Current medical evidence has led experts on PKU to suspect that current therapy for PKU may leave individuals with an increased risk for subtle deficits in brain function. To address this, a group of PKU experts recently (2010) published a 107-page supplement on current topics surrounding this issue to raise awareness in the PKU scientific community.

This supplement, published in the peer-reviewed journal Molecular Genetics and Metabolism, is the first collective work on the psychological and neuropathological perspective in PKU. It involved contributions from 50 PKU experts including psychologists, psychiatrists, geneticists, dieticians, neuroscientists, and biologists from countries all over the world.

We have taken and summarized key points from this expert supplement that we feel would be of interest to people who have PKU and their family members. In addition, we have included newer relevant research that has become publicly available since the supplement was published in early 2010.

The NPKUA would like to thank BioMarin Pharmaceuticals for supporting these materials with an educational grant.

Click on any of the Chapters to see what is in that section.

Table of Contents

  • 1. Introduction: PKU Basics
    • Summary
      • Routine high blood Phe levels during childhood can eause severe problems in the way the brain develops.
        • Starting a Phe-restricted diet soon after birth keeps blood Phe levels within a sale range.
        • Used in this way, a Phe-restricted diet is a proven powerful therapy that dramatically improves outcomes for people with PKU by preventing severe brain damage. However, a Phe—restrieted diet is not a cure for PKU.
      • Did you know that despite treatment with the Phe—restrieted PKU diet, scientists and physicians are still finding evidence for subtle changes in the brains of some PKU people in all age groups studied?
        • This may be a result of the fact that throughout your entire life. even if you maintain a Phe-restricted diet, your blood Phe levels will still be higher than those of someone without PKU. Additionally, new evidence now shows that even short-term spikes in blood Phe levels can cause some IQ changes. This suggests that stable blood Phe levels are as important as low blood Phe levels.
        • Scientists are looking into whether these higher Phe levels may cause subtle changes in the brain that can affect behavior, mood and thinking, even if the Phe levels are in the target range.
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  • 2. Physical Evidence for Altered Brain
        Function in PKU
    • Summary
      • Scientists are currently gathering physical evidence to determine whether the current standard therapy involving a Phe-restricted diet and meeting blood Phe targets can still lead to changes in the brain.
        • Some of the physical evidence scientists have gathered involves brain scans. So far, the evidence shows that a large percentage of people with PKU may have some visible brain abnormalities, even when on diet. There is a reasonable correlation between the amount of brain abnormalities and life time Phe levels, the higher the Phe levels the more brain abnormalities
        • However, it's not yet clear what these changes mean in terms of brain function.
          • Some researchers think that these changes may cause problems in how fast you can process information.
          • However, less than half of the people who have displayed brain abnormalities show any impairment in mental abilities, and these impairments are subtle.
          • The bottom line is that much more research is needed to understand the nature and impact of these brain-scan visual abnormalities in diet-controlled PKU.
        • Another form of physical evidence found that people with PKU may have lower levels of certain brain chemicals called neurotransmitters.
          • The defective enzyme in PKU, PAH, has the job of changing some of the Phe you eat into a different amino acid called tyrosine (Tyr). Tyr is used to make a brain neurotransmitter (messenger) chemical called dopamine. Evidence suggests that changes in PAH function in PKU can cause lower amounts of dopamine in the brain.
          • Some symptoms of low dopamine include drastic mood swings, difficulty paying attention and sleep disturbances.
        • Bear in mind that it is hard to do these studies, so there aren't that many documented cases. More physical evidence is needed to draw any conclusions. The jury is still out, but the evidence is piling up.
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  • 3. Cognitive, Psychological and Behavioural
        Assessment Based Evidence
        for Altered Brain Function in PKU
    • Summary
      • Some researchers gather physical evidence using sophisticated brain imaging machines. There are also other researchers such as psychologists, psychiatrists, and sociologists gathering psychological evidence to determine whether the current PKU standard therapy involving a Phe—restricted diet and meeting blood Phe targets can still lead to changes in the brain.
