Autoimmune diseases


Phenylketonuria (PKU) is an inborn error of amino acid metabolism, which is detectable at early days of a new born, and via regular new born screening.

PKU is associated with the deficiency of an enzyme called phenylalanine hydroxylase (PAH), which catalyzes the hydroxylation of phenylalanine to tyrosine. The deficiency of PAH cofactor, tetrahydrobiopterin (BH4) can also hamper the conversion of phenylalanine to tyrosine.

Amino acids are essential building blocks for the synthesis of proteins and for cellular functions. Some amino acids serve as precursors for the synthesis of others.

An enzyme usually catalyzes the conversion of those precursors to their products. When enzymes are absent or deficient, a buildup of the precursor amino acids occurs, and become toxic to the body. This is what happens in phenylketonuria.  The deficiency o the enzyme, phenylalanine hydroxylase leads to the cellular buildup of phenylalanine, which becomes toxic to the brain.

Signs and Symptoms of PKU

There is no onset sign or symptom of phenylketonuria at birth. The only means of detecting PKU at birth is through routine screening. However, without detection, and treatment, babies usually develop signs of PKU within few months after birth. Some signs of PKU include:

  • Delayed development
  • Red skin rashes with small pimples
  • Retarded IQ and intellectual disability
  • Light eye, skin and hair color
  • Musty body odor caused by phenylacetic acid in the urine or sweat
  • Seizures or tremors


Causes of Phenylketonuria

Phenylketonuria is a rare autosomal recessive and inborn error of metabolism. It is caused by a genetic mutation which affects the coding for the enzyme, phenylalanine hydroxylase or its cofactor, tetrahydrobiopterin.

The deficiency of phenylalanine hydroxylase or tetrahydrobiopterin leads to a buildup of phenylalanine, which leads to brain toxicity and other symptoms of phenylketonuria.

A dangerous buildup of phenylalanine can develop when an individual with phenylketonuria eats protein-rich foods, especially, phenylalanine containing proteinous foods. The high concentration of cellular phenylalanine can cause damage the nerve cells in the brain.



Phenylketonuria is an autosomal recessive pattern that can be inherited through family line. By autosomal recessive inheritance, it means that a person has two copies of the gene that is altered.

When parents who are carrier of one copy each of the altered gene give birth, the child is likely to have PKU.


Treatment of Phenylketonuria

In order to minimize neurological damage, treatment of PKU should be as early as possible. Treatment should be before 10 days after birth, as every 4-week delay in starting treatment has been shown to cause a decline of IQ score by approximately 4 points.

Prevention of neurodevelopment disability requires a life-long commitment to phenylalanine restriction.


Treatment with Phe-restricted diets of phenylketonuria patients

Patients with PKU are restricted to diets containing low Phenylalanine concentrations for life. In this diet plan, severe mental retardation can be prevented effectively. However, this approach is also associated with risk for nutritional deficiencies. It can lead to growth retardation and early-onset osteoporosis.


Amino acid supplementation of Phenylketonuria patients

For patients whom Phe-restricted diet is not tolerable, supplementation with large neutral amino acids (LNAAs) offers an encouraging approach to phenylketonuria treatment. There are four L-type amino acids transporters that are present in the transport system through certain molecules, such as LNAAs, are transported to the brain. LNAAs such as Valine, Leucine, and Isoleucine; the aromatic amino acids, Tyr, Trp, and Phe; and some other amino acids such as Threonine, and Methionine, in order to cross the blood-brain barrier, compete with each other to bind the transporters based on their plasma concentration. So, high LNAAs supplementation thus inhibits plasma Phenylalanine concentration.


Treatment with BH4 chaperone

In patients exhibiting BH4 deficiency, treatment with Phe-restricted diet is ineffective. Such patients are treated with high doses of BH4, which has been shown to correlate with increased PAH activity. The low activity of a defective enzyme in a metabolic pathway can be increased by stabilizing the enzyme with chaperons, and enzyme cofactors such as BH4 can function as chaperones.


Enzyme therapy of Phenylketonuria

Enzyme therapy is another approach for treating PKU. Enzyme substitution with phenylalanine ammonia lyase (PAL) or PAH are the two available types o enzyme therapy. This therapy also converts excess phenylalanine to readily excreted and less toxic products.



Chidubem Olovo is a biochemist, researcher and a content writer.

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