F. J. van Sprang

3-Hydroxydicarboxylic aciduria due to long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency associated with sudden neonatal death: protective effect of medium-chain triglyceride treatment

Two siblings were found to be affected by longchain 3-hydroxyacyl-CoA dehydrogenase deficiency, one of which died suddenly and unexpectedly on the 3rd day of life suffering from extreme hypoketotic hypoglycaemia. The younger sibling started to have feeding problems, lowered consciousness, and liver dysfunction at the age of 5 months. Her urine contained large amounts of C6−C14 3-hydroxydicarboxylic acids and conjugated 3-hydroxyoctanoic acid, as verified by gas chromatography/mass spectrometry. Plasma long-chain acylcarnitine was increased. A clue to the diagnosis was given by the results of a phenylpropionic acid loading test. This revealed small, but significant amounts of conjugated 3-hydroxyphenylpropionic acid (phenylhydracrylic acid) in the patients urine. Subsequently, the activity of long-chain 3-hydroxyacyl-CoA dehydrogenase was found to be deficient in cultured skin fibroblasts. Based on the findings obtained by a medium-chain triglyceride load, a diet enriched in this type of fat was prescribed. On this regimen the patient started to thrive, signs of cardiomyopathy disappeared, and her liver function normalized.

β-Mannosidosis in Two Brothers with Hearing Loss

β-Mannosidosis is a lysosomal storage disorder caused by a deficiency of the enzyme β-mannosidase (EC 3.2.1.25). This inborn error of glycoprotein catabolism has been described for goats (Jones and Dawson, 1981). Recently, two independent papers have appeared on human β-mannosidase deficiency (Cooper et al., 1986; Wenger et al., 1986). We have diagnosed this disorder in two brothers with hearing problems by analysing urinary oligosaccharides and by measuring the enzyme activity in leukocytes and plasma.

3-Methylglutaconic aciduria: a phenotype in which activity of 3-methylglutaconyl-coenzyme A hydratase is normal

Abstract3-Methylglutaconic aciduria has been found in two distinct syndromes. In one there is deficient activity of 3-methylglutaconyl coenzyme A hydratase, and the only clinical manifestation observed has been retardation of speech development. In the other, which includes a majority of the patients studied, we document that the activity of this enzyme in fibroblast extracts is normal. The phenotype of this disorder is one of profound neurological impairment with retarded psychomotor development, hypotonicity and/or spasticity, convulsions or EEG abnormalities, and sensorineural changes in the eye and ear.

Two sistes with isovaleric acidaemia, multiple attacks of ketoacidosis and normal development

Two sisters with isovaleric acidaemia are described. Both had multiple attacks of acetonaemic vomiting, sometimes leading to subcoma. Despite this they showed a completely normal mental development. Biochemical studies, clinical follow-up and attempts at treatment are presented.

New Defects of Pyrimidine Metabolism

The number of inherited defects of the pyrimidine metabolism described so far is small, compared to that of the purine metabolism. Combined deficiency of orotate phosphoribosyltransferase (OPRT) (EC 2.4.2.10) and orotidine 5′-monophosphate decarboxylase (ODC) (EC 4.1.1.23), designated as type I hereditary orotic aciduria, presents with characteristic clinical features such as hypo-chromic anemia with a megaloblastic bone marrow and crystalluria. Only six patients have been described and, as far as we know, new cases have not been discovered recently. ODC deficiency with similar clinical phenomena and leading to increased urinary excretion of orotate and orotidine has been detected in only one patient (1). A third defect, a deficiency of pyrimidine 5′-nucleotidase (Py-5N). (EC 3.1.3.5.) in erythrocytes, is associated with chronic hemolytic anemia and prominent basophylic stippling of the erythrocytes due to accumulated pyrimidine nucleotides. An increasing number of patients have been reported, their detection being facilitated by the typical phenomena. We do not know whether the urinary pyrimidine profile in this condition is abnormal.

Rapid diagnosis of 3-hydroxy-3-methylglutaryl—coenzyme A lyase deficiency via enzyme activity measurements in leukocytes or platelets using a simple spectrophotometric method

Patients with 3-hydroxy-3-methylglutaric aciduria due to a deficiency of 3-hydroxy-3-methylglutaryl Coenzyme A lyase usually present with a life-threatening crisis of hypoglycemia, metabolic acidosis and hyperammonemia. Diagnosis of this inborn error of leucine degradation is usually based upon gas-chromatographic analysis of organic acids in a patients urine. In this paper we describe a simple spectrophotometric method allowing the activity of HMG-CoA lyase to be measured in leukocytes or platelets within a few hours, thus contributing to a rapid, unequivocal diagnosis and subsequent treatment. The validity of the method was established by demonstrating a deficient activity of HMG-CoA lyase in two patients with 3-hydroxy-3-methylglutaric aciduria. Furthermore, using this method, heterozygote detection can be done with great reliability.

Chromatographic determination and mass spectrometric identification of γ-glutamylphenylalanine, a urinary constituent in phenylketonuria

The occurrence of gamma-glutamylphenylalanine in the urine of patients with phenylketonuria could be demonstrated using chromatographic techniques and mass spectrometry. Concentrations ranged up to 35 mg/l. Only a weak correlation between the urinary excretion of this compound and phenylalanine was seen. The ages of the patients investigated ranged from 2 weeks to 18 years. The origin of the dipeptide is discussed.

