By: Anurag Jakkula


Phenylketonuria (PKU) is a rare inherited disease that may lead to cognitive disability and other problems with the central nervous system if not treated properly. The disease is the result of accumulated phenylalanine, an amino acid, in an affected individual’s blood. PKU can cause damage quite quickly if left untreated. Therefore, it is important to gain a deep understanding of the cause of the disease on a molecular level all the way to the disease’s resulting impact on the functioning human organ systems in order to make sure individuals with phenylketonuria live a long and healthy life.

What is Phenylalanine?

In order to gain an in-depth understanding of phenylketonuria, it is extremely important to understand the amino acid which causes this disease, phenylalanine. Phenylalanine is an essential amino acid, meaning that it is obtained through diet (Tinsley). As it is an amino acid, it is needed in order to make proteins during the translation process of protein synthesis. As an amino acid, it is essential for the folding, and therefore, functioning of proteins. Proteins are essential for all organ systems in the human body, such as the nervous system and digestive system.

In addition to serving as an amino acid during protein synthesis, phenylalanine is also essential for the creation of other molecules that have various functions in the human body. Four of these various molecules are tyrosine, epinephrine, norepinephrine, and dopamine.

Tyrosine is another amino acid. The amount of phenylalanine converted to tyrosine is dictated by the amount of tyrosine the human receives through diet. If the human doesn’t receive any significant amount of tyrosine through the diet, as much as around fifty percent of the phenylalanine can be converted to tyrosine (Litwack). An inability to convert phenylalanine to tyrosine is the cause of PKU (Tinsley). Undoubtedly, the large amount of phenylalanine normally converted to tyrosine, which is not able to occur in an individual with PKU, is the reason why PKU’s effects on organ system functions are so large.

The molecules epinephrine and norepinephrine are the molecules that are responsible for the “fight or flight” reaction to stress. Both are neurotransmitters, and are part of the nervous system. Dopamine, a molecule involved with feelings of pleasure, the ability to learn, and memories, is also part of the nervous system (Tinsley).

-phenylalanine molecule

What is The Process of Phenylalanine Breaking Down into Tyrosine in healthy people without PKU?

As mentioned earlier, the inability to break down phenylalanine into tyrosine is what causes PKU. Therefore, it is imperative to gain in depth knowledge of the process of breaking down phenylalanine into tyrosine in order to fully understand PKU. The process occurs in the circulatory system, specifically the liver. An enzyme called phenylalanine hydroxylase works with the molecule tetrahydrobiopterin in order to create a chemical reaction with phenylalanine. A product of this chemical reaction is the amino acid tyrosine. Not all phenylalanine is converted to tyrosine, as some of it is used as an amino acid during the translation of protein synthesis, with the rest being used for the creation of other molecules (Litwack).

What DNA Segments Code For This Process?

Phenylalanine hydroxylase is what drives the chemical reaction in the process of converting phenylalanine into tyrosine. Therefore, it is the DNA that codes for this enzyme which codes for the whole process. It is referred to as the PAH gene. This gene is located in the long arm of chromosome 12 and mutations in this gene are the root cause of phenylketonuria (NIH).

What Kind of Mutations in the PAH Gene Causes PKU?

Mutations in the PAH gene are indeed the root cause of PKU (NIH). However, it is important to understand that mutations are completely random. Therefore, it is extremely unlikely that the parents of a person with PKU or a person with PKU developed the mutation within themselves. Rather, the mutations occurred in their ancestors, causing the recessive alleles that express PKU to be passed down. Therefore, even though mutations are the cause PKU, PKU is obtained from inheritance.

The mutations that are the most common cause of PKU are point mutations (NIH). These are mutations that occurred during DNA replication. During the process, DNA polymerase attaches an incorrect nucleotide, instead of the correct nucleotide complementary to the template strand. During the transcription process of protein synthesis, the mRNA would also have an incorrect nucleotide, as the RNA polymerase constructs mRNA with nucleotides complementary to the DNA strand. In the case of most people with PKU, who have a missense mutation, the incorrect nucleotide codes for a single incorrect amino acid during the translation process (NIH). This causes the resulting phenylalanine hydroxylase to fold incorrectly, which negatively impacts its function. This is due to the fact that with an altered shape, it may not be able to attach to the reactants of the chemical reaction as well for converting phenylalanine into tyrosine. The most common missense mutation which causes PKU is the nucleotide arginine replacing tryptophan at position 408 of the gene (NIH).

