A 5-month-old infant screened newborn-positive for hyperphenylalaninemia was started on a phenylalanine-restricted diet. Despite dietary compliance, the infant developed progressive hypotonia, seizures, and movement disorders. Urine pterin analysis shows reduced biopterin and neopterin. Which enzyme deficiency is the most common cause of this presentation?
- A Phenylalanine hydroxylase (PAH)
- B 6-pyruvoyl-tetrahydropterin synthase (PTPS) ✓
- C Dihydropteridine reductase (DHPR)
- D GTP cyclohydrolase I
Explanation
The presentation is classic for a tetrahydrobiopterin (BH4) synthesis defect causing malignant hyperphenylalaninemia. Unlike isolated PAH deficiency, BH4 is also a cofactor for tyrosine and tryptophan hydroxylases, so dopamine and serotonin synthesis fail, producing progressive neurologic deterioration despite dietary phenylalanine control. PTPS deficiency accounts for roughly 60% of BH4 metabolism defects. DHPR deficiency is less common and shows similar neurologic decline. GTP cyclohydrolase I deficiency causes a rarer form without hyperphenylalaninemia in some variants. Treatment requires BH4 supplementation plus L-DOPA and 5-HTP, not dietary restriction alone.
Reference: Nelson Textbook of Pediatrics, 21st ed.
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Written and medically reviewed by the StethoPrep medical team.