As a pediatric hospitalist that primarily cares for newborns, there is a short but important list of topics that I discuss with parents. This can include the intramuscular dose of vitamin K given to all newborns (unless refused by the parent) to prevent life-threatening bleeding, the hepatitis B immunization given to prevent serious liver disease and even cancer, and recommendations for the prevention of unexpected death during sleep. During my initial exam, while counting digits and pointing out how adorable the new arrival is, I always discuss evidence-based screening procedures that every baby undergoes.

Standard screening for newborns includes a hearing test, screening for critical congenital heart defects with pulse oximetry, and obtaining a transcutaneous bilirubin level. Since the early 1960s, screening of newborns has also involved testing for a steadily increasing number of diseases which aren’t apparent in the early newborn period, including enzyme defects, immune deficiencies, blood disorders, and many, many more. These conditions can result in a wide spectrum of organ injury and impairment, including severe intellectual impairment and even sudden death.

Largely made possible by the efforts of Robert Guthrie, the initial newborn screening programs in the 1960s only included one test. His development of an assay for the amount of the amino acid phenylalanine in drops of whole blood collected on special filter paper, also of his design, allowed for the universal screening for a disease knows as phenylketonuria, or “PKU”. Decades later there are now more than thirty tests included in newborn screening programs, with some variation between states, but it is still commonly referred to as “the PKU” by medical professionals working in nurseries.

What is PKU?

Phenylketonuria (PKU) is a genetic condition caused by a deficiency of phenylalanine hydroxylase enzyme (PAH), which is critical in the conversion of the essential amino acid phenylalanine to tyrosine. Loss of this enzyme results in the build up of excessive amounts of phenylalanine in the blood and urine, which for not entirely clear reasons is harmful to the developing brain. In general, there appears to be interference with brain growth and development, the insulation of axons with myelin, and the synthesis of several neurotransmitters.

PKU effects roughly 1 out of every 15,000 births in the United States, but its incidence varies between populations and countries. Turkey has the highest incidence rate at 1 in roughly 2,500 births. In Japan and Finland, PKU is quite rare with rates of less than 1 in 100,000. PKU is also very rare in African-American populations.

PAH deficiency, and resulting PKU, isn’t an all or nothing situation. In most cases, there is an autosomal recessive inheritance of a defective gene on chromosome 12q24 from two carrier parents, but there are many possible mutations with varying degrees of PAH deficiency and mild to severe clinical presentations. Total PAH deficiency causes classic PKU, the hallmark of which is severe intellectual impairment. Children often will also develop seizures, poor motor function, and an unusual odor often described as a musty or “mousy”. And because tyrosine is further metabolized into melanin, patients with PKU are often very lightly pigmented.

Classic PKU is rarely seen clinically because of the success of newborn screening programs. In the rare untreated patient, clinically-apparent impairment begins in early infancy as phenylalanine levels build and injury to the brain adds up. The progression of intellectual disability becomes most noticeable during early childhood when myelination should be in full swing. In most patients, mental decline stabilizes in adulthood.

How is PKU treated?

Once diagnosed, hopefully in the first week of life, the primary treatment of classic PKU is lifelong dietary restriction of phenylalanine using specialized formulas and medical foods. Babies can be breastfed, although mother’s milk can only safely make up about a quarter of the child’s intake. Children still need to rely on specialized formula. It becomes increasingly difficult to maintain a safe diet as children age because of the poor palatability of available protein substitutes. The services of an experienced dietitian can be extremely helpful in ensuring that patients are receiving optimal nutrition for growth and development.

In recent years, a few drugs have been developed that have shown some clinical usefulness in children with milder forms of PKU. The primary example is tetrahydrobiopterin (BH4), which is a PAH cofactor that maximizes activity of the reduced amount of available enzyme and can lower phenylalanine levels in some patients. There isn’t much long term data, and it is not known if BH4 dosing can replace dietary restriction yet. But it is promising and appears to be very safe.

Maternal PKU can harm a developing fetus

Monitoring and management of elevated phenylalanine levels into adulthood is important for a number of reasons. Even though the potential for IQ loss decreases dramatically after the brain is fully developed, high levels of the amino acid in the blood are associated with mood disorders as well as deficits in attention and processing. But normal phenylalanine levels are especially important in the setting of pregnancy because the developing fetus can be harmed. Harm can occur even when a mother with PKU has normal levels because of the fact that phenylalanine concentrates in the fetal circulation. The clinical presentation of these infants is similar to fetal alcohol syndrome, with poor growth, microcephaly, and subsequent intellectual impairment.

Could a microbial cure for PKU be just around the corner?

Earlier this week, Carl Zimmer reported on a potential new treatment for PKU involving the manipulation of a specific bacterium by synthetic biologists at a company called Synlogic, whose aim is to develop novel “living medicines” to treat a variety of human diseases. It’s a great article that explains the basics of this burgeoning field well, but I’m not convinced that this will be a game changer.

Scientists at Synlogic took a harmless gut bacteria and inserted genes that would turn on once it was in a low-oxygen environment such as the human intestinal tract. Once activated, these genes encode the development of a membrane pump that pulls in phenylalanine and then the production of an enzyme that breaks it down. The resulting waste is excreted and absorbed by the gut, ultimately finding its way into our urine.

Buoyed by studies in mice and primates, Synlogic performed a trial in humans, the results of which have just been announced but have not been published. They had healthy subjects ingest the study bacteria in varying amounts and then consume a high protein meal. They found that the microbial mixture was well-tolerated and that with larger doses there were more breakdown products of phenylalanine found in the subjects’ urine. The next step for the researchers will be to assess blood levels of the amino acid in actual PKU patients.

Conclusion: It’s okay to be optimistic, but don’t get too excited just yet

This is a neat proof of concept kind of result, but let’s not let the hype get too far ahead of the research and the reality. The preliminary studies were in mice and primates, the positive results of which often don’t pan out in human trials. And we don’t know if the increased amount of phenylalanine bits in the urine equate to clinically meaningful reductions in levels in the blood. We also don’t know how much of this stuff people will have to ingest to achieve benefit.

I can more easily see this approach as being potentially helpful in adults with milder forms of PKU whose brains are pretty locked in. At least, I’d need to see some pretty robust data before telling a parent that they don’t have to restrict protein intake in their newborn with classic PKU. I don’t think this is going to replace what we already recommend as primary management, but it may at least end up being cheaper than other pharmaceutical options.

I’ve never been shy about my skepticism of microbiome manipulation as a medical intervention. Other than a few exceptions, primarily fecal transplants for C. difficile colitis and specific probiotics for the treatment and prevention of pouchitis, there isn’t much to it just yet. I sincerely hope that this one is the real deal. I also hope to see these studies published somewhere.


Posted by Clay Jones

Clay Jones, M.D. is a pediatrician and a regular contributor to the Science-Based Medicine blog. He primarily cares for healthy newborns and hospitalized children, and devotes his full time to educating pediatric residents and medical students. Dr. Jones first became aware of and interested in the incursion of pseudoscience into his chosen profession while completing his pediatric residency at Vanderbilt Children’s Hospital a decade ago. He has since focused his efforts on teaching the application of critical thinking and scientific skepticism to the practice of pediatric medicine. Dr. Jones has no conflicts of interest to disclose and no ties to the pharmaceutical industry. He can be found on Twitter as @SBMPediatrics and is the co-host of The Prism Podcast with fellow SBM contributor Grant Ritchey. The comments expressed by Dr. Jones are his own and do not represent the views or opinions of Newton-Wellesley Hospital or its administration.