Joachim Greter

CARNITINE DEFICIENCY INDUCED BY PIVAMPICILLIN AND PIVMECILLINAM THERAPY

Short-term administration of pivampicillin and pivmecillinam resulted in a reduction of serum carnitine concentration and an increase in excretion of acylcarnitine in urine. These changes persisted for more than ten days after cessation of therapy. In seven girls on long-term treatment with a mixture of pivampicillin and pivmecillinam the mean total serum carnitine concentration fell to 15% (7-27%) of pretreatment values. The acylcarnitine fraction was 11-57% of total carnitine, compared with less than 2% before treatment. Muscle carnitine concentrations in two girls treated with the antibiotics for 22 and 30 months were only 10% of the mean reference value. These concentrations in serum and muscle are in the range encountered in patients with carnitine deficiencies of other aetiologies in which life-threatening metabolic crises may arise. The risk of adverse effects from prodrugs that give rise to pivalic acid should be seriously considered, particularly in patients under metabolic stress.

Mitochondrial ATP-Synthase Deficiency in a Child with 3-Methylglutaconic Aciduria

ABSTRACT: We report the finding of mitochondrial ATP-synthase deficiency in a child with persistent 3-methylglutaconic aciduria. The child presented in the neonatal period with severe lactic acidosis, which was controlled by Na-HCO3 and glucose infusions. During the 1st y of life, there were several episodes of lactic acidosis precipitated by infections or prolonged intervals between meals. The excretion of lactate in urine was variable, but there was a persistent high excretion of 3-methylglutaconic acid. The activity of 3-methylglutaconyl-CoA hydratase in fibroblasts was normal. The child had a hypertrophic cardiomyopathy and magnetic resonance images revealed hypoplasia of corpus callosum. The gross motor and mental development was retarded, but there were no other neurologic signs. Investigation of muscle mitochondrial function at 1 y of age revealed a severe mitochondrial ATP-synthase deficiency (oligomycin-sensitive, dinitrophenol-stimulated Mg2+ ATPase activity: 27 nmol × min-1 × (mg protein)-1, control range 223–673 nmol × min-1 × (mg protein)-1. The mitochondrial respiratory rate was low and tightly coupled. The respiratory rate was normalized by the addition of an uncoupler. Low Mg2+ ATPase activity was also demonstrated by histochemical methods. Morphologic examination revealed ultrastructural abnormalities of mitochondria. There was no deletion of mitochondrial DNA. The sequences of the ATP synthase subunit genes of mitochondrial DNA were in accordance with published normal sequences.

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.

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.