Margaret E. O'Flynn

Hyperphenylalaninemia due to dihydropteridine reductase deficiency. Assay of the enzyme in fibroblasts from affected infants, heterozygotes, and in normal amniotic fluid cells

Two infant siblings with modest elevations of serum phenylalanine concentrations had seizures and developmental regression: they died in their second year. Dihydropteridine reductase activity, which can be measured in normal cultured skin fibroblasts, was measured in the younger sibling and was absent. Parents of the two siblings and parents of a previously reported patient all showed 50% or less of the normal dihydropteridine reductase activity in their cultured fibroblasts. Dihydropteridine reductase activity is also present in normal cultured amniotic fluid cells, offering the possibility of prenatal diagnosis. Absence of dihydropteridine reductase results not only in a defect in the conversion of phenylalaning to tyrosine, but also in the biosynthesis of the neurotransmitters, dopamine, norephinephrine, and serotonin. Since deficiencies in these neurotransmitters would not be alleviated by a phenylalanine-restricted diet, it is important to establish the nature of the enzymatic defect in all suspected variants of phenylketonuria.

Folinic acid therapy in treatment of dihydropteridine reductase deficiency

We gave folinic acid to three siblings, and to a fourth child, who have or had dihydropteridine reductase (DHPR) deficiency. The youngest began folinic acid therapy in addition to neurotransmitter precursors and a phenylalanine-restricted diet at age 2 months, and at 2 years of age has near normal development without evidence of neurologic impairment. His older brother began similar treatment at 5 1/2 months of age, when early neurologic findings were evident. At age 6 years his mental retardation and neurologic impairment are less severe than reported in most patients with DHPR deficiency. Little improvement occurred in their sister, who first received treatment at 2 years of age, when she already had severe neurologic impairment. An unrelated boy with profound neurologic impairment showed subtle signs of improvement after he began treatment with folinic acid alone at age 9 years. These results provide evidence that folinic acid is important in the treatment of DHPR deficiency and, if begun early in infancy, may prevent irreversible neurologic damage. The mechanism of folinic acid action in DHPR deficiency may be to increase indirectly the synthesis of 5-methyltetrahydrofolate.

Cognitive development and dietary therapy in phenylketonuric children.

Abstract Phenylketonuric children (now four years of age or older) were given intelligence and language tests to ascertain their present levels of cognitive functioning. These intellectual abilities were then evaluated in relation to the childrens ages at the time diets low in phenylalanine were begun. The influence of distorting nontreatment factors, such as family level of intelligence and sociologic variation, was ascertained by computation of a multiple-regression equation analysis. Examination of the data revealed a consistent inverse relation between present intellectual ability and age of dietary inception. The children treated within one month after birth scored an average of 33 IQ points higher than those for whom treatment was initiated within their fourth and sixth years of life.

72 Phenylalanine Hydroxylase Activity in Hyperphenylalanernia

The recent widespread screening for phenylketonuria among newborn infants has lead to the recognition that not all instances of hyperphenylalanemia is caused by phenylketonuria (PKU). Thispaper describes enzyme studies in four patients with hyperphenylalanemia.Case 1 is a patient with ‘classical’ PKU. Case 2 is an infant who was found to have a plasma phenylalanine (PPA) of 17 mg% at three weeks who showed ‘mild’ PKU. Case 3 is a 35y-ear-old retarded female with PPA values ranging from 6.6 mg % to 11.6 mg % on a regular diet. Case 4 is an infant with a PPA value of 45 mg % at 4 days and 76.4 mg % at 2 ½ weeks. She was treated with low-phenylalanine diet for 15 months and then returned to a regular diet. For the past 7 months on a regular diet, the PPA has ranged between 4.6 mg % and 10.7 mg %. Cases 3 and 4 may be viewed as hyperphenylalanemia without PKU.Phenylalanine hydroxylase was determined by the method of LaDu and Zannoni and fresh liver obtained by biopsy. The results expressed as μM tyrosine14C formed/Gm protein/45 minutes were as follows:These data suggest that the ‘classical’ and ‘mild’ form of PKU probably have the same basic metabolic lesion. They show that hyperphenylalanemia without PKU is not caused by cofactor deficiency and represents a true ‘partial’ PKU as reflected by slightly elevated PPA, delayed clearance of phenylalanine by tolerance test and decrease of phenylalanine hydroxylase in liver. (APS)