What is Phenylketonuria (PKU)?

Phenylketonuria (PKU): A Comprehensive Overview

Definition and Pathophysiology

Phenylketonuria is an autosomal recessive genetic disorder caused by mutations in the phenylalanine hydroxylase gene, which prevents the conversion of phenylalanine to tyrosine, leading to toxic accumulation of phenylalanine in blood and brain tissue. 1

• The enzyme deficiency can also involve the cofactor tetrahydrobiopterin (BH4), resulting in elevated phenylalanine (Phe) levels in both blood and cerebrospinal fluid 2
• Individuals with PKU show very high elevations of phenylalanine in blood (more than 20 mg/dL or >1200 μmol/L) and accumulate phenylketones 1
• The prevalence is approximately 1 in 15,000 births in the United States, with variations among ethnic groups 1
• Average worldwide prevalence is about 1:10,000 newborns 3

Clinical Manifestations

Untreated PKU Consequences

If left untreated, PKU causes severe and irreversible neurological damage that must be prevented through early intervention. 1

• Severe mental retardation and intellectual disability 1
• Microcephaly (small head size) 1, 3
• Language delay and delayed speech 1, 4
• Seizures and epilepsy 1, 3
• Behavioral problems and abnormalities 1, 4, 3
• Eczema 1
• Hypopigmentation (lighter skin, hair, and eye color) 2
• Musty, mouse-like body odor 2

Critical Timing

• Treatment must begin before 7-10 days of life to prevent irreversible brain damage 1
• Phenylalanine levels above 10 mg/dL (approximately 600 μmol/L) require immediate initiation of treatment 1

Diagnosis

Newborn Screening

The American Academy of Family Physicians recommends universal newborn screening for PKU using three main laboratory methods: 1

• Guthrie bacterial inhibition assay 1
• Fluorometric analysis 1
• Tandem mass spectrometry 1

Diagnostic Process

• Newborn blood samples are collected during the first days of life and evaluated to detect abnormally high phenylalanine levels 1
• The diagnostic process requires systematic sample transportation and follow-up to the laboratory 1
• Location and contact with families of babies with abnormal results are essential for confirmatory testing 1
• Early diagnosis through newborn screening is crucial for preventing neurological damage 1

Treatment Approaches

Primary Treatment: Dietary Management

The cornerstone of PKU treatment is a strict low-phenylalanine diet supplemented with specialized amino acid formulas, which has been the mainstay for over 60 years. 1, 5

• This dietary approach must be maintained lifelong to prevent neurological complications 1
• Medical foods and amino acid formulas provide essential nutrients while restricting phenylalanine intake 5, 2
• Major challenges include palatability issues and dietary compliance difficulties 5, 6
• Potential nutritional deficiencies can occur, especially vitamin D and B12 5

Pharmacological Treatments

Tetrahydrobiopterin (BH4/Sapropterin)

Sapropterin dihydrochloride (JAVYGTOR) is FDA-approved for lowering blood phenylalanine levels in responsive patients, though only a minority of patients (usually those with milder PKU) respond to this therapy. 4, 3

• Response is defined as ≥30% decrease in blood Phe levels 4
• In clinical trials, 56% of patients showed response after 8 days of treatment at 20 mg/kg per day 4
• In pediatric patients aged 1 month to 6 years, 61% were identified as responders at Week 4 4
• Must be used in conjunction with a PKU-specific diet, including dietary protein and Phe restriction 4
• Treatment should be discontinued if no adequate biochemical response occurs after one month at 20 mg/kg per day 4

Other Pharmacological Options

• Large neutral amino acids (LNAA) can compete with phenylalanine for transport across the blood-brain barrier 5, 2
• Pegylated phenylalanine ammonia lyase (bacterial enzyme) requires daily subcutaneous injections and can cause adverse immune responses 2, 3

Monitoring Requirements

Blood Phenylalanine Level Monitoring

The American Academy of Family Physicians recommends age-specific monitoring frequencies to maintain blood Phe in the desirable range (120-360 μmol/L): 1

• Weekly during the first year of life 1
• Twice monthly from 1 to 12 years of age 1
• Once monthly after 12 years of age 1
• Twice weekly during pregnancy in women with PKU 1

Treatment Monitoring with Sapropterin

• Blood Phe levels and dietary Phe intake should be assessed frequently during the first month of treatment 4
• More frequent monitoring may be necessary during concomitant administration with certain medications 4

Special Considerations

Maternal PKU Syndrome

Uncontrolled blood phenylalanine concentrations before and during pregnancy pose severe risks to the developing fetus. 4, 7

• Blood phenylalanine concentrations should be maintained between 120 and 360 μmol/L during pregnancy and during the 3 months before conception 4
• Uncontrolled Phe levels above 600 μmol/L are associated with very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies in offspring 4
• Maternal PKU can present as recurrent pregnancy loss, congenital heart disease, microcephaly, intrauterine growth restriction, and neonatal deaths 7
• The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 μmol/L is significantly higher than in pregnant women without PKU 4

Treatment Outcomes

When PKU is diagnosed in newborns and treated appropriately from the start, infants should have normal development and can expect normal life expectancy. 1

• However, suboptimal outcomes in cognitive and executive functioning have been reported in patients who adhere poorly to dietary therapy 5
• Intelligence is typically within normal limits with early treatment, though on average some suboptimal neurocognitive function may persist 3
• Survey data shows less than half (46.7%) of patients maintain blood Phe within the recommended range (120-360 μmol/L) 6
• Younger individuals (≤18 years) are approximately 3 times more successful in maintaining recommended blood Phe levels compared to adults 6

Important Warnings and Precautions

Hypersensitivity Reactions

• Sapropterin can cause anaphylaxis with symptoms including wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash 4
• Treatment must be discontinued immediately if anaphylaxis occurs 4

Hypophenylalaninemia

• Sapropterin may cause dangerously low blood Phe levels (hypophenylalaninemia), especially in pediatric patients younger than 7 years of age 4

Other Adverse Effects

• Upper gastrointestinal mucosal inflammation can occur, presenting with nausea, vomiting, dysphagia, dyspepsia, loss of appetite, or abdominal pain 4
• Hyperactivity, restlessness, fidgeting, or excessive talking may develop 4
• Patients with underlying neurological disorders taking sapropterin with levodopa may experience seizures, exacerbation of seizures, over-stimulation, or irritability 4

Common Pitfalls

• Significant variation exists in newborn screening protocols between different regions, and criteria for defining a positive PKU result vary by location 1
• Genetic and clinical variability of PKU can influence disease presentation and severity 1
• Prolonged hyperphenylalaninemia (high blood Phe levels) results in severe neurologic damage, including intellectual disability, developmental delay, microcephaly, delayed speech, seizures, and behavioral abnormalities 4
• Not all patients respond to sapropterin therapy; response must be assessed and treatment discontinued if ineffective 4, 3
• Dietary protein and Phe intake should not be modified during the sapropterin evaluation period when assessing biochemical response 4