ADHD Gene Falls Inside Reading Disabilities Genetic Region

ADHD and learning disabilities are often seen alongside each other (many actually label ADHD as a learning disability itself, but most of the medical community considers ADHD a separate entity). Now there is some evidence that ADHD and reading related learning disabilities may be genetically linked:

A quick background of genetics: The human body consists of somewhere around 30,000 to 50,000 genes (the numbers actually vary, as actual genetic regions are not fully pinned down, and various regions of DNA called pseudogenes, exhibit genetic qualities themselves). These genes are spread across 23 pairs of chromosomes (one copy per each pair), and have a relatively wide degree of diversity among individuals. These genes are essentially lined up nearby each other, such as houses in a neighborhood. When the genes are transmitted from parent to offspring, the closer two genes are to each other, the more likely they will be passed on together. Thus if an individual has an "ADHD gene" form located right next to, say a gene which has certain forms which increase one's susceptibility to color blindness (this is just a hypothetical example), we would likely expect a greater than normal co-occurrence of ADHD and color blindness.

The ADHD gene in question is often referred to as the Protogenin Gene, located on the 15th human chromosome. If falls in a region flanked not only by what is considered a genetic region implicated for reading disabilities. In addition, this gene is also believed to aid in the physical developments of the nervous system and neuronal cells at the embryonic stage of life.

While these findings are preliminary, they suggest a possible genetic factor for the connection between ADHD and reading disorders (of course we should not overlook the obvious fact that having attentional or concentration difficulties also has a negative impact on one's reading capabilities, especially if required to read complex material for long periods of time). It also lends credence to the growing body of evidence that suggests the role of developmental delays in the onset of ADHD.

ADHD and Handwriting: What's the Connection?

The link between ADHD and Poor Handwriting (Dysgraphia):

It has been well-known for years that individuals with ADHD are often more prone to problems with penmanship, that is, they have trouble producing legible handwriting. But why is this the case? There are several theories out there, and multiple studies showing how effective ADHD treatments can also result in major improvements with a person's handwriting. I will review some of the current findings on the topic:

1. A group in Israel sought to investigate whether the problem with handwriting in ADHD children was due more to underlying language problems (i.e. spelling, formulating sentences, etc.) or more due to the mechanical problem of the physical writing process. While they concluded both were at play, the results of their study seemed to indicate that underlying language difficulties played only a secondary role to the writing difficulties and that the primary cause was due to "non-linguistic deficits". Interestingly, the group did find specific patterns to the frequent mis-spellings of words, instead of a host of random, unrelated errors. This blogger personally found the conclusion of the article's summary to be particularly amusing, as it recommended a "judicious use of psychostimulants".
   
   
2. Continuing on with the "judicious use of psychostimulants" theme, we must investigate the effectiveness of one of the most common types of stimulants for ADHD, methylphenidate (Ritalin, Concerta, Metadate). This drug has elicited a number of positive effects as far as improving both the cognitive and physical aspects of handwriting, as concentration or attentional lapses subside, allowing the thought process and physical act of writing to be performed simultaneously.
   
   However, another study found that even medication with methylphenidate had its limits, and that handwriting gradually deteriorated as the child continued with the writing process. This suggests that for long essays or standardized tests (such as the writing portion of the SAT's, or A.P. exams), medication with methylphenidate or other stimulants may only be useful early on.
   
   
3. Specific Genetic Factors may underlie both ADHD and handwriting problems: There was an interesting study done by a Dutch group which suggests that there may be some sort of genetic factor that inhibits fine motor movements (such as those required for writing) which then make their way over to ADHD. In other words, this study seems to suggest that ADHD is a secondary problem to fine motor problems such as dysgraphia (typically, it's the other way around, where ADHD is considered the primary disorder). This study discovered that non-ADHD siblings (who, by definition, share half of the ADHD child's genes, provided they are not identical twins) of the ADHD children also had difficulties with more complex forms of the writing process, compared to the general population. In other words, these siblings had some degree of impairments with the writing process, but not to the degree of their ADHD siblings.
   
   This suggests that these non-ADHD siblings may have enough genetic "impairments" to share some of the comorbid writing problems as their ADHD counterparts but not enough to manifest an outright diagnosis of ADHD themselves. In other words, the comorbidity (co-occurrence of) ADHD and dysgraphia is apparently not an all-or-nothing phenomena.
   
