The portal for rare diseases and orphan drugs

Exact prevalence is not known but is estimated to be about 1/15,000 births. Significant geographic variability is reported. Caucasians appear to be affected more than other ethnic groups. Males and females are affected equally.

Late diagnosed patients present mostly with progressive developmental delay associated with severe signs including stunted growth, microcephaly, seizures, tremors, eczema, vomiting, musty odor, and subsequently behavioral (hyperactivity) and motor disorders. Untreated patients develop profound, permanent intellectual impairment and deterioration of cognitive performance and motor skills. Demyelination and decreased dopamine, norepinephrine, and serotonin production have been found in patients who do not pursue dietary restrictions into adulthood. Complications later on include exaggerated deep tendon reflexes, tremor, and paraplegia or hemiplegia. In treated patients, clinical signs vary based on treatment and diet compliance, and may include psychiatric disorders such as attention deficit-hyperactivity disorder and depression.

Classical PKU is related to a complete or near-complete deficiency of phenylalanine hydroxylase. The disorder is caused by variants in the PAH gene (12q22-q24.2) coding for phenylalanine (Phe) hydroxylase. The resulting deficiency in phenylalanine hydroxylase leads to toxic accumulation of Phe in the blood and brain.

Classical PKU is usually diagnosed via neonatal screening programs with detection of hyperphenylalaninemia (HPA). Detection is standard in most industrialized countries. PKU is diagnosed at plasma or blood Phe concentrations higher than 120 micromol/L in the untreated state and elevated Phe/Tyr ratio (>2.0). In the absence of early detection through neonatal screening, suspicion is based on clinical signs and symptoms. Diagnosis is confirmed by determination of plasma or blood Phe levels.

Differential diagnosis includes other forms of HPA such as tetrahydrobiopterin (BH4) deficiency. Neonates with increased Phe may have BH4 deficiency or PKU. An abnormal pattern of pterins in dried blood spots or urine or reduced dihydropteridine reductase activity in dried blood spots indicate BH4 deficiency. A BH4 loading test should be performed to determine whether patients are BH4-responsive or unresponsive.

Prenatal testing can be performed by molecular testing of the PAH gene if the disease-causing variants have been identified in an affected family member.

Inheritance is autosomal recessive.

Management involves restriction of dietary Phe, i.e. all high-protein foods, to normalize blood levels thus preventing the cognitive dysfunction, along with Phe-free medical formula to provide protein and other essential nutrients. Patients tolerate less than 250-350 mg of dietary Phe per day. Levels of Phe tolerance should be determined individually on a regular basis. Current recommendations call for lifelong maintenance of limited Phe intake. However, monitoring of levels is essential to avoid deficiencies of Phe and tyrosine. Foods containing aspartame should be avoided as aspartame releases Phe when digested. Female patients should be particularly cautious during pregnancy due to the fetotoxic effects of high maternal plasma Phe. When properly managed, the disease course is mostly favorable, but some neuropsychiatric complications may occur. Treatment and dietary compliance are the most important factors affecting outcome and prognosis.

The prognosis is good when diagnosis is made early and compliance is high.