R Berger

Dihydropyrimidine Dehydrogenase Deficiency Leading to Thymine-uraciluria. An Inborn Error of Pyrimidine Metabolism

Three unrelated patients with excessive thymine-uraciluria due to dihydropyrimidine dehydrogenase deficiency are described. Excretory values (mmol/g creatinine) were: uracil 2.0-10.5, thymine 2.3-7.5, 5-hydroxymethyluracil 0.2-0.9. Orally administered (index patient) uracil and thymine were excreted for the greater part whilst dihydrouracil and S-dihydrothymine were mainly metabolised. Dihydropyrimidine dehydrogenase activities (nmol X h-1 X mg-1 protein) in leucocytes were 0.04, 0.01 and less than 0.01 in the patients, 0.31-1.66 in their parents, and 1.01-4.46 in controls (n = 4). The patients presented with a non-specific clinical picture of cerebral dysfunction.

MEVALONIC ACIDURIA - AN INBORN ERROR OF CHOLESTEROL-BIOSYNTHESIS

The application of combined gas-liquid chromatography mass spectrometry in the analysis of physiological fluids from patients in whom a metabolic disorder is suspected has revealed many new inborn errors of metabolism, especially organic acidurias. Inborn errors have been identified in the conversion of cholesterol into steroid hormones and bile acids (for review see ref. 1). To our knowledge no inborn error of cholesterol biosynthesis has been reported. In view of the important function of cholesterol with respect to synthesis of biolo~cally active steroid compounds and membrane function we wish to report a patient with a persistent urinary excretion of mevalonic acid, a precursor in the synthesis of sterols.

The natural history of liver glycogenosis due to phosphorylase kinase deficiency: A longitudinal study of 41 patients

We report a longitudinal study of 41 patients with liver glycogenosis due to phosphorylase kinase deficiency. In their youth, patients displayed hepatomegaly (92%), growth retardation (68%), delayed motor development (52%), hypercholesterolaemia (76%), hypertriglyceridaemia (70%), elevation of glutamate pyruvate transaminase (56%) and fasting hyperketosis (44%). With age, these clinical and biochemical abnormalities gradually disappeared and most adult patients were asymptomatic.

Deficiency of fumarylacetoacetase in a patient with hereditary tyrosinemia

A patient is described with type I tyrosinemia characterized by urinary excretion of succinylacetone together with increased excretion of tyrosine, p-hydroxyphenyllactic, p-hydroxyphenylpyruvic and p-hydroxyphenylacetic acids. Fumarylacetoacetase was measured in a liver biopsy and found to be very low compared to control liver. Furthermore the mass spectra of succinylacetone and fumarylacetoacetate (methoxime-TMS derivatives) are reported. Control jejunal mucosa, leucocytes and fibroblasts showed no enzyme activity; hence the prenatal diagnosis of this disease by measuring the fumarylacetoacetase activity in cultured amniotic fluid cells is not possible at present.

Lactate as a Cerebral Metabolic Fuel for Glucose-6-Phosphatase Deficient Children

Summary: The main substrates for brain energy metabolism were measured in blood samples taken from the carotid artery and the internal jugular bulb of four children with glycogen storage disease caused by deficiency of glucose-6-phosphatase. Multiple paired arterial and venous blood samples were analyzed for glucose, lactate, pyruvate, D-β-hydroxybutyrate, acetoacetate, glycerol and O2, and the arteriovenous differences of the concentrations were calculated. In the first three patients the substrates were measured in two successive conditions with lower and higher glucose-intake, respectively, inducing reciprocally higher and lower concentrations of blood lactate. In the fourth patient medium chain triglycerides were administered simultaneously with the glucose-containing gastric drip feeding.Lactate appeared to be taken up significantly. It consumed, if completely oxidized, between 40-50% of the total O2 uptake in most cases. Only once in one patient the uptake of lactate switched to its release, when the blood lactate level decreased to normal. D-β-hydroxybutyrate and acetoacetate arteriovenous (AV) differences were small to negligible and these ketone bodies, therefore, did not contribute substantially to the brains energy expenditure. Glycerol was not metabolized by the brain. Lactate thus appeared to be the second brain fuel next to glucose. It may protect the brain against fuel depletion in case of hypoglycemia.

