Göran Steen

3-methylglutaconic aciduria: report on a sibship with infantile progressive encephalopathy.

Choreoathetosis, spastic parapareses, dementia and optic atrophy were the main clinical features in a sibship with progressive encephalopathy of late onset. The urine contained constantly elevated amounts of 3-methylglutaric and 3-methylglutaconic acids. The identity of these metabolites was confirmed by synthesis and mass spectrometry. On leucine loading, the excretion of the metabolites was elevated.

Aliphatic C6−C14 dicarboxylic acids in urine from an infant with fatal congenital lactic acidosis

Abstract A newborn male infant with a severe metabolic acidosis who died one day after birth was found to have high levels of lactic acid in his urine, together with a series of dicarboxylic acids with 6 to 14 carbon atoms chain length. Adipic and suberic acids which occurred in a concentration of ~ 0.05 mmoles/1 were also present in the urine of normal newborns. The concentration in the urine of dicarboxylic acids with 10, 12 and 14 carbon atoms was 0.1, 0.5 and 0.2 mmoles/1. These acids were saturated, monoenic and dienic. The monounsaturated acids were mainly of the cis - Δ 5 configuration. It is suggested that the findings could be consistent with a defect in the normal β-oxidation of fatty acids located at the acyl-CoA dehydrogenase step. The parents to the patient were second cousins; a previous child died 26 h after birth in acidosis. Three cousins to the father also died soon after birth. These facts support the contention that the present case represents an inborn error of metabolism.

ON THE RENAL TUBULAR DAMAGE IN HEREDITARY TYROSINEMIA AND ON THE FORMATION OF SUCCINYLACETOACETATE AND SUCCINYLACETONE1

ABSTRACT. Fällström, S.‐P., Lindblad, B. and Steen, G. (Department of Paediatrics, East Hospital, University of Gothenburg, Gothenburg, Department of Paediatrics, Molndals Hospital, Molndal, Department of Clinical Chemistry, University of Gothenburg, Gothenburg, Sweden). On the renal tubular damage in hereditary tyrosinemia and on the formation of succinylacetoacetate and succinylacetone. Acta Paediatr Scand, 70:315, 1981.–Phenylalanine and homogentisate increase the concentration of succinylacetoacetate and succinylacetone both in serum and urine in patients with hereditary tyrosinemia and therefore increase the excretion of 5‐aminolevulinate. Both phenylalanine and homogentisate cause a tubular proteinuria which is in agreement with our hypothesis that their metabolites maleylacetoace‐tate and fumarylacetoacetate are the toxic compounds in hereditary tyrosinemia. The patient with the highest excretion of succinylacetoacetate and succinylacetone has the slightest tubular proteinuria whereas the one with the lowest excretion of these compounds has the more pronounced tubular proteinuria. It is suggested that this is caused by a difference in the ability to reduce the presumed toxic compounds fumarylacetoacetate and maleylacetoacetate, i.e. the precursors of succinylacetoacetate.

3-Methylglutaconic aciduria in two infants

We studied two children who developed normally for the first 3-4 months of life and then displayed a failure-to-thrive syndrome, regression in psychomotor development, pronounced muscular hypotonia, and liver damage. At the age of about 1-2 years, optic atrophy and spastic parapareses were evident. One child died at the age of 2.5 years the other at an age of 4 years. Both children excreted 3-methylglutaconic acid, 0.1-0.4 mol/mol creatinine and 3-methylglutaric acid, 0.02-0.05 mol/mol creatinine. The excretion of 3-hydroxy-3-methylglutaric acid was not increased. One of the children was available for further biochemical studies. The activity of hydroxymethylglutaryl-CoA lyase (EC 4.1.3.4) was moderately reduced in leucocytes and fibroblasts. During a 21-h fast there was a normal formation of ketone bodies and we conclude that the cause of the syndrome is not a deficiency of hydroxymethylglutaryl-CoA lyase. Normal formation of 14CO2 from [1-14C]isovaleric acid and [2-14C]leucine in fibroblasts and leucocytes apparently excludes a deficiency of methylglutaconyl CoA-hydratase (EC 4.2.1.18).

