Role of BH4 in the Central Nervous System (CNS)
Because BH4 is required for the hydroxylation of aromatic amino acids, its importance in the central nervous system (CNS) becomes immediately apparent. Tyrosine and tryptophan are required for the synthesis of catecholamines and serotonin. A BH4-dependent process can be strongly suspected when normalization of plasma phenylalanine levels occurs following BH4 supplementation. A dose of 5 mg/kg BH4 is the usual recommended dose for correcting peripheral hyperphenylalaninemia. Because BH4 crosses the blood–brain barrier poorly, however, lifelong supplementation with the neurotransmitter precursors L-dopa and 5-HTP, along with carbidopa to enhance CNS delivery, is necessary in most of the disorders mentioned earlier. A much higher dose of BH4, approximately 20 mg/kg, can normalize CSF BH4 levels, but remains prohibitively expensive, and no studies exist as to the possible additional benefit of such a regimen. The higher requirement of tyrosine hydroxylase for BH4 in comparison with tryptophan hydroxylase may explain the more severe impairment in the catecholaminergic system compared with the serotonergic system in many cases.
Nitric oxide synthase is yet another enzyme with an absolute requirement for BH4 for the oxidation of arginine to nitric oxide. The inability to replete normal levels of BH4 in the CNS with oral administration in its currently used doses may be one reason many children with BH4 deficient disorders develop lifelong cognitive and developmental impairments despite other treatments. Nitric oxide also plays a critical role in CNS neuroprotective mechanisms, and reduced efficiency of this enzyme may result in additional ongoing neuronal injury, cell death and vascular dysregulation and injury.
