This article will explore the role of BH4 in neurotransmitter synthesis, its impact on dopamine, serotonin, and nitric oxide, as well as the influence of methylfolate on the BH4 cycle. Additionally, signs and symptoms of low BH4 levels will be discussed.

BH4 plays a critical role in the synthesis of dopamine, serotonin, and nitric oxide, neurotransmitters essential for healthy neurological function. In the synthesis of dopamine, BH4 acts as a cofactor for the enzyme tyrosine hydroxylase, which converts tyrosine to L-DOPA, a precursor of dopamine. Without adequate BH4 levels, dopamine synthesis is impaired, leading to disruptions in neurological function. Similarly, BH4 is essential for the synthesis of serotonin, as it is a cofactor for tryptophan hydroxylase, the enzyme responsible for converting tryptophan to 5-hydroxytryptophan (5-HTP), a precursor of serotonin. Furthermore, BH4 is involved in the synthesis of nitric oxide (NO) as a cofactor for nitric oxide synthase (NOS). NO is a signaling molecule involved in various physiological processes, including vasodilation and neurotransmission.

Folate plays a crucial roles in the BH4 cycle by influencing the availability of BH4.  Methylfolate, the active form of folate, increases the recycling of BH2 to BH4 by increasing DHFR (dihydrofolate reductase) activity. Therefore, adequate levels of methylfolate are necessary for the proper functioning of the BH4 cycle and the synthesis of neurotransmitters.
Folinic acid can also increase BH4 levels and should be used, especially in the presence of folate receptor antibodies.

The role this process plays in children with Down syndrome is important to note as well. BH4 levels have been found to be low in children with Down syndrome. (Aziz 1982)

​In conclusion, tetrahydrobiopterin (BH4) is a critical cofactor involved in the synthesis of dopamine, serotonin, and nitric oxide, neurotransmitters essential for neurological and physiological function. Methylfolate influences the BH4 cycle and is necessary for BH4 synthesis and regeneration. Low BH4 levels can result in a range of neurological, psychiatric, and cardiovascular symptoms. Understanding the role of BH4 and its associated pathways is crucial for optimizing brain health. Working with a nutritionally trained physician who can recommend the right dose of methylfolate when warranted can improve BH4 production and overall brain health.

If you're interested in reading more about this I highly recommend: Tetrahydrobioterin (BH4) Pathway: From Metabolism to Neuropsychiatry

As an Amazon Associate, I earn from qualifying purchases.

​I'll explain the consequences, signs, symptoms and causes of ID as well as the labs used to diagnose it. The answer to ID is not always simply supplementing with iron. As always, the best approach to managing any nutrient deficiency is finding and addressing the root cause.
​

FUNCTIONS OF IRON

• Oxygenation - Iron is best known for its role in hemoglobin synthesis. Hemoglobin is the protein within red blood cells that carries oxygen. Without sufficient amounts of iron the body struggles to make hemoglobin which results in a low oxygen carry capacity of red blood cells. Image 1 shows the heme component of hemoglobin that contains iron which is the actual binding site of oxygen within hemoglobin. All tissues of the body require oxygen to function properly, but the brain is especially sensitive to a decrease in supply of oxygen. ​

• Energy Production - Many enzymes within the body rely on iron as a cofactor to function properly including enzymes within the Citric Acid Cycle. This is a process within mitochondria that our body uses to convert food to energy. Iron is also a cofactor for succinate dehydrogenase, an enzyme within the electron transport chain, another essential step of energy production found within the mitochondria. For more information about supporting mitochondrial function you can read Mitochondria - Why They're Important and What They Need to Function
• Immune System - Both the adaptive and the innate immune system are dependent on iron. While the mechanism behind this function of iron isn't totally understood some aspects have been studied and reported. Iron is important for T cell function and development, which is an energy dependent process. (Cronin, et al. 2019). In addition, ID has been shown to significantly impair cell mediated immunity in children. (Das, et al. 2014)
• Cognitive Function​ - The most energy dependent organ of the body is the brain. For that reason alone, ID can contribute to long term, irreversible, cognitive impairment in children. (Lozoff, et al. 2006). In addition to energy production, iron is critical for myelination of neurons. Myelination is the process of creating the fatty sheath surrounding neuronal processes and fibers that increases the efficiency of neve impulse transmission. Impaired myelination results in slower auditory and visual processing within the brain. (Algarín, et al. 2003) Lastly, ID has been shown to ultimately result in lower IQ in children. A study from 2007 showed treatment with iron did increase IQ points by 4.8 in a 30 children, but these points did not bring IQ up to the same level as that of children without ID.(Agoaglu, et al 2007) Lastly, iron plays a role in the metabolism of monoamines, which includes dopamine, norepinephrine and serotonin. The effect of ID on monoamine neurotransmitters appears to impact boys more than girls. (Burhans, 2005) ​

​

CONSEQUENCES OF IRON DEFICIENCY

Brain:
ID can have long term cognitive and social-emotional impact on children, especially when experienced in infancy. Due to it's role in oxygenation, energy production, myelination and neurotransmitter function. ID during early brain development can impact white matter formation, monamine metabolism and functioning of the hippocampus. (Beard 2008) The hippocampus plays a major role in learning and memory. The brain changes seen in ID can lead to altered brain function that lasts into adulthood. (Georgieff 2011)
 
Myelination of neurons within the brain begins around the seventh month of gestation. After birth the brain rapidly develops over the following two years. This is also the most common stage of development when ID can occur. For these reasons physicians, midwives and other healthcare practitioners working with pregnant women, newborns and infants must be aware of risk factors that can lead to ID. 

Sleep:
Multiple studies and published review articles exist that link ID to sleep issues in infants and children.(Leung, et al. 2020) Given the importance of sleep to childhood development, growth and overall health one can see that this is yet another means by which ID can greatly impact the health of children. Sleep disturbance in children can be one of the biggest challenges to parenting that can impact the well-being of the entire family.

Sleep spindles are EEG waves seen during NREM (non-rapid eye movement) sleep. They represent brain activity that's necessary for memory formation, development of the cerebral cortex and regulation of motor activity. (Andrillon, et al. 2011) ID in 6 month old infants was shown to result in altered sleep spindle patterns. (Peirano, et al. 2007) Alterations in sleep can be long-lasting despite reversal of ID. A group of researchers in Chile found 4 year old children who experienced ID as infants had persistent alterations to their sleep organization (Peirano, et al. 2013)

Due to the brain changes seen in regulation of motor activity in infants with ID, it's no wonder that restless sleep in children is often a result of ID. (Dosman, et al. 2012) Other causes of restless sleep in children exist, but some sleep specialists recommend supplementing with iron in children with restless sleep who also have a ferritin of <50 ug/L. Researchers in 2013 reported, "The most striking single symptom (of ID) was awakening after 1-3 h of sleep followed by screaming, crying, kicking or hitting the legs." (Tilma, et al. 2013)
​
Gross motor skills:
​Researchers at the Center for Human Growth and Development at the University of Michigan in 2006 reported on the effects of ID on gross motor development in children in Costa Rica. Not only are gross motor skills of infants with ID delayed, but "there was no evidence of catch-up in motor development, despite iron therapy in infancy that corrected ID anemia in all cases." (Shafir, et al. 2006) Their findings confirmed that of many others: "Children who have iron-deficiency anemia in infancy are at risk for long-lasting developmental disadvantage as compared with their peers with better iron status." (Lozoff, et al. 1991) These "development disadvantages" extend beyond cognition and include gross motor skills. Shafir, et al later mentioned the dilemma of ID detection without anemia as this is less often detected by practitioners who only use hemoglobin levels to screen for ID. (Shafir, et al. 2008)