        • In fact, psychological evidence in the form of IQ testing was the main evidence to show the dramatic improvements in PKU patients who were treated with the Phe-restricted diet shortly after birth. Prior to current standard PKU therapy, IQ in PKU was dramatically lower in untreated individuals.
          • Although a recent study suggests that short-term spikes in blood Phe levels can cause lower IQ, the vast majority of studies indicate that maintaining a Phe-restricted diet and blood Phe levels within range result in normal IQ.
        • The research focus has shifted away from IQ to determining if more subtle psychological/emotional changes occur in PKU patients adhering to diet therapy.
          • One area of research involves something called executive function (EF) which is deliberate, conscious control over your own thoughts, actions and emotions. Some of the many characteristics of people with EF difficulties include disorganization, being easily frustrated, and poor judgment. The evidence for EF problems in diet-controlled PKU is a mixed bag, with some studies finding problems and some finding none. Researchers are looking to do a Iarge-scaIe Iong-term study on EF in PKU in hope of getting a more accurate picture of what is going on.
          • Another area of research is how quickly you can react to incoming information, process it, understand it and use it. This is known as information processing speed and can be measured by a variety of tasks with time limits. People who suffer from problems in information processing speed might take longer to start/complete complex tasks and appear to struggle. More evidence is required to determine if information processing is affected in diet controlled PKU. However, one strong piece of evidence suggests that if one stays within the current blood Phe range for their age group then information processing will not be affected.
          • The chemical brain imbalances found in PKU are similar to those Found in children with attention deficit hyperactivity disorder (ADHD). For this reason researchers are interested in knowing if ADHD or ADHD symptoms are more common in people with PKU. Symptoms of ADHD fall into one of three large categories: inattention (inability to concentrate), hyperactivity and impulsivity. Using standardized criteria for diagnosing ADHD, researchers have found that people with PKU are more likely to have ADHD or symptoms of ADHD. Surprisingly, only a handful of studies have been done and more research is required to strengthen the possible link between PKU and ADHD.
          • Researchers have also looked for learning disabilities and problems in academic performance in people with PKU. Of the studies done to date, it appears that math skills may be affected in some individuals with PKU. These are small studies and not conclusive by any means.
          • Studies looking at whether psychiatric disorders occur more frequently in PKU showed no significantly different overall rate than the general population. However, psychiatric symptoms have bcen uncovered in some PKU patients that include, but are not limited to, anxiety, depressed moods and phobias. Most convincingly was a recent study clone in adults that showed that higher blood Phe levels were associated with increased self-reported incidences of depression and fatigue.
        • More psychological evidence is needed to determine the nature and frequency of any problems that may be occurring at higher rates in PKU individuals who adhere to their recommended blood Phe targets. However, it is clear that higher blood Phe levels do strongly correlate with many of the psychological and behavioral symptoms observed.
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  • 4. Theories for Elevated Phe Levels Altering
        Brain Function in PKU
    • Summary
      • Phenylketonuria (PKU) is characterized by elevated blood levels of the amino acid phenylalanine (Phe), which is mainly obtained from eating proteins. The symptoms of PKU almost exclusively concern the brain, so how does an elevated blood Phe level affect the brain?
        • The brain is protected bv a surrounding layer called the blood brain barrier (BBB), which allows some material to cross while preventing others. The brain needs certain material to cross the BBB to allow for normal functioning. One of the raw materials the brain requires are amino acids including Phe for building brain proteins and making chemical messengers called neurotransmitters.
        • The way Phe and other amino acids get across the BBB and into your brain are by using transporters. This is similar to a bus (the transporter) carrying people (the amino acids) to a destination, each seat gets taken up by an amino acid and the next stop is the brain. This analogy provides a visual description of the main theory of how elevated blood Phe can affect normal functioning of the brain.
