Phenylketonuria (PKU) Lecture Notes

Overview

• PKU is a rare metabolic disorder causing severe brain disorders
• Accumulation of amino acid phenylalanine (Phe) to toxic levels in blood and brain

Amino Acids

• Amino acids: building blocks of proteins
• Phenylalanine (Phe): essential amino acid (body cannot produce it, must be acquired from diet)
• Tyrosine: produced from Phe by enzyme phenylalanine hydroxylase

PKU Genetics

• Autosomal recessive genetic disorder
• Affects function of phenylalanine hydroxylase enzyme
• Gene located on chromosome 12 with over 600 mutations described
• Degree of enzyme function varies

Symptoms of Untreated PKU

• Severe intellectual disability
• Psychiatric disorders
• Seizures
• Maternal PKU Syndrome (for pregnant women): heart defects, microcephaly, developmental disability in baby

Pathophysiology

• Elevated Phe and reduced tyrosine levels affect brain function
• Phe uses same transporters as tyrosine and tryptophan across blood-brain barrier
• High Phe levels impede transport of tyrosine and tryptophan, lowering dopamine, norepinephrine, and serotonin levels in the brain

Diagnosis

• Routine newborn screening ~24 hours after birth
• Blood sample taken from heel stick
• Measure blood Phe levels; high Phe and low tyrosine indicates PKU
• Confirmation with another blood test for amino acids

Treatment

Dietary Management

• Low Phe diet (essential)
  • Includes medical foods: synthetic protein formulas, low-protein modified foods
  • Eliminate high protein foods: meat, fish, eggs, dairy
  • Measured amounts of some grains, vegetables, and fruits
  • Customized diet by medical professionals based on individual tolerance

Pharmaceutical Treatments

1. Kuvan
   • Cofactor for phenylalanine hydroxylase
   • Improves PAH enzyme activity
   • Used with low Phe diet
2. Palynziq
   • For adults with PKU
   • Enzyme injection under skin daily
   • Metabolizes Phe
   • Substitutes for defective phenylalanine hydroxylase enzyme
   • Effective for many adults but can have serious side effects

Quick Recap

• High Phe and low tyrosine levels in PKU
• Untreated PKU: seizures, severe developmental delay
• Routine newborn screening in developed world
• Early treatment: low Phe diet, amino acid-based medical food, severe protein intake restriction, low-protein modified foods
• Two FDA approved drugs available for PKU treatment