The mechanisms by which deficiency of hepatic phenylalanine hydroxylase causes central nervous system disease are reviewed. The neurological disease appears to be secondary to increased concentrations of phenylalanine and a decrease in the concentrations of other large neutral amino acids, especially methionine and tyrosine, within the central nervous system. This causes a deficiency of the neurotransmitter dopamine, reduced protein synthesis and demyelination. Similar mechanisms appear to be operating when blood phenylalanine concentrations are in the range expected for early continuously treated phenylketonuria.
Conclusion The severe brain disease found in phenylketonuria is caused by a raised blood phenylalanine content which increases the brain free phenylalanine and decreases the concentration of other large neutral amino acids. Brain protein synthesis is decreased, myelin turnover is increased and there are abnormalities in amine neurotransmitter systems.
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Surtees, R., Blau, N. The neurochemistry of phenylketonuria. Eur J Pediatr 159, S109–S113 (2000). https://doi.org/10.1007/PL00014370
- Key words Phenylalanine hydroxylase deficiency
- Central nervous system
- AbbreviationsBH4 tetrahydrobiopterin
- GTP guanosine triphosphate
- GFRP GTPCH feed-back regulatory protein
- GTPCH GTP cyclohydrolase I
- HPA hyperphenylalaninaemia
- PAH phenylalanine 4-hydroxylase
- Phe phenylalanine
- PKU phenylketonuria
- PTPS 6-pyruvoyltetrahydropterin synthase
- SR sepiapterin reductase