Positive Prospects for Phenylketonuria

Positive Prospects for Phenylketonuria

Protein: it’s one of the most vital building blocks in the human body. Flip through a magazine or scroll through a healthy living blog and you’ll be sure to find a reference to the importance of a high-protein diet. However, for a rare few, high-protein foods can cause severe brain damage. People living with phenylketonuria (PKU) cannot metabolize phenylalanine (Phe), one of the 20 human amino acids that make up the proteins we consume.1 Most of us have an enzyme called phenylalanine hydroxylase (PAH), which converts Phe into another amino acid called tyrosine (Tyr). However, patients with PKU have mutations in their PAH gene that prevent the transcription of a functional PAH enzyme.1 Thus, Phe builds up in their bloodstream and brain because defective PAH cannot break it down.1 When left untreated, this build-up can lead to intellectual impairment, as well as a myriad of accompanying symptoms including rashes, seizures, motor deficits, microcephaly, and growth failure.1,2 PKU is autosomal recessive, meaning that it will only occur if both parents pass on a mutated PAH gene to their child.2 It is most prevalent among Caucasians, with a frequency of 1 per 10,000 live births.2


However, for a rare few, high-protein foods can cause severe brain damage. People living with phenylketonuria (PKU) cannot metabolize phenylalanine (Phe), one of the 20 human amino acids that make up the proteins we consume.

The exact mechanism by which Phe accumulates to cause intellectual impairment is not fully understood. However, several physiological changes have been linked to an increased concentration of Phe in the blood, and these may provide clues regarding the mechanism of PKU. The first observation is that PKU patients’ brains have a higher concentration of free Phe, but a lower concentration of Tyr and tryptophan (Trp).3 Phe, Tyr, and Trp are too large to enter the brain on their own, and they need to be transported across the blood-brain barrier by the same transporter.4 Because PAH cannot break down Phe in PKU patients, they have more Phe in their blood competing with Tyr and Trp for access to the transporter.4 Thus, Tyr and Trp may become deficient in the brain. Tyr and Trp are needed for the production of certain neurotransmitters that are important in executive function, such as dopamine, noradrenaline, and serotonin.4 Another observation is that high concentrations of Phe seem to be associated with abnormal myelination of neurons, where younger patients experience delayed myelination and older patients lose myelin.4 If Phe accumulation were to somehow reduce or delay myelination, it could cause slower electrical signalling in the brain.


If a Phe-restricted diet is started early, PKU patients may avoid the development of symptoms.

Phe is one of the nine amino acids that is not produced by the human body.5The only way it can be obtained is through food. Therefore, the current primary treatment of PKU is diet therapy.5 If a Phe-restricted diet is started early, PKU patients may avoid the development of symptoms. A typical diet for a PKU patient involves restriction of foods that are rich in protein, such as meat, eggs, cheese, and nuts.1 However, because the consumption of amino acids other than Phe is still necessary, individuals with PKU take a daily Phe-free dietary protein supplement.1 Most individuals with PKU who have controlled levels of Phe through dietary restriction experience normal social and mental development.1 One study showed that patients who maintained a Phe-restricted diet had a decreased rate of eczema, asthma, mental disorders, headache, hyperactivity, and hypoactivity when compared to patients who discontinued their Phe-restricted diet.6 They also had higher intellectual and achievement test scores.6 Although treatment by diet therapy has largely been successful, strict adherence is vital. However, diet therapy decreases quality of life and thus makes compliance difficult. Limiting dietary choices can be frustrating for PKU patients, especially children, who want to be able to enjoy the same foods as their peers.1 Although diet therapy is successful in managing PKU, it would be valuable to develop a new treatment that does not impact quality of life so dramatically.


The effects of Phe can have rapid and potentially irreversible effects on the brain, so it is vital to screen for PKU early.

The effects of Phe can have rapid and potentially irreversible effects on the brain, so it is vital to screen for PKU early. If newborns with PKU are started on a Phe-free diet immediately, the build-up of Phe and the resulting symptoms can be prevented. All newborns in Canada and the US, and many more countries around the world, are tested for PKU. The first mass screening test for high blood Phe concentration was developed in the 1960s by Robert Guthrie and is still used today.7 There are also newer and more cost-effective methods of newborn screening, such as tandem mass spectrometry.1 Historically, newborn screening required a separate test for each disorder, but tandem mass spectrometry allows for the quantification of many different molecules of interest within a single procedure.8 Screening identifies elevated Phe levels in a blood sample taken from a newborn’s heel.9


Current research in the PKU field is focused on developing new treatments for PKU that will not reduce quality of life as radically as diet therapy. Sapropterin dihydrochloride, marketed under the name Kuvan, was approved by Health Canada as a medication for PKU in 2010.1,10 Kuvan is a commercial form of BH4, a chemical compound that naturally enhances PAH activity.11 Increasing PAH activity can increase Phe tolerance in PKU patients, permitting more flexibility in their dietary choices.11 However, only about 20% of PKU patients have a PAH mutation that is sensitive to BH4.1 In this subset of patients a single daily dose of Kuvan can maintain stable serum Phe levels for over 24 hours.12 Research regarding Kuvan’s long-term effects is ongoing. Nevertheless, Kuvan is a promising medication that can improve the dietary freedom and thus quality of life in a small number of PKU patients.


