Phenylketonuria (PKU)

Overview

• PKU is a rare metabolic genetic disorder.
• Leads to severe brain disorders due to accumulation of phenylalanine (Phe) in blood and brain.
• Phenylalanine is an essential amino acid - must be acquired from protein-containing foods.

Biochemical Pathway

• Phenylalanine Hydroxylase: Enzyme that converts Phe to tyrosine.
• Tyrosine: Precursor for neurotransmitters important for brain development.

Genetic Aspects

• Autosomal recessive disorder with over 600 mutations.
• Affects the function of phenylalanine hydroxylase enzyme.
• Gene located on chromosome 12.

Pathophysiology

• Elevated Phe and reduced tyrosine alter brain function.
• Phe, tyrosine, and tryptophan use the same transporters across the blood-brain barrier.
• High Phe levels block transporters, reducing dopamine, norepinephrine, and serotonin.

Clinical Manifestations

• Untreated PKU leads to:
  • Severe intellectual disability
  • Psychiatric disorders
  • Seizures
• Maternal PKU Syndrome: High Phe levels in pregnant women can cause defects in the baby.

Diagnosis

• Routine Newborn Screening:
  • Conducted 24 hours after birth.
  • Heel stick blood sample to measure blood Phe levels.
• Confirmation: Further testing if high Phe and low tyrosine levels detected.

Treatment

• First Line Therapy: Low Phe diet
  • Medical foods: Low or no Phe formulas, modified low protein foods.
  • Eliminate high protein foods (meat, fish, eggs, dairy).
  • Controlled intake of certain grains, vegetables, and fruits.
• Pharmaceutical Treatments:
  • Kuvan: Cofactor for phenylalanine hydroxylase, used with low Phe diet.
  • Palynziq: Enzyme injection for adults, substitutes defective enzyme, has potential serious side effects.

Summary

• PKU results in elevated Phe, reduced tyrosine, causing seizures and developmental issues.
• Routine newborn screening in the developed world.
• Treatment involves low Phe diet with medical foods and two FDA-approved drugs.

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