Biomedical subjects
Publications and source records attributed to C Jakobs.
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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.
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.
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.
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.
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.
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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.
Phytanic acid is a saturated, branched-chain fatty acid which as a consequence of the presence of a methyl group at the 3-position cannot be degraded by beta-oxidation. Instead, phytanic acid first undergoes alpha-oxidation to yield pristanic acid which can be degraded by beta-oxidation. The structure of the alpha-oxidation pathway and its subcellular localization has remained an enigma although there is convincing evidence that 2-hydroxyphytanic acid is an obligatory intermediate. We have now studied the degradation of 2-hydroxyphytanic acid in both rat and human liver. The results show that 2-hydroxyphytanic acid is converted to 2-ketophytanic acid in homogenates of rat as well as human liver. Detailed studies in rat liver showed that the enzyme involved is localized in peroxisomes accepting molecular oxygen as second substrate and producing H2O2. 2-Ketophytanic acid formation from 2-hydroxyphytanic acid was found to be strongly deficient in liver samples from Zellweger patients which lack morphologically distinguishable peroxisomes. The latter results not only provide an explanation for the elevated levels of 2-hydroxyphytanic acid in Zellweger patients but also suggest that the subcellular localization of 2-hydroxyphytanic acid dehydrogenation is identical in rat and man, i.e., in peroxisomes.
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Amniocentesis was performed in four pregnancies at risk for Canavan disease (CD). In all families both parents were of Ashkenazi-Jewish origin and harboured the C854 mutation in the cDNA of the aspartoacylase gene. Using DNA analysis of the amniotic cells, three fetuses were predicted to be non-affected and one fetus was predicted to be affected. The concentration of N-acetylaspartic acid (NAA) in the amniotic fluid was in agreement with these results. In urine samples of the three newborns predicted to be non-affected, the concentration of NAA was normal. Tissues of the aborted fetus were not available. We conclude that DNA analysis is probably a reliable method for prenatal diagnosis of CD.
We report our cumulative experience for the prenatal diagnosis of succinic semialdehyde dehydrogenase (SSADH) deficiency in seven 'at-risk' pregnancies from four unrelated families. Prenatal diagnosis was performed by determination of 4-hydroxybutyric acid (4-HBA) concentration in amniotic fluid using isotope-dilution gas chromatography-mass spectrometry in conjunction with assay of SSADH activity in biopsied chorionic villus and/or cultured amniocytes. In three of four pregnancies predicted as affected, confirmation was obtained by demonstration of deficient SSADH activity in fetal tissues. Our results suggest that determination of 4-HBA concentration in amniotic fluid combined with enzyme determination in cultured or biopsied tissue represents a reliable method for the prenatal diagnosis of SSADH deficiency.,
In two sibs antenatal ultrasonography revealed identical intracranial calcification, ventricular widening and microcephaly. The first pregnancy was artificially terminated at 19 weeks. Post-mortem examination of the brain revealed destructive calcification and extracerebral neuronal heterotopia. The second sib went to term but died 48 h after birth from irreversible lactic acidosis. Autopsy showed extensive encephalopathy with cavitation and calcification in the cerebral hemispheres, polymicrogyria, multiple neuronal heterotopia, partial callosal dysgenesis, and severe Leigh syndrome, together forming a continuum of early and late brain disruption. Mitochondrial respiratory chain abnormalities, mainly affecting complexes I and IV, and deficiency of pyruvate dehydrogenase complex were detected in skeletal muscle and in liver. A normal functioning of the respiratory chain was found in the fibroblasts. Analysis of mtDNA from muscle, liver and blood revealed normal amounts of intact mtDNA without any of the known point mutations associated with MELAS, MERRF or Leigh syndromes. The early fetal disruption and necrotic changes in the brains of sibs indicate a specific genetically determined disorder which affects neuronal migration, a finding not previously associated with respiratory chain disorders. The present disorder may mimic antenatal congenital infectious encephalopathy because of the combined finding of microcephaly and destructive intracerebral calcification.
