Phenylketonuria (PKU) is a rare inherited metabolic disorder. It disrupts the body’s ability to process an amino acid called phenylalanine. Phenylalanine is found in many protein-containing foods. When not properly broken down, it accumulates and causes serious health issues. Understanding the main cause of PKU is crucial for diagnosis, treatment, and prevention of complications.
What Is the Main Cause of Phenylketonuria?
1. The Genetic Basis of Phenylketonuria
The main cause of PKU is a mutation in a gene that encodes an enzyme called phenylalanine hydroxylase (PAH). This enzyme normally converts phenylalanine into another amino acid called tyrosine. Tyrosine is important for producing proteins, neurotransmitters, and pigments.
Role of Phenylalanine Hydroxylase
PAH works in the liver. It adds a hydroxyl group to phenylalanine, changing it into tyrosine. When PAH is defective or missing due to gene mutations, phenylalanine builds up in the blood and other tissues. This excess phenylalanine becomes toxic, especially to the brain.
Genetic Mutations Causing PKU
PKU is caused by mutations in the PAH gene located on chromosome 12. More than 500 different mutations have been identified. These mutations lead to:
- Complete loss of PAH enzyme activity
- Partial reduction of enzyme function
- Production of unstable or inactive PAH enzymes
The severity of PKU depends on the type of mutation and the remaining enzyme activity. Classic PKU results from almost no PAH activity. Milder forms are linked to partial enzyme deficiencies.
2. Inheritance Pattern of Phenylketonuria
PKU is inherited in an autosomal recessive manner. This means a child must inherit two defective copies of the PAH gene—one from each parent—to develop the disease. Parents who each carry one mutated gene usually do not have symptoms. They are called carriers.
Risk of Passing PKU to Offspring
- If both parents are carriers, each child has a 25% chance of having PKU.
- A 50% chance of being a carrier like the parents.
- A 25% chance of inheriting two normal copies of the gene.
Genetic counseling is recommended for families with a history of PKU to understand these risks.
Biochemical Effects of PAH Deficiency
Without sufficient PAH activity, phenylalanine accumulates in the blood, cerebrospinal fluid, and brain tissue. This excess causes multiple harmful effects:
Neurotoxicity: High phenylalanine disrupts normal brain development and function.
Decreased tyrosine: Tyrosine levels fall, affecting the synthesis of dopamine, norepinephrine, and melanin.
Impaired neurotransmission: The imbalance in amino acids interferes with neurotransmitter production and brain signaling.
These biochemical disturbances explain the intellectual disability, seizures, behavioral problems, and hypopigmentation seen in untreated PKU.
3. Other Causes and Related Disorders
While PAH mutations cause classic PKU, other rare forms arise from defects in enzymes or cofactors involved in phenylalanine metabolism:
Tetrahydrobiopterin (BH4) Deficiency: BH4 is a cofactor needed for PAH activity. Deficiencies lead to hyperphenylalaninemia but require different treatment.
Dihydropteridine Reductase Deficiency: This affects BH4 recycling and can cause PKU-like symptoms.
These variants emphasize the importance of biochemical and genetic testing for accurate diagnosis.
Screening and Early Diagnosis
Most countries perform newborn screening to detect elevated phenylalanine levels shortly after birth. Early diagnosis allows for timely treatment to prevent intellectual disability and other complications.
Screening Methods
- Tandem mass spectrometry to measure phenylalanine and related metabolites.
- Genetic testing for PAH mutations.
Conclusion
In summary, phenylketonuria is caused primarily by mutations in the PAH gene. These mutations lead to defective or absent phenylalanine hydroxylase enzyme activity. This causes phenylalanine to accumulate and disrupt normal brain development. Understanding this cause is critical for managing and preventing the effects of PKU.
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