BH4 deficiency is a very rare inborn error of metabolism, and is estimated to account for 1-2 % of cases of HPA. BH4 deficiency is an autosomal recessive genetic condition and can result from deficiencies of any of the five different enzymes involved in BH4 synthesis and regeneration. BH4 is a necessary co-factor for PAH. Therefore, BH4 deficiency impairs PAH activity leading to a biochemical situation similar to PKU, with HPA resulting from deficient conversion of Phe to tyrosine. In addition, since BH4 is also a necessary co-factor for both tyrosine hydroxylase and tryptophan hydroxylase, BH4 deficiency causes deficiencies in the downstream neurotransmitter products of these amino acids including catecholamines and serotonin. Dietary limitation of whole protein or Phe intake is often not necessary with BH4 treatment. However, since BH4 does not cross the blood brain barrier, concomitant therapy with neurotransmitter precursors, i. e. levodopa and 5-hydroxytryptophan, may be necessary to boost central nervous system substrate levels for catecholamine and serotonin synthesis, respectively.
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Footnotes
(1) Kuvan(R) is a potential treatment option in those PKU and BH4-deficient patients who are responsive to BH4 treatment. According to published literature, 20 to 50 % of PKU patients are responsive to treatment with Kuvan(R).
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