What is phenylketonuria (PKU) and how should it be managed?

What is Phenylketonuria (PKU)?

PKU is a genetic disorder where your body cannot properly break down an amino acid called phenylalanine (found in protein), causing it to build up in your blood and brain, which leads to severe intellectual disability, seizures, and behavioral problems if left untreated. 1

Understanding the Condition

PKU is an inherited disease that you are born with, affecting approximately 1 in 15,000 babies in the United States. 1 The condition occurs when both parents pass on a defective gene for an enzyme called phenylalanine hydroxylase. 2, 3

What Happens in Your Body

• Normal metabolism: Your body converts phenylalanine (from protein foods) into another amino acid called tyrosine using a specific enzyme. 2
• In PKU: This enzyme doesn't work properly, so phenylalanine accumulates to toxic levels in your blood and brain. 3
• The damage: High phenylalanine levels cause brain dysfunction, leading to severe mental retardation, microcephaly (small head), seizures, behavioral disorders, and skin/hair/eye lightening if untreated. 1, 2

How PKU is Detected

Your baby was diagnosed through newborn screening performed in the first days of life using a blood spot test. 1 This screening uses tandem mass spectrometry to measure phenylalanine and tyrosine levels. 1 After the initial positive screen, confirmatory testing with quantitative plasma amino acid analysis was performed to establish the diagnosis. 1

How PKU Must Be Managed

Lifelong dietary restriction of phenylalanine is absolutely necessary—this is not optional and must continue throughout your entire life to prevent brain damage and maintain normal cognitive function. 4, 5

Dietary Treatment: The Foundation

What You Must Do

• Severely restrict natural protein intake from meat, fish, eggs, dairy, nuts, beans, and regular bread/pasta. 4, 5
• Consume phenylalanine-free medical formulas daily to meet your protein and nutritional needs—these are medically necessary, not optional. 4, 5
• Use modified low-protein foods (special breads, pastas, baking mixes) to meet energy requirements. 4, 5
• Measure and track every gram of protein you consume to stay within your prescribed phenylalanine allowance. 4

Target Blood Levels

Your phenylalanine levels must be monitored regularly and kept within specific ranges: 4, 5

• Children under 12 years: 2-6 mg/dL (120-360 μmol/L)
• Adolescents and adults over 12 years: 2-15 mg/dL (120-910 μmol/L)
• Women planning pregnancy: Less than 6 mg/dL starting at least 3 months before conception 4, 5
• During pregnancy: 2-6 mg/dL throughout all trimesters 4

Monitoring Schedule

Blood phenylalanine testing frequency depends on your age: 4

• First year of life: Weekly
• Ages 1-12 years: Twice monthly
• After age 12: Monthly
• During pregnancy: Twice weekly

Each monitoring visit should include blood phenylalanine measurement, dietary intake review, and nutritional status assessment. 5

Additional Treatment Options

Sapropterin (Kuvan®)

Sapropterin is the only FDA-approved medication for PKU and may allow you to eat more natural protein if you are a responder. 4

• This medication works by activating your residual enzyme activity. 4
• Response cannot be predicted by genetic testing alone—you must undergo formal testing to determine if you respond. 4
• If responsive, sapropterin can increase your dietary phenylalanine tolerance by two- to threefold, significantly improving quality of life. 4
• Long-term therapy should be maintained in responders. 4

Large Neutral Amino Acids (LNAA)

LNAA supplements block phenylalanine absorption from the intestine and at the blood-brain barrier, reducing blood phenylalanine by approximately 40%. 4 However, LNAA are currently limited to adolescents and adults and are absolutely contraindicated during pregnancy because they do not lower phenylalanine sufficiently to protect the developing fetus. 4

Critical Warnings

Never Discontinue Treatment

Stopping your diet in adulthood causes neuropsychiatric deterioration, including problems with attention, processing speed, and executive function, even if your IQ appears stable. 4, 5 Case reports document severe deterioration in adults who discontinued dietary treatment. 4

Pregnancy Planning is Essential

If you are a woman with PKU, unplanned pregnancy with poor phenylalanine control will cause severe birth defects in your baby, including intellectual disability (>90% risk), microcephaly (up to 67%), and congenital heart defects (8-12%). 4, 5

• You must achieve phenylalanine levels below 6 mg/dL at least 3 months before conception. 4, 5
• Maintain levels between 2-6 mg/dL throughout pregnancy. 4
• This may require hospitalization to achieve rapid dietary control if you become pregnant unexpectedly. 4

Aspartame is Toxic to You

Aspartame (artificial sweetener in diet sodas, sugar-free gum, many medications) breaks down into phenylalanine and is absolutely contraindicated. 6 Always check medication labels and use alternatives sweetened with saccharin, sucralose, acesulfame potassium, stevia, or monk fruit. 6

Common Pitfalls to Avoid

• Inadequate formula intake: The phenylalanine-free formula is not optional—it provides essential amino acids, vitamins, and minerals you cannot get from your restricted diet. 5, 7
• Assuming you can relax the diet as an adult: Lifelong treatment is mandatory; poor metabolic control correlates with worse attention, reaction time, and cognitive performance at any age. 4, 5
• Not preparing for pregnancy: Women with lower IQs (<85) achieve metabolic control later in pregnancy and have worse fetal outcomes, but when optimal control is achieved regardless of maternal IQ, outcomes improve. 4
• Ignoring subtle cognitive changes: Even with normal IQ, poor phenylalanine control affects processing speed and attention—these deficits matter for daily functioning. 4, 5

The Bottom Line

PKU is a lifelong condition requiring daily vigilance, but with proper treatment started early and maintained throughout life, you can expect normal development, normal life expectancy, and intelligence within normal limits. 1 The key is strict adherence to your phenylalanine-restricted diet, regular monitoring, and working closely with your metabolic clinic team. 4