Another treatment currently being explored is enzyme substitution therapy. This therapy involves treating patients with phenylalanine ammonia lyase (PAL), an enzyme that breaks down Phe to compounds that are excreted in the urine.13 In a 2018 phase 3 clinical trial, patients treated with PAL showed a statistically significant improvement in blood Phe concentration after eight weeks of treatment.13 Most participants did not have a severe adverse reaction to the treatment.13 However, further research on this treatment is required before it becomes approved for general use.


Finally, gene therapy is currently under investigation as a potential cure for PKU. In gene therapy, non-mutated copies of the gene of interest (in this case, PAH) are inserted into the patient’s genome. Thus far, it has only been explored in animal models.10 Rebuffat et al. (2010) took mice that were deficient in PAH and injected a vector into their muscles to correct the PAH gene. After the treatment, they observed restored PAH activity and decreased serum Phe levels that lasted 8-10 months.14 Other studies have noted similarly promising results of gene therapy as a potential treatment for PAH. However, far more research is required before gene therapy becomes feasible. The technique of gene insertion must be refined and clinical trials must be run before it is approved for therapeutic use.


Nevertheless, the future of PKU management is bright. Current newborn screening procedures and diet therapy have dramatically reduced the average severity of the disease. Although diet therapy impairs quality of life in PKU patients, it is an effective treatment for the interim while new and exciting possibilities – Kuvan, enzyme substitution therapy, and gene therapy – are being explored. Hopefully, a world where patients with PKU can eat their favourite foods to their heart’s content is just on the horizon.


Works Cited:

1. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet, 2010;376:1417-1427. https://doi.org/10.1016/S0140-6736(10)60961-0

2. Williams RA, Mamotte CDS, Burnett JR. Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev, 2008;29(1):31-41.

3. McKean CM. The effects of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain. Brain Res, 1972;47:469-476. https://doi.org/10.1016/0006-8993(72)90653-1<.p data-preserve-html-node="true">

4. Surtees R, Blau N. The neurochemistry of phenylketonuria. Eur J Pediatr, 2000;159(Suppl 2):109-113.

5. Amino acids. MedlinePlus web site. https://medlineplus.gov/ency/article/002222.htm. Accessed April 3, 2018.

6. Koch R, Burton B, Hoganson G, et al. Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis, 2002;25(5):333-346.

7. Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics, 1963;32:338–343.

8. Sweetman L. Newborn screening by tandem mass spectrometry. Clin Chem, 2001;47(11):1937-1938.

9. Phenylketonuria (PKU) test. HealthLinkBC web site. https://www.healthlinkbc.ca/medical-tests/hw41965. Accessed April 5, 2018.

10. About PKU. Canadian PKU and Allied Disorders Inc. web site. http://canpku.org/about-pku-2. Accessed April 5, 2018.

11. Kör D, Yılmaz BŞ, Bulut FD, Ceylaner S, Mungan NÖ. Improved metabolic control in tetrahydrobiopterin (BH4), responsive phenylketonuria with sapropterin administered in two divided doses vs. a single daily dose. J Pediatr Endocrinol, 2017;30(7):713-718. doi:10.1515/jpem-2016-0461

12. Levy HL, Milanowski A, Chakrapani A, et al. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria a phase III randomised placebo-controlled study. Lancet, 2007;370:504-510. doi:10.1016/S0140-6736(07)61234-3

13. Harding CO, Amato RS, Stuy M, et al. Pegvaliase for the treatment of phenylketonuria: a pivotal, double-blind randomized discontinuation Phase 3 clinical trial. Mol Genet Metab, 2018. https://doi.org/10.1016/j.ymgme.2018.03.003

14. Rebuffat A, Harding CO, Ding Z, Thony B. Comparison of AAV pseudotype 1, 2, and 8 vectors administered by intramuscular injection in the treatment of murine phenylketonuria. Hum Gene Ther, 2010;21:463–77. doi:10.1089/hum.2009.127


Cite This Article:

Hunter R., Chan G., Palczewski K., Zhang B., Lewis K., Ho J. Positive Prospects for Phenylketonuria. Illustrated by W. Y. Wu. Rare Disease Review. September 2019. DOI:__.

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When One Door Closes, Another Opens...

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