          • Imagine that elevated blood Phe in PKU can lead to Phe taking up more seats on the bus, which may cause two things:
            • More Phe gets transported into the brain
            • Less of the other amino acids that share this bus get transported to the brain because Phe is taking up their spots!
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  • 5. Current and Promising PKU Therapies
        and Assessments
    • Summary
      • The challenge of sticking to the restricted diet is a major reason why scientists and researchers are looking for alternative and/or supporting PKU therapies to the Phe-restricted diet. The goals of these therapies range from improving the taste and variety of low-Phe foods in an effort to improve adherence, to providing a cure for PKU so that diet restrictions would no longer be required. They can be categorized into one of 3 categories: 1) Food and Drug Administration (FDA)—approved drugs that have gone through rigorous testing standards for safety and efficacy: 2) medical foods (which do not require FDA approval); and 3) experimental gene replacement and enzyme substitution therapies that have yet to be approved for use.
        • FDA—approved drugs lor PKU
          • Sapropterin therapy (BH4; tetrahydrobiopterin; sapropterin; Kuvan®):
            Studies have shown that taking daily pills of sapropterin Iower and stabalize blood Phe level in some people with PKU. Sapropterin is available by prescription and is meant as an additional therapy to the Iow-Phe diet. To determine if sapropterin therapy will work, the physician puts the patient on the drug tor a trial period and evaluates its effectiveness.
        • Medical foods
          • Large neutral amino acid (LNAA) therapy (PreKUnil, NeoPhe, PheBLOC):
            LNAA therapy aims to decrease the amount of Phe entering the circulation and the brain. Several formulations of LNAA are commercially available. In theory, LNAA therapy might be useful for all people with PKU, but it is only recommended for older teens and adults due to its unknown safety and effectiveness for younger PKU patients.
          • Glycomacropeptide (GMP): GMP is a protein derived from goat milk during cheese making that is almost free of Phe. According to those surveyed. it has a better taste than current protein substitutes. Experts believe if more and better-lasting low-Phe protein options become available, patients with PKU are more likely to adhere to the Iow-Phe diet. Some GMP-containing products are already on the market for PKU, such as BettermilkTM with GMP. Experts feel that many more GMP—containing products will be available for PKU in the near future.
        • Not yet approved experimental gene replacement and enzyme substitution therapies
          • Enzyme substitution therapy (PEG-PAL): Enzyme substitution therapy substitutes the activity of an enzyme for the deficient PAH enzyme in PKU. The enzyme substitution allows Phe to be broken down, thereby decreasing blood Phe levels. Results of a Phase 1 human clinical trial showed substantial blood Phe reductions with no reported serious safety concerns. Phase 2 studies with a larger population of PKLJ patients receiving varying doses of PEG-PAL are currently underway.
          • Hepatocyte transplantation: PAH, the defective enzyme in PKU, resides in liver cells (hepatocytes). A promising line of research involves replacing some of the defective liver cells with liver cells that have normal PAH activity, causing Phe levels to drop and become normal.
          • Gene therapy: Gene therapy would introduce a functional and stable PAH gene into PKU individuals to supplement or replace the defective PAH gene, thereby providing a cure for PKU. However, the technology required is still experimental and safety issues are substantial. Several laboratories have achieved varying degrees of success in correcting PAH deficiency in PKU mouse models using gene therapy, but there are no existing human trials.
      • Psychological issues have been under-diagnosed or insufficiently treated in many metabolic clinics. In addition, patients have limited access to psychologists familiar with metabolic disorders. It is a goal of PKU health practitioners to be able to provide an "early warning" system that would routinely assess psychological and emotional health in PKU patients. Once detected, appropriate and timely therapy can be provided. Experts envision a uniform and routine set of psychological assessments administered at metabolic clinics. This would allow clinics to provide routine and reliable screenings for psychological and emotional problems in people with PKU of all ages.
        • Results from a recent study using this model showed that 29% of patients screened positive for psychiatric distress. More adults than children tested positive (43% vs. I7%). In addition, patients who screened positive had significantly higher blood Phe levels.
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  • References and a Glossary of Terms