Behavior:
​Last, but not least, is the long-term social-emotional issues that can result from ID. Infants and toddlers who experience ID have been found by "virtually every case-controlled study" to be "more wary, hesitant, solemn, unhappy, kept closer to their mothers" (Lozoff, et al. 2006) Once again, these effects were are not necessarily reversible once ID is treated. These effects can be long-term. Parents and teachers had reported more social problems, anxiety/depression and attention problems in children who previously experienced ID.(Lozoff, et al. 2006) Attention problems are also common among children and young adults who were iron deficient as infants. Researchers from Department of Psychology and Social Behavior, University of California, Irvine stated, "Participants with chronic, severe ID in infancy performed less well on frontostriatal-mediated executive functions, including inhibitory control, set-shifting, and planning." (Lukowski, et al. 2010) These and results from other studies show that executive function, impulsivity and decision-making in adolescents and young adults can be impacted by previous ID in infancy. Experts from Division of Child Development and Community Health at the Universty of California in San Diego went so far as to say, "Youth with a known history of IDA would benefit from monitoring for emotional volatility and inattention, both during childhood and at adolescence, as they become more independent and have the potential to engage in serious risk behaviors." (East, et al. 2018)
​

SYMPTOMS OF IRON DEFICIENCY

​The most common symptom of ID in children is fatigue. However, fatigue can manifest very differently in children than it does in adults. Children who are tired can actually present as hyperactive as they continuously move in order to avoid falling asleep during the day. It's commonly referred to as "tired-wired". Fatigue can also present as behavioral issues that include lack of focus, irritability and even aggression. Fatigue from ID is due not only to the low oxygen carrying capacity of red blood cells but also to low activity of the enzymes mentioned above needed for energy production within mitochondria.

DIAGNOSIS OF IRON DEFICIENCY

For these reasons, assessing iron status in children is very important. This is done through a blood draw that includes a serum iron, TIBC, % saturation and ferritin. The ferritin level is the most accurate means of assessing overall iron status in the absence of infection and inflammation. (WHO, 2011) Ferritin is an intracellular protein that stores iron and releases it as needed. It helps maintain a stable amount of iron in the body by storing it when there's too much and releasing it when there's too little. Because it can be elevated in the presence of infection or inflammation it shouldn't be the only means used to assess iron status.(Kell and Pretorius 2014) Many doctors will only assess iron status based on hemoglobin (Hb) levels. This is a poor means of assessing iron status as Hb levels will be low in those with long-standing ID and will miss early onset ID.
​

CAUSES OF IRON DEFICIENCY

Malabsorption is a major cause of ID. There are multiple factors within the gut that can contribute to malabsorption. 

Gut factors that impact iron absorption:

• stomach acidity (pH)
• microbiome
• infections
• inflammation
• biofilm

Iron can be found within the body in two states: Fe2+ and Fe3+. The form that's absorbable by the body is Fe2+. Iron takes this form in a low pH (acidic) environment. This low pH is created by gastric acid production within the stomach. Without gastric acid or when gastric acid production is blocked by an acid blocker like Omeprazole (Prilosec) or Ranitadine (Zantac) iron absorption will also be blocked. Taking supplemental iron may be helpful but if the pH environment within the GI tract is not remedied then the supplemental iron will not be absorbed. Iron that is not absorbed causes GI irritation, upset tummies and constipation. 

Iron is absorbed from the duodenum which is in the uppermost part of the small intestines. ​Abnormally high levels of bacteria or yeast here will result in malabsorption of iron and other micronutrients.

Iron is an essential element for nearly all living organisms including bacteria within the gut. These bacteria fundamentally get served iron first and we get the leftovers. In this way elevated levels of bacteria in the small intestine reduces the amount of iron available for absorption. Our bodies essentially play iron tug-of-war with bacteria in the gut. Taking iron as a supplement also nourishes this elevated level of bacteria in the gut, potentially making the root cause of ID worse. 

A fascinating way that bacteria scavenge iron is through iron chelating compounds called siderophores. These siderophores are some of the strongest iron binding agents known. They possess a higher affinity for iron than host transport proteins do. Bacteria secrete siderophores that bind to iron then harvest the siderophores as a means to collect iron from their environment. (Miethke and Marahiel 2007) The tug-of-war continues as the host cells secrete, a protein that binds siderophores. (Wilson, et al, 2016) This battle for iron underscores it's importance not only to human health but to the health of all organisms including bacteria.

One pathogenic bacteria that's worth noting for its dependence on iron is Klebsiella pneumoniae. The presence of this bacteria in the gastrointestinal tract has been implicated as "most likely triggering factor involved in the initiation and development of" two autoimmune conditions Ankylosing Spondylitis and Crohn's Disease. (Rashid, et al. 2013)

Pathogenic (disease causing) as well as commensal (healthy, symbiotic) bacteria within the gut create biofilm. They will pull positively charged ions (cations) from their environment in order to strengthen their biofilm. These cations are often in the form of magnesium, calcium and iron. Dr. Rodney Donlan from the CDC has written, "...divalent cations such as calcium and magnesium, which have been shown to cross-link with the polymer strands and provide greater binding force in a developed biofilm." (Donlan 2002) "Metal cations, such as calcium, magnesium, and iron have been implicated in maintaining matrix integrity." (Kostakioti, 2013) Using these minerals as supplements can actually worsen a biofilm situation in the presence of a pathogenic bacteria. Some examples of pathogenic bacteria that do this are Pseudomonas aeruginosa, Campylobacter jejuni and Klebsiella pneumoniae. (Kang and Kirienko, 2018; Oh, et al, 2018; Chen, etal 2020)  Researchers in India showed that limiting iron availability through the use of an iron antagonizing agent helped to reduce biofilm formation by K. pneumoniae. (Chhibber, et al. 2013) They also reminded us that "Free iron is critical for the growth of biofilm associated bacteria."

Hepcidin is the key regulator of systemic iron homeostasis that is released by the liver in response to inflammation and iron overload. It works by blocking iron absorption in the duodenum. Inflammation, autoimmune disease, critical illness, some cancers and chronic kidney disease all result in elevated hepcidin which will reduce iron absorption. (Ruchala and Nemeth 2015) While testing hepcidin levels would be ideal in determining the cause of ID, it's currently not readily available through routine laboratories.(Girelli, et al. 2016) However, knowing the mechanisms that control hepcidin can help clinicians understand the means by which these physiologic states can interfere with iron absorption.

Malabsorption of iron can also occur in the presence of a riboflavin deficiency (Agte, et al. 1998, Powers, et al. 1998),  which can be seen as an elevated glutaric acid on an organic acid test as well as through signs and symptoms:

Signs and symptoms of a riboflavin deficiency include:

• glossitis (red, swollen tongue)
• angular cheilitis (rash or cracks in the corners of the mouth)
• cracked, dry lips
• irritated mucosal membrane of the mouth
• sore throat
• moist, scaly skin inflammation
• hearing loss
• choking, swallowing, feeding issues
• tongue and/or facial weakness
• sensory gait ataxia (clumsy, staggering walk)
• dysphonia – inability to produce sound due to laryngeal weakness

For more information about riboflavin deficiency I recommend reading Riboflavin (vitamin B-2) and health.

Aside from the above mentioned gut issues, the most common cause of ID in children is lack of iron in the diet.  Iron from meat (heme iron) is more easily absorbed than non-heme (plant-based) iron. Ensuring foods rich in iron, both heme and non-heme, are part of the diet of pregnant women and children can go a long way to prevent issues associated with ID.

