Niels Jacob Brandt

Urinary excretion of succinylacetone and δ-aminolevulinic acid in patients with hereditary tyrosinemia

Succinylacetone was excreted in the urine from four patients, with hereditary tyrosinemia i.e., two patients with the severe infantile type with fatal outcome and two patients with less severe juvenile form. In the urine from two patients with neonatal transient tyrosinemia and from normal individuals succinylacetone was not detectable. The urinary excretion of delta-aminolevulinic acid was also increased in all patients with hereditary tyrosinemia compared to patients with neonatal transient tyrosinemia and to normal individuals. The results presented support the hypothesis of a deficiency of fumarylacetoacetase in hereditary tyrosinemia. Furthermore an analytical method for the quantitative determination of succinylacetone in urine using GC-MS is described.

Studies on glutaryl-CoA dehydrogenase in leucocytes, fibroblasts and amniotic fluid cells. The normal enzyme and the mutant form in patients with glutaric aciduria

Three patients with glutaric aciduria have been shown to possess a partial but severe defect of the enzyme glutaryl-CoA dehydrogenase in isolated leucocytes and cultured skin fibroblasts. They could readily be distinguished from heterozygotes by measuring the activity of this enzyme, as shown in a study of the two families involved. The activity of glutaryl-CoA dehydrogenase in normal cultured amniotic fluid cells was comparable to the activity in normal cultured skin fibroblasts indicating the possibility of prenatal diagnosis. Without flavin adenine dinucleotide added to the assay mixture, the activity of glutaryl-CoA dehydrogenase in fibroblasts from normal individuals was very much reduced and similar to the activity in the patients, but after addition of flavin adenine dinucleotide to saturation the activity increased 20-fold in normal subjects while only a very slight increase could be demonstrated in the patients. The Michaelis constant for the substrate glutaryl-CoA was similar for both normal and patient cell lines. The optimum assay conditions for the enzyme in cultured fibroblasts from normal individuals have been established. In contrast to our patients, we found no activity in a fibroblast cell line from a patient with glutaric aciduria diagnosed elsewhere.

Glutaric aciduria in progressive choreo‐athetosis

The clinical symptoms in a 10‐year‐old girl with progressive dystonic cerebral palsy are described. The biochemical findings were dominated by large amounts of glutaric acid in the urine. The disorder is caused by impairment of the degradation of glutaryl‐CoA.

ABO and Rh phenotyping of foetal blood obtained by foetoscopy

Blood samples taken from the foetus by foetoscopy early in the 2nd trimester of pregnancy can be used for reliable blood grouping. However, the sampling technique is not perfect. In 5 out of 15 pregnant women, no foetal blood was obtained, although between 1 and 10 samples were taken on each occasion. One‐third of 56 samples from the 10 women contained foetal blood.

Prenatal diagnosis of galactosaemia in six pregnancies -- possible complications with rare alleles of the galactose 1-phosphate uridyl transferase locus.

We describe our experience in prenatal diagnosis of six foetuses at risk for galactosaemia. In one family the parents were both shown to be double heterozygotes at the galactose 1‐phosphate uridyl transferase (Gal‐PUT) locus, the mother having a Duarte Suppl.Los Angeles and the father a Duarte Suppl.galactosaemia genotype. The foetus (and an older brother previously thought to have classical galactosaemia) was also a Duarte/galactosaemia double heterozygote. In the other five families, the parents and three foetuses were heterozygous carriers of the galactosaemia gene, one of the foetuses had galactosaemia, and one was homozygous for the normal gene. It is concluded that by a combination of family studies and assay of cultured amniotic cell Gal‐PUT, accurate prediction of the foetal Gal‐PUT genotype is now possible.

Postnatal changes in thyroid hormones and hormone-binding proteins in mother and infant with TBG deficiency

Serial blood determinations of T4,T3,TSH,TBG,TBPA and albumin were made in a girl with partial TBG deficiency and her mother, who was suspected to suffer from hypothyroidism. In the girl normal se-TSH, low total se-T4 and se-T3 and a se-TBG level at 50% of normal for age and maturity were found at the 8th day of life. Se-TBPA and se-albumin value were normal. During a period of 22 months, the low se-TBG level remained unchanged; se-TBPA and albumin increased normally. Se-T3 but not se-T4 increased. In the mother the se-TBG level was (6 weeks after the delivery) similar to that of nonpregnant adults, but decreased gradually to a level, which was 50% of normal, indicating a TBG deficiency in the mother as well. A study of the family revealed 2 affected females with a se-TBG at about 50% and 3 affected males with a se-TBG at about 20% of normal level. An X-linked inheritance was suggested. The significance of the different postnatal pattern of TBG changes in mother and infant with partial TBG deficiency remains to be revealed.

HLA typing and congenital, primary hypothyroidism

An association has been demonstrated between HLA-antigens and thyroid diseases such as Graves disease, Hashimotos thyroiditis and subacute thyroiditis.The significance of HLA types in the pathogenesis of congenital hypothyroidism has not been clarified. Recently, a study from Japan showed an increased frequency of HLA-Aw24 in congenital hypothyroidism (N Engl J Med 1980; 303:226). An American study did not confirm this finding, but could not exclude the possibiloty that HLA-B18 may be increased in patients with congenital hypothyroidism (N Engl J Med 1980;303: 1177).In a study of HLA-A, B and C types in - so far - 24 Danish patients with congenital hypothyroidism we did not find any association between the HLA types and the congenital dysplasia of the thyroid gland. In particular, the frequencies of Aw24 and B18 antigens were both lower in the patients than in the controls.

Clinical and Hormonal Findings in Cases of Congenital Hypothyroidism discovered by Neonatal Screening

In the Danish nationwide screening for congenital hypothyroidism (measurement of TSH (RIA) in wholeblood collected on PKU-cards) 18 patients were found among 89.000 newborns. At diagnosis, the ranges of plasma concentration of hormone- and hormone-binding proteins were: TSH: 219-1128 mU/1, T4: 10-74 nmol/1, T3: 0.32-2,83 nmol/1, TBG: 197-390 nmol/1, TBPA: 2319-4569 nmol/l, Alb: 351-494 μmol/l. The number of clinical signs were negatively correlated with plasma T3 concentration. The infants were treated with a daily dose of 50-100 μg sodium L-thyroxine. During treatment plasma T3 reached level of healthy fullterm babies within a few days, plasma T4 within 1 week and plasma TSH within 3 weeks of treatment. Plasma Alb and plasma TBPA concentrations decreased following 1 week of therapy, plasma TBG concentration increased in some patients. After 1 month plasma Alb was still decreased, whereas plasma TBG and plasma TBPA were above pretreatment levels in half of the patients.The therapeutical consequences of these findings are open for discussion.