RESULT: Thrombosis (venous, arterial, or both) occurred in 6 of 11 patients with homocystinuria (age, 0.2 to 8 years). All six also had the factor V Leiden mutation. One patient with prenatally diagnosed homocystinuria who was also heterozygous for factor V Leiden has received warfarin therapy since birth and has not had thrombosis (age, 18 months). Of four patients with homocystinuria who did not have factor V Leiden, none had thrombosis (ages at this writing, 1 to 17 years). Three women who were heterozygous for both homocystinuria and factor V Leiden had recurrent fetal loss and placental infarctions. CONCLUSIONS: Patients with concurrent homocystinuria and factor V Leiden can have an increased risk of thrombosis. Screening for factor V Leiden may be indicated in patient with homocystinuria and their family members.

Adolescent↗
PubMed1996

A case of tyrosinaemia type I with normal level of succinylacetone in the amniotic fluid.

Prenatal diagnosis of tyrosinaemia type I can be achieved in cultured amniotic cells and in chorionic villus material by testing the activity of fumarylacetoacetate hydrolase and by DNA analysis, and in amniotic fluid by succinylacetone measurement. This specific metabolite can be measured either by gas chromatography-mass spectrometry or by delta-aminolevulinate dehydratase inhibition assay. In a series of 65 at-risk cases tested with the enzyme inhibition assay, one case out of the 18 with the disease had a normal level of succinylacetone. This case is presented.

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↗
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

Prenatal diagnosis of galactosemia.

The experience from three different European centres with the prenatal diagnosis of galactose-1-phosphate-uridyltransferase (GALT) deficiency is presented and the question whether or not there is a need for prenatal diagnosis of this disorder is discussed. Most prenatal diagnoses (n = 50) have been performed by assay of GALT activity in cultured amniotic fluid cells. The assay used is reliable and clearly distinguishes homozygous affected fetuses (n = 11; 0%-2.3% of mean control enzyme activity) from non-(homozygous)-affected fetuses. The GALT assay for cultured amniocytes was adapted to assay the enzyme directly in chorionic villi. The experience with chorionic villi comprises 23 cases with 5 affected fetuses (0%-4.2% of mean control enzyme activity). In 36 cases galactitol was determined in amniotic fluid supernatant by gas chromatography-mass spectrometry. This method also differentiated affected (n = 11; galactitol 5.9-10.6 mumol/l) and unaffected pregnancies (galactitol 0.23-1.6 mumol/l) clearly and has the advantage of providing a result within a day or two after amniocentesis. Prenatal diagnosis of galactosemia is undertaken rarely and sometimes for the wrong reasons, but it should perhaps be considered more seriously until better methods of treatment are established.

Amniocentesis↗
PubMed1995

Galactitol in galactosemia.

Urinary galactose and galactitol excretion in controls is age-dependent with the highest concentrations at a younger age. Untreated patients with classical galactosemia excreted highly elevated amounts of galactitol (8000-69,000 mmol/mol creatinine; controls 3-81) which did not correlate with galactose excretion. After treatment, galactose excretion returned to normal in all patients whereas galactitol excretion (45-900 mmol/mol creatinine) remained above the age-matched control range. The excretion of galactitol (96-170 mmol/mol creatinine) in untreated compound heterozygotes was much lower although still above the age-matched control levels, and it returned to normal after treatment. In untreated classical galactosemia patients the galactitol in plasma (120-500 mumol/l) was markedly elevated (controls 0.08-0.86 mumol/l); under treatment, the galactitol concentrations (4.7-20 mumol/l) remained above the control range in all. There was no correlation with age nor with galactose-1-phosphate and UDP-galactose levels. Two untreated compound heterozygotes had elevated plasma galactitol (6.0 and 63 mumol/l) which, when treated, returned to normal.

Age Factors↗
PubMed1995

Underlying disorders associated with severe early-onset preeclampsia.

OBJECTIVE: Our purpose was to determine whether patients with severe early-onset preeclampsia have hemostatic or metabolic abnormalities that are associated with a tendency to vascular thrombosis. STUDY DESIGN: A total of 101 patients with a history of severe early-onset preeclampsia were tested at least 10 weeks post partum for the presence of hyperhomocysteinemia (methionine loading test), protein C, protein S, and antithrombin III deficiency, activated protein C resistance, lupus anticoagulant, and immunoglobulin G and/or M anticardiolipin antibodies. RESULTS: Of the 101 patients, 39 (38.6%) had chronic hypertension. Of the 85 patients tested for coagulation disturbances, 21 (24.7%) had protein S deficiency. Of the 50 patients tested for activated protein C resistance, 8 (16.0%) were positive. Of the 79 patients tested for hyperhomocysteinemia, 14 (17.7%) had a positive methionine loading test. Finally, 95 patients were tested for anticardiolipin antibodies; 27 (29.4%) had detectable immunoglobulin G and/or M anticardiolipin antibodies. CONCLUSION: Patients with a history of severe early-onset preeclampsia should be screened for protein S deficiency, activated protein C resistance, hyperhomocysteinemia, and anticardiolipin antibodies, since these results may have an impact on counseling for and pharmacologic management in future pregnancies.

Antibodies, Anticardiolipin↗
PubMed1995

Congenital lacticacidemia caused by lipoamide dehydrogenase deficiency with favorable outcome.

A 5-year-old boy had recurrent vomiting and lethargy with lacticacidemia and ketoacidemia since birth. Lipoamide dehydrogenase deficiency was found in muscle and fibroblasts. Therapy with sodium dichloroacetate, thiamine, and carnitine was associated with reduction of the severity and frequency of the decompensation episodes and near normal plasma lactate levels. At 5 years of age, the patient has normal cognitive function and moderate motor impairment.

Acidosis, Lactic↗
PubMed1995

Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease.

Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (< or = 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL-1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.

Adult↗
PubMed1995

D-2-hydroxyglutaric aciduria.

Hydroxyglutaric aciduria is detected by gas chromatographic-mass spectrometric analysis, and the D and L forms are quantified by chemical ionization with deuterated internal standards. Patients have recently been described who accumulate the D form, and they appear to be quite different from those with the more common L form. Experience is reported with three patients and an animal model with D-2-hydroxyglutaric aciduria. The phenotype appears to include mental retardation, macrocephaly, hypotonia, seizures, and involuntary movements, although neurologic and systemic manifestations of the disorder varied considerably between individual patients, even within the same family.

Animals↗