Newborn With Phenylalanine Elevation and Consanguineous Parents
A 5-day-old term infant is lethargic and feeding poorly. Newborn screening shows phenylalanine 1,250 μmol/L (normal <120) and tyrosine 25 μmol/L (normal 20–120). Blood glucose is 60 mg/dL, ammonia 55 μmol/L, and there is no metabolic acidosis. The infant is breastfed. The parents are first cousins; a maternal aunt has intellectual disability. A tetrahydrobiopterin (BH4) loading test is given, and phenylalanine remains above 1,000 μmol/L after 24 hours. Urine pterins are normal. Genetic testing later shows both parents are heterozygous for a pathogenic PAH variant. The mother asks whether the defect is in phenylalanine hydroxylase or in BH4 synthesis, what the recurrence risk is for future children, and whether tyrosine will need to be supplemented. A resident states that the aunt's affected status alone proves a 25% recurrence risk.
1. Interpret the BH4 loading test and urine pterins. Is the defect in PAH or BH4 synthesis? Explain the tyrosine and phenylalanine findings.
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The BH4 loading test shows no fall in phenylalanine, and urine pterins are normal. In BH4 synthesis or recycling defects, BH4 is deficient or not recycled; pterins are usually abnormal and phenylalanine may fall after BH4. Here the cofactor is present and pterins are normal, so the defect is in phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine to tyrosine. With PAH deficiency, phenylalanine accumulates (1,250 μmol/L) and tyrosine is low (25 μmol/L). The high phenylalanine is neurotoxic, causing lethargy and poor feeding; it also explains the risk of intellectual disability if untreated. This is classic PKU, not a BH4 cofactor defect.
2. Both parents are heterozygous for a pathogenic PAH variant. Calculate the recurrence risk for a future sibling and explain why the resident's stated 25% is correct but the reasoning is wrong.
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For two carrier parents (Aa × Aa), the offspring probabilities are 25% AA unaffected noncarrier, 50% Aa carrier, and 25% aa affected. Thus the recurrence risk for an affected sibling is 25%. The resident's number is correct, but the aunt's affected status alone does not prove that both parents are carriers or that the condition is autosomal recessive; the parental genetic testing does. The aunt's history is supportive but not sufficient, because the aunt could be affected for another reason. Genetic counseling should use the confirmed parental genotypes.
3. Outline the dietary rationale. Why must phenylalanine not be eliminated completely, and why is tyrosine conditionally essential?
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Phenylalanine is an essential amino acid, so it cannot be eliminated entirely; the goal is to restrict intake enough to keep blood phenylalanine in the target range (commonly 120–360 μmol/L for infants) while providing enough for growth. A phenylalanine-free formula supplies other amino acids and energy, and measured amounts of breast milk or regular formula supply phenylalanine. Tyrosine becomes conditionally essential because the PAH block prevents its synthesis from phenylalanine; it must be supplied in the diet. Monitoring includes blood phenylalanine, tyrosine, growth, and developmental assessment. Over-restriction causes phenylalanine deficiency and poor growth; under-treatment causes phenylalanine neurotoxicity.