   
4. Differences in hand-eye coordination and motor control problems are more pronounced in the left hand for ADHD vs. non-ADHD children: We have previously investigated key brain regions commonly associated with ADHD, including differences in relative brain region size, use of brain regions, bloodflow patterns, brain electrical activity patterns, sense of smell, the relationship to alcoholism, brainwave patterns, and genetic differences targeting specific brain areas.
   
   However, it is worth noting that these brain regional differences are often not laterally symmetric, that is they may only be on the left side or right half of a particular brain region. This lopsidedness may play a role in manual dexterity and motor coordination differences between ADHD and non-ADHD individuals, which appear to be even greater in the left hand (which, in most cases the non-dominant one).
   
   The article which found this discrepancy between the different sides of the body goes on to suggest that testing for fine motor coordination in ADHD kids would be better suited for the left hand, since the effects are more pronounced. This leads to this potentially intriguing question: If handwriting is done with the dominant hand, does it stands to reason that handwriting difficulties are just the tip of the iceberg with regards to immensely greater fine motor difficulties? In other words, if an ADHD child is having trouble writing with his or her dominant right hand, how bad would the fine motor deficits be if they needed to use their left hand for something like catching a baseball, or shooting a left-handed layup in basketball?
   
   Based on this finding, it appears that poor handwriting may be just one aspect of a much larger fine motor disability. Another possibility, however, is that using one's non-dominant hand requires a higher order cognitive process than utilizing one's dominant hand for a routine task. This possibility may actually carry some weight, as we have seen in previous posts how discrepancies between ADHD and non-ADHD individuals begin to balloon as the cognitive processes become increasingly more difficult.
   
   This also seems to jive with the underlying genetic component of these disorders proposed by the ADHD sibling study in the previous point, in which the non-ADHD siblings had trouble only with the higher-order writing processes and not the more automatic ones (such as doing a simple task with one's dominant right hand). Unlike the Israeli study, this seems to favor more of an underlying cognitive discrepancy as the main culprit of poor handwriting in ADHD, as opposed to a more "mechanical" one.
   
   
5. The genetic discrepancies in ADHD and fine motor impairments may be one of motor timing: Going back to the genetic aspects of ADHD and motor impairments such as dysgraphia for a moment, it is worth mentioning another finding by a group investigating difficulties in timing fine motor applications in ADHD children. This study utilized tests such as pressing a button on self-determined one second intervals (and measuring how close the child's perceived timing matched up with "real" one-second intervals), tapping one's finger as many times as possible within a given time limit (a relatively common test for individuals with ADHD and related disorders) and tests which measured reaction timing to moving objects and visible changes (which may have direct implications as to how well a child would perform in a sport involving reacting to moving objects, such as baseball, lacrosse, or tennis). Based on these tests, the authors concluded that the motor impairments in the ADHD children were more likely due to timing issues as opposed to generalized motor problems.
   
   As a blogger's note, this might explain some of the difficulties in the handwriting mechanics, such as crossing "t's" and dotting "i's", which essentially involves hitting a "target" on the paper, or keeping up with a teacher while taking notes (which is a very time-dependent process which often requires a fast execution of handwriting numbers, letters, diagrams, and symbols).

A number of books on the subject of ADHD and writing disorders show actual handwriting samples of children on and off medication for ADHD. The differences are astounding. Additionally, differences in complexity and eloquence in creating stories are often extremely pronounced depending on the mode of expression. For example, actual cases involving gifted children with ADHD have highlighted how a child can concoct an thorough, detailed, and well-rounded story orally, but when asked to write out the same story, he or she is scarcely able to construct even a single, legible, coherent paragraph.

This brings up the important issue as to whether children with ADHD should be afforded opportunities to use different modes of communication for their assignments, such as dictating or typing as opposed to handwriting. It appears that for many, the actual process demanded of ADHD children for actually writing may rob or ferret away the majority of their cognitive capacity, resulting in a barren landscape of creativity or eloquence.

Given the fact that many children with ADHD respond positively to alternative learning or expressive styles such as predominantly auditory (dictating) or kinesthetic (typing) means of expression, numerous questions surrounding the degree of accommodation for these ADHD children must be addressed. It is my personal hope that the findings of some of these studies will shed some light onto the mechanical and cognitive impairments of the physical writing process for children with ADHD will help shape an educational environment to help these children to flourish.

