ON THE MECHANISM OF BRAIN DYSFUNCTION IN HYPERPHENYL-ALANINEMIA

Abstract

A high phenylalanine (Phe) level, such as observed in untreated or poorly controlled PKU, results in inhibition of the oligodendroglial specific ATP sulfurylase, the first enzyme of sulfate activation. A decreased rate of synthesis of sulfatides results from this inhibition and consequently there are less acidic glycolipids available to protect, particularly myelin basic protein, from proteolytic degradation. This leads to an increased turnover of myelin which is not compensated by an increased rate of synthesis. The myelin sheath disintegrates and the initially formed labile synaptic contact regress. As a result there will be fewer synaptic contacts in the mature brain. As the proper formation of synapses is recognized as the basis of the dynamic integrative capacities of the central nervous system, the scenario outlined above provides a mechanism for the brain dysfunction. Experimental evidence for several steps of this scenario is available: inhibition of ATP-sulfurylase, localization of the Phe-sensitive ATP-sulfurylase in those areas of the brain most affected by the high Phe condition, the developmental profile of the Phe sensitive ATP-sulfurylase, precisely coinciding with myelination, i.e. active during the vulnerable period of brain development, increased vulnerability to proteolytic degradation and turnover of myelin in the absence of acidic glycolipids. Since inhibition of ATP-sulfurylase is not limited to Phe, but can be observed with other amino acids as well, the scenario may be of a quite general nature.