The Role of the Blood-Brain Barrier
Blood-brain barrier kinetics18
It is known that Phe crosses the blood-brain barrier (BBB) through specialized receptors in the L-type delivery system. Phe has the highest affinity of any of the large neutral amino acids (LNAA) for this receptor. Clinical presentation has been shown to correlate with the binding rate of Phe for these receptors, as well as intracerebral Phe levels. Patients with slower Phe binding show fewer symptoms of PKU even with comparable serum Phe levels.
Phe competes with other amino acids for BBB transport
The BBB may play another role in the onset of PKU symptoms. The L-type delivery system transports not just Phe, but all of the LNAAs, as well as non–amino acid neurotransmitter precursors such as L-DOPA. Under normal conditions, the transport system is nearly saturated so that the elevation of any one of the LNAAs that compete for the same binding site will inhibit the binding of the others. Because Phe is known to have a higher affinity for the L-type delivery system, an excess of Phe is likely to block out other amino acids. Given the role of the LNAAs in brain function, this could partially explain some of the neurological deficits in PKU.
A complicated mechanism involving multiple factors
The current data suggest that a combination of factors, including physical changes in the brain as well as imbalances in neurotransmitter concentrations, are likely responsible for the symptomatology of PKU. The variability in clinical presentation, as well as the low genotype-phenotype correlation, can be attributed to the complexity of the biochemical pathways combined with the variability of interindividual characteristics.
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