A 6-year-old presents with progressive intellectual disability, fair complexion, musty odor, and eczema. Plasma phenylalanine is 1400 micromol/L. Phenylalanine hydroxylase (PAH) activity is <1% of normal. The patient is started on sapropterin (BH4 analogue). Sapropterin would be expected to benefit which specific subset of PKU patients?
- A Those with null/null genotype with no PAH protein produced
- B Those with biopterin defects (PTPS or DHPR deficiency causing BH4 deficiency)
- C Those with missense mutations resulting in misfolded but structurally competent PAH protein ✓
- D Those with PAH mutations affecting the regulatory ACT domain
Explanation
Sapropterin (synthetic BH4) is a pharmacological chaperone that stabilizes misfolded PAH protein. It is effective in BH4-responsive PKU, which predominantly occurs in patients with missense mutations that produce structurally destabilized but catalytically competent PAH enzyme. The excess BH4 shifts the folding equilibrium toward the functional conformation, increasing residual enzyme activity. Patients with null/null genotypes produce no PAH protein and therefore cannot benefit from BH4 supplementation. Biopterin synthesis/regeneration defects (PTPS, DHPR deficiency) do respond to BH4 but through a different mechanism — supplementing the deficient cofactor rather than acting as a chaperone. Testing for BH4 responsiveness requires a loading test before initiating therapy.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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Written and medically reviewed by the StethoPrep medical team.