At a Glance

Phenylketonuria (PKU) is an inherited disorder of metabolism of the essential amino acid phenylalanine due to a defect in phenylalanine hydroxylase (PAH). Phenylalanine (PHE) is present in all protein containing foods, and individuals with PKU will have elevated levels of PHE.

PKU is inherited in an autosomal recessive manner. Autosomal recessive inheritance means the individual has inherited two abnormal copies of the PAH gene (each gene containing a mutation). Both parents of an individual with PKU are carriers and do not manifest any symptoms of disease.

Infants and children with PKU typically develop signs of gradual, progressive neurological disease. When untreated, children develop severe mental retardation (IQ typically < 60). This disease is characteristic for a distinctive mousy odor due to an accumulation of phenylacetic acid (typically present when phenylalanine levels are elevated). Children also demonstrate lightly pigmented skin and hair (typically blonde), as well as dry skin or eczema. They also typically have a history of poor weight gain and growth and are microcephalic. Neurological symptoms include seizures with electroencephalogram (EEG) abnormalities, tremors, and ataxia, whereas others have spasticity and Parkinsonian-like symptoms, as well as hyperactivity, aggression, anxiety, and poor social interaction.

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What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Phenylketonuria can be diagnosed through measurement of phenylalanine in plasma amino acids. Because of the defective enzyme, tyrosine (TYR) is not produced, so affected individuals have an elevated PHE/TYR ratio (typically >2.0 when untreated). All infants born receive a newborn screening (NBS) test, ideally between 24 and 72 hours after birth, and PKU is included on all current panels. Screening for PKU was the first NBS started in the 1960s. Following discovery of an elevated PHE level, a suspected infant should have a blood PHE level performed for confirmation. Typically, the degree of elevation of PHE is correlated with the severity of the enzyme block.

In classic PKU, levels are typically greater than 1200 µM at diagnosis and untreated infants develop symptoms as described. Mild PKU is found with levels between 600 and 1200 µM. Infants with mild hyperphenylalaninemia have PHE levels less than 600 µM and typically do not have symptoms of PKU. (Table 1)

Table 1.
Phenylalanine Tyrosine
Elevated Decreased

Following diagnosis, affected individuals should be placed on low-protein, PHE-restricted diets. Levels of PHE should be monitored on a monthly basis throughout life to monitor degree of protein and PHE restriction and to avoid over-restriction that would contribute to poor growth and development from malnourishment. Levels may be performed through blood PHE levels on plasma amino acid profiles or collected on serial NBS filter paper cards for ease of shipping and handling.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Elevations of phenylalanine may also be seen in nonfasting amino acid samples or liver disease, such as in Tyrosinemia type 1 or other congenital or acquired liver disease, although the PHE/TYR ratio is often normal. Elevations of other amino acids are often present and reveal a nonspecific pattern. Samples with mild elevations should be repeated on a fasting, early morning collection.

Infants with elevations of PKU should have blood and urine collected simultaneously for biopterin screening. Disorders of biopterin metabolism also cause elevations of PHE. Tetrahydrobiopterin (BH4) is an essential cofactor for PAH, and disturbance of BH4 production leads to elevations of PHE, as well as deficiencies of production of L-dopa, dopamine, norepinephrine and epinephrine, serotonin, melanin, and citrulline.

Disorders of biopterin metabolism include the enzymes guanosine triphosphate cyclohydrolase (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), pterin-4a-carbinolamine dehydratase (PCD), dihydropterin reductase (DHPR), and sepiapterin reductase (SR). However, the autosomal dominant from GTPCH and SR deficiencies do not cause hyperphenylalaninemia. Common clinical symptoms of biopterin metabolism include neurological deterioration, hypotonia, dystonia, seizures, irritability, and microcephaly. Possible treatments for these disorders may include L-dopa (for dopa-responsive dystonia) with carbidopa, serotonin, and folinic acid, which may provide significant improvement in clinical symptoms if treated early.

What Lab Results Are Absolutely Confirmatory?

Confirmation of PKU is performed through DNA sequencing and detection of two mutations known to be associated with disease. If mutations are uncertain or inconsistent with PHE levels, then testing of parents for carrier status should be performed.

Enzyme analysis is not typically needed.

What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?

Following prompt diagnosis and treatment of an infant in the first few weeks of disease, a child should have normal neurological development and not develop the other disease sequelae. Individuals who are noncompliant with dietary PHE restriction may develop neurological symptoms, including poor attention, hyperactivity, aggression, social withdrawal, and intellectual disability. The degree, duration, and severity of elevated blood PHE levels is directly correlated to neurological disability over time, with the first 6 years of life being most critical for strict PHE control. The target blood PHE level and dietary PHE tolerance is dependent on patient age and is part of the clinical management of the patient. Ongoing clinical management with close monitoring of dietary protein is important to ensure adequate growth and development.

Another form of PKU has been described in women with PKU who are pregnant. Women who do not maintain control of their PHE levels give birth to children with congenital abnormalities, including developmental delay, facial dysmorphism, congenital heart disease, and microcephaly. This maternal PKU syndrome is due to the teratogenic effect of elevated PHE levels during pregnancy.

What Factors, If Any, Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Caution must be given to units of measure of PHE levels. Different laboratories may report blood levels as µM (µmol/liter) or as mg/dL (10 uM equals 600 mg/dL).

Urine amino acids are typically not helpful for quantification and long-term management decisions.

Normal or low PHE levels may reflect malnutrition or over-restriction of dietary protein.

An NBS performed too early or before adequate nutrition or protein is provided will provide a false-negative result.

Normal ranges are also dependent on patient age with greater levels being tolerated with increased age.