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The frequency and types of congenital heart disease in offspring from pregnancies in women with hyperphenylalaninemia were examined in the international prospective Maternal Phenylketonuria Collaborative Study. Relationships of congenital heart disease in offspring to the basal blood phenylalanine level in the mother, metabolic control through diet during pregnancy, and phenylalanine hydroxylase mutations in mother and offspring were determined. The 416 offspring from 412 maternal phenylketonuria pregnancies that produced live births and 100 offspring from the 99 control pregnancies were included in this examination. Thirty-four of the 235 offspring (14; 95 CI, 10.2 to 19.6) from pregnancies in phenylketonuric women with a basal phenylalanine level ≥ 900 M (15 mg/dL) normal blood phenylalanine < 120 M (2 mg/dL) and not in metabolic control phenylalanine level ≤ 600 M (10 mg/dL) by the eighth gestational week had congenital heart disease compared with one control offspring (1) with congenital heart disease. One offspring among the 50 (2) from mothers with non-phenylketonuria mild hyperphenylalaninemia also had congenital heart disease. Coarctation of the aorta and hypoplastic left heart syndrome were overrepresented compared with expected percentages among those with congenital heart disease in the general population. A basal maternal phenylalanine level > 1800 M (30 mg/dL) significantly increased the risk for bearing a child with congenital heart disease (p0.003). Phenylalanine hydroxylase mutations in the mothers and offspring did not have an independent relationship to congenital heart disease but were related through the basal maternal phenylalanine levels. The data in this study indicate that a basal maternal phenylalanine level of 900 M may be a threshold for congenital heart disease, that women with the most severe degree of phenylketonuria are at highest risk for bearing such a child, and that prevention of the congenital heart disease requires initiation of the low phenylalanine diet before conception or early in pregnancy with metabolic control no later than the eighth gestational week.

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is considered a rare inherited mitochondrial fatty acid oxidation disorder. Less than 10 patients have been reported, diagnosed on the basis of ethylmalonic aciduria and low SCAD activity in cultured fibroblast. However, mild ethylmalonic aciduria, a biochemical marker of functional SCAD deficiency in vivo, is a common finding in patients suspected of having metabolic disorders. Based on previous observations, we have proposed that ethylmalonic aciduria in a small proportion of cases is caused by pathogenic SCAD gene mutations, and SCAD deficiency can be demonstrated in fibroblasts. Another - much more frequent - group of patients with mild ethylmalonic aciduria has functional SCAD deficiency due to the presence of susceptibility SCAD gene variations, i.e.625G>A and 511C>T, in whom a variable or moderately reduced SCAD activity in fibroblasts may still be clinically relevant. To substantiate this notion we performed sequence analysis of the SCAD gene in 10 patients with ethylmalonic aciduria and diagnosed with SCAD deficiency in fibroblasts. Surprisingly, only one of the 10 patients carried pathogenic mutations in both alleles, while five were double heterozygotes for a pathogenic mutation in one allele and the 625G>A susceptibility variation in the other. The remaining four patients carried only either the 511C>T or the 625G>A variations in each allele. Our findings document that patients carrying these SCAD gene variations may develop clinically relevant SCAD deficiency, and that patients with even mild ethylmalonic aciduria should be tested for these variations.

Amniotic fluid was collected at inductive amniotomy or just prior to delivery following full-term uncomplicated pregnancies. Table I lists the means, ranges, and standard deviations for the concentrations of amino acids obtained by ion-exchange chromatography of 16 specimens of amniotic fluid. Each specimen contained the following 22 amino acids: taurine, aspartic acid, threonine, serine, glutamine, proline, glutamic acid, citrulline, glycine, alanine, α-aminobutyric acid, valine, cystine, methionine, isoleucine, tyrosine, phenylalanine, ornithine, lysine, histidine, and arginine. In addition, tryptophan, which could not be detected by the ion-exchange chromatographic method employed, was found in each specimen by paper chromatography. The amino acids present in amniotic fluid were the same as those found in samples of maternal vein, umbilical artery, and umbilical vein serum (table II). Comparisons were made in the concentrations of several amino acids among amniotic fluid, maternal serum, umbilical artery and vein serum, and perinatal urine (table II). Taurine was present in considerably greater concentration in amniotic fluid than in maternal serum. This amino acid is also present in large quantities in umbilical artery and vein serum (table II) and is by far the greatest single contributor to the total free amino acid pool in perinatal urine [1]. In contrast, amino acids such as leucine, valine, and threonine, which are present in much smaller amounts in amniotic fluid than in either maternal or umbilical serum, are found in even lower concentrations in perinatal urine [1]. These comparisons suggest that amniotic fluid is derived from at least three sources, maternal blood, fetal blood, and fetal urine, a finding compatible with existing evidence [3, 24, 27, 30].

We have found a genetic trait of arginase deficiency in erythrocytes (RBC) of Macaca fascicularis(crabeater macaque). Measurements of arginase activities and arginine concentrations in RBC, and information derived from breeding experiments indicated that arginase activities in RBC are 12.59 mmoles/g hemoglobin (Hb)/hr (range: 8.36–15.24) in normal monkeys, 4.40 mmoles/g Hb/hr (sd ± 2.37) in hetero-zygotes for this trait, and less than 0.05 mmoles/g Hb/hr in homozygotes for this trait. Concentrations of arginine in erythrocytes are less than 0.01 $mUmoles/ml packed cells in both normal and heterozygous monkeys, and 0.975 $mUmoles/ml packed cells (sd ± 0.556) in homozygous monkeys.

Newborn blood from three siblings with prolidase deficiency contained no detectable prolidase activity. Umbilical cord blood contained no prolidase activity in one sibling and only 6.8 of control activity in another sibling. In prolidase deficiency the enzyme defect is expressed at birth, well before the appearance of skin ulcers, and is demonstrable in filter paper specimens of blood obtained for routine screening.