Tetrahydrobiopterin (BH4) is a critical cofactor for phenylalanine hydroxylase (PAH). In BH4-deficient PKU (atypical PKU), which additional neurotransmitters are deficient, explaining the severe neurological phenotype?

• A GABA and glutamate, because BH4 is required for glutamate decarboxylase
• B Serotonin and dopamine, because BH4 is also required for tryptophan hydroxylase and tyrosine hydroxylase ✓
• C Acetylcholine and norepinephrine, because BH4 is required for choline acetyltransferase and dopamine beta-hydroxylase
• D Histamine and substance P, because BH4 is required for histidine decarboxylase

Explanation

BH4 (tetrahydrobiopterin) is the essential pterin cofactor for three aromatic amino acid hydroxylases: phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH, rate-limiting step for catecholamine synthesis), and tryptophan hydroxylase (TPH, rate-limiting step for serotonin synthesis). It is also a cofactor for nitric oxide synthases (NOS). In BH4-deficient PKU (due to defects in GCH1, PTS, QDPR, or PCBD1), PAH activity is impaired (hyperphenylalaninaemia) but additionally TH and TPH are non-functional, causing severe deficiency of dopamine, norepinephrine, and serotonin. Treatment requires BH4 supplementation plus L-DOPA/5-hydroxytryptophan neurotransmitter precursors in addition to phenylalanine restriction.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.