Gene deletions in the PAH gene are also a cause of PKU in some people (Lee). This mutation occurred due to DNA polymerase skipping the attachment of a few nucleotides, causing a reading frame change in the DNA. For example, if a DNA’s sequence is ATGCATGC, and AT is deleted in the middle, the sequence would change to ATGCGC. Once this DNA is converted to mRNA during the transcription process, the mRNA would be complementary to ATGCGC, meaning that the mRNA would have an altered reading frame as well. In the translation process of protein synthesis, the tRNA’s various anticodons match and bind to the mRNA sequence in order to sequence amino acids. tRNA binds to three nucleotides at a time. The sequence of the three nucleotides dictates which tRNA anticodon binds to which codon, and therefore, dictates which amino acid is placed in the sequence. The change in codon reading frame due to the deletion changes the entire amino acid sequence after the deletion. This mutation in the PAH gene would lead to an incorrect amino acid sequence, which would severely impact the folding of the resulting phenylalanine hydroxylase enzymes. The incorrect folding would prevent the phenylalanine hydroxylase from binding to the necessary reactants for carrying out the chemical reaction to convert phenylalanine into tyrosine.

Gene duplications are also found to be a cause of PKU(Lee). This mutation occurred in the process of meiosis, or the process of producing gametes for reproduction. More specifically, gene duplications occur during crossing over in prophase 1. During this process, Homologous chromosomes exchange genetic information. However, during this process, a chromosome may receive too much genetic information, which leads to a gene duplication in this chromosome. Unequal crossing over which gives the long arm of chromosome 12 too much genetic information may impact the PAH gene. In this case, the amino acid sequence in the protein synthesis of phenylalanine hydroxylase would be altered, causing the enzyme to fold and function incorrectly.

Other mutations have also been found to be the cause of PKU in various ethnic groups. These three mutations are just a few, with missense and deletions being the most common, respectively (Lee).

How is the Mutated Allele Inherited?

The allele that expresses the mutation that causes phenylketonuria is recessive (NIH). Therefore, a person must have two recessive alleles in order to have the disease. If the parents are homozygous dominant, meaning that neither of the parents carry an allele for phenylketonuria, the child has no chance of carrying an allele which expresses phenylketonuria, and consequently, has no chance of inheriting the disease either. If one parent is homozygous dominant, while the other is heterozygous(one healthy allele and one mutated) or homozygous recessive(and therefore having the disease), the child would still not inherit the disease, as the dominant allele masks the recessive allele. However, the offspring would definitely carry the allele for phenylketonuria. If one parent is homozygous recessive while the other is heterozygous, the child would have a fifty percent chance of inheriting PKU, and would definitely carry the allele that expresses it. If both the parents are heterozygous, the child has a twenty-five percent chance of inheriting phenylketonuria, and a seventy five percent chance of carrying the allele which expresses phenylketonuria. If both the parents have phenylketonuria, and are therefore, homozygous recessive, the child has a one-hundred percent chance of inheriting phenylketonuria, as the child would definitely be homozygous recessive for the trait.

How Does the Disease Impact Human Health?

People with phenylketonuria are unable to convert phenylalanine into tyrosine in the liver. A large portion of the phenylalanine is unable to be used for any processes, as only so much of it is used as an amino acid for protein synthesis and for making molecules other than tyrosine. This phenylalanine accumulates in the circulatory system/blood(Encyclopedia Britannica), disrupting the homeostatic process of keeping phenylalanine at healthy levels in each organ system of the human body.

