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Phenylketonuria provides a human model for the study of the effect of phenylalanine on brain function. Although irreversible mental retardation is preventable through newborn diagnosis and dietary phenylalanine restriction, controversy exists regarding the effects of increased concentrations of phenylalanine in older patients. We have studied ten older, treated, phenylketonuric patients using a triple-blind, multiple trials, crossover design. Each patient was tested at the end of each of three 1-wk periods of high or low phenylalanine intakes. Tests included a repeatable battery of neuropsychological tests, analysis of plasma amino acids, and measurement of urine amino acids, phenyl organic acids, dopamine, and serotonin. In all 10 patients, plasma phenylalanine rose (9004,000 AM). In 9 of 10 patients there was an inverse relationship between plasma phenylalanine and urine dopamine excretion. When blood phenylalanine was elevated, these patients had prolonged performance times on neuropsychological tests of higher but not lower integrative function. Urinary serotonin fell during phenylalanine loading in six patients. The concentration of phenylacids in the urine was not proportional to the plasma phenylalanine at concentrations below 1.5 mM. In one patient, neither performance time nor dopamine excretion varied as blood phenylalanine rose or fell. We interpret these data as follows: blood phenylalanine above 13 mM impairs performance on neuropsychological tests of higher integrative function, this effect is reversible, and one mechanism may involve impaired biogenic amine synthesis.

ABSTRACT. Although dietary leucine restriction and supplemental glycine are used to treat patients with isovaleric acidemia [deficient isovaleryl-CoA-dehydrogenase (E.C. 1.3.99.10)], little quantitative information is available regarding their optimum relationship. Herein we compare different glycine supplements and quantitate isovalerylglycine produced in two patients with clinically different forms of isovaleric acidemia during restricted leucine intake and during oral leucine loading. We found that under stable conditions of leucine restriction, 150 mg glycine/kg/day is an optimum glycine supplement and that glycine supplements of more than 250 mg/kg/day may result in reduced isovalerylglycine production; that when isovaleric acid accumulation is increased, glycine supplements to 600 mg/ kg/day will increase isovalerylglycine production; and that the phenotype of isovaleric acidemia is related not only to the extent of impaired isovaleryl-CoA dehydrogenase, but also the ability to detoxify accumulated isovaleryl CoA to isovalerylglycine. (Pediatr Res 24: 9-13, 1988)

supplemental l y c i n e. Added g l y c i n e augments conversion o f i s ov a l e r i c a c i d QIvA) t o i s o v a l e r y l g l y c i n e (IVG) through g1ycine-Nacylase. The optimum g l y c i n e dosage f o r management o f i s o v a l e r i c acidemia i s n o t known. I n t h i s study we evaluate a 9 year o l d female whose c u l t u r e d f i b r o b l a s t s have 4% o f c o n t r o l i s o v a l e r y l-CoA dehydrogenase a c t i v i t y. Glycine supplements between 0 and 600 mg/kg/d were compared a t weekly i n t e r v a l s w i t h r e s t r i c t e d l e u c i n e i n t a k e (54 mg/kg/d) and a f t e r acute l o a d i n g w i t h l e u c i n e (120 mg/ kg). Under r e s t r i c t e d l e u c i n e i n t a k e IVG e x c r e t i o n rose from 12.3 t o 33.6 nunolslgm c r e a t i n i n e when g l y c i n e supplements were i ncreased from 0 t o 50 mg/kg/d. As g l y c i n e supplements o f 100 and 150 mg/kg/d were added, maximum e x c r e t i o n o f IVG continued; however, when increased t o 300 (F plasma gly=978 pM) and 600 mglkgl d (F plasma gly=2547.5 vM) IVG e x c r e t i o n f e l l t o 13.8 and 16.3 mmoles/gm c r e a t i n i n e , r e s p e c t i v e l y (N1 plasma gly=219 pM). When acute l e u c i n e loads were compared a t g l y c i n e supplements o f 190 mg/kg/d (x plasma gly=424 pM) and 600 mg/kg/d (x plasma gly=1636

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