Effect of experimental hyperphenylalaninemia on myelin metabolism at later stages of brain development.

Myelination is the most important process in postnatal maturation of the nervous system and during this period the growing infant passes through a "vulnerable period" during which irreversible brain damage can occur if the neonate is subjected to a potential neurotoxin. This study was undertaken to investigate the mechanisms by which chronic hyperphenylalaninemia interferes with myelin metabolism, beyond the neonatal period of rapid myelination, at a time when myelin continues to accumulate. Rats of 25 days of age were placed on a hyperphenylalanimenia (HyPhe) inducing diet of 5% phenylalanine plus 0.4% alpha-methylphenylalanine (alpha MP) at 25 days of age to approximate plasma phenylalanine levels of an untreated human PKU patient (1.5 mM). The HyPhe group exhibited approximately a 15% decrease in the amount of myelin protein throughout the 70 days of the study. The rate of incorporation of 3H-lysine into both TCA precipitable whole brain proteins or myelin proteins did not vary from the HyPhe group and a weight matched control group (WMC). Therefore, this loss of myelin could not be attributed to a hypo-myelination. The turnover of whole brain proteins also was unaffected by the HyPhe treatment; however, the turnover of myelin proteins in the HyPhe group was dramatically different (t 1/2 = 3 days) from that of the WMC group (t 1/2 = 36 days) or a group treated with only alpha MP (t 1/2 = 26 days).