Neuronal lesions in the cerebellum following the administration of excess phenylalanine to neonatal rats.

Abstract

Conditions necessary to create a laboratory model in the albino rat to approximate the biochemical abnormalities in human phenylketonuria were studied. Such a state could only be achieved during the first postnatal week when activity of hepatic phenylalanine hydroxylase is only 30–50% of normal adult values. During this time, subcutaneous injections of phenylalanine every 12 hours resulted in: (1) sustained 5 to 8 fold elevations of phenylalanine concentrations with maintenance of relatively normal tyrosine levels in blood; (2) maximum phenylalanine/tyrosine ratios of 20:1 approaching levels previously reported for human phenylketonuria; and (3) the existence of the preceding biochemical abnormality during a period when brain, and cerebellum in particular, is undergoing rapid maturation. Light microscopic study of the brains of 50-day-old rats subjected to chronic neonatal hyperphenylalanemia revealed neuropathologic lesions limited to the cerebellum. The cytoplasm of Purkinje cells was vacuolated and heterochromatin severely decreased in granular cell nuclei. Axons showed different degrees of swelling manifested in formalin-fixed paraffin sections as a sponginess of white matter. Because this latter change was less apparent in perfused, plasticembedded material, this sponginess may be secondary to osmotic and chemical changes causing myelin disruption in abnormal axons. Although prior biochemical and pathologic studies in both neonatal hyperphenylalanemia in the rat and human phenylketonuria have placed a major emphasis on abnormalities of myelin, the present study reveals a vulnerability of developing neurons. This vulnerability is manifested by cytoplasmic lesions in Purkinje cells and nuclear lesions in granule cells.