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Hello, my name is Mike Shelby and I’m going to be talking about phenylketonuria, also known as PKU. PKU is a genetic metabolic condition involving the inability to properly metabolize the amino acid phenylalanine (Phe). This disorder can cause severe neurological damage, and it therefore typically requires those with PKU to adhere to a special, Phe-restricted diet.
I’m going to begin with a brief introduction explaining PKU, along with an overview of the history and prevalence of PKU in the United States. Next I’ll discuss the primary physiological mechanism through which PKU causes disease symptoms. I’ll then discuss the dietary modifications often used to treat PKU. And lastly, I’ll conclude by discussing some of the challenges for those with PKU, along with some of the latest research on the disease and its implications for the future prognosis of this condition.
PKU is an autosomal genetic metabolic disease of amino acid metabolism affecting the enzyme phenylalanine hydroxylase, or PAH. This is due specifically to a genetic mutation that can result in either insufficient synthesis of PAH or synthesis of dysfunctional PAH caused by incorrect amino acid sequencing along its protein structure. Because PAH converts Phe into Tyrosine (Tyr), PAH deficiency can lead to excess Phe in the bloodstream along with low levels of Tyr.
PKU was originally discovered in 1934 by a Norwegian physician named Asbjorn Folling. He named the condition “imbecillitas phenylpyruvica” because of its tendency to cause mental retardation in patients with elevated urinary levels of phenylpyruvic acid. After about a year the disease was re-named “phenylketonuria” by a British geneticist in reference to the fact that phenypyruvic acid is a phenylketone molecule. The pathological mechanisms of PKU were elucidated by researchers over the next decade, and by 1951 British doctor Evelyn Hickmans and German doctor Horst Bickel developed the first dietary treatment for the disease. Their study resulted in the observation that a low Phe diet led to improved cognitive and behavioral outcomes in those with PKU.
By 1961, an American doctor named Robert Guthrie developed an accurate and simple screening test for PKU called “The Guthrie Test,” which gained widespread use in the United States over the next few years. Today all 50 dates mandate some form of newborn screening for PKU, many of which still use the Guthrie Test..
PKU is a considerably rare disorder, affecting only about 1 in every 10,000 to 15,000 infants born in the U.S. Nevertheless, universal screening for this disease is important because neurological damage caused by PKU can be easily avoided with proper nutritional intervention.
To elaborate on what I discussed briefly already, the PAH enzyme—synthesized primarily in liver and kidney cells—is required for hydroxylation of the essential amino acid Phe into the nonessential amino acid Tyr. This means that PAH in healthy individuals adds a hydroxyl functional group to the phenyl ring of Phe. Because a genetic mutation in those with PAH deficiency limits or inhibits this metabolic pathway, any Phe that is not used up for proteins in normal growth and maintenance (such as building of muscle tissue) will remain in the blood intact, and the body will be unable to make its own Tyr.
This image illustrates the metabolic pathway involved in Phe conversion to Tyr. To summarize the process from left to right, Phe is derived from dietary protein. Some Phe is needed for tissue proteins like muscle and protein hormones like the pancreatic hormone glucogon. This means that even those with PKU need at least some minimal intake of Phe. Normally Phe is converted into Tyr by the PAH enzyme via hydroxylation. Without this enzyme, Phe builds up into phenylpyruvate in the bloodstream, with breaks down further into pehnyllactate and phenylacetate. Tyr normally is used for a variety of unique physiological functions, such as melanin synthesis primarily in epidermis melanocytes and synthesis of the neurotransmitter dopamine in brain cells. These functions can become impaired if dietary intake of Tyr is insufficient.