BIOCHEMICAL-STUDIES ON THE ENZYMATIC DEFICIENCIES IN HEREDITARY TYROSINEMIA

Experiments are described on the effects of succinylacetone and fumarylacetoacetate on delta-aminolevulinic acid dehydratase, methionine adenosyltransferase and p-OH-phenylpyruvate dioxygenase. delta-Aminolevulinic acid dehydratase from human erythrocytes is inhibited non-competitively by succinylacetone (Ki 0.03 mumol/l) and by fumarylacetoacetate (Ki 0.06 mumol/l). The inhibition by succinylacetone is not prevented by dithiothreitol, but the inhibition by fumarylacetoacetate is not observed if dithiothreitol is present. Methionine adenosyltransferase, partially purified from rabbit liver, is not inhibited by succinylacetone but is inhibited by fumarylacetoacetate: 69% inhibition is observed at 1 mmol/l. Human liver p-OH-phenylpyruvate dioxygenase is not inhibited by succinylacetone or fumarylacetoacetate. It is concluded that secondary enzyme deficiencies observed in hereditary tyrosinemia (delta-aminolevulinic acid dehydratase, methionine adenosyl transferase) are the result of inhibition by succinylacetone and fumarylacetoacetate, accumulating as a result of a primary deficiency of fumarylacetoacetase.

Prenatal diagnosis of pyruvate carboxylase deficiency.

Abstract Deficient pyruvate carboxylase activity was found in the amniotic fluid cells obtained from a pregnancy at risk for pyruvate carboxylase deficiency. The results were corroborated by four independent laboratories. The diagnosis was confirmed by the demonstration that pyruvate carboxylase activity was undetectable in all the tissues examined from the aborted fetus. This represents the first prenatal diagnosis of pyruvate carboxylase deficiency.

A new case of dihydropyrimidine dehydrogenase deficiency

SummaryWe present the clinical and biochemical features of a boy with dihydropyrimidine dehydrogenase deficiency, which seem to underline a disease entity of developmental retardation, epilepsy and muscular hypertonia.

Mevalonate kinase deficiency in a child with cerebellar ataxia, hypotonia and mevalonic aciduria

Mevalonate kinase deficiency has been documented in an 8-year-old child who presented with cerebellar ataxia, hypotonia and mevalonic aciduria. The activity of mevalonate kinase in extracts of cultured skin fibroblasts derived from the patient was approximately 2% of the mean value for controls. Family studies were carried out on the mother, the father and a sister, all of whom were clinically well. Mevalonate kinase activity in extracts of cultured skin fibroblasts and transformed lymphoblasts derived from the parents of the patient were 43%–52% of the mean control values. These data are consistent with an autosomal recessive mode of inheritance for mevalonate kinase deficiency.

DIHYDROPYRIMIDINE DEHYDROGENASE-DEFICIENCY LEADING TO THYMINE-URACILURIA - AN INBORN ERROR OF PYRIMIDINE METABOLISM

The number of known inherited defects of pyrimidine metabolism is small. At least for a part this may be due to the fact that there is no typical end product, such as uric acid in purine metabolism. Furthermore, urinary pyrimidines are not easily accessible for simple chromatographic screening. However, metabolites such as uracil, thymine and orotic acid can be detected with the routine gas-liquid chromatography procedure for organic acids using ethyl acetate extraction and trimethylsitylation (Wadman et aI., 1984) if their concentrations are strongly elevated. By this method we established a persistently excessive excretion of thymine and uracil in a 4-year-old boy, whose urine was screened for inborn errors of metabolism. Later another patient was discovered in the same way. In a third patient the same abnormality was found using 2-dimensional thin layer chromatography according to van Gennip et al. (1978). This metabolite profile suggested a deficiency of dihydropyrimidine dehydrogenase (EC 1.3.1.2) (DHPDH) as the underlying deIect. The main site of DHPDH is th6 liver, but the enzyme has also been demonstrated in leukocytes (Goedde et al., 1968). In the present paper the establishment of DHPDH-deficiency in the leukocytes of the three patients is described. Excretory levels of thymine, uracil and of a third metabolite, 5-hydroxymethyluracil, are given.