A ONE-YEAR, CONTROLLED STUDY OF THE EFFECT OF LOW-PHENYLALANINE DIET ON PHENYLKETONURIA
Authors: Hsia David Y.-Y. , Knox W. Eugene , Quinn Karl V. , Paine Richmond S. 
Published: December 2021

Twenty-four patients with phenylketonuria from the state institutions of Massachusetts were divided into 12 matched pairs, comparable as to age, sex, intelligence and length of institutional placement. One member of each pair was selected by lot to receive a phenylalanine deficient diet for a 12-month period, the other member of the pair receiving a control diet identical in appearance and flavor. The identity of the control and experimental patients was not known to those caring for them. Five unpaired, institutionalized patients and five outpatients also received low-phenylalanine diets.

At the end of a test period of 12 to 15 months, the patients were evaluated in terms of adequacy of chemical control and changes observed in intelligence, behavior, skin condition, hair color, seizures and electroencephalograms.

Although prolonged therapy of patients with low-phenylalanine diets is generally feasible while they are at home with their parents and under close medical observation, the program seems more difficult to achieve on a large scale in an institutional setting. A number of patients receiving the diet developed malnutrition severe enough to require discontinuance of the diet for temporary periods. The low-phenylalanine diet is undoubtedly dangerous unless the patients are closely observed.

It is impossible to know whether or not the diet is achieving the desired chemical effect of reduction of phenylalanine to normal concentrations in the blood, unless the plasma concentration of phenylalanine is followed. Estimation of phenylalanine in plasma is a more difficult test than that for urine phenylpyruvate, but is essential since plasma concentration may remain high when the urine is negative. Extremely low values for phenylalanine in plasma may require slight increase in phenylalanine intake. Death in status epilepticus has been reported, possibly associated with extremely rapid decrease in phenylalanine in the plasma to nearly zero. Without this chemical control apparent failure, based on nonachievement of chemical control, might be erroneously ascribed to uselessness of the diet.

Possible beneficial effect on intelligence was limited to four patients, 6 months, 7 months, 1½ years and 3 years of age at the time the diet was begun. Improvement in skin condition, behavior, and possibly in electroencephalograms, was obtained in older individuals, but such benefits would not seem to justify the difficulties and dangers of dietary therapy.

These observations, together with the reported results of other investigators, support the tentative conclusion that the metabolic disturbances associated with the elevated concentration of phenylalanine in the plasma, characteristic of phenylketonuria, interfere with normal cerebral development rather than with the function of a normally developed brain.

Recognition of phenylketonuria at the earliest possible age, and prompt institution of dietary control, are essential if the possible therapeutic benefits of a low-phenylalanine diet are to be conclusively evaluated.