Thursday, April 23, 2009

Phenylketonuria (PKU) or ADHD?

ADHD vs. Phenylketonuria: A possible misdiagnosis?

If you’ve never heard or seen the term phenylketonuria (PKU) before, you are not alone. However, here’s a quick experiment. Go look at the back of a 2-Liter bottle of diet soda. Near the bottom of the back label, you will probably see a small warning label that says something along the line of “Phenylketonurics: contains phenylalanine” (individuals with phenylketonuria are often referred to as phenylketonurics).

The reason that this warning is on the back of only diet sodas and not regular ones is because the artificial sweetener Aspartame (Nutrasweet) contains the amino acid phenylalanine as one of its two primary components. When phenylketonurics, take in large amounts of this artificial sweetener, they get a large buildup of this amino acid in their bloodstream which they have trouble clearing. As a result, they often suffer a number of physiological problems, in, but not limited to, the nervous system.

The conversion process of phenylalanine to dopamine and how it relates to ADHD:

Phenylketonurics are those individuals who, for typically genetically predetermined reasons, are unable to break down and process the amino acid phenylalanine. This process actually has several implications that can relate to ADHD. We have spoken extensively about the neurochemical dopamine in various other posts. In general, chemical imbalances of this important neurotransmitter are frequently at the helm of ADHD and related disorders (typically shortages of dopamine are found in the "gaps" between neuronal cells, and most stimulant medications for ADHD work by resetting dopamine levels within these gaps). As we can see below, the body can actually manufacture this important brain chemical from various sources or starting materials, including phenylalanine (providing that the individual is capable of manufacturing all of the necessary enzymes in the conversion process. For PKU patients, this conversion process is hindered, and typically leads to shortages of dopamine). A rough sketch of the conversion process is listed below:

So what’s the point?

I have highlighted the chemical changes above, using different colors to represent the enzymes used and the chemical changes that these enzymes are responsible for (note the red and blue colors). As we can see above, the first step of the metabolism of phenylalanine to dopamine is done by adding a hydroxyl ("OH") group to phenylalanine, converting it to another amino acid, tyrosine. The chemical change is highlighted in red. (As an interesting side note, tyrosine is sometimes used as an ADHD supplement or auxiliary to medication treatment, even though the effectiveness of tyrosine for treating ADHD is questionable. Note that if one with PKU were to start with tyrosine, they would bypass the step of the chemical process of converting phenylalanine to tyrosine, which would help with the deficient enzyme phenylalanine hydroxylase. This enzyme will be addressed further down in the post).

Further modifications carry it to the product dopamine, which require two other enzymes (as a side note, the conversion of tyrosine to dopamine, in addition to the two enzymes listed above, also requires an adequate supply of iron. This is one reason why maintaining ample iron stores is necessary in combating ADHD and related disorders, and why an iron deficiency can elicit some of the negative behaviors characteristic of ADHD patients). As an aside, we have previously investigated how iron deficiency can affect both ADHD and sleep disorders and how iron supplementation can potentially offset the toxic effects of lead in ADHD patients.

You'll notice that the first step of the conversion process is blocked for individuals with PKU. This is due to a mutation in the gene that codes for this enzyme, the phenylalanine hydroxylase gene. For reference sake, the phenylalanine hydroxylase gene is located on 12th human chromosome. Remember that it is the mutated form(s) of the gene that can lead to PKU, the vast majority of the human population carries the regular form.

Fortunately, phenylketonuria is a rare genetic disorder, affecting less than one percent of the population. This is due, in part, to the fact that it must be present in both parents to be passed on to a child. It is almost always detected in most newborn screenings. However, it is possible to be missed, especially if a milder form is present. While there are several key differences, some of its symptoms mimic problems that correlate with attention deficit disorders. These include:

  • Hyperactivity
  • Erratic Arm and Leg Movements (can be similar to tics or Tourette's-like behavior, which often accompanies ADHD individuals as a comorbid disorder)
  • Social immaturity and impairment of mental skills
  • Learning disabilities

As we can see, these four traits are classic behaviors seen in many children diagnosed with ADHD. The first two are more characteristic of the hyperactive/impulsive or combined subtypes of ADHD, the fourth is more tied to the inattentive form of the disorder, and the third can fall into any of the categories. Interestingly, both ADHD and PKU disorders share a common brain region of deficit, the prefrontal cortex.

Key Differences Between ADHD and PKU:

As we can see, there are a number of features and methods in place such that the possibility of misdiagnosing ADHD as PKU and PKU as ADHD by a skilled professional is relatively small. However, in addition to PKU, there are genetic deficiencies which result in compromised activity of the phenylaline hydroxylase enzyme by around 5 to 10%. While these deficiencies are milder than in full-fledged phenylketonuria, it does bring up a critical point that intermediate states do exist between being diagnosed with PKU and not having PKU. It is possible that individuals in this potentially vulnerable intermediate state of enzyme deficiency may be more susceptible to disorders such as ADHD. Of course, this is just a personal hypothesis.

Nevertheless, the main goal of this post was to highlight some of the key genetic, physiological and behavioral overlaps of the two disorders. It is my personal belief that looking for common underlying trends between even the most disparate disorders can offer a wealth of information into some of the underlying causes of the individual disorders that we would otherwise miss. In other words, I think we often sell our selves short by not digging "deep" enough in our investigations of the fundamental causes of diseases and disorders such as ADHD and phenylketonuria.

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Anonymous said...

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shashank said...

Here is a link to more information about the genetics of Phenylketonuria that was prepared by our genetic counselor and which has links to some useful resource for those dealing with this condition: There is also a number listed for anyone who wants to speak to a genetic counselor by phone. I hope it helps. Thanks, AccessDNA

Anonymous said...

how do you test for PKU and are there foods to avoids if your child has it? would ADHD meds work if your child has PKU instead?

Anonymous said...

pku is currently tested for by a heel stick shortly after birth now.
very important to head of the symptoms caused from undiagnosed pku. Mandatory tests began in the US approximately 1967

Anonymous said...

As a person with PKU, it is possible for people with PKU to have ADHD if they do not follow the low protein diet at some point of their life. Also, people with PKU have a genetic mutation of each of the 2 genes for the production of the PAH enzyme, but there are people who are carriers of PKU without having PKU because they only have a mutation on 1 gene. They would be at a higher risk for ADHD, especially if they consume Aspartame.

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Thanks for posting this. Soon to be moms should be wary of this. After giving birth, their newborn should undergo necessary laboratory tests or newborn screening to determine early inborn diseases and defects.