D. Rating

Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid

The association of fetal and neonatal distress, birth measurements, major malformations, and minor anomalies was studied prospectively in 14 infants of women with epilepsy who were receiving valproic acid (VPA) monotherapy and in 12 infants of women with epilepsy who were receiving VPA in combination with other anticonvulsant drugs. Comparison was made with 26 matched-pair controls and 116 controls from a larger study of antiepileptic drugs. During the first trimester, total VPA serum concentrations were well above therapeutic levels (100 to 184 micrograms/ml) in two women receiving high VPA doses (2000 and 1500 mg daily). Although dosage remained the same, serum concentrations decreased during pregnancy to therapeutic levels (33.9 to 57.0 micrograms/ml). The VPA percent free fraction increased in the third trimester and was threefold higher at birth. Almost half of the infants exposed to VPA monotherapy were distressed during labor, and 28% had low Apgar scores. Fetal and neonatal distress may be caused by the high VPA percent free fraction during labor and at birth. Mean body measurements at birth after VPA monotherapy were comparable to those in the matched control group, but were reduced in the group of infants receiving VPA combination therapy. Four infants exposed to VPA monotherapy were born with major malformations. The median number of minor anomalies was four times higher in infants whose mothers received VPA alone or VPA combination therapy than in controls. Seven infants had a pattern of craniofacial and digital anomalies that was distinctly different from that observed after in utero exposure to other anticonvulsant medications. The occurrence of major malformations and the number of minor anomalies may be dose related.

Succinic semialdehyde dehydrogenase deficiency: an inborn error of gamma-aminobutyric acid metabolism.

Gamma-hydroxybutyric aciduria is a disorder of gamma-aminobutyric acid metabolism in which a compound of known neuropharmacologic activity accumulates. We have studied two patients in whom high levels of gamma-hydroxybutyric acid were found in blood, urine and cerebrospinal fluid. A coupled assay has been developed which estimates succinic semialdehyde dehydrogenase activity in isolated human lymphocytes. The mean activity of succinic semialdehyde dehydrogenase in a control and the four parents and two healthy siblings of these patients was 8.8 +/- 1.9 pmol . min-1 . mg-1 protein. In the patients the activities were 0.8 and 1.1 pmol . min-1 . mg-1 protein, approximately 9-13% of control. In the presence of saturating amounts of NAD+, lymphocyte sonicates, derived from the patients accumulated a significant amount of 14C-succinic semialdehyde from 14C-gamma aminobutyric acid, whereas none could be detected in controls. The data suggest a deficiency of succinic semialdehyde dehydrogenase in these patients, the first documented defect of the metabolism of gamma-aminobutyric acid in man.

GABA in Cerebrospinal Fluid of Children with Febrile Convulsions

Summary: In 23 children with febrile convulsions the concentration of y‐aminobutyric acid (GABA) in lumbar cerebrospinal fluid (CSF) was measured by a radioreceptor assay. The mean CSF GABA concentration of 134 (range, 73–294) pmoles/ml was significantly lower than that of 16 seizure‐free children serving as controls, who had 210 (range, 117–475) pmoles/ml. The reduction in CSF GABA levels in patients with febrile convulsions was not reflected in plasma GABA concentrations. These data provide further evidence that impairment of GABA neurotransmission may contribute to an increased seizure propensity.

4-Hydroxybutyric aciduria: A new inborn error of metabolism. I. Clinical review

Atactic syndromes in childhood are difficult to classify and only few conditions are well defined and characterized by specific biochemical abnormalities e.g. IgA deficiency in Louis Bar syndrome (McKusick 20890), elevated serum levels of phytanic acid in Refsum’s disease (McKusick 26650) or a s-lipoproteinaemia in Bassen-Kornzweig syndrome (McKusick 20010). In 1981 we observed a Turkish boy who suffered from a non-progressive ataxia with muscular hypotonia. He excreted large amounts of 4-hydroxybutyric acid (GHB) in his urine. The biochemical findings in this boy led us to postulate a deficiency of succinic semialdehyde (SSA) dehydrogenase, as the first recognized inborn error of GABA metabolism (Jakobs et al., 1981).

Low CSF GABA concentration in children with febrile convulsions, untreated epilepsy, and meningitis.

SummaryIn 14 children with epilepsy, 51 with febrile convulsions and 22 with meningitis gamma-aminobutyric acid (GABA) concentrations in lumbar CSF were determined. While the mean for CSF GABA concentrations for all epileptic children was unchanged [144 (range: 73–285) pmol/ml; controls: 148 (range: 90–243) pmol/ml] extraordinarily high GABA levels were found in the CSF of two children on valproate (525 and 557 pmol/ml) and remarkably low GABA concentrations in hitherto untreated epileptic children [109 (range: 67–176) pmol/ml]. Children with febrile convulsions [103 (range: 63–170) pmol/ml] and acute meningitis [105 (range: 65–171) pmol/ml] had significantly decreased CSF GABA concentrations (P<0.001 and P<0.02 compared with controls). The data indicate that valproate intake increases dramatically the GABA concentrations in the CSF of epileptic children. Furthermore, the study supports the concept that low GABAergic activity within the CNS may be one cause for an increased seizure frequency.ZusammenfassungBei Kindern mit Epilepsie (n=14), mit Fieberkrämpfen (n=51) und einer akuten Meningitis (n=22) konnte die GABA-Konzentration des lumbalen Liquor cerebrospinalis bestimmt werden. Patienten mit Epilepsie [144 (73–285) pmol/ml] und Kontroll-Probanden [148 (90–243) pmol/ml] hatten nahezu identische GABA-Konzentrationen. Ungewöhnlich hohe GABA-Werte fanden wir bei 2 Patienten unter einer Valproinat-Therapie (525 bzw. 557 pmol/ml) und bemerkenswert niedrige bei den Kindern, die anläßlich der Manifestation ihrer Epilepsie und vor Beginn einer antiepileptischen Behandlung untersucht werden konnten. Bei Fieberkrämpfen [103 (63–170) pmol/ml] oder zu Beginn einer akuten Meningitis [105 (65–171) pmol/ml] waren die GABA-Liquorkonzentrationen im Vergleich zu den Kontrollen signifikant erniedrigt. Unsere Untersuchungen stützen das Konzept, daß eine niedrige GABA-Aktivität des ZNS mit einer der Gründe sein könnte, daß cerebrale Anfälle entstehen und fortdauern.

