A mom and "wholistic" chiropractor's musings and roadmap with Down syndrome

Archive for the ‘supplements’ Category

Histamine liberation for speech (and other things) in Trisomy 21 Down syndrome.

This post is courtesy of Dixie Lawrence.  You can learn more about hacking gene over-expression in Trisomy 21/ Down syndrome at http://trisomy21research.org/

Overall for me clinically- this has been testing and performing well.  I do find sometimes I need to give some additional methylation support to help make this work energetically.  I have been seeing great results with it clinically and personally- as Connor is also on this protocol and has definitely had an increase in his verbal skills, including saying some sentences (age 2 yrs).

Dosing right now is widely varied based on the person.  In some cases, children will start to have sleep disturbance when too much histamine in the brain is liberated.  Just drop back on the dose.  We are also watching to see if the mango or papaya exacerbates constipation in some.  Start with 1/8 tsp, in the morning, and work up on dose until you see results and or sleep issues.  For some patients, this has worked at 1/8 tsp, others are up to 1 tbsp.

From Trisomy 21 Research Facebook Group

Dixie Lawrence- “At present, we have identified a protein that is very low in the DS brain in the majority of children. This protein triggers the development of neurons associated with speech created initially during development by the human speech gene,

FOXP2.
The protein is called HRF, histamine Release Factor, also known as TCTP. It was initially believed that FOXP2 ( a Forkhead box gene) was not active beyond the developmental phase but we now know that most genes belonging to this family actually remain active during life. Years ago, scientists believed that, because neurons do not divide, you were born with a lifetime compliment of them. That assumption was proven incorrect. New neurons are produced regularly throughout natural life in the hippocampus.

We have been able to locate this protein in a few natural substances. We know that they work on HRF as they are all natural histamine liberators. In fact, the regular ingestion of these specific fruits may well be one of numerous reasons why some children with DS have excellent speech while others have moderate to severe impediments. Many things, besides the low levels of HRF may effect speech in DS. Since this post first appeared a few months ago, we have been able to determine that the use of fruit powders containing HRF/TCTP does indeed improve speech and learning in DS.

One thing you need to understand is that histamine isn’t just a protein that responds to allergies, it is a very important neurotransmitter. The human brain requires it for numerous functions, one of which is human speech.
Another thing you need to keep in mind is that it is not histamine that is unavailable but the substance that releases histamine. Histamine itself cannot effect FOXP2, the problem is with the protein, HRF. So feeding your children foods high in histamine will not help. Further, Dr. Swenson has located information indicating that supplementing the diet with histamine may actually make things worse as in the presence of histamine, HRF shuts down. This reaction is similar to the reaction seen in examining the thyroid. TSH activates in the absence of thyroxine and becomes elevated triggering the thyroid gland to create and release its hormones. Once the thyroid releases thyroxine, or you supplement it, TSH levels drop in response.

At this point there are a few things that may Give your children foods or powders containing Histamine Release Factor, Mango and Papaya powder seems to be most effective. Make sure the gut is healthy by using a good probiotic.
During the past few months of trial, we now know that we can elevate brain histamine using fruits or fruit powders containing this protein.
As a neurotransmitter, low brain histamine does explain numerous oddities in our children’s biochemistry, in particular, growth. The majority of children with DS, despite normal human growth hormone levels, remain very small in comparison with their same aged neuro typical peers. Despite treatment with human growth hormone, though growth is improved, most remain somewhat short in stature. Histamine is a prominent factor in growth.

Another point that is extremely important is that new neurons find the DS brain a hostile environment as there are many other genes and proteins that inhibit their development. It will be critical to address them (as we do now with TNI) or any new FOXP2 neurons will not survive.

It is critically important, for this to be effective, that your child is on the entire Nutrivene protocol. This will prevent oxidation and genes that harm new neurons from prevailing. In the meantime, please take a few minutes to read the following article to familiarize yourselves with the neurotransmitter, histamine.
There is no test for HRF levels at this time. However, you can surmise it is low if: your child doesn’t grow well, has poor speech, has allergies, has low immunity….even though treated. But it is only a small percentage who have normal levels.