Bedwetting ADHD Kids and Depressed Dads: Is there a connection?

ADHD and Bedwetting (Nocturnal Enuresis): How are the two related?

There is a relatively recent publication that came out within the last couple of weeks on the relatively high rate of occurrence in bed wetting (enuresis) among ADHD children, which I believe is worth sharing. We have previously investigated this ADHD and bed wetting connection (note that bed wetting may be more likely to be seen alongside the inattentive subtype of ADHD). However, this study offers some additional insight into this strange association between the two disorders. Here are some important points worth mentioning:

• Overlapping Drug Treatment for ADHD and bedwetting: It stands to reason that if a particular drug or agent is effective in treating multiple disorders, there may be a distinct possibility that those two or more disorders may share some type of underlying cause(s) or defect(s). For example, Tofranil or Imipramine, a drug used to treat enuresis and depressive disorders can possibly be useful as a treatment option for ADHD. We have also investigated the potential role of Reboxetine as a potential ADHD treatment in previous entries. Some work has found Reboxetine to be useful in treating therapy-resistant enuresis as well.

• Prevalence of Enuresis in ADHD: Enuresis refers to urinary incontinence which is limited to the night-time. Additionally, the term is typically limited to individuals over the age of 5 (i.e. a 3-year-old child who frequently pees in their pants would not be considered as suffering from enuresis, at least in the context of this study). The article cites other studies in which the rate of bedwetting (enuresis) in ADHD is as high as 30%, although other studies have it down around 10-20%. Still, compared to the general population, (factoring in things such as the age of the child, of course)the high rate of bed wetting in ADHD is especially noteworthy. There is some evidence from other studies that ADHD and enuresis may be more intricately linked than previously imagined. For example, one particular study has shown that treating urinary incontinence has a higher rates of failure in children with ADHD vs. non-ADHD children.
  
  
• The role of Oppositional Defiant Disorder (ODD) on Bed wetting: The study examine several different psychiatric disorders which frequently occur alongside of (or are comorbid to) ADHD. These include depression, anxiety disorders, obsessive compulsive disorders, tic disorders, nail biting, bruxism (teeth grinding), conduct disorders and oppositional defiant disorders. However, out of all of these different disorders which often appear alongside ADHD, the only one which exhibited a statistically significant correlation to increases in bedwetting was oppositional defiant disorder. Interestingly, oppositional defiant disorders have been associated with bedwetting in other ADHD studies.
  
  As its name suggests, Oppositional Defiant Disorder is a disorder in which a child exhibits disobedience, irritability and hostility towards authority figures beyond the range of normal age-appropriate behaviors. Of course there is a significant gray area with regards to what is age appropriate, especially when the child's environment is considered. Nevertheless, Oppositional Defiant Disorder (or ODD) is much more than just routine temper tantrums. Oppositional Defiant Disorders may also be associated with auditory processing issues and ADHD. It is somewhat interesting that anxiety disorders, which have also been correlated to oppositional behaviors, did not elicit a significant positive correlation to bed wetting.
  
  
• The autonomic nervous system as a potential underlying cause of ADHD, bedwetting and Oppositional Defiant Disorders: The autonomic nervous system is the part of the nervous system responsible for involuntary muscle actions such as digestive processes, blood vessel contraction, etc. It is subdivided into the sympathetic and parasympathetic nervous systems, which often act in a sort of "push-pull" opposition to each other. For example, the sympathetic nervous system does things such as boosting heart rate and constricting blood vessels, while the parasympathetic nervous system is in charge of activities such as reducing heart rates and relaxing sphincter muscles (which plays a role in bladder control).
  
  Typically, the sympathetic and parasympathetic components of the nervous system are kept in balance, but this balance may be thrown out of whack and result in numerous disorders. For example, it is believed that the parasympathetic nervous system is over dominant in cases of Oppositional Defiant Disorders (ODD). The study found that for ADHD and Oppositional Defiant Disordered children, functions such as heart rate were controlled excessively (if not almost exclusively) by the parasympathetic portion of the nervous system (while non-ODD and non-ADHD children had both sympathetic and parasympathetic controls operating on their heart rates. This suggests a common underlying imbalance among the different components of the nervous system which is common to ADHD and ODD individuals and often separates them from the non-ADHD'ers. Interestingly, other studies have indicated that bedwetting or generalized incontinence problems may also be caused by an overactive parasympathetic nervous system, which suggests that ADHD, ODD and night-time bedwetting may all share some underlying causes within the nervous system.

