Clinical Guidance

The phenotypes in individuals with phenylalanine hydroxylase (PAH) deficiency include PAH deficiency treated from birth and late-diagnosed or untreated PAH deficiency. In addition, maternal phenylketonuria (MPKU) syndrome is important to consider in offspring of mothers with inadequately treated PAH deficiency during pregnancy, as elevated blood phenylalanine (Phe) concentrations are toxic to the developing fetus .

Diagnostic Criteria

Recently published recommendations from the American College of Medical Genetics and Genomics (ACMG) for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency supplement the published ACMG guidelines .

Suggestive Findings

A diagnosis of PAH deficiency should be suspected due to an out-of-range newborn screening (NBS) result prior to onset of suggestive findings or manifestations of PAH deficiency .

Scenario 1: Out-of-Range Newborn Screening (NBS) Result

NBS for PAH deficiency is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify phenylalanine (Phe) and tyrosine (Tyr) concentrations by tandem mass spectrometry (MS/MS). For information on NBS by state in the United States (US), see www.newbornscreening.hrsa.gov/your-state.

Management Guidelines

Recently published guidelines for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency in the United States (US) supplement the published guidelines of . European guidelines have also been published . Most other international guidelines largely align with the US recommendations with some variation in the acceptable blood Phe concentrations, especially in older individuals (i.e., adults).

Evaluations Following Initial Diagnosis

Surveillance Guidelines

For those with untreated blood Phe concentrations 360 mol/L, the ACMG recommendations for monitoring of blood Phe concentration and nutritional status are summarized in .

Table 4.

Phenylalanine Hydroxylase Deficiency: Recommended Biochemical Monitoring

Age Group | Phe Monitoring | Type/Timing of Routine Nutritional Monitoring | Routine Clinical Visit Follow Up