Succinic Semialdehyde Dehydrogenase Deficiency

A coupled assay using [14C]4-aminobutyric acid and a direct assay using [14C]succinic semialdehyde have been designed to assay te activity of succinic semialdehyde dehydrogenase in a patient with 4-hydroxybutyric aciduria and family members. In the coupled assay less than 3% of control succinic semialdehyde dehydrogenase activity was found in lysates of lymphocytes isolated from whole blood of the patient. In the direct assay there was no detectable activity of the enzyme in lysates of isolated lymphocytes or cultured lymphoblasts. Results indicated the parents to be heterozygous carriers carriers of the abnormal gene, consistent with an autosomal recessive inheritance.

Development of N-demethylase activity measured with the 13C-aminopyrine breath test.

The 13C-aminopyrine (AP) breath test was used to measure the normal development of N-demethylase activity in 25 children, aged 2 days to 14 years, with normal liver function. Five mg of 13C-AP per kg body weight were administered orally. After AP-demethylation by the hepatic mixed function oxidase system 13CO2 excess was analysed in expired breath by mass spectrometry. In the first days of life no 13C excretion could be detected in unstimulated newborns. N-demethylase activity then slowly increased and reached adult levels by two years of life. Though the range of normal values showed considerable scattering, patients with liver disease or with enzyme induction following anticonvulsant therapy could be well discriminated. This study of the 13C-aminopyrine breath test in children provides evidence for the assumption that hepatocellular function and development of specific enzymatic activities can be measured by such non-invasive methods. It may be expected that breath tests making use of a broader spectrum of 13C-labeled substrates will prove applicable to study prenatal inducibility and other aspects of developing hepatocellular and intestinal function of children in health and disease.

Effect of subchronic treatment with (-) 8 -trans-tetrahydrocannabinol ( 8 -THC) on food intake, body temperature, hexobarbital sleeping time and hexobarbital elimination in rats.

In a series of experiments in rats it was possible to prove that δ8-THC has the same type of effectiveness as the stereo-isomeric δ9-THC.Body temperature was reduced to 35.5‡ C 90 min after injection of 10 mg/kg δ8-THC; 5 mg/kg δ8-THC extended the duration of hexobarbital sleeping time from 119 min in control animals to 205 min. Following treatment with δ8-THC for 9 and 10 days the effects on hypothermia and prolongation of sleeping time were less pronounced than in acute experiments. Body temperature dropped to 36.4‡ C 90 min p.i. and the duration of hexobarbital sleeping time was only extended to 156 min. This attenuation of effects after subchronic THC treatment was regarded as due to the development of tolerance.In order to exclude the possibility that the extension of sleeping time might be due to an effect of THC on hexobarbital metabolism, the hexobarbital concentration in cerebral tissue and blood was determined 30, 60, 90 and 120 min after the administration of 100 mg/kg hexobarbital-Na. There was no difference in hexobarbital elimination between rats treated with THC in a single dose or over a 10-day period and control animals.

4-Hydroxybutyric Aciduria: A New Inborn Error of Metabolism. III. Enzymology and Inheritance

4-Hydroxybutyric aciduria is an inborn error in the metabolism of 4-aminobutyrate (GABA) that is of particular interest because of the accumulation of a neuropharmacologically active compound (Jakobs et al., 1981; Divry et al., 1983). We have localized the defect in this condition to succinic semialdehyde dehydrogenase activity (SSDH, succinic semialdehyde: NAD+ oxidoreductase, EC 1.2.1.24) using an indirect coupled assay in which the precursor was U-14C-GABA. Heterozygosity could not be demonstrated with that assay. We have now developed a sensitive direct assay for SSDH using enzymatically prepared U-14C-succinic semialdehyde. Lysates of lymphocytes have been employed and the enzymatic product, 14C-succinic acid, has been quantified by liquid partition chromatography (LPC). It is the purpose of this report to present the activities of SSDH in lysates of lymphocytes isolated from whole blood of two patients with this disorder, their parents and siblings. The data establish the molecular defect as a deficiency of succinic semialdehyde dehydrogenase and are consistent with an autosomal recessive mode of inheritance.

The prognostic value of eeg patterns in epilepsies with infantile spasms

By scoring EEG patterns (hypsarrhythmia = 10, absence of sleeping patterns = 10, focal epileptic discharge = 5, general-treatment or in whom infantile spasms never disappeared even during ACTH. A low voltage EEG did not have any ending ACTH therapy free of seizures showed lower scores compared to those infants relapsing after the end of ACTH treatment or in whom infantile spasms never disappeared even during ACTH. A low voltage EED did not have any prognostic significance. Using EEG scores it might be possible to separate non-responders and responders after 3 weeks of ACTH therapy, thus shortening ACTH treatment in non-responding infants.