Introduction: Previous studies have given conflicting results as to whether or not folate metabolism is altered in Down syndrome. Folate is necessary to facilitate metabolism of one-carbon units. Folate accepts one-carbon units from one-carbon unit donors, including formiminoglutamate (FIGLU). Folate deficiency leads to accumulation of FIGLU and impairment of one-carbon unit metabolism. FIGLU is a functional measure of folate deficiency. Materials and Methods: Archived anonymized amniotic fluid specimens were obtained from normal pregnancies and those with Down syndrome. Gas liquid chromatography/mass spectrometry was used to quantitate FIGLU, which is elevated in folate deficiency. A tetra-deuterated FIGLU was used as a standard, and single-ion monitoring was performed. Nonparametric statistical analysis was performed with the Mann-Whitney U test. Results: FIGLU was significantly lower in pregnancies with Down syndrome. The median FIGLU level was 0.9 µmol/l in amniotic fluid from fetuses with Down syndrome. The median FIGLU level was 1.3 in amniotic fluid from control fetuses. This difference was statistically significant (p = 0.009). No statistically significant differences were found with histidine or glutamate. Discussion: There was no evidence of folate deficiency. FIGLU was decreased, not increased. Decreased FIGLU might result from accelerated activity of one or more genes on chromosome 21, by a gene dosage effect. Genes which might explain the reduced FIGLU include one which degrades FIGLU (glutamate formiminotransferase-cyclodeaminase), one which participates in purine synthesis, and one which degrades homocysteine (cystathionine-β-synthase).

Summary:Purpose: Valproate (VPA) is a teratogenic anticonvulsant (AED), but vitamin supplementation has been suggested to limit the effect of VPA on the fetus. Maternal urinary metabolites were monitored to assess the metabolic effects of VPA before and after vitamin supplementation.Methods: A pregnant woman with epilepsy receiving VPA and ethosuximide (ESM) was given high-dose multivitamins from 13 to 28 weeks' gestation. Maternal urinary metabolites were measured throughout the pregnancy by gas chromatographylmass spectrometry.Results: Before multivitamin supplementation began, the patient had significantly increased excretion rates of a-ketoglutarate, 6-lactate, pyruvate, lactate, methylmalonate, and other metabolites compared with normal pregnant women. During multivitamin supplementation, many previously increased excretion rates decreased significantly. Fetal head growth was normal up to 30 weeks, but then lagged. Bitemporal narrowing was noted at birth.Conclusions: VPA may cause metabolic abnormalities in pregnancy. Many biochemical abnormalities attributable to VPA in this patient were corrected with high-dose multivitamin supplementation. The specific relation between biochemical abnormalities and VPA teratogenesis remains to be determined. Key Words: Valproate-Pregnancy-Vitamins-Urinary metabolites.Valproate (VPA) is a teratogenic antiepileptic drug (AED). A fetal VPA syndrome includes neural tube defects, bitemporal narrowing, and other structural abnormalities (I). The deleterious effects of VPA are not Iimited to organogenesis. Recent literature indicates that functional neurologic deficits have been seen on longterm follow-up after fetal VPA exposure (2-5). Concern about VPA should extend to the second and third trimesters, during which central nervous development continues.Numerous mechanisms have been postulated for the adverse effects of VPA. These include hyperammonemia, mitochondria1 dysfunction, carnitine deficiency, and coenzyme A depletion (6). VPA-induced vitamin deficiencies have also been reported to cause teratogenic effects in animals (7,8) and toxic effects in humans (9,lO). Vitamin supplementation was shown to attenuate the teratogenic (7,8) To prevent the teratogenic effects of VPA, Thurston and Hauhart ( 1 1) recommended that pantothenate, a precursor to coenzyme A, be supplemented in the first trimester of human pregnancy. We report maternal urine metabolites in a patient receiving VPA and ethosuximide [ESM; not a significant teratogen (12)] for seizures, before and after supplementation with pantothenate and high-dose multivitamins (HDMVs). CASE REPORTA 31-year-old, white woman, G4, P2, A l , who was seen at 8 weeks' gestation, had both petit ma1 (six/day) and grand ma1 seizures (one or twolyear) of unknown etiology since age 12. Her seizures were controlled with VPA (1,500 mg/day) and ESM (500 mg/day). Folate (2 mg/day) was prescribed to prevent birth defects. She had been advised to avoid pregnancy while taking VPA. Standard prenatal vitamins (Prenate 90 Ultra; Bock Pharmaca...

Introduction: Organic acids were examined from normal and Down syndrome pregnancies to identify possible differences between the amniotic fluid from fetuses with Down Syndrome compared with that of normal fetuses. Materials and Methods: Amniotic fluids were obtained from prior amniocenteses. Forty-one normal and 22 Down syndrome specimens were assayed using gas chromatography/mass spectrometry. Results and Discussion: 5-Hydroxycaproate, methylsuccinate, α-ketoglutarate, and adipate were significantly elevated in Down syndrome, suggesting riboflavin deficiency. Phenylpyruvate was also significantly elevated in fetuses with Down syndrome. Phenylpyruvate inhibits the metabolism of tetrahydrobiopterin, which is necessary for neurotransmitter metabolism. Elevated phenylpyruvate is consistent with previous research, suggesting a disturbance of tetrahydrobiopterin metabolism in Down syndrome. Conclusion: Organic acid markers for B₂ deficiency are elevated in the amniotic fluid of fetuses with Down syndrome. Elevation of phenylpyruvate may impair neurotransmitter metabolism. Organic acid markers for B₁₂ levels are not different between the Down syndrome and normal group.

Introduction: Some studies of children with Down syndrome have found mild abnormalities in the metabolism of pyridoxine (vitamin B₆); therefore the present question is whether such abnormalities might also be present in the amniotic fluid of fetuses with Down syndrome. Materials and Methods: Archived specimens of amniotic fluid were obtained from chromosomally normal and from fetuses with Down syndrome. Gas chromatography/mass spectrometry quantitized B-related metabolites, including oxalate, xanthurenate, kynurenine and 4-pyridoxic acid. Results: Oxalate, a marker of pyridoxine deficiency, was elevated in the amniotic fluid of fetuses with Down syndrome. This result was statistically significant. The other marker results were not statistically significant. Conclusion: A marker of pyridoxine deficiency, oxalate is elevated in the amniotic fluid of fetuses with Down syndrome. These results in amniotic fluid are consistent with previous studies done in the urine of young children.

Introduction: Disorders of carbohydrate metabolism, in particular galactosemias, may be associated with mental retardation. For this reason, simple carbohydrates were investigated in the amniotic fluid from normal and Down syndrome fetuses. Materials and Methods: Amniotic fluid specimens were obtained from a cytogenetic laboratory. These were archived specimens from prior amniocenteses. Gas-Liquid chromatography/mass spectrometry was used for the assays. Results and Discussion: Gluconic acid was higher in Down syndrome than in normal amniotic fluid (p=0.039). This finding requires confirmation. Gluconate may be seen with therapeutic gluconates such as iron, zinc and calcium gluconate. There was a trend (p = 0.07) toward elevation of dulcitol in the Down syndrome group. Dulcitol, also known as galactitol, is a toxic metabolite seen in galactosemia. This finding may benefit from further investigation with a larger sample size.