Sulfite oxidase deficiency: clinical, neuroradiologic, and biochemical features in two new patients.

Sulfite oxidase deficiency is characterized by severe neurologic dysfunction, dislocation of the lenses, and the accumulation and excretion of inorganic sulfite, thiosulfate, and S-sulfocysteine. We present the clinical, radiologic, and biochemical findings in two patients with this condition. In both, neurologic problems started soon after birth and progressed rapidly to profound mental retardation, microcephaly, blindness, and spastic quadriparesis. Seizures were a persistent problem throughout the course of their illness. The neurologic abnormalities were associated with progressive destruction of brain tissue. We established the diagnosis of sulfite oxidase deficiency by demonstrating the characteristic abnormal metabolites in urine. However, commonly used screening procedures do not detect these compounds, and dislocation of the lenses is usually a late feature of the disease. As a result, the diagnosis may be easily overlooked, especially during infancy. Specific investigations for sulfite oxidase deficiency are indicated for any baby with severe, progressive neurologic disease.

"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.

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.

Hyperammonaemia and lactic acidosis in a patient with pyruvate dehydrogenase deficiency.

A patient who presented in the newborn period with severe lactic acidosis and hyperammonaemia has been shown to have a specific defect in the pyruvate dehydrogenase complex. The secondary inhibition of ureagenesis in this patient appears to be due to a functional deficiency of carbamyl phosphate synthetase.

Immunochemical analysis of normal and mutant forms of human pyruvate dehydrogenase.

Pyruvate dehydrogenase (PDH) deficiency has been described in many patients with primary lactic acidosis. However, there are very few cases in which a structural defect in the complex has been clearly demonstrated. Measurement of the activity of the PDH complex in cultured human cells has proved unreliable, and a combination of structural and functional studies are required to make a definitive diagnosis. For this reason, an immunochemical strategy has been developed to complement direct enzyme assay in the detection and further characterization of PDH deficiency. We illustrate the usefulness of this approach by describing defects in the alpha-subunit of the pyruvate decarboxylase component of the PDH complex in two patients with primary lactic acidosis. In one patient, there is no immunologically cross-reacting material corresponding to this subunit. In the second patient, there appears to be an intrinsic structural defect in the subunit which restricts dephosphorylation (and hence activation) of the inactive phosphorylated complex.

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 fibroblast extracts was 4% of the mean control value. A high fat, low carbohydrate diet led to symptomatic hypoglycaemia, 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.

Malonyl coenzyme A decarboxylase deficiency.

A patient is described with a deficiency of the mitochondrial enzyme, malonyl CoA decarboxylase - an inborn error of metabolism not recognized previously. The enzyme defect was first suspected because of persistent excretion of malonic and methylmalonic acids in urine in a child with repeated episodes of vomiting, some requiring hospitalization. Disturbances of lipid metabolism were demonstrated.

Metabolism of malonic semialdehyde in man.

Malonic semialdehyde is formed in the alternative pathway of propionate metabolism and in the catabolism of beta-alanine. Studies of these pathways in cultured cells from a patient with mitochondrial malonyl-CoA decarboxylase deficiency indicate that malonic semialdehyde is directly converted into acetyl-CoA in man.

Deoxyribose-5-phosphate aldolase deficiency--a harmless inborn error of metabolism.

Evidence is presented that a deficiency of 2-deoxyribose-5-phosphate aldolase was present in a previously described patient who excreted metabolites of 2-deoxyribose in his urine. Minor clinical abnormalities present did not appear related to this disorder.