OBJECTIVE: To study possible relationships between abnormal placental perfusion, hypoxemia and impaired fetal nutrient supply. STUDY DESIGN: Umbilical artery flow velocity waveforms were assessed in high risk pregnancies and compared with controls. Three groups were studied. In group I (n = 13) the pulsatility index (PI) was within normal limits, in group II (n = 9) PI was > 2 S.D. in the presence of positive end diastolic velocities and in group III (n = 13) end diastolic velocities were absent. pH and PO2 levels and concentrations of amino acids, glucose and lactate were measured in umbilical blood obtained at cesarean section (n = 35). RESULTS: An inverse correlation was found between concentrations of essential amino acids concentrations and the pulsatility index in the umbilical artery (P = 0.03). No correlation with hypoxemia was found (P = 0.32). The glycine/valine ratio was significantly increased in the groups with abnormal Doppler velocity indices (P = 0.02). Glucose concentrations were significantly reduced in the case of absent end diastolic velocities (P = 0.001). No significant differences were found between the three groups concerning lactate concentrations and acid-base balance parameters. CONCLUSIONS: These findings, especially the increased glycine/valine ratio, which is characteristic for kwashiorkor, indicate that abnormal placental perfusion is associated with impaired fetal nutrient supply, in the presence of a normal fetal oxygenation.
PURPOSE: Hyperhomocysteinemia is associated with arteriosclerotic and thromboembolic events. The homocysteine-lowering effect of combined treatment with vitamin B6 plus folic acid has never been explored in a large group of patients with vascular disease. Therefore we studied the effects of at least 6 weeks treatment with these vitamins in 72 patients with cardiovascular disease and mild hyperhomocysteinemia (defined as an increase of the plasma homocysteine level after methionine loading greater than 97.5 percentile of age-matched control subjects but less than 200 mumol/L). METHODS: The existence of mild hyperhomocysteinemia was investigated in 309 consecutive patients under 50 years of age with peripheral arterial occlusive disease, cerebral arterial occlusive disease, or coronary artery occlusive disease. All patients with an abnormal loading test result were treated with vitamin B6, 250 mg daily, plus folic acid, 5 mg daily. After 6 weeks of treatment a second methionine loading test was performed to assess the homocysteine-lowering effect. RESULTS: Mild hyperhomocysteinemia was detected in 72 patients (23%), 33 (46%) of whom also had hyperhomocysteinemia when fasting. Treatment with vitamin B6 plus folic acid normalized the postload plasma homocysteine concentration in 66 of the 72 patients (92%), whereas fasting hyperhomocysteinemia was normalized in 30 of 33 (91%) patients. In six patients therapy failed to achieve normalization of the postload homocysteine levels. In three of these patients, the same treatment was continued for an additional 6 weeks, and in the remaining three patients betaine was added to the treatment regimen. After 6 weeks of additional treatment all six patients had normal postload plasma homocysteine concentrations. CONCLUSION: The prevalence of mild hyperhomocysteinemia in young patients with arterial occlusive disease is high. Simple and inexpensive therapy with vitamin B6 plus folic acid will normalize homocysteine metabolism, as assessed by the homocysteine plasma level after methionine loading, in virtually all these patients.
D-2-Hydroxyglutaric aciduria was documented in a newborn who presented with seizures, hypotonia, cortical blindness, a movement disorder, and developmental delay. Her clinical presentation differs from that of patients with L-2-hydroxyglutaric aciduria and a single previously reported patient with D-2-hydroxyglutaric aciduria. Cerebrospinal fluid levels of gamma-aminobutyric acid were elevated, while biogenic amine metabolites were normal. The movement disorder in our patient and in those with L-2-hydroxyglutaric aciduria suggests involvement of the basal ganglia in the disease process. Prenatal diagnosis of an affected fetus was accomplished during a subsequent pregnancy.