Tyrosinemia and tyrosyluria in healthy prematures: Time courses not vitamin C-dependent

Tyrosyluria and for a part also tyrosinemia were studied in 60 healthy prematures of various birth weights and gestational ages. The first analyses were performed between the 6th and the 14th day after birth. A normal milk diet was given and the protein-intake was between 3 and 4 g/kg. After the first collection of urine half the patients received extra ascorbic acid, 100 mg/kg daily. Urinary analyses of tyrosine and p-hydroxyphenyl metabolites were performed once a week, until the excretion of p-hydroxyphenylpyruvic plus p-hydroxyphenyllactic acids was lower than 5 mmoles per gram creatinine. In 22 out of the 60 prematures (or 37%) a tyrosyluria of more than 5 mmoles/g creatinine and in 19 out of 44 (43%) patients analysed serum tyrosine was higher than 5 mg/100 ml at first analysis. No inverse correlation between tyrosyluria and tyrosinemia on the one hand and birth weight and gestational age on the other hand existed. But in children with a delayed intra-uterine development the incidence of tyrosyluria was higher as prematurity was more pronounced. Ascorbic acid had no effect on the rate of disappearance of tyrosyluria. It was concluded that the addition of extra vitamin C to the diet of prematures is not useful for the normalization of tyrosine metabolism.

Novel storage products in humanβ-mannosidosis

Lysosomal fl-mannosidase (EC 3.2.1.25) is the final enzyme involved in the catabolism of the oligosaccharide side-chains of glycoproteins. Following the description of caprine fl-mannosidosis in the early 1980s, several human patients with a deficiency of this enzyme were described (Cooper et al., 1986; Wenger et al., 1986; Dorland et at., 1988). Defects in lysosomal enzymes usually lead to storage and urinary excretion of incompletely catabolized oligosaccharides. Identification of these urinary excretion products may be helpful in establishing the diagnosis. In human fl-mannosidosis only an abnormal amount of the disaccharide mannosyl-fi(1--.4)-N-acetylglucosamine (Manfi(1-~4)GlcNAc) has been reported so far, in contrast with the much larger and more complex oligosaccharides observed in a-mannosidosis. Generally the structures of the excreted metabolites are those predicted based on the inherited deficiencies of specific exoglycosidases and the coincident action of an endo-fl-N-acetylglucosaminidase which cleaves the linkage between the two GlcNAc residues of the di-N-acetylchitobiose core. Here we describe the occurrence of a sialyloligosaccharide which is probably formed by enzymatic synthesis from the storage product Manfl(1 ~4)GlcNAc as substrate. Furthermore, the characterization is described of a urinary carbohydrate-urea conjugate.

A patient with sarcosinaemia

Sarcosinaemia (McKusick 26890) is a relatively rare inherited metabolic disorder affecting the demethylation step in the formation of glycine. To date, sixteen patients have been reported (Levy et al., 1984). The first twelve cases were detected as a result of the investigation of clinically preselected patients. Developmental delay was the most frequent symptom in these patients, although they suffered from a variety of other complaints such as growth retardation, vomiting and failure to thrive. The Massachusetts metabolic disorders screening programme brought to light four additional patients who all had normal !Qs (Levy et al., 1984). Our patient, a girl, was the third child of healthy parents; the second child was stillborn. The patient was born after a 34-week pregnancy (birthweight 1700 g, length 43 cm). She was nursed in the neonatal intensive care unit because of a respiratory distress syndrome for 10 days. During the intubation the child had no spontaneous respiration and she was severely hypotonic and cyanotic. On the fifth day of life she was given an exchange transfusion because of hyperbilirubinaemia (292/zmol L-I). At the age of 18 months she was readmitted because of mental and motor retardation. Her growth was also retarded (length p3, weight <p3): The results of a psychological test showed that she functioned at a level of 51 weeks when her chronological age was 95 weeks. Her motor development was even more delayed; she neither sat nor crawled at this age. Our standard programme for the investigation of inborn errors of metabolism, including chromatographic analysis of urinary amino acids, organic acids, purines and pyrimidines, (oligo)saccharides and mucopolysaccharides, revealed a striking sarcosinuria as the only abnormality. The sarcosine excretion amounted to 9.45 mmol L1, 1.42 mmo124 h1. A subsequent analysis of plasma amino acids showed sarcosine to be highly increased at 532 ~mol L -1 (normally: not detected). All other amino acids including glycine were present in normal concentrations. On admission to the Childrens Hospital a trial for treatment of the sarcosinaemia was devised which involved the sequential reduction of the protein (or methionine) and choline intake, and supplementation with pharmacological doses of riboflavin (2x25 mg daily) and folic acid (3 x 10 mg daily). None of the therapeutic measures had any effect on the urinary excretion of sarcosine: the 24 h excretion varied from 1.42-3.74mmol over a three month period. Neither were the plasma sarcosine levels influenced by the treatment: values between 532 and 873 txmolL -1 were