Phenylalanine Hydroxylase Deficiency

CLINICAL CHARACTERISTICS

The phenotypes in individuals with phenylalanine hydroxylase (PAH) deficiency include PAH deficiency treated from birth and late-diagnosed or untreated PAH deficiency. Maternal phenylketonuria (MPKU) syndrome occurs in offspring of mothers with inadequately treated PAH deficiency during pregnancy and results from the toxic effects of elevated blood phenylalanine (Phe) concentrations on the developing fetus. PAH deficiency treated from birth is characterized by the following, even with adherence to a low Phe diet: (1) a modest but measurable decrease in intellectual functioning as well variable impairments in executive function, attention, and fine motor functions; (2) an increased prevalence of mental health concerns including anxiety and depression; and (3) neurologic problems (including hypertonia, paraplegia, movement disorders, and seizures), which may improve or resolve with lowering blood Phe concentration. Late-diagnosed or untreated PAH deficiency is characterized by irreversible neurocognitive impairment (intellectual disability), neurobehavioral/psychological issues, neurologic manifestations (motor disturbances including movement disorders and seizures), and microcephaly. Although lowering blood Phe concentration sometimes improves neurobehavioral/psychological issues and motor disturbances, it does not reduce neurocognitive impairment. MPKU syndrome is characterized by intellectual disability, neurobehavioral/psychiatric manifestations, congenital heart defects, and other birth defects.

DIAGNOSIS/TESTING: The diagnosis of PAH deficiency is established in all neonates following an out-of-range newborn screening result with (1) biochemical testing (plasma amino acid analysis) and (2) molecular genetic testing to identify the causative biallelic pathogenic variants to confirm the biochemical diagnosis of PAH deficiency and inform clinical management and genetic counseling.

MANAGEMENT

Lifelong treatment of all individuals with an untreated blood Phe concentration greater than 360 μmol/L with an age-appropriate Phe-restricted diet and Phe-free protein supplementation with medical foods (amino acid or glycomacropeptide based). In certain individuals, FDA-approved pharmacologic therapies may include sapropterin dihydrochloride, sepiapterin, and/or enzyme substitution therapy (pegvaliase). Because treatment for affected individuals of all ages can be difficult, the support of an experienced health care team consisting of physicians, metabolic dietitians, genetic counselors, social workers, nurses, nurse practitioners, and psychologists is essential for all individuals with PAH deficiency and their parents/caregivers. Teaching should include information on malnutrition and growth failure, the side effects of dietary treatment. Therapy needs are greater for individuals with late diagnosis and resultant neurodevelopmental deficits. As PAH deficiency is a lifelong disorder with varying age-related implications, smooth transition of care of affected individuals from a pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Regular individualized screening for early identification of the manifestations of PAH deficiency treated from birth and late-diagnosed or untreated PAH deficiency is required. Aspartame, an artificial sweetener often added to soft drinks, foods, and some medications, is metabolized in the gastrointestinal tract into Phe and aspartate. Persons with PAH deficiency should either (1) avoid products containing aspartame or (2) when using such products calculate total Phe intake in order to adapt diet components accordingly. If the pathogenic variants in the family are known, molecular genetic prenatal testing of a fetus at risk can be performed via amniocentesis or chorionic villus sampling to allow for treatment at birth of an infant known to be affected. Any at-risk newborn sib who did not have prenatal testing should be evaluated immediately after birth for PAH deficiency by measuring blood Phe concentration to allow for earliest possible diagnosis and treatment. Older at-risk sibs – even those who are apparently asymptomatic – should be evaluated for PAH deficiency given the significant variability in the clinical manifestations of previously undiagnosed PAH deficiency. Preconception: achieve and maintain maternal blood Phe concentration at <360 µmol/L for three months prior to conception; provide genetic counseling regarding the teratogenic effects of elevated maternal blood Phe concentration on the developing fetus. Pregnancy: maintain maternal blood Phe concentration at 120-360 µmol/L during pregnancy and monitor dietary intake to ensure that dietary nutrients are adequate. Postpartum: monitor blood Phe concentrations of mother and infant as needed.

GENETIC COUNSELING

PAH deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Children born of one parent with PAH deficiency and one parent with two normal alleles are obligate heterozygotes. If the mother is the affected parent, MPKU syndrome is a critical issue. Females with PAH deficiency should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (i.e., MPKU syndrome) when they reach childbearing age. Once the PAH pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for PAH deficiency are possible.