E. A. Haan

“Cerebral” lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis

Six patients are described with a combination of early onset of neurological symptoms, gross cerebral changes and elevated concentrations of pyruvate and lactate in cerebrospinal fluid. Although at least five of the six patients appear to have a generalised defect in pyruvate metabolism, reflected in deficient pyruvate dehydrogenase activity in cultured fibroblasts, systemic acidosis was not a problem clinically and blood pyruvate and lactate concentrations were only slightly raised. The localisation of significant clinical and biochemical problems to the central nervous system, coupled with the difficulties in making the diagnosis if analysis of cerebrospinal fluid (CSF) is not performed, lead us to term this condition “cerebral” lactic acidosis.

Malonyl coenzyme A decarboxylase deficiency. Clinical and biochemical findings in a second child with a more severe enzyme defect

A second child with a more severe deficiency of malonyl CoA decarboxylase is described. He is mildly mentally retarded and presented with vomiting, a seizure, hypoglycaemia and mild metabolic acidosis during a urinary tract infection. The urine contained increased, amounts of malonic, methylmalonic, succinic, adipic, glutaric and suberic acids. Mitochondrial malonyl CoA decarboxylase activity in cultured fibrobast extracts was 4% of the mean control value. A high fat, low carbohydrate diet led to symptomatic hypyglycaemia, a moderate metabolic acidosis and excretion in the urine of large amounts of the same organic acids and 3-hydroxybutyrate. Only relatively small quantities of malonic, methylmalonic and succinic acid were excreted in the urine when the boy was fed an isocaloric low fat, high carbohydrate diet. Acute fat and lysine loads led to increased excretion of malonic acid in the urine without affecting the excretion of the other organic acids.Experience with this patient, suggests that malonyl CoA decarboxylase serves an important function in the mitochondrion by preventing accumulation of malonyl CoA. The importance of the enzyme is best seen when fat is the main metabolic fuel. The mechanisms by which malonyl CoA produces its complex metabolic effects remain to be elucidated.

Severe illness caused by the products of bacterial metabolism in a child with a short gut

An 8-year-old boy with a short gut had six episodes of metabolic acidosis and neurological dysfunction over a 1 month period. The neurological features consisted of a depressed conscious state, confusion, aggressive behaviour, slurred speech and ataxia. The organic acid profile of urine demonstrated increased amounts of lactic, 3-hydroxypropionic, 3-hydroxyisobutyric, 2-hydroxyisocaproic, phenyllactic, 4-hydroxyphenylacetic and 4-hydroxyphenyllactic acids. Of the lactic acid 99% was d-lactic acid. The anaerobic gut flora consisted almost entirely of Lactobacilli in unusually large numbers. A course of vancomycin prevented further episodes. A urinary organic acid profile may be diagnostic when a person with a short gut develops metabolic acidosis or an unusual encephalopathy and bacterial metabolites should be considered in other patients with unusual combinations of organic acids in the urine.

Carrier detection in ornithine transcarbamylase deficiency.

We have studied six known heterozygotes for ornithine transcarbamylase (McKusick 31125; OTC) deficiency. All had abnormal results when tested by measurement of urine orotic acid after protein loading. Duodenal mucosa OTC assay detected fewer of the known heterozygotes but was a useful supplementary test. Urine orotic acid excretion after protein loading is influenced by age and results from women being tested must be compared with those from controls of appropriate age.

Succinic semialdehyde dehydrogenase deficiency—A further case

McKusick, V. A. and Neufeld, E. F. The mucopolysaccharide storage diseases. In Stanbury, J. B., Wyngaarden, J. B., Frederickson, D. S., Goldstein, J. L. and Brown, M. S. (eds.) The Metabolic Basis of Inherited Disease, McGraw-Hill, New York, 1983, pp. 751-777 MueUer, O. T., Honey, N. K., Little, L. E., Miller, A. L. and Shows, T. B. Mucolipidosis II and III. The genetic relationships between two disorders of lysosomal enzyme biosynthesis. J. Ciin. lnvest. 72 (1983) 1016-1023 Pollard, A. C., Carey, W. F., Nelson, P. V., Poulos, A. and Hill, G. N. Enzymotogical diagnosis of a group of lysosomal storage diseases. Review of a 5-year experience with 1600 patient sample referrals. Med. J. Al~st. 2 (1980) 549-553 Poulos, A. and Beckman, K. The bile salt activation of leucocyte sphingolipid hydrolase activity and the modifying effects of Triton X-100. CIin. Chim. Acta 107 (1980) 27-35 Poulos, A. and Pollard, A. C. A rapid method for the estimation of [3-galactocerebrosidase, 13-glucocerebrosidase and sphingomyelinase activities in leucocytes. Clin. Chim. Aeta 72 (1976) 327--335 Wiebel, F. and Baserga, R. Early alteration in amino acid pools and protein synthesis of diploid fibroblasts stimulated to synthesise DNA by addition of serum. J. Cell. Physiol. 74 (1969) 191-202

