Abstract
Two siblings with dihydropteridine reductase (DHPR) deficiency were examined, who showed convulsions and severe mental retardation despite dietary control of blood phenylalaninemia. The patients showed low levels of 5-hydroxyindole-acetic acid, homovanilic acid and folate in cerebrospinal fluid, which accounts for their neurological damage. Early diagnosis of hyperphenylalaninemia due to tetrahydrobiopterin (BH_4) deficinecy is very important, because their treatment is different from that of classic phenylketonuria. We developed two diagnostic methods for BH_4 deficiency. One is a method for assaying DHPR in dried blood spots on filter papters. Another is a high-performance liguid chromatographic assay for the measurement of various forms of pterins in filter paper spots of urine. A newborn infant with multiple carboxylase deficinecy was observed with tachypnea, seizures and metabolic ketoacidosis. The organic acid pattern was consistent with deficient in vivo activity of at least three biotin-dependent carboxylases: propionyl CoA carboxylase (PCC), methylcrotnyl CoA carboxylase (MCC), pyruvate carboxylase (PC). An administration of pharmacologic doses of biotin resulted in immediate improvement from the clinical and metabolic status. Fibroblasts from the patient were found to have deficient acitvities of PCC, MCC, PC and acetyl CoA carboxylase (ACC) and have abnormal holocarboxylase synthetase (HCS) activity with a highly elevated Km for biotin. These results show that the primary defect is in HCS. A deficiency of ACC, a cytosolic enzyme, besides mitochondrial carboxylase suggests that at least a common subunit of the HCS system is shared by mitochondria and cytosol in humans.