Lastly, it should not go unmentioned that certain phenolic compounds are strong inhibitors of iron absorption. (Merceles and Hunstein 2011, Lesjak, et al. 2014)  Polyphenols that are given as supplements such as EGCG, curcumin, resveratrol and quercetin can all result in decreased absorption of non-heme iron. Heme iron is found only in meat, poultry, and seafood. Non-heme iron is found in plants like whole grains, nuts, seeds, legumes, leafy greens and most iron supplements. While phenolic compounds have multiple healing properties including neuroprotection, anti-cancer, anti-inflammatory and anti-histamine their potential side effects, especially when used at higher pharmaceutical doses, should be monitored. Checking serum iron and ferritin levels regularly in those who use these substances is an ideal way to monitor this potential side effect.
​

TREATMENT OF IRON DEFICIENCY

You can now see that treating ID can be a little more complicated than just supplementing with iron given all of the above information, especially the role that bacteria in the gut can play in iron absorption. While giving children with ID an iron supplement seems like the quickest, easiest solution, in some situations it can make the root cause of the problem worse. We sometimes don't recommend iron supplementation in patients who have obvious gastrointestinal issues and stool testing can be done immediately. It's imperative that clinicians working with children with ID have an understanding of all factors involved in iron absorption in order to optimize the health of these children as safely and efficiently as possible.

It's important to assess for gastrointestinal issues when other causes of ID are not readily evident. This is best done through a comprehensive stool analysis that can be ordered and interpreted by a trained functional medical or Naturopathic physician. These stool tests are able to detect pathogenic and commensal bacteria in the gut that can impact iron absorption. You can read more about stool analysis options on this page of our website: Stool Test Options.

Choosing the right form of iron to give as a supplement is important as well. Iron that is not absorbed causes GI irritation and constipation. Dark or black stools that are seen after the start of iron supplementation is a sign of poor iron absorption. Non-heme iron supplements are the standard for iron supplementation, but come in many forms. Many standard iron supplements come as iron sulfate which is not easily absorbed and subsequently is more likely to cause gastrointestinal side effects. Iron bisglycinate is a form of iron that is bound to glycine which makes it more absorbable and less likely to cause gastrointestinal issues. The taste  of both of these forms of iron can be a problem for most children who cannot swallow capsules.

Micronised microencapsulated iron pyrophosphate is a form of liquid iron that solves both issues of absorption and taste. Micronisation is the process of reducing particles to a smaller size often with the goal of increasing absorption. Microencapsulation is the process of coating small particles with a substance that will either protect it from being broken down in digestion or increase its absorption. Using a phospholipid bilayer or liposome as the protective layer increases absorption of iron pyrophosphate and blocks the iron from coming into contact with taste buds in the mouth, masking the iron flavor. "Micronised microencapsulated ferric pyrophosphate (MMFP) is a recently developed formulation characterised by a higher intestinal bioavailability due to the small particle size distribution at nanometer level. " (Pappalardo, et al. 2019)

Lactoferrin is a natural glycoprotein that is one of the main proteins found in human breast milk. It's an iron binding protein that is involved in regulation of iron absorption in the bowel as well as inflammation within the body, having both pro- and anti-inflammatory properties. It also has anti-bacterial properties and helps breakdown biofilm as it sequesters iron away from bacteria.(Giansanti, et al. 2016) "Its ability to limit iron availability to microbes is one of its crucial amicrobial properties" (Kell, et al. 2020) 

Bovine lactoferrin can be taken as a supplement and has been shown to increase total serum iron, red blood cell count, hemoglobin, and hematocrit of pregnant women experiencing ID anemia. (Rosa, et al. 2017) They were given 100 mg of lactoferrin twice a day. Taking lactoferrin also decreased their IL-6 level, which is a cytokine involved in inflammation. Infants who received bovine lactoferrin added to their formula were shown to have accelerated neurodevelopment by one year old and improved language by 18 months old. (Li, et al. 2019)

Vitamin C (ascorbic acid) is a powerful enhancer or non-heme iron absorption. Taking an iron supplement together with a vitamin C supplement can greatly improve iron absorption. "Ascorbic acid forms a chelate with ferric (Fe3+) iron in the low pH of the stomach which persists and remains soluble in the alkaline environment of the duodenum." (Ems, et al. 2020) 
​

CONCLUSION

It is critical that ID be detected as early as possible and prevented in infancy to prevent irreversible long term effects. Managing ID safely and effectively can be a complex process. In some children it can be solved as simply as taking an iron supplement. For other children, it can involve looking deeper for the source of the problem in order to treat it safely and effectively. Taking the right steps, using the right supplements and running the right tests can go a long way to prevent the long term effects that ID can have on a child's health and development.

WARNING: The Federal Trade Commission mandates that prior to openly discussing any issues related to COVID 19 the following disclaimer be conspicuously placed in front of any article relating to COVID 19:

• NONE OF THE PRODUCTS DISCUSSED IN THIS ARTICLE HAVE BEEN PROVEN IN DOUBLE BLIND PLACEBO STUDIES TO CURE PREVENT OR TREAT COVID 19. THE SCIENTIFIC ARTICLES SUPPORTING THE DISCUSSION OF THE EFFICACY OF TREATMENTS AND PRODUCTS RELATED TO COVID 19 ARE NOT DOUBLE BLIND PLACEBO STUDIES OF THE PRODUCT ITSELF.
• ACCORDING TO THE FTC, NO PRODUCT HAS BEEN PROVEN IN DOUBLE BLIND PLACEBO STUDIES TO PREVENT OR CURE COVID 19.
• THIS ARTICLE IS FOR INFORMATIONAL PURPOSES ONLY AND IT IS NOT INTENDED AS A REPLACEMENT FOR DIAGNOSIS OR TREATMENT BY YOUR DOCTOR.​

By now most of us have heard of coronavirus or COVID-19.  If you don't know, the World Health Organization (WHO) announced it is officially a pandemic as of March 11, 2020.  Does that mean we should panic​? No. It means we should work even harder to ensure we and our children have a strong, healthy immune system. You may have heard that the coronavirus is a mild infection for young, healthy individuals and those who are experiencing more serious respiratory consequences and even death are those who are elderly and have some underlying health condition(s) that lead to the increased complications. Are children with Down syndrome among that group? It's definitely possible, but as of now, no reports of children or adults with Down syndrome contracting the virus have been reported. The risk factors for the increased rate of mortality in those who contracted coronavirus include:

• Hypertension
• Diabetes
• Coronary Heart Disease

This is according to a report published March 11, 2020 in the Lancet (Zhou 2020). Looking further at their data, we can see the lab findings of the non-survivors are also notable. They revealed a low lymphocyte count, high lactate dehydrogenase, higher creatine kinase than survivors, high hs-CRP, higher d-dimer than survivors, high ferritin and higher Il-6 than survivors. Several of these lab findings point to increased inflammation (ferritin, hs-CRP and IL-6). As well, a high lactate dehydrogenase denotes damaged tissues that have spilled their contents into the bloodstream.

Should we take extra precautions with children with Down syndrome during this pandemic, keeping them away from big events, public places, and definitely away from those with a fever or cough? Well, yes, especially for some of them. Only take your child to a hospital or clinic if absolutely necessary. I'll explain why and what we can do specifically for our children with Down syndrome that may result in a better outcome if  they were to be exposed to COVID-19.

It was announced in 2017 that Down syndrome could be re-categorized as an immune system disorder (Green 2017) based on new research that showed elevated levels of pro-inflammatory cytokines, IL-6, MCP-1, IL-22 and TNF-α seen in blood samples of 165 individuals with Down syndrome. As with many studies, the researchers placed blame entirely on the presence of the extra chromosome despite saying "most of the proteome changes observed in people with DS correspond to proteins encoded elsewhere in the genome". What this means is the proteins involved in the immune changes seen were not even encoded by chromosome 21. This research left parents even more worried, with no explanation of why this occurred or how to help their children. Research like this that implies the only aspect of physiology that is impacting the health of those with Down syndrome is their extra chromosome isn't seeing the forest for the trees. I'll explain below the other factors that can increase these inflammatory cytokines.

