Clinical characteristics: Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders. The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1,200 μmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment.
Diagnosis/testing: PAH deficiency can be detected by newborn screening in virtually 100% of cases based on the presence of hyperphenylalaninemia using tandem mass spectrometry on a blood spot obtained from a heel prick. The diagnosis of PAH deficiency is established in a proband with:
A plasma phenylalanine concentration persistently above 120 µmol/L (2 mg/dL) and altered ratio of phenylalanine to tyrosine in the untreated state with normal BH4 cofactor metabolism;
The finding of biallelic pathogenic variants in PAH by molecular genetic 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). A proportion of individuals with PKU benefit from adjuvant therapy with sapropterin. Large neutral amino acid (LNAA) transporters may also decrease the plasma Phe concentration in affected adolescents and adults. Non-classic HPA: individuals with plasma Phe concentrations above 600 μmol/L are treated in most centers. It is debatable whether those with plasma Phe concentrations consistently below 600 µmol/L (10 mg/dL) require dietary treatment. Neuropsychiatric testing may be considered to identify learning differences in affected individuals with referral to developmental services, as indicated.
Surveillance: Regular monitoring of plasma Phe, Tyr, and plasma amino acid concentrations in individuals with classic PKU; regular assessment of growth and micronutrient needs; assessment of developmental progress and screening for mental illness at every visit.
Agents/circumstances to avoid: Aspartame, an artificial sweetener that contains phenylalanine.
Evaluation of relatives at risk: Newborn sibs of an individual with PAH deficiency 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.
Pregnancy management: To minimize or prevent teratogenic effects of phenylalanine, women with PAH deficiency should follow a 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 that target levels are met in addition to adequate energy intake with the proper proportion of protein, fat, and carbohydrates. Evaluation for fetal anomalies using high-resolution ultrasound and fetal echocardiogram.
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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PAH pathogenic variants have been identified in an affected family member.
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