Phenylketonuria
Phenylketonuria (PKU)
1. Introduction and Overview
Definition:
Phenylketonuria (PKU) is a rare autosomal recessive metabolic disorder caused by a deficiency in phenylalanine hydroxylase (PAH), the enzyme responsible for converting phenylalanine to tyrosine. The resulting accumulation of phenylalanine leads to toxic effects on the central nervous system, particularly during early development.
Epidemiology:
• Global Prevalence: 1 in 10,000–15,000 live births globally.
• Regional Variations: Higher prevalence in certain populations (e.g., Ireland and Turkey). Lower prevalence in East Asian populations.
• Age-Specific: Primarily a pediatric condition identified in newborns via screening programs.
• Sex-Specific: No significant gender predilection.
Clinical Significance:
• Public Health Relevance: One of the first disorders included in newborn screening programs due to its preventable neurodevelopmental complications.
• Impact: Without treatment, PKU leads to severe intellectual disability, behavioral issues, and seizures.
2. Etiology
Primary Causes:
• Genetic Mutation:
• Mutations in the PAH gene located on chromosome 12q23.2, leading to reduced or absent enzyme activity.
• Rarely, PKU may result from defects in the tetrahydrobiopterin (BH4) cofactor metabolism.
Risk Factors:
• Consanguinity: Increases the likelihood of autosomal recessive inheritance.
• Ethnicity: Higher incidence in Caucasians and certain ethnic groups.
3. Pathophysiology
Normal Metabolic Pathways:
• Phenylalanine, an essential amino acid, is normally converted into tyrosine by the enzyme PAH, using BH4 as a cofactor.
• Tyrosine serves as a precursor for dopamine, norepinephrine, epinephrine, and melanin synthesis.
Disruption in Pathways:
• Enzyme Deficiency: PAH deficiency leads to an accumulation of phenylalanine and reduced levels of tyrosine.
• Toxic Effects: Elevated phenylalanine levels impair myelination, neurotransmitter synthesis, and synaptic plasticity in the brain.
Systemic Effects:
• CNS toxicity leads to intellectual disability, microcephaly, and movement disorders.
• Decreased tyrosine contributes to hypopigmentation due to reduced melanin synthesis.
Compensatory Mechanisms:
• Alternative pathways convert phenylalanine into phenylketones (e.g., phenylpyruvate, phenylacetate), which are excreted in the urine.
4. Clinical Features
Symptoms:
1. Neurological:
• Intellectual disability (if untreated).
• Behavioral issues (e.g., hyperactivity, irritability).
• Seizures and tremors.
2. Developmental:
• Growth retardation.
• Delayed psychomotor milestones.
3. Other Features:
• Musty odor of sweat and urine (due to phenylacetate).
Signs:
• Physical Examination:
• Hypopigmentation of skin, hair, and eyes (due to reduced melanin).
• Microcephaly.
• Eczematous rash.
Stages and Classification:
1. Classical PKU:
• Severe enzyme deficiency with plasma phenylalanine levels >1200 µmol/L (>20 mg/dL).
2. Mild PKU:
• Partial enzyme activity with levels of 600–1200 µmol/L (10–20 mg/dL).
3. Non-PKU Hyperphenylalaninemia (HPA):
• Phenylalanine levels <600 µmol/L (<10 mg/dL).
Differential Diagnosis:
• BH4 deficiency disorders.
• Tyrosinemia.
• Maple syrup urine disease (MSUD).
5. Diagnostic Approach
Clinical Evaluation:
• History: Family history of metabolic disorders or consanguinity.
• Newborn Screening:
• Mandatory in many countries using tandem mass spectrometry to measure blood phenylalanine levels.
Laboratory Investigations:
1. Biochemical Tests:
• Elevated plasma phenylalanine (>120 µmol/L or >2 mg/dL).
• Decreased tyrosine levels.
2. Confirmatory Tests:
• Genetic testing for PAH mutations.
• BH4 loading test to differentiate classical PKU from BH4 deficiency.
Imaging:
• MRI of the brain in untreated cases may show white matter changes and cerebral atrophy.
Diagnostic Criteria:
• Plasma phenylalanine >360 µmol/L (>6 mg/dL) confirms the diagnosis of PKU.
6. Management
Acute Management:
• Rarely required unless presenting with acute metabolic crisis.
Chronic Management:
1. Dietary Modifications:
• Low-phenylalanine diet: Exclusion of high-protein foods (e.g., meat, dairy, eggs).
• Special medical formulas for infants and children.
• Adequate intake of tyrosine, vitamins, and minerals.
2. Medications:
• Sapropterin dihydrochloride (BH4): For responsive cases to enhance residual PAH activity.
• Pegvaliase: An enzyme substitution therapy for refractory adult PKU.
3. Monitoring and Follow-Up:
• Regular monitoring of blood phenylalanine levels (target: 120–360 µmol/L).
• Neurodevelopmental assessments in children.
7. Prognosis
Natural History:
• Without treatment, leads to severe intellectual disability and neurological impairment.
• Early diagnosis and dietary intervention allow normal development.
Impact of Treatment:
• Lifelong dietary adherence ensures good neurological outcomes.
• Poor compliance leads to behavioral problems and learning disabilities.
8. Complications
1. Primary Disease-Related:
• Irreversible intellectual disability (if untreated).
• Growth retardation.
2. Treatment-Related:
• Nutritional deficiencies due to restrictive diets.
• Poor compliance leading to metabolic decompensation.
9. Prevention
1. Primary Prevention:
• Genetic counseling for at-risk couples.
• Prenatal testing for PAH mutations in high-risk families.
2. Secondary Prevention:
• Universal newborn screening programs.
3. Tertiary Prevention:
• Regular dietary monitoring and adherence to prevent complications.
10. Patient Education
• Disease Information: Explain PKU as a lifelong condition that requires strict dietary management.
• Dietary Guidance: Education on low-phenylalanine foods and proper use of medical formulas.
• Self-Monitoring: Importance of regular phenylalanine level checks.
• Compliance: Emphasis on the role of diet in preventing neurological complications.
11. Recent Research and Advances
• Gene Therapy: Experimental approaches targeting PAH gene replacement.
• Enzyme Substitution Therapy: Advances in pegvaliase for adults with poor dietary compliance.
• Maternal PKU Management: Improved strategies to prevent fetal complications.
12. Case Studies
Case Example:
• A 2-week-old newborn identified via routine screening with plasma phenylalanine of 1500 µmol/L. Managed with a low-phenylalanine diet and sapropterin, achieving normal developmental milestones by age 3.
13. References
• Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376(9750):1417-1427.
• Harrison’s Principles of Internal Medicine, 21st Edition.
• Guidelines from the American College of Medical Genetics and Genomics (ACMG).