GUT HEALTH
  
In our clinical experience, many children and adults with Down syndrome have gastrointestinal issues that can increase these same pro-inflammatory cytokines listed above. Those gastrointestinal issues include irritable bowel syndrome, candida overgrowth, small intestinal bacterial overgrowth and microbiome dysbiosis. All of these gastrointestinal conditions have revealed a similar pattern of increased inflammatory cytokines seen in the 2017 study. (Schirmer 2016, Kumamoto 2011, Steele 2001, Komatsu 2001, Li 2017). A team of gastroenterologists in Spain reported inflammatory bowel disease in three patients with Down syndrome and discussed the possible connection between these two conditions. (Souto-Rodríguez 2014) Optimizing gastrointestinal microbiome, reducing gastrointestinal inflammation and optimizing gut motility could lead to a reduction in the immune dysfunction often seen in those with Down syndrome. You can read Gut Motility - Driver of the Microbiome for more information about how to optimize gut motility. To reduce gut inflammation we often recommend a gluten-free, dairy-free diet for all of our patients with Down syndrome.  "Patients on a GCD (gluten-containing diet) had more bowel movements per day, greater intestinal permeability, and greater inflammatory cytokine levels compared to patients on a GFD (gluten-free diet)." (Niland and Cash 2018)

​Supporting all aspects of gut health is beyond the scope of this article. We recommend that parents not ignore symptoms of gastrointestinal inflammation as simply expected in those with Down syndrome but explore ways to optimize gut health.  These symptoms include:
​

• Bloating
• Constipation
• Nausea
• Reflux
• Low/high appetite
• Abdominal pain
• Poor weight gain or growth

At the very least, if you've been considering a gluten-free/dairy-free diet for your child with Down syndrome now is the time. An anti-inflammatory diet that includes foods contained in the image below can be very healing for the gut as well.

ANTI-VIRALS

Again, there are many here that can be discussed, but two stand out that are specific to those with Down syndrome in light of coronavirus as well. Those are Vitamin A and glycyrrhizin.  

VITAMIN A

The malabsorption study of children with Down syndrome cited above also reported vitamin A among the deficiencies seen. (Abalan 1990) Years later researchers in Spain stated "Children with DS between two and six years old show a significantly lower serum retinol." (Chávez 2010) Before considering vitamin A supplementation it's wise to get a blood test to check for a deficiency and discuss supplementation with a nutritionally trained physician. Overdosing of vitamin A is possible and toxic to the body. "Mental status changes are common following Vitamin A intoxication. In addition, there is a risk for seizures, headache, and blurred vision (due to elevated intracranial pressure). Chronic toxicity can lead to alopecia, anorexia, pruritus, dryness of mucous membranes, muscle and bone pain and hyperlipidemia." (Olson 2019)

Vitamin A given in safe doses can greatly enhance the body's immune response. It's been shown in animal studies to increase serum levels of IgG, IgM, and IgA. (Huang 2018) Levels of these immunoglobulins can be tested in humans, as we often do on our patients. We have found low levels of each of these immunoglobulins in our patients with Down syndrome to varying degrees in each of them.  

A study of 2,774 children in Bogotá, Colombia found "Vitamin A and hemoglobin concentrations were inversely related to rates of morbidity in school-age children." (Thornton 2014) From a global perspective in light of the recent spread of COVID-19 it should be noted that vitamin A deficiency is a major public health problem around the world.(Timoneda 2018) This could likely contribute to more serious complications from COVID-19 in those who are vitamin A deficient given the important role that vitamin A plays in lung health. 

LICORICE (GLYCYRRHIZIN) - EDITED 3/14/2020

​Previously I wrote of the potential benefits of glycyrrhizin, the active constituent of licorice, due to its antiviral properties. As well researchers in Germany tested glycyrrhizin against two clinical isolates of coronavirus (FFM-1 and FFM-2) from patients with SARS. "glycyrrhizin was the most active in inhibiting replication of the SARS-associated virus." (Cinatl 2003) Other researchers in Germany confirmed their findings and stated, "Glycyrrhizin (GL) was shown to inhibit SARS-coronavirus (SARS-CoV) replication in vitro." (Hoever 2005)

In "Potential natural compounds for preventing 2019-nCoV infection" Chen and Du also discussed the use of glycyrrhizin. They pointed out that COVID-19 enters the host lung cells via ACE2 receptors on the surface of the cell. "Targeting ACE2 holds the promise for preventing 2019-nCoV infection." (Chen and Du 2020) They went on to add, "Given the low toxicity of glycyrrhizin, its anti-virus effects on SARS and its potential interaction with ACE2, it’s worthwhile to test its efficacy against 2019- nCoV infection." (Chen and Du 2020)

Despite this, I'm retracting my recommendation of glycyrrhizin based on information that was published February 29, 2020.  A team of researchers and doctors in China reported low potassium levels, hypokalemia, being linked to severity of lab results in patients who contracted COVID-19. "Body temperature, CK, CK-MB, LDH, and CRP were significantly associated with the severity of hypokalemia (P<0.01). 93% of severe and critically ill patients had hypokalemia which was most common among elevated CK, CK-MB, LDH, and CRP." (Li 2020) 

Glycyrrhizin can cause renal potassium loss and subsequent high blood pressure. (Allcock 2015) Given that hypertension is among the co-morbid conditions seen in non-survivors of this novel coronavirus infection, and low potassium is linked to severity of aberrant lab results, it would be wise to avoid glycyrrhizin at this time. It should also be noted that the papers from Chen and Du and Li, et al are in pre-print, which means they have not been peer-reviewed and should not be used to guide clinical practice.

SUMMARY OF TIPS TO DISCUSS WITH YOUR CHILD'S DOCTOR
​

• Anti-inflammatory diet (gluten-free, dairy-free)
• No refined sugar, absolutely none at this time
• B vitamins as warranted and tolerated
• Vitamin D
• Vitamin C
• Quercetin
• Liposomal Glutathione
• Vitamin A (use with caution)​
• Obtain current labs that include CBC, serum B12, serum vitamin A, histamine, glutathione, homocysteine and immunoglobulins. Discuss all potential causes of aberrant results with your child's physician.
• More tips on boosting the immune system can be found by reading Boosting Immunity: Functional Medicine Tips on Prevention & Immunity Boosting During the COVID-19 (Coronavirus) Outbreak​​

Many children with Down syndrome and autism experience gastrointestinal issues. (Chaidez 2014, Holmes 2014) The consequences of this can be a major contributing factor to nutrient deficiencies and cognitive issues that are common in both of these conditions. Low muscle tone that is common in children with both of these conditions is a significant factor impacting gut health.

Let's start by briefly reviewing gastrointestinal anatomy. Basically the gut largely consists of smooth muscle.  It is essentially a muscular organ (Image 1). The interior lining of these muscles, the mucosa, is where the very important task of secretion and absorption occurs. 

If tone in the skeletal muscle of a child is low then the same factors that are causing skeletal muscle tone to be low will also cause low tone in smooth muscles of the intestines as well.  This low muscle tone in the intestines leads to slow gut motility.  When gut motility is slow bacteria and yeast can't be cleared properly and get backed up in the small intestines. This leads to small intestinal bacterial overgrowth (SIBO) and/or yeast overgrowth (Image 3). Researchers at the University of California stated, "Depending on the flow rate and the frequency of contractions, the bacterial density profile exhibits varying spatial dependencies." in their paper titled "Bacterial growth, flow, and mixing shape human gut microbiota density and composition." (Cremar 2016) In other words, the level of bacteria in the gut is dependent on gut flow or motility. How much the gut is able to move plays a significant role on the quantity and balance of healthy bacteria within the gut.

