PKU varies significantly by ethnicity and geographic region. Globally, it affects about 1 in 10,000 to 15,000 newborns. In Europe, the prevalence in Ireland and Turkey can be approximately 1 in 4,000, whereas in Finland, it is about 1 in 100,000. Prevalence is low in people of African or Asian ancestry. Due to widespread newborn screening and early treatment, severe forms of PKU are very rare in many developed countries.

PKU is caused by mutations in the PAH gene which provides instructions for making phenylalanine hydrolase. The gene is located on chromosome 12 and is inherited in an autosomal recessive pattern (see RareShare Guide on Chromosomal Nomenclature and Rareshare Guide on Genetic Inheritance). Affected individuals must inherit two copies of the defective gene, one from each parent, to manifest the disease. The accumulation of high levels of phenylalanine in the body leads to symptoms.

Symptoms depend heavily on whether a patient receives early diagnosis and treatment. In untreated PKU, newborns usually appear healthy at birth and symptoms develop within a few months. They include the following:

• Neurological: Intellectual disability (often severe), seizures, tremors, and delayed development.

• Physical: "Musty" or "mousy" odor to the breath, skin, or urine (due to excess phenylacetate).

• Dermatological: Eczema (skin rashes) and lighter skin, hair, and eyes (hypopigmentation) due to low melanin production.

• Behavioral: Hyperactivity, psychiatric disorders, and social/behavioral problems.

• Microcephaly: Abnormally small head size.

For treated PKU patients who start a low-phenylalanine diet immediately after birth, there may be no or mild symptoms. However, if management wavers (especially in adolescence or adulthood), they may experience:

• Difficulty concentrating ("brain fog")

• Anxiety and depression

• Slowed information processing

Early diagnosis of PKU is critical to prevent brain damage and occurs through several methods:

• Newborn screening: In most developed countries, all newborns are screened for PKU within the first 24-48 hours of life through a simple blood test (heel prick test). This test measures phenylalanine levels in the blood.

• Confirmatory testing: If screening results are abnormal, confirmatory testing includes measuring plasma amino acid levels, with phenylalanine concentrations typically exceeding 20 mg/dL (normal is less than 2 mg/dL) in classic PKU. The ratio of phenylalanine to tyrosine is also evaluated.

• Genetic testing: Molecular genetic testing can identify mutations in the PAH gene, confirm the diagnosis, and help with family planning and carrier testing.

• Prenatal diagnosis: For families with a known history of PKU, prenatal testing through chorionic villus sampling or amniocentesis can detect the condition before birth.

There is no cure for PKU. The cornerstone of PKU treatment is lifelong dietary management to keep blood phenylalanine levels within a safe range, typically 120-360 µmol/L (2-6 mg/dL). This can be accomplished by:

• Dietary restriction: Patients follow a low-phenylalanine diet, which severely restricts high-protein foods including meat, fish, eggs, dairy products, nuts, beans, and regular flour. Aspartame, an artificial sweetener found in diet sodas, contains phenylalanine and must be avoided. Some patients take vitamin and mineral supplements because of the dietary restrictions.

• Medical foods: Patients consume specially formulated medical foods and protein substitutes that provide essential amino acids without phenylalanine to support normal growth and development.

• Monitoring: Regular blood tests to monitor phenylalanine levels are essential throughout life, with frequency depending on age and metabolic control.

• Medications may include Sapropterin (Kuvan), a synthetic form of BH4 (tetrahydrobiopterin) that can help patients with certain PAH mutations better process phenylalanine, allowing for a more relaxed diet (about 20-50% are responders);  and Pegvaliase (Palynziq), an enzyme substitution therapy approved for adults who cannot maintain adequate phenylalanine control through diet alone.

Special considerations for women with PKU during pregnancy include maintaining strict metabolic control before conception and throughout pregnancy to prevent maternal PKU syndrome, which can cause birth defects, intellectual disability, and heart defects in the baby regardless of the baby's genetic status.

With early detection and treatment, the prognosis for PKU is excellent. Managed appropriately, most individuals can achieve normal or near normal lifespan, growth and cognitive development, living productive and independent lives. If treatment is delayed past early infancy, brain damage can be irreversible. Current guidelines recommend staying with the PKU diet for life.

1. van Spronsen FJ, Blau N, Harding C, Burlina A, Longo N, Bosch AM. 2021. “Phenylketonuria.” Nat Rev Dis Primers. 7(1):36. doi: 10.1038/s41572-021-00267-0. PMID: 34017006; PMCID: PMC8591558.

2. National Organization for Rare Disorders (NORD):  Phenylketonuria.

3. Cleveland Clinic:  Phenylketonuria (PKU).