Propionyl-CoA carboxylase deficiency: case report, effect of low-protein diet and identification of 3-oxo-2-methylvaleric acid 3-hydroxy-2-methylvaleric acid, and maleic acid in urine

Vomiting, lethargy and metabolic acidosis were the main initial symptoms of metabolic disease in a 1 month old girl. Her older sister had died from a similar disease, considered to be Reyes syndrome, at an age of 15 months. The urine of the present case contained 2-methylcitric acid, 3-hydroxypropionic acid, N-propionylglycine, 2-hydroxy-3-methylbutyric acid, N-tiglylglycine, 3-hydroxyvaleric acid and glutaric acid. These metabolites are all known to be associated with propionyl-CoA accumulation. Free propionic acid was not detected in the urine. In addition, the urine contained 3-oxo-2-methylvaleric acid and 3-hydroxy-2-methylvaleric acid, probably formed by condensation of two molecules of propionyl-CoA. The identity of these metabolites was confirmed by synthesis. An elevated urinary concentration of maleic acid and fumaric acid was another constant abnormality. The activity of propionyl-CoA carboxylase in leucocytes was about 20% of the normal activity. The girl was teated with a low-protein diet since the diagnosis was made at an age of 1 month, and her psychomotor development was satisfactory at an age of 2 1/2 years. She had a few episodes of acidosis during infections.

Urinary metabolites of vinyltoluene in the rat.

Abstract o -Vinyltoluene, m -vinyltoluene, and p -vinyltoluene were given ip to rats and urine was analyzed for acidic metabolites by gas chromatography combined with mass spectrometry. Different derivatives were prepared and used to identify the structure of the metabolites. Eleven different types of metabolites were found, although all these metabolites were not produced from each of the vinyltoluene isomers. The metabolites identified were the following: methylphenylethylene glycol, methylmandelic acid, methylphenylglyoxylic acid, hydroxymethylphenylethylene glycol, carboxyphenylethylene glycol, hydroxymethylphenylglyoxylic acid, methylbenzoylglycine, methylphenylacetylglycine, vinylbenzoylglycine, N -acetylcysteine conjugate of methylphenylethanol, and glucuronide of methylphenylethylene glycol. More than 90% of all metabolites recovered were excreted during the first 24 hr. For the sum of all metabolites, there was an approximately linear relation between given dose and recovered amount of metabolites. Repeated daily administration was not followed by any appreciable increase in metabolite excretion, i.e., no enzyme induction phenomenon was apparent.

Isoprenoid biosynthesis in multiple sclerosis

ABSTRACT – Recently discovered metabolites in urine have suggested a defect of isoprenoid metabolism in multiple sclerosis. Lymphocyte HMG‐CoA reductase was found unaffected however, and so was lymphocyte biosynthesis of geraniol, farnesol and squalene from mevalonolactone. The level of dolichol in white matter of an MS brain was similar to that of a control sample. Serum ubiquinone, on the other hand, was decreased in multiple sclerosis. Ubiquinone in serum was both age‐dependent and related to serum cholesterol. Active as well as stable MS displayed a decreased level of serum ubiquinone, and a reduced ubiquinone‐cholesterol ratio. These results are compatible with a deficient ubiquinone biosynthesis in multiple sclerosis.

Isoprenoid biosynthesis in multiple sclerosis, II. A possible role of NADPH

Abstract Genetic predisposition in MS, influence of fat consumption on the disease, and excretion ofiipid metabolites in urine led us to investigateisoprenoid metabolism in this disease. Ubiquinone concentration and biosynthesis was normal in lymphocytes. Cytochrome oxidase, which contains an isoprenoid side chain, was normal in activity. Cholesterol biosynthesis from acetate was found to be elevated in MS, and so was triglyceride biosynthesis. Increased biosynthesis may offer a very simple explanation to all the metabolites excreted (3‐methylglutaconic acid, 2‐hydroxy‐2‐methyl‐3‐butenoic acid and adipic acid). Increased biosynthesis may be caused by an elevated NADPH/NADP ratio, since such an elevation may also account for many other biochemical anomalies in MS. Elevated NADPH/NADP ratio may be of direct importance in the pathogenesis.

The fat meal test of malabsorption: some further experience

A fat meal test was evaluated in 21 healthy controls, 14 pathological controls and 11 malabsorption patients. The amount of fat used was 1 g per kg body wt, and the time for the post-cibal blood sampling was 2 h after the start of the meal. Combining serum triglyceride determination and serum turbidity measurement, the malabsorption group was fully discriminated from the control groups.