Bacteria and yeast in the gut are very much alive and continuously growing and reproducing.  The rate at which they are growing and reproducing must match the rate at which they are being eliminated from the body through constant sloughing and evacuation of the bowels.  If these rates are not properly in sync with one another due to slow gut motility then a build up of bacteria and yeast within the small intestines can easily occur.  

SIBO can have a significant impact on the overall health of the body.  Nutrient absorption can be greatly impaired by SIBO. Micronutrients like vitamin B12, A, D and E, iron, thiamine, nicotinamide can be depleted due to malabsorption. (Dibaise 2008) Deficiencies in several of these nutrients, especially vitamin B12 and thiamine, can negatively impact nervous system function, which will be discussed for its role in gut motility below. Malabsorption from SIBO has also been linked to poor growth in children as well. (Donowitz 2015)

Propionic acid is a short chain fatty acid that is produced by bacteria in the gut. Propionic acidemia (elevated levels of propionic acid) has been studied as potential a contributing factor to autism.  Derrick MacFabe, MD has conducted extensive research to support this and discussed his findings in "Autism, Mitochondria and the Microbiome".  Elevated levels of propionic acid have been shown to impair brain function in animal models, corroborating MacFabe's work. (Choi 2018)  Gut motility is a major factor impacting levels of propionic acid. (Prasa 2004) Symptoms of propionic acidemia include frequent vomiting, lethargy, refusal to feed, and hypotonia.  The mechanism behind elevated propionic acid is clear given that this short chain fatty acid is produced by bacteria in the gut, which will be present in higher concentration when gut motility is low.

Because the gastronintestinal tract is a muscular system it is heavily dependent on a healthy nervous system. The enteric nervous system is the division of the nervous system that exclusively controls the gut. It includes mesh-like branches, called plexus, that innervate the muscles of the gut as seen in yellow in Image 7.

Muscles require energy in order to contract in the form of ATP (adenosine triphospate). ATP is generated by mitochondria.  It naturally follows that mitochondrial dysfunction will lead to low muscle tone and slow gut motility. Gastrointestinal symptoms of mitochondrial dysfunction include poor appetite, gastroesophageal sphincter dysfunction, constipation, dysphagia, vomiting, gastroparesis, GI pseudo-obstruction, diarrhea, or pancreatitis and hepatopathy. (Finsterer and Frank 2016) 

Nutrients that support mitochondrial function and therefore support gut motility include:
​

• Carnitine
• CoQ10
• B Vitamins
• ​Ribose
• T3/T2 hormone
• Creatine

Of those compounds listed above the one most noted for it's effects on gut motility is carnitine. Researchers in Japan studied carnitine levels in 27 patients with severe motor and intellectual disabilities. They found that the severity of their constipation correlated significantly with the levels of carnitine found in their blood samples. They supplemented carnitine in those who were deficient and saw a significant reduction in their constipation. (Murata, et al 2014) This has also been the experience of many parents using carnitine to help their child with slow gut motility. 

For a more thorough look at mitochondrial dysfunction, how to test for it and how to treat it you can read Mitochondria - Why They're Important and What They Need to Function

The video below shows how muscles use ATP to contract or essentially shorten.

Slow gut motility (hypomotility) can be seen as early as infancy, especially in the presence of congenital hypothyroidism.  Screening methods to detect congenital hypothyroidism are imperfect and vary from state to state within the United States. Kugelman, et al wisely stated, "Physicians should use their clinical judgment and experience even in the face of normal newborn thyroid screening test and reevaluate for hypothyroidism when there is a clinical suspicion." (Kugelman 2009) Delayed passing of meconium, umbilical hernia, infrequent bowel movements, colic, abdominal distention and reflux should all be clues to the physician to investigate hypothyroidism and the root causes of hypothyroidism in any infant regardless of their genetics.  Schmaltz summarized the signs of hypothyroidism in the newborn in the table seen in Image 9 and included abdominal distention due to hypomotility. (Schmaltz 2009)

Because bile and pancreatic enzymes are essential for digestion and absorption of nutrients, children who experience malabsorption, like those with Down syndrome and autism (Chaidez et al 2014, Abalan et al 1990), may benefit from efforts to increase CCK levels.  One must be careful not to ​increase CCK too much, however, as increased levels have been linked to anxiety due to it's impact on the central nervous system. (Skibicka and Dickson 2013) CCK increases colonic motility (Jun 2011), yet it is also known to induce a delay in gastric emptying.  

Ways to increase CCK:

• Increase fats in the diet, especially olive oil
• Protein with every meal 
• Optimize stomach acid (HCl) production (Image 11)
• Include beans in the diet (Bourdon et al 2001)

Be careful with beans in the diet for those with small intestinal bacterial overgrowth (SIBO) as the fiber and sugars in beans can cause increased gas and bloating. Focus on olive oil and protein. The amount of protein an average child needs is approximately half their weight (lbs) in grams. So, a 40 pound child will only need approximately 20 grams of protein per day.  You don't want to give too much protein to a child with SIBO either as the excess levels of bacteria in the gut can produce ammonia from the protein.

Serotonin (5-HT) is best known for it's impact on mood and low levels being linked to depression.  However, it has other functions within the body, including it's impact on gut motility. After all, 95% of 5-HT is made in the gut. To add to that "Intestinal 5-HT has been found to modulate enteric nervous system (ENS) development and neurogenesis, motility, secretion, inflammation, sensation, and epithelial development." (Terry 2017) 

5-HT is made from tryptophan, an essential amino acid. Essential amino acids are those that our bodies can't make and must be obtained from the diet.  About 90% of tryptophan is used to make nicotinamide (vitamin B3), a cofactor needed for energy production within the body. (Lugo-Huitrón, et al 2013) The other 10% is used to make 5-HT in a process that is dependent on vitamin B6. The availability of tryptophan can therefore influence the production of 5-HT in the body. To learn more about how tryptophan is used to make both nicodtinamide and 5-HT watch the video below.

5-HT is secreted from enterochromaffin cells that are widely distributed throughout the gut. They're a type of neuroendocrine cell that sense pressure and stretch, which is typically from a bolus of food within the lumen of the gut. In response to these sensations they secrete serotonin, in addition to many other hormones needed for optimal digestion, which results in a contraction of the smooth muscles ultimately propelling the bolus of food along. 

One very important factor that can lead to a decrease level of 5-HT within the gut is inflammation.  A disruption in the balance if bacteria and yeast within the gastrointestinal microbiome is a major cause of inflammation within the gut. (Nishida, et al 2018) Researchers in the Netherlands have stated "...in a state of inflammation, not only high levels of proinflammatory cytokines are produced but also altered levels of neurotransmitters, such as serotonin, a derivative of tryptophan metabolism, are detected in the gut." (Waclawiková and Aidy 2018)

So, we have another vicious cycle: disturbed microbiome → inflammation → low serotonin → slow gut motility → disturbed microbiome → etc.

Despite signs and symptoms often being obvious in those with slow gut motility,  testing can be done to detect the level of gut motility in those with more vague signs and symptoms.  Some of these can be done at home and some require the help of a physician.

A simple, at home test involves the use of activated charcoal.  This can be obtained cheaply in capsule form.  Activated charcoal is used often in research to test gastrointestinal transit in animal studies, typically in mice.  Activated charcoal is often used at home and in hospital settings to absorb orally ingested poisons.  It's a good thing to have on hand in any home with small children for this purpose. It's not absorbed by the body and remains in the gut. Due to it's dark color it can be easily detected in stool.  For this reason, it makes for a great tool to measure bowel transit time.  Capsules can be opened or swallowed whole depending on the age and skill of the child.  The number of capsules used will depend on the age of the child.  Adults can use 4-6 capsules, young children can take 2-4 capsules and toddlers can take 2 capsules. Capsules are given all at once right after a bowel movement.  Activated charcoal has almost not flavor, but a slightly gritty texture. It can be mixed in juice to help young children get it down.  It will make the juice pitch black so consider putting it in an opaque cup so the child isn't put off by the color.  Note the date and time the charcoal was given. Inspect every bowel movement under bright light after the charcoal is given, looking for signs of black in the stool.  Write down the date and time the charcoal is first seen.  This is the time it took for the charcoal to pass through the digestive tract. Calculate the number of hours between when capsules were swallowed and when the first sign of black color appeared in the stool. Continue to examine every stool, and note the time and date when the black color has completely disappeared.  An optimal bowel transit time for children and adults is 18-24 hours.  Anything less than 18 hours is considered a fast transit time, more than 24 hours is a sign of slow gut motility.

Below is a video of Dr. Jasmine Zia from UW Medicine explaining the collection process for the hydrogen breath test. One can easily see how conducting this test for small children can be quite difficult. It may, however, be a good option for older children and certainly for adults.

It's important to address the root cause of gut motility issues and not simply use laxatives or diuretics to alleviate the symptoms.  Treatment for slow gut motility should be very individual because the underlying cause can be different in different children. Remember: children with genetic conditions are as individual as anyone else and don't all require the same supplements or treatment.

The main underlying causes to address when considering treatment include:
​

• ACh synthesis
• Micronutrient deficiencies
• Methylation issues (needed for choline synthesis)
• Nervous system function
• Mitochondrial function
• Thyroid hormone function
• HCl, gallbladder and pancreatic function
• Inflammation
• Diet

Herbs

Herbs that improve gut motility can be very helpful to alleviate the symptoms until the root cause can be uncovered and addressed. They can also be helpful to break the vicious cycle of malabsorption secondary to elevated levels of yeast and bacteria. Below are some of my favorite and most effective herbs to help improve gut motility.  

Zingiber officinale (Ginger) is, by far, the one we most often recommend for children due to it's tolerable flavor and high safety profile. Many studies support ginger's long history of use for gastrointestinal symptoms of nausea, vomiting and general dyspepsia.  It decreases gastric emptying time, meaning the stomach empties more quickly after the administration of ginger.  Researchers in Taiwan reported, "...gastric half-emptying time was less after ginger than placebo ingestion." (Wu, et al 2008) Ginger can be used fresh in cooking, made into a tea and sweetened with a little honey, purchased as encapsulated powder or purchased as an alcohol-free glycerite that's then mixed with apple sauce or food.

Iberis Amara (Candytuft) is the main ingredient of Iberogast.  This is a popular herbal formula used in Europe but can also be found in the US. Its often recommended for those with SIBO due to it's ability to increase gut motility. Other ingredients in Iberogast include Mentha piperita L., Matricaria chamomilla, Glycyrrhiza glabra, Angelica archangelica, Angelica archangelica, Silybum marianum, Melissa officinalis and Melissa officinalis. These herbs work synergistically to help optimize digestion and gut motility. German researchers found Iberis amara extract created "clear differences" in the symptoms of IBS over placebo in a multicenter, prospective, double-blind, randomized parallel group comparison. (Reichling and Saller 2002) Ten years later it was stated, "Double-blind and randomized studies versus placebo or active control found statistically significant effects of STW 5 (Iberogast) on patients’ symptoms with a comparable efficacy to a standard prokinetic." (Ottillinger, et al 2012). You can find prescribing information on the package insert here.

Bacopa monnieri (Brahmi) is an Ayurvedic herb that has been used for centuries in children. Adverse effects are rarely reported, but one side effect that it can have is increased intestinal motility. It has acetylcholinesterase inhibition properties, which means it increases levels of acetylcholine within the body.  This ultimately results in improved cognition and improved gut motility. (Aguiar and Borowski 2013)  

Aloe vera juice is a common, safe and effective remedy for constipation. It helps alleviate gut permeability due to it's anti-inflammatory and soothing properties.  One of the key components of aloe is barbaloin which is metabolized to aloe-emodine-9-anthrone by intestinal bacteria. Aloe-emodine-9-anthrone increases intestinal motility. (Hong, et al 2018) 

Foeniculum vulgare (Fennel seed) is more commonly know for it's effects on relieving gas. This makes it a very popular and effective remedy for helping babies with colic. Fennel also has been shown to stimulate the smooth muscles of the small intestines. (Alexandrovich, et al 2003) It can be given as a tea or fennel essential oil that is labeled for oral consumption can be used in very small doses.

Osmotic diuretics

Osmotic diuretics do nothing to optimize gut motility and only act as bandaids to the problem by making stool softer. The most commonly prescribed pharmaceutical agent prescribed to those with slow gut motility and constipation is polyethylene glycol - 3350, known as MiraLAX in the US or Movicol and Macrogol in other countries.  It works by drawing water into the large intestine resulting in softer stool that is easier to pass. It does not improve gut motility and definitely doesn't address the root cause of slow gut motility. Other, safer and more natural osmotic diuretics exist and include magnesium oxide and high dose vitamin C.  We highly encourage our patients to avoid Miralax given the controversy over it's safety. (Welch 2017) Miralax is not labeled for use in those under 17 years of age and is only to be used for occasional, short term constipation. The label clearly states “use no more than 7 days” because it should not be used to address chronic constipation. (Image 11)  My biggest concern with it being used for chronic constipation is it addresses the symptom of constipation yet leaves the underlying cause unaddressed. Several of these underlying causes mentioned above can result in permanent neurological damage to very young children.

Probiotics 

Probiotics should be considered carefully when treating children with gastrointestinal motility issues. In some they can improve gut motility and in others they can aggravate constipation and symptoms of SIBO. Recall that SIBO is an increased level of bacteria in the small intestines, therefore, probiotics can aggravate it. Taking a probiotic with the right strains is extremely important as well. ​

​Bacteria in the gastrointestinal microbiome serve many roles for it's human host. They are involved in nutrient metabolism, vitamin synthesis, short chain fatty acid synthesis that supports the lining of the gut, phenol metabolism, immune system homeostasis and xenobiotic and drug metabolism. (Jandhyala, et al 2015) In 2014 a team of scientist at the Alimentary Pharmabiotic Centre in Ireland reported that neurotransmitter synthesis can also be added to that list. (Clarke, et al 2014) The term endocrine is defined as "Pertaining to hormones and the glands that make and secrete them into the bloodstream through which they travel to affect distant organs" (medicinenet.com) Clarke and his team argue that the gut microbiome acts as an endocrine organ because of it's ability to secrete compounds that act on distal organs such as the brain. They include a list of bacterial strains and the neurotransmitters that are produced by these specific strains seen in Image 12.  Several of these strains listed are considered pathogenic like Klebsiella penumoniae, Hafnia alvei and Morganella morganii.  The presence of these strains within the gut microbiome can result in increased gut motility seen as diarrhea potentially due to their production of serotonin and histamine which can increase gut motility. (Fabisiak, et al 2017)

Studies supporting the connection between the gut microbiome and the central nervous system, aka the gut-brain axis, are numerous. ​We can see a direct link between the brain and the gut with the production of acetylcholine by Lactobacillus plantarum.  The production of acetylcholine, as stated early, not only will support cognition but will also help to optimize gut motility by stimulating the enteric nervous system. L. plantarum should definitely be included in a probiotic given to someone with slow gut motility.

Clinical evidence reveals the eradication of pathogenic bacteria and yeast along with the replenishment of beneficial bacteria within the gut often results in an optimization of gut motility, nutrient absorption, neurotransmitter balance, improvements in mood and behavior, immune system function, cognition and overall health of the host.  This is supported by research and statements from experts such as, "The gut microbiome affects virtually all aspects of human health." (Mohajer, et al 2018)

A comprehensive stool analysis that includes markers like calprotectin, esosinophil protein X, secretory IgA levels, short chain fatty acids, fecal fats, along with the presence of commensal bacteria strains and pathogenic bacteria, yeast and parasites can aide in guiding an appropriate program aimed at improving the gut microbiome.  This task is often not a simple one and in some cases can take years of optimizing diet, supplements, antimicrobials, probiotics and herbal prokinetics. The amount of time and effort it can take to correct gut microbiome imbalance can depend on how extensive the initial cause of the imbalance was, such as number of rounds of oral antibiotics or years of proton pump inhibitor use. The presence of biofilm can slow the process as well if not properly addressed.  We often tell patients, "This isn't a one and done process".  The patients who we see the best results with are those who are able to run functional medical testing like organic acid and comprehensive stool analysis as early as possible and are able to repeat testing at regular intervals (every 3-6 months) to assess the effectiveness of the current treatment program and make necessary adjustments.

Gastrointestinal motility represents one of the major control systems of gut microflora by moving bacteria and yeast out of the body at a rate that is balanced with their rate of reproduction. Gastrointestinal dysbiosis cannot be addressed if gut motility is not optimized. Treating dysbiosis with antimicrobials (herbal or pharmaceutical), probiotics and diet without addressing gut motility will only result in continued ill-health, frustration and money lost on supplements and treatment that don't result in long term effects.

The lumen of the gut can be compared to a river. Environmental biologists know very well that the flow of a river dictates the diversity and health of the river. It's been stated, "A river's flow is its heartbeat. Because we have dammed so many rivers and lakes, our freshwater ecosystems are losing species and habitats faster than any other type of ecosystem." (Internationalrivers.org)  If the river is slowed and becomes stagnant algae and microbes will grow at a rate that is faster than the river moves them along. This will create an imbalance in the ecosystem of that river that chokes out other life, ultimately creating an unhealthy river.

A free flowing river results in less build up of algae, higher oxygen levels, more diversity of life and ultimately a much healthier river.

We couldn't live without acetylcholine (ACh).  It's an important neurotransmitter within the body and, in fact, was the very first neurotransmitter discovered. The moving title of this article was chosen to impress upon the reader the importance of this neurotransmitter to processes within the body that require movement, from skeletal muscle or smooth muscle.  It's also vitally important for brain function, playing a key role in memory, learning and cognition. It functions to relay signals from one neuron to another in the central nervous system and from a neuron to a muscle fiber in the peripheral nervous system. The production of ACh, symptoms and causes of deficiency and how best to treat low ACh will be discussed, but first we'll start with a basic physiology lesson to help you appreciate the function of ACh within the nervous system.

The nervous system is divided into two branches called the autonomic and somatic nervous systems.  The autonomic nervous system is our "automatic" nervous system that we cannot voluntarily control. If you get sweaty when nervous or your heart rate increases when you're excited that's your autonomic nervous system controlling your body's response.  Your somatic nervous system is your "voluntary" nervous system.  This part of the nervous system controls skeletal muscles, like those in my fingers as I type this. You can see from image 1 that ACh is used in both of these branches of the nervous system.

The autonomic nervous system is further divided into the sympathetic and parasympathetic branches of the nervous system. The parasympathetic nervous system is engaged most of the time in a healthy person. The sympathetic nervous system becomes engaged during times of stress or excitement. The sympathetic branch uses ACh to relay messages but also uses epinephrine and norepinephrine. The parasympathetic nervous system relies solely on ACh to function properly. The parasympathetic nervous system is important for proper digestion, gut motility, salivary flow, lacrimation (tears) and bladder function. The nerve fibers of the parasympathetic nervous system originate from the brain stem and sacral region. The parasympathetic nerve fibers originating from the brain stem are cranial nerves III, VII and IX. Cranial nerve X, the vagus nerve, also contains parasympathetic nerve fibers.  A well-functioning vagus nerve is extremely important for all aspects of digestion including stomach acid secretion, pancreatic secretion, bile flow and peristalsis, which is the wave of muscle that moves food through the intestines. (Stakenborg, 2013) The vagus nerve is also very important for regulating heart rate.  ACh creates an inhibitory response to cardiac muscle resulting in a slowed heart rate. This is different than other receptors within the parasympathetic system that result in a general increase in activity.

By reviewing the different functions of the sympathetic and parasympathetic nervous system in image 2 one can already start to get an idea of what a deficiency in ACh might look like.  The symptoms of deficiency are as follows:

Because ACh is so important for nervous system conduction within the brain, a deficiency in ACh has been linked to Alzheimer's disease (AD) and dementia. (Francis, 2005) The enzyme that breaks down acetylcholine is called acetylcholinesterase. Several drugs have been developed for the treatment of Alzheimer's disease that inhibit this enzyme thus increasing ACh levels. These drugs are donepazil, rivastigmie, galantamine. These drugs have not been shown to reverse the effects of AD, they merely stabilize or slow the rate of cognitive decline. As well, some patients don't respond at all to them. (O'Brien, 2010) They also have many side effects due to their systemic effects of increasing ACh levels throughout the body when the goal is to increase ACh in the brain alone. Some of the side effects include nausea, vomiting, diarrhea, muscle cramps, weight loss, headache, insomnia, hallucinations, fatigue, hypertension and frequent urination. (medicine.net)

It's possible that the decline in acetylcholine levels in AD and dementia are due to a deficiency in the precursors needed to make it.  So, let's talk about how acetylcholine is made next.

The synthesis of acetylcholine is actually fairly simple as a whole, yet complex in the details.  To make acetylcholine we need choline and an acetyl group. The preferred source for the acetyl group is acetyl CoA which is derived from pyruvate, the end product of glycolysis. Research showing this dates as far back as 1936 when scientists incubated animal brain cells in various medium and found that glucose, pryuvate and lactate all equally resulted in an increase in ACh production. Oxygen was needed as well. They stated, "We know now, of course, that acetylCoA (AcCoA) is required for ACh biosynthesis and that it must be the substance produced during the combustion of glucose, lactate or pyruvate in the brain that gives rise to ACh." (Quastel, 1936) Their work was corroborated by researchers in 1979 who stated, "Acetylcholine is synthesized from acetyl CoA and choline in the cytoplasm. Glucose and pyruvate are the preferred precursors of the acetyl carbons of acetylcholine in adult mammalian brain." (Gibson, 1979)

The enzyme that cleaves the acetyl group from acetyl CoA and attaches it to choline is choline acetyltransferase (ChAT) as seen in image 3. 

So, how do we then get acetyl CoA from glucose and pyruvate? This is where it gets a little more complicated. Those who have studied and understand the Citric Acid Cycle will recognize this information. For those who haven't studied this: the Citric Acid Cycle is a key process involving many steps by which mitochondria make energy. This process is heavily dependent on B vitamins.  Image 4 shows the many steps and enzymes involved in this process along with the B vitamins that act as cofactors for those enzymes.  The one enzyme I will focus on here is PD that is seen below pyruvate at the top of image 4.  PD stands for pyruvate dehydrogenase.  It's role is to convert pyruvate into acetyl-CoA.

I've discussed pyruvate dehydrogenase before in my lecture "Thiamine Deficiency in Children with Special Needs".  I've posted the whole lecture below for those who want to know all of the details.

Essentially PD is dependent on adequate levels of thiamine (B1), riboflavin (B2), alpha lipoic acid and niacinamide (B3).  In addition, the precursor to coenzyme A (CoA) is pantothenic acid (B5).  All of these B vitamins must be present in adequate amounts in order for acetyl CoA to be made. (Stacpoole, 2012) Particularly noteworthy is the role that thiamine plays in ACh production.  "The role of thiamine as a crucial coenzyme in neuronal metabolism of carbohydrates and neurotransmitters, especially acetylcholine, has been well elucidated." (Hirsch, 2011) The administration of benfotiamine, a form of thiamine, alone has been shown to reverse the symptoms of Alzheimer's disease, which has been linked to low ACh levels. (Pan, 2016)

Deficiencies in these B vitamin cofactors is most often due to gastrointestinal malabsorption. Yeast overgrowth is a common cause of malabsorpton, especially of B vitamins.  The best testing to determine a need for these B vitamins is organic acid testing.  Results like the ones seen in image 5, for example, indicate a significant deficiency in B1, B2, B3 and B5.  These are results for a child who has Down syndrome and is likely also deficient in ACh due to her B vitamin deficiencies, not her extra chromosome.  The deficiencies in this child were due to small intestinal bacterial and fungal/candida overgrowth. Addressing these deficiencies along with the root cause of malabsorption is key to optimizing ACh synthesis.

That leaves us to discuss choline as the other important half of acetylcholine.  Choline is an essential nutrient that must be obtained from the diet. Because it is water-soluble the body does not store it, so daily consumption of this nutrient is important for consistent production of acetylcholine to occur. Some choline synthesis within the body is possible, however the production of choline is heavily dependent on a properly functioning methylation cycle.  Many genetic and environmental variables exist around methylation.

Foods highest in choline include eggs (yolks) and meat, so vegans and vegetarians are at risk for being low in choline.  Supplementation is possible by taking lecithin sourced from soy or sunflower. Lecithin is rich in phosphatidylcholine (PC), which is a precursor to choline. Citicoline and CDP-choline are other forms of choline that have been shown to enhance memory and cogntion. (Gareri, 2015; Fioravanti, 2006) Choline bitartrate should be avoided. It's the most commonly used form because it's the cheapest.  It also is the least reliable form for impacting brain levels of choline (Lippelt, 2016) I prefer PC over other sources of choline because the production of PC is the second largest draw on methylation than all other process that require methylation combined. (Bertolo, 2013) Image 5 shows the production of PC from phosphatidylethanolamine via PEMT (phosphatidylethanolamine N-methyltransferase), a process that occurs in the liver. Because cell membranes consist largely of PC the body is required to make it often to keep up with cellular repair and growth.  By supplying PC as a supplement this eases up on methylation and allows more methyl groups to be used for other methylation dependent processes.

As well, supplementing with PC has been shown to increase acetylcholine synthesis.  Dr. Steven Zeisel from the Department of Nutrition, School of Public Health and School of Medicine at the University of North Carolina stated, "Acetylcholine synthesis can be influenced by the availability of choline...its manipulation by changing the diet is likely to be a powerful tool for improving human performance.". (Zeisel, 2006)

The stage of life that has been shown to be most dependent on dietary choline is fetal development. Dr. Zeisel has written, "Choline is critical during fetal development, when it influences stem cell proliferation and apoptosis, thereby altering brain structure and function." (Zeisel, 2006) Researchers recently tested two groups of mothers who were in their third trimester of pregnancy. They supplemented one group with 480 mg of choline per day and the second group received 980 mg of choline per day.  They then followed up by testing the infants at 4, 7, 10 and 13 months old for processing speed and visuospatial memory. Their results showed "maternal consumption of approximately twice the recommended amount of choline during the last trimester improves infant information processing speed." (Canfield, 2018)

Genetic variations in mothers can alter choline requirements as well. Specifically variations in PEMT and MTHFR1 genes can alter endogenous synthesis of choline. Maternal dietary choline intake can influence global gene methylation and ultimately gene expression in the unborn child. (Bennett, 2016). Because not all mothers know their PEMT or MTHFR1 gene status supplementing with choline during pregnancy at approximately 980 mg per day, as was done in the study above, may help to ensure adequate levels are available for proper infant brain development.  In addition, vegans are at high risk for being choline deficient and should definitely consider supplementing.  Vegetarians who eat eggs daily are less likely to be deficient. One egg contains about 150 mg of choline.

Because many people are looking to avoid the side effects from pharmaceutical cholinesterase inhibitors, natural cholinesterase inhibitors have grown in popularity in recent years.  Using such compounds to address ACh deficiency does not address the root cause. The root cause of ACh deficiency is most often rooted in a deficiency in one or several of the precursors needed to make it. The preferred means to address ACh deficiency is to provide the body with necessary precursors in amounts that have been determined to be individual for each person based on diet, labs, history and symptoms. Using cholinesterase inhibitors can include side effects as it's interfering with the body's ability to naturally eliminate excess ACh when needed. I'll list a few of these compounds below, but want to highlight that root cause should be addressed first. In addition, when working with children it's important to use natural cholinesterase inhibitors with the fewest side effects and highest record for safety.

Huperzine A is extracted from Huperzia Serrata, a firmoss, which has been used for various diseases in traditional Chinese medicine for fever and inflammation. It has potent cholinesterase inhibition activity. (Wang, 2006) While it has been shown to be effective for improving memory due to mechanisms other than just cholinesterase inhibition (Zhang, 2008), it has not traditionally been used in children and no studies exist reporting it's efficacy or safety in children. Use in children has been deemed "possibly safe" when taken for less than one month. (WebMD)

Potential side effects include nausea, diarrhea, vomiting, sweating, blurred vision, slurred speech, restlessness, loss of appetite, contraction and twitching of muscle fibers, cramping, increased saliva and urine, inability to control urination, high blood pressure, and slowed heart rate. (WebMD)

For these reasons, along with focusing on addressing root cause, I don't typically recommend using Huperzine A in my patients.

Because choline has been shown to optimize brain development and methylation is necessary for optimal choline synthesis, choline supplementation in the Down syndrome model has been tested. Dr. Barbara Strupp and her team at Cornell University have done some very important and clinically relevant work in this area.  They first wrote about the potential benefit of choline supplementation prenatally in pregnant mothers carrying an infant with Down syndrome in 2016.  In this review article they explain the cognitive deficits related to cholinergic pathways in mice that are engineered to have an extra chromosome (Ts65Dn mice) that correlates with that in human trisomy 21.  They stated, "Using the Ts65Dn mouse model of DS/AD, our group has identified a putative novel therapeutic intervention that holds great promise for improving cognitive outcome and offering neuroprotection to the cholinergic projection system in DS; namely, supplementing the maternal diet with additional choline during pregnancy and lactation." (Strupp, 2016)

They moved on in 2017 with researching actual maternal choline supplementation (MCS) in the Ts65Dn mouse model.  They were able to state, "These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD." (Strupp, 2017)

In 1986 a report of supplementing phosphatidylcholine in a 2.5 year old child with Down syndrome was published. They reported no other supplements given. After 7 months "The child showed a definitive increase in speech and language skills as well as general motor skills which exceeded same aged Down Syndrome peers experiencing like training programs." (Cantor, 1986)

Remember, every child with Down syndrome is unique. Some may have a significant need for addressing ACh deficiency and some may not.  "With full trisomy, intuitively it might be assumed that expression levels of triplicated genes are 1.5-fold that of the euploid population. However, this is not so." (Strydom, 2016)