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:

• IQ: Most individuals with ADHD typically fall within the normal range on most IQ tests (however, cases of abnormally high or low IQ scores certainly exist). For individuals with PKU, however, a depressed IQ is almost always seen (PKU is a relatively common cause of mental retardation). For example, in a British study, it was found that IQ scores for children with PKU hovered around 90. The IQ scores were closely correlated to the ability of the individual treatments to keep the phenylalanine levels below a specific benchmark in the blood. In addition, differences in subscores, indicate a possible deficit in spatial processing. Interestingly, visual-spatial deficits are often present in ADHD and its comorbid disorders as well.
  
  
• Head size: Abnormally small head sizes are often seen in PKU. While smaller relative volumes in specific brain regions are often seen in ADHD, the overall head size differences are typically not as pronounced as for PKU. Interestingly, the effects of smaller head sizes and brain regions for both PKU and ADHD, respectively found the differences to be much more pronounced in boys than in girls. Note that we have previously discussed several other gender differences in ADHD.
  
  
• Onset of symptoms: In general, PKU symptoms are fully manifested in the first two years of life. These include both mental and physical impairments. While symptoms of ADHD can often begin to appear early on, they often do not fully appear until much later in life. As a result, difficulties in pinning down age-specific aspects of ADHD persist.

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.

Celiac Disease causes ADHD Symptoms

One of the biggest challenges in diagnosing and treating ADHD is trying to separate it out from other disorders that often present similar-looking symptoms. One such disorder is known as celiac disease. When gluten (a type of plant protein found in corn and wheat) is ingested in individuals with celiac disease, an inflammatory response in the upper portion of the small intestine occurs. When repeatedly challenged by gluten exposure, damage can occur to this portion of the digestive system, which leads to painful symptoms and impaired digestive and absorptive function.

The latter is of particular interest, since we have seen in other posts that nutrient deficiencies can lead to or exacerbate the onset of certain ADHD symptoms. For example, iron has been shown to be a useful supplement in treating certain underlying factors in ADHD, as seen in previous posts. It is thought that a celiac disease-damaged system can contribute to iron deficiency, likely through impaired iron absorption, thus presenting a challenge to the ADHD patient.

Interestingly, celiac disease has also been linked to other neurological disorders such as depression and depressive-like symptoms. This may be due to poor absorption of the amino acid tryptophan (which is found in high concentrations in turkey, and is a big reason why turkey can make a person sleepy). Tryptophan is converted to another important agent in the body called serotonin, which is often found to be reduced in patients with depression and other related symptoms (sugar and milk can also give a temporary rise in serotonin levels, which is why ice cream and chocolate are often "comfort foods").

In addition to depressive behaviors, possible connections have been identified between celiac disease and other metabolic disorders such as diabetes and thyroid problems. We have explored the possible connection between ADHD and thyroid dysfunction in a previous post. Additionally, there is a possible connection between celiac disease and other symptoms or common ADHD comorbid disorders such as epilepsy, dyslexia (which is thought to be a possible result of impaired gluten breakdown), anxiety disorders and social phobias and impaired sensory functions.

The good news to all this is that a gluten-free diet (which, unfortunately, can be very difficult to administer due to the prevalence of wheat in the Western diet) has been shown to ameliorate most of these negative symptoms. A study done on celiac disease patients and ADHD symptoms found that after treating patients with a gluten-free diet for 6 months, a number of ADHD-like symptoms subsided. The study used a method called Hypescheme, which is a type of computerized checklist used to quantify and analyze data involving ADHD and related disorders in a statistically significant fashion.

Statistically-significant improvements were seen in the following areas: attention to detail, duration of attention span, ability to complete tasks, distractibility, fidgety behavior, leaving a seat (when expected to remain seated), noisy disruptions and answering questions prematurely.

However, statistically significant improvements were not seen in other categories characteristic of ADHD. These include: losing/forgetting materials as well as restless and interruptive behaviors.

In previous posts, we have seen that certain treatments may be favorable for either inattentive ADHD type behaviors, hyperactive-impulsive ADHD behavior, or a combination of the two, called the ADHD Combined Subtype. It is interesting to note that the gluten-free diet results in improvements in characteristics that may be considered either "inattentive" (task completion, attention to detail, distractibility) or "hyperactive-impulsive" (fidgeting, noisy behavior and blurting out answers prematurely). While many studies on the possible connection between food additives and ADHD (see last paragraph of this post for more on this) seem to highlight the hyperactive side of the disorder, this celiac disease study seems to indicate a more mixed improvement across the whole spectrum of the disorder when a gluten-free diet is introduced.

Given the fact that many individuals who have celiac disease lack many of the outward signs of digestive symptoms of the disorder, and the fact that there are so many potential overlapping factors between the symptoms of ADHD and celiac disease, it is quite possible that you or your child's ADHD may be a misdiagnosis of an underlying cause of celiac disease or a related disorder. I therefore strongly recommend individuals who are diagnosed with the disorder of ADHD (especially those who have had poor or adverse responses to previous treatments) to consider testing for celiac disease. This of course, is not meant to knock the competence of most physicians and other professionals, but rather a plea to eliminate a potentially common misdiagnosis through a relatively simple procedure. Several antibody-based tests can be used to detect celiac disease or related disorders with relative ease.

In general, there has been a lengthy debate over the connection between ADD and ADHD and food allergies. While previous studies had certainly performed, a landmark study was done in the mid 1970's by Dr. Benjamin Feingold which sought to link the relationship between food additives and food coloring and hyperactivity. Numerous studies have since followed on this topic, many of which have supported Feingold's hypothesis and many which have refuted it. As a result, a number of physicians began to recommend elimination diets in an attempt to control attention deficits and hyperactive behavior. We will be investigating the original Feingold article and summarize the effectiveness of these elimination diets in treating ADHD symptoms in the near future.