Episodes of severe metabolic acidosis in a patient with 3-methylglutaconic aciduria

Persistent excretion of 3-methylglutaconic acid was found in a 6-month-old infant with multiple minor physical malformations and delayed development. During two episodes of intercurrent viral illness, the patient developed severe metabolic acidosis and excreted large amounts of lactate, 3-hydroxybutyrate and acetoacetate. The excretion of 3-methylglutaconic acid did not change during these episodes, nor did it increase following leucine loading. In vitro studies suggest that in this patient, as in the majority of other patients with 3-methylglutaconic aciduria, a primary defect in leucine metabolism is not responsible for the biochemical abnormality.

5,10-Methylenetetrahydrofolate reductase deficiency. Clinical and biochemical features of a further case

We report the case of a boy with 5,10-methylenetetrahydrofolate reductase deficiency. The clinical features consisted of severe mental retardation, spasticity and seizures remaining static to 7 years of age followed by a phase of rapid deterioration and death at 7 1/2 years of age. The main biochemical findings were homocystinaemia, homocystinuria, a normal methionine level in plasma and cerebrospinal fluid, an increased excretion of methionine in urine and a very low level of folate in the cerebrospinal fluid. The activity of 5,10-methylenetetrahydrofolate reductase was greatly reduced in the patients lymphocytes and liver.

Difficulties in assessing the effect of strychnine on the outcome of non-ketotic hyperglycinaemia. Observations on sisters with a mild T-protein defect

Sisters with a mild variant of non-ketotic hyperglycinaemia resulting from a defect in the T-protein of the glycine cleavage system had different clinical outcomes. The older sister was ascertained at 6 months of age because of mental retardation. She received only brief treatment with sodium benzoate from 11–15 months and at 15 years of age is profoundly retarded and has epilepsy. The younger sister was diagnosed 36h after birth, was treated with strychnine, sodium benzoate and arginine from the neonatal period and at 27 months of age is only moderately retarded and free of seizures. The possible role of strychnine in the improved outcome is discussed.

Properties of Succinic Semialdehyde Dehydrogenase in Cultured Human Lymphoblasts

A direct assay has been developed for succinic semialdehyde dehydrogenase in sonicates of human lymphocytes and Epstein-Barr Virus transformed cultured lymphoblasts. Enzyme activity was quantified by incubating cell extracts with uniformly labeled [14C]succinic semialdehyde and monitoring the conversion to [14C]succinic acid. Radiolabeled products were separated by liquid partition chromatography on hydrated silicic acid. Kinetic properties and requirements of succinic semialdehyde dehydrogenase in lymphoblast sonicates were investigated in order to determine optimal conditions for the direct assay. Enzyme activity was stimulated by dithiothreitol, ammonium and potassium ions and 0.1% Triton X-100. The concentrations for half maximal activation by ammonium and potassium were 5.2 and 13.7 mM respectively. The mean activity of succinic semialdehyde dehydrogenase in assays in which equimolar NADP+ had been substituted for NAD+ was 19% of the activity of assays which contained NAD+. Substrate Michaelis constants were 21 and 30 microM for NAD+, and 26, 42 and 70 microM for succinic semialdehyde. The enzyme displayed a pH optimum between 8 and 9 and demonstrated a slight temperature activation between 37 degrees and 45 degrees C. A deficiency of succinic semialdehyde dehydrogenase activity was documented in cultured lymphoblasts derived from a patient with gamma-hydroxybutyric aciduria.

A carbamylphosphate synthetase deficiency with no detectable immunoreactive enzyme and no translatablemRNA

A lethal carbamylphosphate synthetase (CPS: EC 6.3.4.16) deficiency (McKusick 23730) was found in a newborn girl; who presented on the second day of life with acute hyperammonaemia, hypotonia, seizures and who died in a coma 6 days after birth. The activity of the mitochondrial urea cycle enzymes, CPS and ornithine transcarbamylase (OTC: EC 2.1.3.3) were measured on a needle biopsy sample taken from liver and showed that CPS was 1.4% of the normal mean (0.09 nmol/min/mg protein) whereas OTC activity was normal (110 nmol/min/mg protein). Immunological analysis of the liver sample showed no detectable immunoreactive CPS and confirmed the presence of normal levels of OTC. RNA was extracted from postmortem liver andin vitro translation experiments showed that there was no translatable CPSmRNA and confirmed that no CPS protein was synthesized in this child. The absence of translatablemRNA is explicable in terms of a genetic defect which results in a failure to synthesizemRNA for CPS, or synthesis of a defective form ofmRNA which is not translated.