One of the major disease symptoms of PKU is neurological impairment, which can potentially lead to permanent mental retardation. Although the mechanisms for this are not fully understood, research indicates that the molecular characteristics of the Phe amino acid plays a role in this. Specifically, Phe is generally classified as a large, neutral amino acid (LNAA) due to its relatively large size and non-polarity. Other LNAAs include tryptophan, leucine, isoleucine, and the Phe metabolite Tyr. LNAAs access the brain through molecules that transport them across the blood brain barrier, but LNAAs must compete for these carriers. When transport molecules become oversaturated with one LNAA—such as Phe—they cannot transport other important LNAAs into the brain. This is one (perhaps of many) mechanism many researchers believe is responsible for the long term neurological effects of untreated PKU. When high levels of Phe overwhelm these LNAA transporters, Tyr uptake is reduced, leading to reduced dopamine levels. Similarly, reduced uptake of tryptophan might decrease brain levels of the neurotransmitter serotonin, which is a metabolite of that amino acid. Without these critical neuronal messenger molecules, brain function can become impaired. It is therefore important for healthcare practitioners to be knowledgeable about these possible mechanisms in order to effectively communicate the seriousness of untreated PKU.
Just to provide some perspective, this image illustrates the blood brain barrier, through which Phe and other LNAAs are transported.
Routine genetic screening of newborn infants for PKU is important because it allows those with PKU to adopt therapeutic diets as early as possible, usually before any long term cognitive damage can occur. Low Phe diets are an effective way to maintain good health for those with PKU. This gives parents of PKU infants the opportunity to become educated and prepared for proper care of their child throughout his or her life.
One way healthcare practitioners can help parents with a PKU infant is by providing them with some items that might help with caring for a PKU infant, such as information materials, PKU appropriate recipes, and general kitchen tools like those shown in the image above.
Because the PAH deficiency mutation can affect the enzyme functionality differently for different people (e.g. some might be able to convert small amounts of Phe to Tyr while others might be unable to accomplish this at all), diets are individualized for each patient. This is often accomplished with the assistance of a Registered Dietitian. Some individuals with PKU might tolerate small amounts of dietary Phe better than others, allowing them to occasionally include some higher protein foods in their diet. The severity of the condition for others, however, might warrant extremely low protein diets to the degree where even certain starchy vegetables and breads might contain too much protein.
Despite individual differences, generally a PKU diet can include many fruits, vegetables, low protein grains, and pure fats like olive oil and coconut oil. The image of the PKU diet bulls eye above illustrates this well, with the “best” foods—such as fruits and vegetables—located near the center, and the less ideal, higher protein foods—such as meats, fish, and dairy products—located along the outer ring. It likely goes without saying that, with such a limited choice of dietary options, long term adherence to a low-Phe diet can be a challenge for many with PKU. With that said, many can benefit greatly from basic cooking skills to learn how to approach meals creatively and thoughtfully.
According to most major health organizations—such as the American Academy of Pediatrics, the World Health Organization, and the Academy of Nutrition and Dietetics—breast milk provides optimal nutrition for infants, and should form the basis of nutrition for at least the first 6 to 12 months of infancy. This is true even for infants with PKU. In a 2012 study published in the Journal of Pediatric Nursing, researchers compared Phe blood levels in breastfed PKU infants with those in formula-fed PKU infants. They found a positive correlation between breastfeeding frequency and normalized Phe levels. This suggests that breast milk might provide PKU infants with just enough Phe for healthy growth and development (~120-360 μmol/L), without exceeding dangerous levels of the amino acid.
The study authors do not, however, address how breastfed infants might acquire Tyr in the absence of PAH, and so this area of research likely requires further study.
Although breast milk is an ideal food for infants, some infants might need formula supplementation for a variety of reasons. Parents can find many different formulas on the market, such as the one shown here. PKU formulas provide all essential amino acids except for Phe. In addition, these phenyl-free products typically also provide Tyr to make up for insufficient Tyr from Phe metabolism. Some formulas might also supplement the diet with additional nutrients, such as vitamins and minerals that might be deficient in such a low protein PKU diet. For example, formulas might include the essential omega-3 fatty acid α-linolenic acid (ALA)—along with its derivatives docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)—as these are typically abundant only in high protein foods, like fish, eggs, and some nuts and seeds. On the other hand, Linoleic acid, an essential omega-6 fatty acid, is usually more abundant in the diet and easier to obtain in a typical PKU diet. In fact, dietary intake studies show that it is consumed in excess by many Americans.