• Connection to Parental Depression: I personally found this observation to be interesting. The study found that the prevalence of bedwetting in ADHD children was higher if the father (but not the mother) of the child was suffering from some sort of major depressive illness. The article did not express an opinion as to whether these depressive symptoms were due in part to the child's bed wetting problems or whether there was some underlying mechanism at work.

• ADHD medications may Influence Enuresis: The authors highlight some other works in which popular ADHD medications may either increase or decrease the risk of bedwetting in ADHD children. For example, the article highlighted a case study (by the same author) in which treatment with methylphenidate induced nocturnal enuresis. Methylphenidate is one of the most common ADHD drugs, and often goes by the common trade names Ritalin, Concerta, Metadate and Daytrana (the patch form of the drug). Of course this is based on only one individual case, but for those of you who have read this blog on a frequent basis, will know that I like to report on some of these abnormal occurrences (for reference sake, here is an earlier blog post I have done on the possible connection between methylphenidate and excessive talking. While based on an isolated case report, I believe that this zany potential side effect was at least worth a mention). On the flip side, however, the non-stimulant alternative ADHD drug, Atomoxetine (Strattera) can be a useful treatment for enuresis. This blogger would personally like to see additional studies on whether ADHD children with a comorbid bedwetting condition actually saw a better reduction in their ADHD symptoms while on Strattera than while on methylphenidate. If this were the case, then bedwetting may actually served as a useful tip-off as to which type of ADHD medication would work best for that particular child.

Strattera (Atomoxetine) response may be affected by SLC6A2 gene

About a month ago, we were discussing the ADHD gene SLC6A2. Located on the 16th human chromosome, different variations of this SLC6A2 gene are believed to play at least somewhat of a determining factor as to the genetic predisposition towards attention deficit hyperactivity disorders (ADHD). We saw that this gene was also correlated to anxiety and depression-like symptoms (which commonly occur along many ADHD patients) and that these genetic factors were slightly stronger in girls.

Atomoxetine (Strattera) is a non-stimulant alternative to medication treatment for ADHD. Unlike most stimulant medications, which interfere and regulate the pathways of the neurotransmitter dopamine, atomoxetine acts upon the pathway of the neuro-signaling agent norepinephrine. While dopamine-related stimulant medications for ADHD can worsen accompanying anxiety and depressive-like disorders (extreme caution is necessary when prescribing stimulants if a severe co-illness of anxiety or depression is present alongside ADHD), Strattera has shown to extremely beneficial in the co-treatment of depressive-like illnesses, especially when used alongside the SSRI class of antidepressant drugs.

A recent publication in the journal Neuropsychopharmacology highlights the potential connection between variations of the "ADHD gene" SLC6A2 and the effectiveness Strattera (Atomoxetine) for treating ADHD.

It is important to remember that for most genes, there are slight variations in the different forms within the human population. For most, these small changes in DNA do not result in any major physiological differences, but for some, even a change of one or two units of DNA can make a huge impact on biological functions, such as response to a specific medication. We have previously discussed how both the Catechol O-Methyltransferase (COMT) and CREM genes, may both dictate different dosing levels for ADHD medications.

Based on the SLC6A2 and Strattera study, it appears that individuals with specific gene variations of the SLC6A2 gene had a significantly more positive response to atomoxetine (based on a common behavioral rating process typically used to assess ADHD and related disorders), than were others with different variations of the gene. These effects were seen even when another gene (the CYP2D6 gene, located on the 22nd human chromosome and is responsible for the metabolism of atomoxetine/Strattera) was taken into account.

We will hopefully discuss these findings in more detail later, but the main point to drive home from all of this is the concept of how individual gene variation (i.e., which specific forms of a particular gene one has), can play a major role in predicting whether:

1. An individual will even respond to particular drug (such as Strattera for ADHD), and
2. Whether that individual's particular forms of these genes predispose him or her to requiring a higher (or lower) than normal dosage level than otherwise physiologically similar individuals to achieve the desired effects.

This blogger personally believes that we have just begun to scratch the surface in investigating the power of gene-medication interactions, and how these interactions will shape the landscape for ADHD treatment.

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.