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PKU: Basics, History, and Treatment Approaches

Authors: Ramez Hassanen (1) Sara Salameh (2) Mahee Patel (3) Saniya Vaish (4)

Editor: Sabina Maskey, Ph.D.


Author Affiliations: Hunter College (1) George Mason University (2) University High School (3) John P. Stevens High School (4)


Introduction

 

Phenylketonuria (PKU) is a rare autosomal recessive disorder that causes a deficiency in the production of the enzyme Phenylalanine hydroxylase (PAH) 1. This enzyme converts the amino acid Phe (Phenylalanine) into tyrosine. If PAH is not abundant in the bloodstream, Phenylalanine accumulates which could lead to neurodegenerative diseases, such as PKU. People diagnosed with PKU have shown signs of intellectual disability, behavioral problems, and many other mental disorders. This article discusses the transition in metabolic medicine from chemical applications to genetic approaches. In particular, using gene-editing techniques to regulate/lower the Phe levels in PKU patients2. 


History of PKU


In 1934, Dr. Asbjørn Følling examined two severely mentally underdeveloped children and detected the presence of phenylpyruvic acid in their urine using classical organic chemistry methods. This discovery marked the identification of what would later be termed phenylketonuria (PKU), an inborn error of metabolism4. Subsequent investigations revealed the same substance in the urine of eight additional patients with intellectual disabilities. Følling demonstrated that PKU follows an autosomal recessive genetic pattern, likely caused by a block in phenylalanine metabolism. He also pioneered the use of phenylalanine loading tests to identify asymptomatic carriers of the trait. PKU was the first metabolic disorder known to impact mental function, establishing it as a model disease for understanding genetic and biochemical influences on neurological conditions.

 

Figure 1- Dr Asbjørn Følling with one of his patients.3

 

PKU Influences in Clinical Chemistry and Metabolic Medicine 


Dr. Asbjørn Følling set a precedent for using chemistry to diagnose and treat patients as he experimented with PKU. Before diagnosing his first patient, Dr. Følling used traditional examinations such as physical and urine tests. All tests came back normal except for one of Følling’s tests, in which he added a few drops of acidified ferric chloride solution to the urine samples. This test is typically used to detect acetoacetic acid, and from this test, he found that his patients did indeed have this chemical substance present in their urine.


Figure 2- Lofenalac is an infant powder formula prescribed to replace milk in the diets of Phenylketonuria (PKU) sufferers in the infant and child stage.4


This allowed Følling to isolate the unknown material from the urine, and after further testing, he found that it was phenylpyruvic acid, a result of the lack of the enzyme phenylalanine hydroxylase. After finding a way to diagnose patients with PKU, a meal plan was later developed that included a Phe-free diet with a protein replacement (Lofenalac), the first medical food in the US, and other key nutrient foods (Figure 2).

 

PKU research contributed to biochemical concepts like metabolic pathways and sparked new research into the correlation between genes and proteins3. Furthermore, screening programs were established and later made mandatory for every child after birth. Overall, these advances in medical practices were made possible by the chemists who used their expertise to diagnose and devise a meal plan to treat PKU properly.


The Role of PAH and its Impact on our Bloodstream




Figure 3- Phenylalanine metabolism in PKU. Phenylalanine hydroxylase (PAH) catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.2 

 

Phenylalanine hydroxylase is a liver enzyme produced by the PAH gene, which is mainly responsible for the conversion of the amino acid, Phenylalanine, into Tyrosine which is another amino acid5. This conversion takes place with the help of a molecule called tetrahydrobiopterin (BH4) which assists in carrying out the chemical reaction (Figure 3). This conversion is crucial as tyrosine is a precursor for several important neurotransmitters such as norepinephrine, dopamine, and epinephrine which are essential for brain function and development3. It is also used to make and regulate several hormones for the thyroid, and it can produce melanin for skin and hair.


