Phenylketonuria. Also known as phenylalanine hydroxylase (PAH) deficiency, this autosomal recessive disease is caused by mutations in the PAH gene. PAH metabolizes phenylalanine to tyrosine, and homozygotes have diminished or absent enzyme activity. This leads to abnormally high levels of phenylalanine, resulting in progressive intellectual impairment, autism, seizures, motor deficits, and neuropsychological abnormalities (Blau, 2010). Because phenylalanine competitively inhibits tyrosine hydroxylase-which is essential for melanin production, afected individuals also have hair, eye, and skin hypopigmentation. More than 500 PAH gene mutations have been characterized, and the carrier frequency is 1 in 60, such that the disease afects approximately 1 in 15,000 newborns (American College of Obstetricians and Gynecologists, 2017 c). Prompt diagnosis and restriction of dietary phenylalanine beginning early in infancy are essential to prevent neurological damage, and all states mandate newborn screening for phenylketonuria (PKU).
Phenylalanine restriction alone would result in inadequate protein consumption, and phenylalanine-free amino acid-based supplementation is required. lso, in 2007, a synthetic form of the P AH cofactor tetrahydrobiopterin (sapropterin) was approved for PKU treatment. Approximately 25 to 50 percent of afected individuals are sapropterin-responsive and may experience a significant decline in phenylalanine levels and improvement in neuropsychiatric symptoms (Vockley, 2014). Lifelong maintenance of phenylalanine concentrations in the range of 2 to 6 mg/dL (120 to 360 �mol/L) is necessary to prevent worsening neurocognitive and psychiatric problems (American College of Obstetricians and Gynecologists, 2017 c). Fortunately, even those who have previously discontinued therapy may experience improved neuropsychological function with treatment.
During pregnancy, women with PKU whose phenylalanine levels remain above the recommended range are at risk to have otherwise normal (heterozygous) ofspring who sustain in utero damage as a result of being exposed to toxic phenylalanine concentrations. Phenylalanine is actively transported to the fetus. Hyperphenylalaninemia raises the risk for miscarriage and for PKU embryopathy, characterized by intellectual disability, microcephaly, seizures, growth impairment, and cardiac anomalies. Among women on unrestricted diets, the risk to have a child with intellectual disability exceeds 90 percent, microcephaly occurs in more than 70 percent, and as many as 1 in 6 children have cardiac defects (Lenke, 1980). he Maternal Phenylketonuria Collaborative Study, which included 572 pregnancies followed more than 18 years, reported that maintenance of serum phenylalanine levels in the recommended range between 2 and 6 mg/dL signiicantly reduced the fetal abnormality risk and resulted in childhood IQ scores in the normal range (Koch, 2003; Platt, 2000). Preconceptional counseling and consultation with providers from experienced PKU centers is recommended.