Tetrahydrobiopterin (BH4) is the cofactor for phenylalanine hydroxylase. BH4 deficiency can cause hyperphenylalaninemia indistinguishable from classic PKU on newborn screening. What additional neurological features distinguish BH4-deficient hyperphenylalaninemia from classic PKU?

• A Albinism and white hair due to reduced tyrosinase activity
• B Renal Fanconi syndrome due to phenylpyruvate accumulation in proximal tubules
• C Hypertension due to excess catecholamine synthesis
• D Progressive neurological deterioration despite phenylalanine restriction, due to monoamine neurotransmitter deficiency ✓

Explanation

BH4 is also an essential cofactor for tyrosine hydroxylase (converts tyrosine → L-DOPA → dopamine) and tryptophan hydroxylase (converts tryptophan → 5-HTP → serotonin). Therefore, BH4 deficiency impairs monoamine neurotransmitter synthesis (dopamine, serotonin, norepinephrine) independent of phenylalanine levels. Even with successful dietary phenylalanine restriction that normalizes blood Phe, these patients show progressive neurological deterioration: movement disorders, seizures, hypotonia. Treatment requires BH4 supplementation PLUS neurotransmitter precursors (L-DOPA, 5-HTP). Neonatal screening must include pterins (biopterin, neopterin) and enzyme activity to distinguish BH4 deficiency from PAH deficiency.

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

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