Experimental Gene Therapy Approaches for PKU

 

Figure 4- How AGT's PKU Gene Therapy Works6


Various gene editing technologies are being developed to reverse the effects of PKU. Forms of gene editing, such as prime editing and base editing, are effective in treating the PAH deficiency associated with PKU. First, prime editing can be used to rewrite genetic sequences, allowing for an increase in the PAH gene and better regulation of Phe build-up in the blood. Another form of gene editing being researched is base editing. Base editing allows for the precise replacement of one letter in DNA sequences with another. AGT editing, also known as Adenine Base Editing, is one of the most viable options for gene editing to treat PKU7. With the use of AGT editing and lentivirus vectors, synthetic genes can not only restore normal function of PAH production in liver cells but also prevent faulty and mutated PAH from being produced6(Figure 4). Although trials in mice and lab-grown liver cells indicate these methods to be effective, further research must be conducted on these treatments to administer them in clinical trials safely.

 

Conclusion

 

To better treat and diagnose modern PKU, it is important to first understand the history of the disease and its metabolic impacts. Only through a comprehensive understanding of the disease is it possible to find new treatments for it, such as gene editing. With the use of new gene therapy technologies, PKU patients can seek treatment and prevent further intellectual disabilities without needing to make strict and difficult-to-follow changes to their lifestyles5 . However, more research is needed to apply such technology to real patients in clinical trials8 . This research can positively change the lives of millions who were born with PKU, allowing them to live without fear.

 

Glossary

  1. Autosomal Recessive Disorder- A type of genetic condition occurs when an individual inherits two copies of a mutated gene, one from each parent. These disorders are found on one of the autosomes, the non-sex chromosomes.

  2. Gene-editing techniques- Computation methods that allow scientists to alter the DNA of an organism. These methods can be used to add, remove, or modify genotypes at specific locations in the genome.

  3. Inborn Error of Metabolism- A group of rare genetic disorders where the body cannot properly metabolize nutrients into energy. The defects can lead to a buildup of toxic substances or a decrease in compounds needed for sustaining life.

  4. Metabolic Pathways- Series of chemical reactions occurring within a cell that led to the conversion of one or more substances into another.

  5. Neurotransmitters-  These are chemical messengers that transmit signals across a chemical synapse, from one neuron to the receiving neuron.

  6. Lentivirus Vectors- A form of gene editing in which viruses that have been modified safely by scientists can deliver synthetic genes to cells

  7. Adenine Base Editing-A form of gene editing in which Adenine is replaced with Guanine in DNA sequences without disrupting the DNA structure.

  8. Newborn Screening- A medical procedure where newborn babies are assessed for certain genetic, metabolic, hormonal, and functional conditions that can hinder their normal development.

  9. Clinical Trials- Research studies that test how well new medical approaches work in people.


Citations

  1. adminNki2019. 85th Anniversary. Crossing Norway For A Cure. March 5, 2019. Accessed September 10, 2024. https://crossingnorway.com/2019/03/05/85th-anniversary/

  2. Elhawary NA, AlJahdali IA, Abumansour IS, et al. Genetic etiology and clinical challenges of phenylketonuria. Hum Genomics. 2022;16(1):22.

  3. Messner D. On the Scent: The Discovery of PKU. Science History Institute. May 12, 2012. Accessed September 10, 2024. https://www.sciencehistory.org/stories/magazine/on-the-scent-the-discovery-of-pku/

  4. Lofenalac. Patent Yogi LLC. March 12, 2016. Accessed September 10, 2024. https://patentyogi.com/historical-inventions/lofenalac/

  5. Flydal MI, Martinez A. Phenylalanine hydroxylase: Function, structure, and regulation. IUBMB Life. 2013;65(4):341-349. doi:10.1002/iub.1150

  6. Gene Therapy for PKU: Using Viral Vectors to Treat Phenylketonuria. American Gene Technologies. Accessed September 12, 2024. https://www.americangene.com/pipeline/phenylketonuria-pku/

  7. Homepage. The Medical Biochemistry Page. Accessed September 12, 2024. https://themedicalbiochemistrypage.org/

  8. Woolf LI, Adams J. The Early History of PKU. Int J Neonatal Screen. 2020;6(3):59. doi:10.3390/ijns6030059


 
 
 

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