Patient Presentation
A pediatrician’s teenage son who was studying chemistry was reading the ingredient label on a carbonated beverage can and said, “There’s several things here that I can’t even pronounce, but why does it have a specific warning for this thing called aspartame?” The pediatrician smiled and said, “That is an interesting story about using microbiology and chemistry for trying to identify and stop a disease called Phenyloketonuria or PKU before it can hurt babies.” She then went on to briefly explain the history of PKU screening and how it’s linked to the artificial sweetener aspartame.

Discussion
Phenylketonuria (PKU) is an autosomal recessive genetic disease. The PAH gene is found on chromosome 12 and has more than 600 mutations associated with it. The incidence varies but PKU is primarily found in Caucasian populations. The PAH gene codes for phenylalanine hydroxylase (PAH) which catalyzes the amino acid phenylalanine (Phe) to tyrosine. PAH uses a cofactor called tetrahydrobiopterin (BH₄) in this process. With a deficiency in PAH, Phe accumulates and can cause severe cognitive impairment and global developmental delay, microcephaly, seizures, poor growth and poor skin pigmentation. Tyrosine also decreases and along with it its products of melanin, L-thyroxine and catecholamine neurotransmitters. The exact cause of the PKU clinical problems may be an accumulation of Phe, deficiency in Tyrosine products or another cause but is unknown exactly currently.

The mainstay of treatment is a low protein, low phenylalanine diet. Phe is an essential amino acid so some Phe must be supplied in the diet but the amount is highly individualized based on the specific mutation, age and other specific needs of the individual. Specialized formula that is Phe-free is used for infants with children and adults using similar alternative formulas as part of their overall diet. The diet centers on consuming mainly fruits and vegetables. Low protein grains are also used, along with much smaller amounts of whole proteins along with Phe-free formulas. Food products for medical diets are more commonly available in recent years with reportedly improved taste and variety, but they can also be more expensive to purchase. Phe blood levels are monitored closely and changes in the diet are made to provide enough but not too much Phe in the diet. A dietician is critical for assisting the patient and family with the diet. The diet is usually recommended throughout the patient’slifetime but in some cases is less restrictive when the patient is an older child or adult.

Other potential treatments for individual patients include Sapropterin dihydrochloride, a BH₄ agonist, enzyme replacement therapy, large neutral amino acid therapy (a competitive carrier of Phe) and gene therapy.

Because PKU is autosomal recessive, the risk in subsequent pregnancies with the same parents is 25%. Female PKU patients who themselves wish to have families of their own have their own challenges. The risk of PKU in her partner is low and therefore there is a relatively low risk of her having a child with PKU (~2% in North American populations) but the child will at least carry the gene. The bigger risk is that Phe is actively transported across the placenta so the fetal level exceeds the mother’s level. High levels of Phe can be devastating to the fetus causing severe developmental delay, seizures, congenital heart defects and other problems. Therefore there are strict recommendations for female PKU patients to begin a strict diet before they wish to become pregnant and during the pregnancy to mitigate any of these effects.

Learning Point
Aspartame (L-aspartyl-L-Phemethyl ester) is an artificial sweetener that metabolizes to Phe, L-aspartic acid and methanol. It was first discovered in 1965, and approved by the US Federal Drug Administration in 1981. It is commonly used in a huge number of foods, drinks, candy, desserts, gum/mints etc worldwide, but is also in medicines, vitamins and skim milk powder. All medication formulations must be checked before they can be used by patients, and as formulations change often they need to be checked each time the medication is dispensed. A pharmacist is important member of the patient’s care team.

PKU was first described by Asbjørn Følling (1888-1973) in 1934. In the late 1950’s Dr. Robert Guthrie (1916-1995) developed an easy to do diagnostic test using blood spots on special filter paper (often called Guthrie cards) to detect the level of Phe by a bacterial inhibition assay. This was introduced into clinical practice in the 1960s because it was simple, inexpensive and cost-effective; it has become the quintessential test for preventative screening. Over time, testing for PKU became standard in all 50 US states, and many countries across the world. Because of its success, additional tests have been added to the blood spot or newborn screening (exact diseases tested for vary by location) and the methods of detection have changed with the advances in technology. Tandem mass spectrometry is currently used to detect PKU.

Questions for Further Discussion
1. What diseases do your newborn screening test screen for?
2. For patients that have a positive newborn screening test, howare they contacted and appropriate followup managed? What is the general practitioner’s role in this process?

Related Cases

Disease: Phenylketonuria | Genetic Brain Disorders

Symptom/Presentation: Genetic Disorder | Inborn Error of Metabolism | Developmental Delay

Specialty: Genetics | Medical History | Neonatology | Pharmacology / Toxicology | Preventive Medicine and Health Maintenance

Age: Fetus and Mother | Newborn

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Phenylketonuria

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Williams RA, Mamotte CDS and Burnett JR. Phenylketonuria: An Inborn Error of Phenylalanine Metabolism. Clin Biochem Rev. 2008 Feb; 29(1): 31-41.

Casey L. Caring for children with phenylketonuria. Can Fam Physician. 2013 Aug;59(8):837-40.

Brosco JP, and Paul DB. The Political History of PKU: Reflections on 50 Years of Newborn Screening. Pediatrics. 2013 Dec; 132(6): 987–989.

Groselj U, Tansek MZ, Battelino T. Fifty years of phenylketonuria newborn screening – A great success for many, but what about the rest? Mol Genet Metab. 2014 Sep-Oct;113(1-2):8-10.

Sharman R, Sullivan KA, Jones T, Young RM, McGill J. Executive functioning of 4 children with hyperphenylalaninemia from childhood to adolescence. Pediatrics. 2015 Apr;135(4):e1072-4.

Committee Opinion No: 636: Management of women with phenylketonuria. Obstet Gynecol. 2015 Jun;125(6):1548-50.

Aspartame. Wikipedia.
Available from the Internet at https://en.wikipedia.org/wiki/Aspartame (rev. 11/1/2015, cited 12/4/15).

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital