Healthy polyphenols from food can be categorized into flavenoids and non-flavenoids (image 3).  Polyphenols are abundant micronutrients found in our diet.  They've been linked to preventing degenerative diseases like cardiovascular disease, cancer and dementia (1,2,3). Their exact mechanism of action isn't completely understood.  What is known is that they have anti-inflammatory and anti-oxidant properties (4,5,6).  

In addition to the above mentioned benefits polyphenols have been studied for their effect on those with Down syndrome.  These studies give some insight into the possibility that polyphenols have epigenetic properties and impact the expression of the DYRK1A gene, found on chromosome 21.  This gene codes for the enzyme Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A.  This enzyme plays a roll in cell proliferation (increase in number of cells) and brain development.  As with many genes, over-expression and under-expression of the same gene can be a problem.  Given that those with Down syndrome have an extra copy of chromosome 21 the over-expression of DYRK1A is considered to be a strong candidate gene for learning defects associated with Down syndrome (7).  

The polyphenol that has been most tested for it's impact on those with Down syndrome due to it's known ability to inhibit DYRK1A expression is EGCG (Epigallocatechin gallate).  Researchers in Spain tested EGCG in children with Down syndrome and found it "significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life" (8). EGCG has also been shown to play a role in preventing Alzheimer's disease which occurs in 100% of those with Down syndrome (9).

More evidence exists supporting the impact that polyphenols have on genetic expression.  In 2013 Pan reported, "Over the past few decades, polyphenols, which are widely present in foods such as fruits and vegetables, have been shown to exhibit a broad spectrum of biological activities for human health. Polyphenols reverse adverse epigenetic regulation by altering DNA methylation and histone modification, and they modulate microRNA expression or directly interact with enzymes that result in the reactivation of silenced tumor suppressor genes or the inactivation of oncogenes."(10). Susanne Henning and her team at the UCLA School of Medicine also reported in 2013 that EGCG does, in fact, inhibit DNA methylation (11). Cancer ican be prevented by inhibiting DNA methylation because methylation can block the expression os tumor suppressor genes.  You can read more about DNA Methylation in by blog post here.

Another popular polyphenol that has a lot of research supporting it's use in neurodegenerative diseases is resveratrol (12).  Resveratrol is found in red grapes and Japanese knotweed. It, too, has been tested in those with Down syndrome, but studies are few.  Researchers in Italy have reported "the natural polyphenol resveratrol, which displays a neuroprotective action in various human diseases but never tested in DS, restores oxidative phosphorylation efficiency and mitochondrial biogenesis."(13).  Many parents have started using resveratrol in their children with Down syndrome and are reporting immediate and clear increases in speech and cognition when starting resveratrol.  Unfortunately, no published studies exist currently to support this.

Ultimately, the multiple ways that dietary polyphenols positively impact human health cannot be denied.  But, is there a point that they can cause any harm or do they have any side effects? The answer is, "Yes".

Phenols need to be processed, metabolized and modified within the body in order to work properly.  The main enzyme that's involved in the processing of phenols is phenol sulfotransferase (PST).  This enzyme is heavily dependent on sulfur as you might be able to tell from it's name.  So, the intersection of sulfation and phenol metabolism within the body is an important one.  I'll start by talking about sulfation.

You can see from these steps that if sulfur in the diet, sulfur absorption, B6 or molybdenum are deficient this can create problems in a wide arrary of biological activities, including the activity of the PST enzyme.  When this enzyme is not supported by adequate levels of sulfate it creates an overload of phenols that are not processed properly.  Unfortunately there is no test for this.  It's based solely on symptoms, however there are some labs that can give clues to an impaired sulfation system. 

Some clues to sulfation issues with in the body on labs can be a high taurine in the urine.  This is termed "taurine wasting".  This is the body's means of removing toxic sulfite when it isn't converted properly to sulfate. The body "chooses" taurine because it is high in sulfur.  This creates an actual taurne deficiency. Supporting the SUOX enzyme with molybdenum can help to rememdy this.  In fact, researchers in Germany found a 20-fold increase in urinary taurine levels in those who were deficient in molybdenum (14). If B6 deficiency is seen on an organic acid test in an elevated xanthuernic acid, kynurenic/quinolinic acid then supplementing with B6 can also help support the CDO enzyme.

In addition to phenol overload, parents using polyphenols for their children should also know that phenols are strong infibitors of iron absorption (15) which can already be a problem for some children, especially those with gastrointestinal disorders. I often recommend to not start EGCG or resveratrol until ferritin is closer to 40 ng/mL or at least to take an iron supplement when needed, but as far from taking the phenolic compound as possible (i.e., iron at bedtime and EGCG with breakfast). As well, EGCG inhibits the catechol-o-methyltransferase enzyme (COMT) that breaks down estrogen, epinephrine and norepinephrine (adrenalin) (16).  Parents should be mindful of a potential increase in adrenalin when using EGCG.

Lastly, there are some that may have a mutation in their PST enzyme (17), making it work more slowly despite sufficient sulfate.  It's been estimated in unpublished data by Dr. Rosemary Waring that approximately 80-90% of children with autism struggle with the function of this enzyme either because of low sulfate levels or because of a defect in this enzyme that detoxifies environmental toxins, food dyes, additives, some medications, phenols made by the body and phenols obtained in the diet.

The first step is to remove or greatly reduce all high phenol foods and supplements for at least 2 weeks to see if symtpoms improve.  If they do, avoiding high phenol foods and supplements does not have to last forever. The goal is to support the PST enzyme by increasing sulfate blood levels.  Because sulfate can be difficult to absorb in the GI tract using epsom salt baths with magnesium sulfate on a nightly basis is an excellent way to increase sulfate in the body.  As well, taking molybdenum, B6 and magnesium can also support the sulfation pathways.  

Click on the image below to open a printable pdf to refer to often during the 2 weeks of avoiding foods high in phenols:

In addition to the above steps there also is an enzyme that can be taken as a supplement that helps process phenols.  It's xylanase.  The products below have been used successfully by many parents when helping their children with phenol overload.  I don't recommend simply starting this enzyme.  Removing high phenol foods and supplements for two weeks is the first step to lower the phenol load within the body.  Then slowly introduce high phenol foods with one of these enzymes. Only after no reactions are seen should high phenol supplements like EGCG and resveratrol be reintroduced.

Ultimately, parents should know that just because a supplement or compound comes from nature does not mean that it doesn't have side effects, especially when given in higher doses than would be obtained from food as in the case of supplements.  The benefits from these compounds can be great when the child's body is ready for it and all necessary cofactors are in place for it to work optimally. We all want to ensure that our children are given supplements that are helping them and not causing harmful side effects.

​The process by which mitochondria make energy in the form of ATP is complicated but can be broken down into four basic steps:

1. Glycolysis
2. Pyruvate Oxidation
3. Citric Acid Cycle (Krebs Cycle or Tricarboxylic Acid Cycle - TCA)
4. Electron Transport Chain (Oxidative Phosphorylation)

I will focus on the steps that occur within the mitochondria only. Those are the Citric Acid Cycle and the Electron Transport Chain. These last two steps can only occur in the presence of sufficient amounts of oxygen. When oxygen levels are low, like in sleep apnea or during times of intense exercise when oxygen demand from muscles exceeds available oxygen, pyruvate cannot be shuttled into the mitochondria. Lactic acid fermentation is used instead which is much less efficient and generates only two ATP molecules.
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The following video reviews the basic steps in the Citric Acid Cycle. Keep in mind, this is a basic representation and there are many other factors that are involved.  You should also know that ubiquinone is CoQ10.

The NADH and FADH2 that are generated from the TCA carry their electrons to the electron transport chain where they are used in the final step to make energy as shown in the video below. Check out that cool ATP synthase complex at the end....like mini turbines in every cell!

All of these processes work together in what's called "Cellular Respiration", so named because it's how our cells use oxygen (image 2).

I made this "puzzle" years ago to use for my students (image 3) and still have it on my bookshelf. I used to have them print it, cut out all of the parts and put it together at home. They would receive an extra point on their exam if they sent me a photo of it assembled. Typically the students who found it fun and helpful really didn't need the extra point on their exam.

It's easy to see here how our bodies work like well-oiled machines when provided with everything it needs to function properly. For every one molecule of glucose the body is able to make approximately 35 molecules of ATP: two from glycolysis, one from the TCA and 32 from the electron transport chain. Sometimes it makes less when this process isn't working as efficiently.

If you're craving even more information on this topic, this chapter of the The Cell by Alberts B, Johnson A, Lewis J, et al. outlines these processes in much greater detail: The Mitochondrion.

The areas of highest mitochondrial activity, based on the rate of ubiquinone reduction and oxidation, are the heart, kidney and liver (1). As well, because the brain is the most metabolically active organ in the body it is vulnerable to disruptions in mitochondrial function. 

Most conventional medical doctors are not trained to recognize mitochondrial dysfunction. Research supporting mitochondrial dysfunction as a clinical entity is vast and growing. However, as is often the case, much of this research is not incorporated into every day medical practice.

Several researchers have reported a connection between mitochondrial dysfunction and autism (2,3,4). In addition, mitochondrial dysfunction in Down syndrome has been well-established (5). Many biomedical clinicians have already come to accept that mitochondrial dysfunction is something to look for and treat in children with autism and other special needs. As well, many parents are seeing notable improvements in their children's health and development when mitochondria dysfunction is detected and addressed.

Because so many organs and processes of the body are dependent on ATP and the mitochondria that makes it, symptoms can be vague and impact many organ systems.  These symptoms include:

• Low muscle tone
• Difficulty swallowing
• Failure to thrive
• Learning disability
• Fatigue
• Delayed gut motility
• Heat/cold intolerance
• Migraines
• Lactic acidosis
• Liver disease
• Immune system problems
• Heart problems
• Kidney problems
• Neurological problems
• Autonomic dysfunction

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You can see how easily a doctor might dismiss these symptoms as Chronic Fatigue Syndrome, Irritable Bowel Syndrome or no diagnosis is made and "there's nothing that can be done". Many times pharmaceutical drugs will be used that mask these symptoms yet never really help the patient nor address the root cause of the patient's problem.

What do mitochondria need in order to function properly?

All of the above steps don't just magically happen. Each of the steps requires an enzyme to make it happen and those enzymes have cofactors that are required in order for them to work. In addition, nutrients don't just automatically cross into the mitochondria; some are shuttled in with carriers.
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Compounds they require to function properly:

1. CoQ10
2. B Vitamins
3. L-Carnitine
4. D-ribose
5. Iron
6. Alpha lipoic acid (6)
7. Thyroid hormone (T3 and T2)

CoQ10 is a fat soluble substance; hence its position within the inner cell membrane of the mitochondria.  It has three reduced states:

1. Ubiquinone - fully oxidized, missing both electrons it's capable of carrying
2. Semiquinone - missing one electron
3. Ubiquinol - fully reduced, carrying both electrons it can can carry

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Ubiquinone is typically used as a supplement when mitochondria support is the goal. Ubiquininol can be used as an antioxidant because it carries two electrons that can be used to limit the damage caused by reactive oxygen species (ROS). ROS create damage because they have an unpaired electron that is seeking to be matched with another electron. This extra electron can be gained from lipids within the body or from DNA, which damages these structures. Ultimately antioxidants are electron donors and ubiquinol is one of many electron donors that serve as antioxidants. The role of CoQ10 within the mitochondria is as an elecron carrier, so ubiquinone is best. CoQ10 has been shown to lower levels of oxidized purines, which are the damaged pieces of DNA that occur as a result of oxidative stress, in cells of those with Down syndrome (7).

B vitamins are needed as enzyme cofactors for each step of the TCA and within the electron transport chain (image 4). These B vitamins can quickly become depleted in a diet that contains processed grains because those grains provide glucose but are stripped of the bran and germ that contain B vitamins to help our bodies get energy from the glucose. Deficiencies in B vitamins are also very common in those who have an imbalance in their gut flora like small intestinal bacterial overgrowth (SIBO) or candida overgrowth (8).

Carnitine has one role in the body and that is to shuttle fatty acids into the mitochondria so that they can be used for energy. That's it. It does nothing else. Carnitine is synthesized in the body from lysine and methionine. It's also obtained through eating meat, especially red meat, hence it's name (carne = meat). In 2005 researchers tested carnitine's impact on mitochondria function in aging rats. They found that it improved the function of the TCA and the flow of electrons through the electron transport chain (9).  In addition, children with Down syndrome have been shown to have lower carnitine levels than typical children (10). Because mitochondrial function has been linked to cognition (11) it follows that carnitine supplementation can help dementia and cognitive impairment that is linked to mitochondrial dysfunction.  In fact, researchers in the UK found that acetyl l-carnitine did improve cognition in those with mild cognitive impairment and mild Alzheimer's disease (12). Acetyl l-carnitine is the form of carnitine that crosses the blood brain barrier, so it's preferred when support of cognition is the goal.

Lastly, carnitine deficiency has been shown to cause delayed gut motility leading to vomitting after meals, oral drooling, delayed gastric emptying and constipation (13). This makes sense given how much muscle function is impacted by mitochondria function and optimal gut motility is a consequence of healthy muscle function.

Iron deficiency is the most common nutrient deficiency worldwide. One of the main symptoms of iron deficiency is fatigue. This is, in part, due to iron's role as a cofactor in several enzymes found within the TCA as well as the electron transport chain.

Alpha lipoic acid (ALA) is a fatty acid that is synthesized within mitochondria and acts as a very potent antioxidant. It can also be obtained in the diet in the form of lipoyllysine and is highest in animal tissue (kidney, heart, liver) and green plants like spinach and broccoli (18). In addition to being an antioxidant ALA is also required as a cofactor for one of the enzyme complexes that makes up pyruvate dehydrogenase. This enzyme complex converts pyruvate (made from glucose) to acetyl-CoA that is the entrance point for the TCA. It's thought that ALA deficiency doesn't exist as the body typically makes what it needs. However, supplementing with ALA has been shown to support brain health, cardiovascular health, heavy metal chelation, insulin function and inflammation (19, 20). It's repeatedly been shown to work well when supplemented together with acetyl l-carnitine (21,22, 23, 24).

Thyroid hormone is often overlooked for it's vital role in mitchondrial function.  There are several forms of thyroid hormone, thyroxine (T4), triiodothyronine (T3), 3,5 diiodo-l-thyronine (T2) and monoiodothyronine (T1). Each of these forms are named based on the number of iodine atoms attached to them.  The two forms that play an important role in mitochondria function are T3 and T2. T3 is often called "active" thyroid hormone because it's necessary for the function of every cell within the body. T3 acts as a transcription factor within the cell, literally turning on certain genes within the nucleus of each cell that contribute to the function of that cell. T3 and T2 hormone work in a similar manner within the mitochondria; they turn on mitochondrial genes that code for key proteins with the electron transport chain (image 6).  

The good news is that mitochondrial function can be assessed through blood and urine tests as well as symptoms.  These tests include:

• Plasma free carnitine and acylcarnitine
• Urine organic acid test (TCA cycle intermediates, lactic acid, pyruvic acid, ketone and fatty acid oxidation, 3-methylglutaric, 3-hydroxyglutaric, 3-methylglutaconic)
• Plasma amino acids, alanine:lysine ratio or elevated alanine (27)

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Not all doctors will order these tests, nor will they know how to interpret them. It's important to work with a doctor who has training or is educated to understand these tests. Interpreting these labs is both simple yet complicated. For example, if carnitine levels are low supplementation is warranted. Other markers that indicate a need for carnitine are urinary fatty acids, adipic and suberic acid. When they are elevated in the urine it indicates that they are not being shuttled into mitochondria and not being used, hence the need for carnitine. Doses recommended are in the range of 20-100 mg/kg/day for children (28). Elevated urinary pyruvic acid can indicate a need for alpha lipoic acid as well as B1, B2 and B3. Elevated intermediates of the TCA in the urine can indicate a need for cofactors of the enzyme needed to convert that intermediate to the next step of the TCA, typically these are B vitamins. This information is greatly simplified and assessment of what each patient needs to support their individual mitochondrial needs requires an evaluation from a trained physician.

I reported on the outcome of helping a 14 month old boy with Down syndrome in my blog post Customized Treatment for Children with Down Syndrome. His initial organic acid test results indicated significant mitochondrial dysfunction with several elevations in his TCA intermediates as well as very high adipic and suberic acid levels, indicating a need for carnitine. He was only supplemented with carnitine and treated for gastrointestinal dysbiosis, which was the greatest contributing factor to his B vitamin deficiencies. His repeat organic acid results as well as his improved development and cognition indicated that mitochondria function had improved. 

Many children with special needs (Down syndrome, autism, and others) would benefit from screening for mitochondrial dysfunction. The long term impact to health and cognition if mitochondrial dysfunction goes unaddressed are profound. The benefits of supporting mitochondrial function are far-reaching for the patient given the many organ systems that are impacted by cellular energy production.

Mitocondrial dysfuntion is currently not recognized by conventional medical physicians who often choose to prescribe pharmaceuticals for symptoms in lieu of addressing the root cause of disease. Fortunately physicians who are trained in mitochdondrial function exist and include Functional Medicine practitioners, Naturopathic physicians, Biomedical doctors and MAPS doctors.