Phenylketonuria (PKU)

Test

• Bacterial inhibition assay to measure blood phenylalanine
• Using a cut-off level of 4 mg/dL, miss 16% under 24 hours, 2% over 48 hours old
• Guthrie bacterial inhibition test: the prototype of metabolic screening tests relying on bacterial inhibition.  Filter paper is saturated with heel-stick blood, allowed to dry, small disks are punched out for use in tests.  Bacillus subtilis is spread uniformly on agar.  Inhibitory amino acid analogs block specific metabolic pathways.  Bacterial can grow only if exogenous amino acids competitively overcome the block.  Can test in this manner for phenylalanine, leucine, methionine, galastosemia, histidine, and tyrosine.  Antibiotics can also inhibit growth, however, causing false negatives.
• False positives (1-3% of cases)
• non-PKU hyperphenylalanemia (1/60,000)
• pterin defect with secondarily hyperphenylalanemia
• transient elevation, acute galatosemia
• False negatives
• incorrect age, s/p transfusion
• urine screening unreliable in infants

Genetics

• Autosomal recessive
• 1:10,000 to 1:25,000 in US
• 1:6,000 in Ireland, Scotland and among the Yemenite Jews
• Frequently seen with biopterin and dihydropteridine reductase deficiencies
• DNA mutation heterogenous

Pathology

• Most commonly causes by a deficiency of phenylalanine hydroxylase leading to an accumulation of phenylalanine, which impairs the development of the central nervous system

Diagnosis

• Rarely diagnosed before 6 months and usually only after mental retardation is obvious
• Paler and fairer than siblings because melanin formation is competitively inhibited by high phenylalanine levels
• Progressive developmental delay in the first year of life, severe mental retardation, seizures, autistic-like behavior and a peculiar odor.  Hyperactivity and eczema also common.

Treatment

• Dietary restriction of phenylalanine is highly effective if begun before the infant is 4 weeks old.  Diet requires protein restriction and avoidanace of aspartame.

Acknowledgment

Also see other Inborn Errors of Metabolism.
 

Genetics

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