The primary cause of high levels of phenylalanine in the body is a genetic disorder called Phenylketonuria (PKU). This condition is inherited and results from a change or mutation in the phenylalanine hydroxylase (PAH) gene. The PAH gene is responsible for providing instructions to create the enzyme needed to break down phenylalanine.
The Role of the PAH Gene and Enzyme
Phenylalanine is an amino acid, a building block of protein, found in most protein-rich foods and some artificial sweeteners like aspartame. Normally, the PAH enzyme converts phenylalanine into another amino acid, tyrosine. In individuals with PKU, the mutation in the PAH gene leads to a reduced amount or complete lack of the functional PAH enzyme.
When the PAH enzyme is deficient or absent, phenylalanine cannot be properly metabolized. This causes phenylalanine to build up in the blood and other body tissues. This excessive accumulation, known as hyperphenylalaninemia, can be toxic to the brain and nervous system, leading to various health problems.
Inheritance Pattern of PKU
PKU is an autosomal recessive disorder. This means that a child must inherit two copies of the altered PAH gene—one from each parent—to be affected by the condition. Parents who carry one copy of the mutated gene are typically unaffected themselves but are carriers. The frequency of this disorder is estimated to be approximately 1 in 10,000 in the general population.
Factors Contributing to High Phenylalanine Levels
The primary factor causing high phenylalanine levels in someone with PKU is the consumption of phenylalanine-containing foods. These include:
- Meat
- Fish
- Eggs
- Milk and cheese
- Nuts and seeds
- Grains like bread and pasta
- Legumes
- Foods and drinks containing aspartame
Even with a PKU diagnosis, the severity can vary, from mild to moderate to severe, depending on the specific gene change and the resulting enzyme activity.
Other Potential Causes (Hyperphenylalaninemia)
While PKU is the most common cause, high phenylalanine levels (hyperphenylalaninemia) can also result from a deficiency in tetrahydrobiopterin (BH4). BH4 is a substance that helps the PAH enzyme work effectively to break down phenylalanine. Deficiencies in the enzymes responsible for creating or recycling BH4 can also lead to hyperphenylalaninemia. Atypical PKU is considered an ultra-rare condition.
Maternal PKU
High phenylalanine levels can also pose risks during pregnancy if the mother has PKU and does not manage her diet effectively. This condition is known as maternal PKU. High levels of phenylalanine in the mother's blood can be toxic to the developing fetus, potentially causing serious health issues. Maintaining safe blood phenylalanine levels, typically between 120-360 µmol/L, is crucial during pregnancy.
Comparison: PKU vs. BH4 Deficiency
| Feature | Phenylketonuria (PKU) | BH4 Deficiency |
|---|---|---|
| Primary Cause | Mutation in the PAH gene | Deficiency in BH4 (cofactor for PAH enzyme) |
| Enzyme Activity | Reduced or absent PAH enzyme | Reduced PAH activity due to lack of BH4 |
| Inheritance | Autosomal Recessive | Autosomal Recessive |
| Treatment | Primarily dietary restriction of phenylalanine | BH4 supplements and sometimes neurotransmitter therapy |
Conclusion
In summary, the primary cause of high phenylalanine levels in the body is the genetic disorder Phenylketonuria (PKU), resulting from mutations in the PAH gene that impair the breakdown of phenylalanine. Other, rarer causes involve deficiencies in the BH4 cofactor. Effective management, typically through dietary restriction of phenylalanine, is essential to prevent the accumulation of this amino acid and its associated health complications. Understanding the genetic basis of PKU highlights the importance of newborn screening and early intervention.
Learn more about the specific gene mutations associated with PAH deficiency through resources like OMIM.
