Phenylketonuria
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Direct answer
Untreated classical phenylketonuria, an autosomal recessive deficiency of phenylalanine hydroxylase, diverts excess phenylalanine into phenylpyruvate and phenylacetate and produces severe intellectual disability, fair hair and skin, eczema, seizures and a mousy urine odour. The enzyme needs tetrahydrobiopterin (BH4), oxygen and ferrous iron to convert phenylalanine to tyrosine, so about 1–2 per cent of hyperphenylalaninaemia is instead a BH4-synthesis or regeneration defect with additional neurotransmitter shortage. Newborn screening — Guthrie's bacterial inhibition assay historically, tandem mass spectrometry increasingly — detects it before brain damage, and a phenylalanine-restricted diet started in the first weeks preserves normal intellect.
What you must remember
- Phenylalanine hydroxylase works only in the liver; tyrosine becomes conditionally essential when the enzyme fails, which is why treated patients receive tyrosine supplementation within the restricted diet.
- Classical untreated patients have plasma phenylalanine above 20 mg/dL (normal under 2 mg/dL) with phenylpyruvate, phenyllactate and phenylacetate in urine — the last gives the mousy or musty odour.
- Hypopigmentation follows the tyrosine shortage: melanin falls, so PKU children in the Indian context are noticeably fairer than siblings, with light-brown hair and pale retinae.
- Guthrie test: dried blood spot on filter paper, Bacillus subtilis growth inhibited by beta-2-thienylalanine is restored by excess phenylalanine — a bacterial inhibition assay; sampling is best at 3–5 days of age after 48 hours of protein intake.
- Ferric chloride urine test turns green with phenylpyruvate; the colour is transient and other aminoacidurias give their own hues.
- BH4 defects (GTP cyclohydrolase, 6-pyruvoyl tetrahydropterin synthase, dihydropteridine reductase) lower dopamine, serotonin and catecholamines as well, so neurological deterioration continues despite diet unless BH4, L-dopa and 5-hydroxytryptophan are given.
- Treatment: phenylalanine-restricted (not phenylalanine-free) medical diet, since phenylalanine is an essential amino acid; aspartame (aspartyl-phenylalanine methyl ester) is contraindicated.
- Maternal PKU: uncontrolled maternal phenylalanine causes microcephaly, congenital heart disease and intellectual disability in a heterozygous fetus — strict control before conception is essential.
- Large neutral amino acids (LNAA) share the brain's amino-acid transporter, so high phenylalanine starves the brain of competitors; incidence is roughly 1 in 10,000–15,000 live births.
From a dried blood spot to a protected brain
A heel-prick sample collected on day 4 shows raised phenylalanine; before any panic, the laboratory separates the possibilities. Plasma quantitative amino acids confirm hyperphenylalaninaemia, then BH4 loading and urinary pterins (neopterin and biopterin) separate phenylalanine hydroxylase deficiency from a BH4 defect, because missing the latter means a child who deteriorates despite diet. In classical disease the infant is started within the first two weeks on a phenylalanine-free amino-acid formula titrated to keep blood phenylalanine in the treatment band (commonly 2–6 mg/dL), with measured natural protein supplying just enough phenylalanine for growth, plus tyrosine. Follow-up is lifelong at metabolic centres: growth, diet adherence, and during adolescence the special problem of maternal PKU — a young woman must return to strict diet before conception, because even a phenotypically normal mother with blood phenylalanine above 10 mg/dL risks a structurally damaged baby. Saprodin-termed BH4 (sapropterin) can be trialled: responsive patients relax the diet somewhat, though Indian access to sapropterin remains limited, which is why diet remains the backbone of therapy here.
Where students slip
Students assume the Guthrie test directly measures the enzyme; it measures phenylalanine (metabolite screening) — enzyme assay in fibroblasts or liver is the confirmatory route for the hydroxylase itself. The second error is designing a phenylalanine-free diet: zero intake is lethal, because the amino acid is essential; exams ask precisely this. Third, attributing every fair, retarded child to PKU neglects the differential, including albinism and hypothyroidism — but the combination of mousy urine odour plus fair hair plus seizures plus a positive ferric chloride green is PKU until proven otherwise. Finally, remember screening must occur after milk feeds begin; testing at 24 hours yields false negatives.
Frequently asked questions
What does the Guthrie test measure and on what principle?
Blood phenylalanine on a dried spot, by bacterial inhibition: Bacillus subtilis growth is checked by beta-2-thienylalanine and re-enabled only by excess phenylalanine — growth halos therefore flag hyperphenylalaninaemia.
Why are untreated PKU children fair-complexioned?
Phenylalanine hydroxylase deficiency starves the tyrosine pool from which melanin is made, so hair, skin and iris pigmentation is lighter than expected for the family, a useful sign in Indian families.
How are BH4-dependent hyperphenylalaninaemias distinguished clinically?
They worsen neurologically despite diet (drooling, rigidity, seizures) because BH4 is also cofactor for tyrosine hydroxylase and tryptophan hydroxylase; urinary pterin profiles and BH4 loading tests clinch the diagnosis, and treatment adds BH4 with neurotransmitter precursors.
Why must maternal PKU be controlled before conception?
Excess maternal phenylalanine crosses the placenta and is teratogenic to a genetically normal fetus — microcephaly, cardiac defects, growth retardation — so strict phenylalanine restriction must begin pre-pregnancy and continue throughout gestation.
Why is aspartame dangerous in PKU?
Aspartame is digested to phenylalanine (plus aspartate and methanol), effectively a phenylalanine supplement; sugar-free drinks and gums can destabilise otherwise well-controlled patients.