Phenylalanine Hydroxylase Deficiency


Disease characteristics. Phenyalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders including phenylketonuria (PKU), non-PKU hyperphenylalaninemia (non-PKU HPA), and variant PKU. Classic PKU is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity; without dietary restriction of phenylalanine, most children with PKU develop profound and irreversible mental retardation. Non-PKU HPA is associated with a much lower risk of impaired cognitive development in the absence of treatment. Variant PKU is intermediate between PKU and non-PKU HPA.

Diagnosis/testing.PAH deficiency can be diagnosed by newborn screening in virtually 100% of cases based upon detection of the presence of hyperphenylalaninemia using the Guthrie microbial or other assays on a blood spot obtained from a heelprick. PKU is diagnosed in individuals with plasma phenylalanine (Phe) concentrations higher than 1000 µmol/L in the untreated state; non-PKU HPA is diagnosed in individuals with plasma Phe concentrations consistently above normal (i.e., >120 µmol/L), but lower than 1000 µmol/L when on a normal diet. Molecular genetic testing of the PAH gene is used primarily for genetic counseling purposes to determine carrier status of at-risk relatives and for prenatal testing.

Management.Treatment of manifestations: Classic PKU: a low-protein diet and use of a Phe-free medical formula as soon as possible after birth to achieve plasma Phe concentrations of 120-360 µmol/L (2-6 mg/dL) or 40-240 µmol/L (1-4 mg/dL); supplementation with 6R-BH4 stereoisomer in doses up to 20 mg/kg daily based on individual needs. Non-PKU HPA: It is debated whether those with plasma Phe concentrations consistently below 600 µmol/L (10 mg/dL) require dietary treatment. Prevention of primary manifestations: Same as Treatment of manifestations. Surveillance: regular monitoring of plasma Phe and Tyr concentrations in individuals with classic PKU. Agents/circumstances to avoid: aspartame, an artificial sweetener that contains phenylalanine (or calculate intake of Phe in aspartame and adapt diet accordingly). Testing of relatives at risk: Newborn sibs of an individual with PKU who have not been tested prenatally should have blood concentration of Phe measured shortly after birth (in addition to newborn screening) to allow earliest possible diagnosis and treatment. Other: for women with PAH deficiency, Phe-restricted diet for at least several months prior to conception in order to maintain plasma Phe concentrations between 120 and 360 µmol/L (2-6 mg/dL); after conception, continuous nutritional guidance and weekly or biweekly measurement of plasma Phe concentration to assure adequate energy intake with the proper proportion of protein, fat, and carbohydrates.

Genetic counseling.PAH deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis of PAH deficiency is possible in pregnancies at 25% risk either when molecular genetic testing has revealed the disease-causing mutations in the PAH gene in an affected family member, or when linkage analysis has identified informative markers. Prenatal testing is available for pregnancies at risk if the disease-causing mutations have been identified in an affected family member.