Through blood flow, the excess accumulated phenylalanine is transported to the central nervous system, or brain. Here, if the phenylalanine accumulates, significant damage to metabolic processes can occur. This leads to a decreased production of neurotransmitters. The resulting nerve cell damage in an untreated baby with PKU can be observed in its behavior as soon as within four to six months of birth. This shows that phenylketonuria is indeed a serious and rapid damaging disease. It is of extreme importance for newborns to be tested for the disease within weeks of birth. Older individuals with PKU are often observed to have nerve demyelination. The excess phenylalanine causes the destruction of myelin sheath that insulates fibers (Encyclopedia Britannica). Signals are not able to be sent as efficiently, and signals can even be sent incorrectly to different nerve fibers. This is due to the loss of the insulator, myelin sheath, which normally keeps electrical signals traveling efficiently and accurately. This leads to progressive cognitive dysfunction, causing symptoms such as mental retardation and epileptic seizures (Encyclopedia Britannica).

The retention of phenylalanine in other tissues causes a decrease in the formation of melanin. Visible effects of this decrease in melanin production is seen in the integumentary system. People with phenylketonuria often have very fair skin and blond hair as a result. People with PKU also often have blue eyes as the result of little melanin in their eye tissue (Encyclopedia Britannica).


As previously mentioned, it is of extreme importance for newborns to be checked for PKU within weeks of birth, as it is a disease which can result in rapid damage to the central nervous system if treatment is not provided.

The most effective treatment is to put the affected individual in a low protein diet immediately (Encyclopedia Britannica). The human body’s organ systems do not have a feedback loop in place in order to respond to excess phenylalanine in the circulatory system. Homeostasis in the amount of phenylalanine retained in the body cannot be achieved in people with phenylketonuria. Therefore, homeostasis in phenylalanine levels must be achieved through other means.

A person with PKU inputs less phenylalanine into their digestive system by having a low protein diet. By eating foods low in phenylalanine, less phenylalanine is inputted into the circulatory system. Some of this low amount of inputted phenylalanine is used to make molecules other than tyrosine. The result is a limited amount of phenylalanine accumulating in the circulatory system, and therefore, a limited amount reaches the central nervous system. This ideally limits neural damage to insignificant levels(Encyclopedia Britannica). By altering diet to a low protein diet, a person with PKU lowers the input of phenylalanine into the digestive system in order to force the homeostasis of phenylalanine levels throughout the human body.

However, by eating a low protein diet, a person with phenylketonuria is unable to gain the other essential amino acids needed for protein synthesis. Therefore, people with PKU are given phenylketonuria-free amino acid drinks. In addition, a low protein diet may be hard to adhere to. A protein called glycomacropeptide can be used in solid foods to make food more appealing. Glycomacropeptide, as it only contains traces of phenylalanine, can be purified to be phenylalanine-free (Encyclopedia Britannica).


- Foods that a PKU patient cannot consume

What Did You Learn?


1. What enzyme breaks down phenylalanine into tyrosine?

Phenylalanine hydroxylase breaks phenylalanine into tyrosine.

2. Gene duplications are found to be a cause of PKU. During which process do these mutations occur?

Gene duplications that cause PKU occur during meiosis.


Lee, Yong Wha. “Mutation Analysis of PAH Gene and Characterization of a Recurrent Deletion Mutation in Korean Patients With Phenylketonuria.” PubMed, 31 Oct. 2008,

Litwack, Gerald. “Phenylalanine - an Overview | ScienceDirect Topics.” ScienceDirect, 2018,,-Phenylalanine%20is%20an&text=Tyrosine%20is%20a%20nonessential%20amino,to%20tyrosine%20in%20the%20body.

“Phenylketonuria | Genetic Metabolic Disease.” Encyclopedia Britannica, 21 May 2020,

Tinsley, Grant. “Phenylalanine: Benefits, Side Effects and Food Sources.” Healthline, 17 Aug. 2016,

“PAH Gene.” U.S. National Library of Medicine, 7 July 2020,,acid)%20obtained%20through%20the%20diet.

“Phenylketonuria.” U.S. National Library of Medicine, 20-07-07,


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