Phenylketonuria (PKU)

Pathophysiology

1) cause is defective conversion of phenylalanine to tyrosine 2) three clinical subtypes with different enzyme defects have been described 3) type 3 has the worse prognosis

Signs and Symptoms

Untreated – 1) severe mental retardation and neuropsychiatric disturbances (hyperactivity and seizures) 2) hypopigmented skin and hair 3) eczema 4) mousy odor

Characteristic Test Findings

Laboratory – 1) phenylalanine levels are normal at birth 2) increased serum and urine phenylalanine levels after initiation of feeding 3) prenatal diagnosis through genetic analysis for specific PAH gene mutations and markers 4) screening after birth is via the Guthrie bacterial inhibition assay

Biochemistry

1) type I – defect is in PAH 2) type II – defect is in dihydropteridine reductase 3) type III – defect is in 6-pyruvoyl-tetra-hydropterin synthase 4) types II and III also have abnormalities in tyrosine and tryptophan metabolism

Inheritance/Epidemiology

1) autosomal recessive inheritance 2) occurs 1/10,000 3) type I is most common in whites and Asians 4) increased phenylalanine levels in the mother will cause mental and growth retardation in fetus as phenylalanine crosses the placenta 5) defective PAH gene is on 12q24.1 6) most gene defects causing PKU are missense mutations

Treatment

1) dietary restriction of phenylalanine must begin in the first 3 weeks of life to prevent mental retardation (a small amount of phenylalanine is needed for normal growth 2) an experimental phenylalanine lyase has been tried to promote degradation in the gut and to lessen dietary restrictions 3) only type I is amenable to dietary control alone 4) type II may also need levodopa, folinic acid, or 5-hydroxytrytophan

Tips for USMLE

if a fair-skinned 6 week old infant who was normal at birth is brought to the pediatrician with a scaly skin rash, irritability, and a musty odor, think PKU