Phenylalanine Alters the Mean Power Frequency of Electroencephalograms and Plasma L-DOPA in Treated Patients with Phenylketonuria

Abstract

ABSTRACT. Phenylketonuria is a human model for the study of the effects of phenylalanine on brain function. We found previously a correlation between high blood phenylalanine, prolonged performance times on neuropsychological tests of higher integrative function, and decreased urinary dopamine in 10 patients. In this protocol we examine changes in triplicate of plasma dihydroxyphenylalanine (L-DOPA) and the mean power frequency of the electroencephalogram in eight additional older patients with phenylketonuria using longer intervals in a blinded, cross-over design. Mean power frequency was obtained by Fourier transform of the power spectrum from traditional eight channel electroencephalograms. Plasma L-DOPA was quantitated by radioenzymatic methods. In all patients statistically significant decreases were found in the mean power frequency of the electroencephalogram and in plasma L-DOPA when plasma L-phenylalanine increased. These findings were reversible and correlated in the reverse direction when plasma L-phenylalanine was reduced. PKU is the prototypic experiment of nature by which adverse effects of high circulating blood phenylalanine on human brain structure and function are studied. Two different pathological phenomena are postulated as caused by elevated concentrations of phenylalanine. First, in the developing human brain, from fetal life to 6 months of age, irreversible changes in myelin, brain structure, and neuronal migration are described (1-5). Second, elevated blood phenylalanine concentrations may impair the fully myelinated human brain by reversible mechanisms involving neurotransmitter production (6-9). This latter phenomenon Received April 2. 1986: accepted June 6, 1986. Address all correspondence and request for reprints to Dr. Louis J. Elsas, Medical Genetics, Emory University, 2040 Ridgewood Drive, Atlanta, GA 30322.This work was supported by Grant 12-1 10 from the March of Dimes and a Grant 2-MOI-RR00039-25 from the National Institutes of Health.has considerable importance when one considers the adverse effects of diet discontinuation on intellectual achievement and behavior of early treated, 6 yr olds with PKU (10).Recently, we approached the issue of developing noninvasive, sensitive discriminants of brain function by quantitating catecholamine production and neuropsychological tests of performance in patients with high and low blood phenylalanine concentrations. In this study we found prolonged performance times in tests of higher integrative function but not for tests of lower integrative function when plasma phenylalanine rose (8). When plasma phenylalanine concentration was elevated, urinary excretion of dopamine decreased (8). Since in well patients it is not ethical to measure neurotransmitters in brain or cerebrospinal fluid and since neuropsychological tests are subject to many variables such as the individual's competence, environmental conditions, and rapport with examiners, we sought better tests which were safe, noninvasive, repeatable, and subject to statistical analysis. W...

Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria

“…The individual time courses of our measured brain versus plasma Phe levels (not shown) appear to confirm a large individual spread in kinetic parameters. 1 H-MRS. As in earlier studies (8,9,11), it was possible to quantitate by 1 H-MRS cerebral Phe concentrations in patients with PKU, thereby confirming the usefulness of 1 The preload values of Phe were somewhat different between the two series. It seems quite possible that this small difference is caused by the first dose of LNAAs taken before the baseline measurement.…”

“…Untreated PKU leads to disturbed brain development with profound retardation, microcephaly, epilepsy, and other neurologic symptoms, which can be widely prevented by early institution of a Phe-restricted diet. Elevated Phe levels also acutely impair brain function in early treated, and thus normally developed, patients, which was proved using neuropsychologic tasks and electroencephalogram (EEG) spectral analysis (1)(2)(3).…”

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