Of course, after an infant has been weaned from breast feeding, he or she will likely have to use Phe-free formulas for life. From childhood through adulthood, those with PKU have the best health outcomes with a strict adherence to a low-Phe diet. With that said, higher dietary Phe is more dangerous for an infant than an adult because his/her brain is still growing and developing. Once they become adults, they might better tolerate a slight increase in dietary Phe.
Here are a couple images showing some foods that someone with PKU might eat. On the left is a lunch containing some fruits, vegetables, and some specially formulated, low-protein foods, likely designed for those with amino acid metabolic conditions like PKU. Similarly, the image on the right shows some fruits and vegetables with low protein grain-based products.
I’ll now summarize some of the challenges for those living with PKU. First, as I’ve already discussed, this diet can be very restrictive. While compliance with a low-protein diet might be easier for infants and toddlers who are fed by parents in a relatively isolated environment, such a diet can become problematic once the child begins school and is exposed to other food choices.
Second, the diet might lead to poor food choices due most calories coming from carbohydrates for many. It might therefore be easy for those on such diets to eat too many high glycemic, refined carbohydrates, potentially leading to insulin resistance, metabolic syndrome, and cardiovascular disease.
Third, the lack of fat in the diet could also be an issue. Fruits, vegetables, and special low-Phe foods tend to be low in fat. However, this might be addressed by incorporating low protein sources of healthy fats, such as the monounsaturated, omega-9 oleic acid from olive oil, avocado oil, and macadamia oil. These fats would also be useful to increase absorption of fat soluble vitamins from dietary sources.
Illustrating some of the difficulties with a PKU diet is evidence that PKU adolescents might be more likely to be obese and have lower bone density than non-PKU adolescents. This is revealed by a study conducted by Doulgleraki et. al. and published in the International Journal of Endocrinology and Metabolism. In that study, researchers examined bone, muscle, and fat mass in 48 PKU patients and compared them to 57 control patients. Those with PKU had higher body fat and lower bone density, but this was especially true for those with low adherence to a proper PKU diet (for example, there was a positive correlation between blood Phe levels and body fat). This indicates that strict low-Phe dietary adherence can be important not only for neurological health but also for bone and body composition health.
One area of PKU research with some promising results involves the therapeutic use of LNAAs other than Phe as a method of inhibiting uptake of Phe across the blood brain barrier. Studies have shown that this can be an effective way to essentially protect the brain from potential damage from excess Phe in the blood. Nonetheless, more research is likely needed before this can become a standard therapy for those with PKU.
Although PKU is a rare disorder, it can lead to serious neurological impairment. For this reason, it is critical for healthcare practitioners to regularly screen for PKU, and to be able to communicate effectively with a PKU infant caregiver about the importance of a lifelong, low-phenylalanine diet. This diet can be limited, but with careful planning and creativity—possibly with the help of a Registered Dietitian—a PKU appropriate diet can be both nutritious and appetizing. Thanks to scientific advancements and neonatal screening tests, those with PKU can now live long, healthy, happy lives in ways that weren’t easily possible just a few decades ago.
![[Untitled image of phenylalanine molecule]. Retrieved February 7, 2015, from: http://2.bp.blogspot.com/-
Wkdb_hXz5dk/UFYzNPc6esI/AAAAAAAAAQ0/nl8y_J5-Wa8/s1600/phenylalanine.png
[Untitled image of formula product for PKU infants]. Retrieved February 7, 2015, from: http://nutricia.co.uk/files/uploads/First_spoon.png](https://image.slidesharecdn.com/7aab893f-75f9-4e32-b16c-5be6901c2cc1-160807145728/85/PKU_MikeShelby-1-320.jpg)
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[DNA double helix]. Retrieved February 8, 2015, from:
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