HRF isn’t the only issue. A major cause of the lack of speech is vaccine toxicity. While we’re trying detox methods, and praying, we don’t know if the damage from vaccines is reversible. We do have a protocol for detoxing that has been very effective.

There is no way other than an autopsy to see if your child’s brain HRF is or isn’t low. The evidence is very clear that it is low in the majority of kids who 1) may have speech deficits, are short in stature, have poor immune response, vision problems. There may be a way to determine levels in the brain eventually but not at this time.

Brain histamine levels are low in AD
https://www.ncbi.nlm.nih.gov/pubmed/21618891

A FOXP2 mutation is not at all what we are talking about. In human beings a mutation – a fault – in the FOXP2 gene results in apraxia and studdering along with other speech defects. But here we are talking about the formation of FOXP2 neurons. You can test for a FOXP2 mutation but you can’t really test for low HRF in the brain. It may be that your child does have a mutation, we now have enough data to be comfortable that a single FOXP2 mutation can be over come by upregulating this protein. It is the protein, HRF that regulates FOXP2 and causes the production of speech neurons. Histamine, that is elevated by giving your child histamine liberators, may control the migration of these neurons. However, in children with two mutated FOXP2 genes, it is unknown whether we can upregulate HRF to sufficient levels to produce these important neurons. A mutation in the FOXP2 gene may result in either the creation of far too few neurons or in the production of damaged neurons. In that case, your child may have complete apraxia of speech. Still, you need to upregulate brain histamine due to the critical role it plays in normal brain function.

HRF, also known as TCTP. It is important that you understand that this protein has two identifiers. HRF and TCTP are the identical protein. It is identical in chemical structure in both plant and human form.
There is a plethora of research but right now, the rest are not important to the current discussion though they may well be in months to come.

HRF is low in DS
https://www.ncbi.nlm.nih.gov/pubmed/11172935

Evidence that low histamine during cortical development results in disruption of FOXP2 neurons does not necessarily mean that histamine, given exogenously, could result in the development of new FOXP2 neurons but it does not mean that nothing can be done as it has been established that FOXP2 continues to express throughout life. One indicator is that there exist cases where speech has been fully restored after brain damage or stroke demonstrating that these neurons are either repaired or gradually replaced.

More importantly, histamine is a critical neurotransmitter that has not yet been addressed in DS, regardless if addressing it can restore or encourage speech.
The brain will never function properly if we neglect this.

There are other histamine related problems in the DS brain, such as fewer receptors. This would be expected with low histamine as these are chemical receptors. H3 has been implicated in Alzheimer’s disease, Down Syndrome and other neurological diseases and disorders.

Histamine-N-methyl transferase (HMT) is low in DS. This enzyme inactivates the histamine neurotransmitter and in the presence of low histamine we would expect it to be low. There is very little to inactivate.

Basically, we have to ask ourselves whether all of these variations in brain histamine are a combined defect in the histamine neurotransmitter or if they are directly related to the low levels of HRF found in the DS.

At present, we theorize that the relationship between receptors, inactivator, neurotransmitter, lack of FOXP2 neurons, slow growth, poor immune response, poor vision, etc. may all stem from what may be a catalyst and that catalyst may be HRF. We do not presently know this but what we do know is that we must do whatever we can to try to correct this deficit.

To begin at the beginning seems to be a logical target. We have a little more thinking to do before discussing whether or not a low histamine diet would be helpful. But it does seem likely that a diet high in HRF may be of some benefit. So let’s start there.

The relationship between antihistamines and the higher incidence of Alzheimer’s disease is yet one more consideration. People with DS seem to live a lifetime exposed to what equals the result of antihistamine usage. It is likely, then, that histamine levels is also related to the development of cognitive decline in DS.
The following are the highest readily available foods that actually contain TCTP (HRF). Adding them to your child’s diet may not encourage the production of FOXP2 neurons but it may raise brain histamine levels. We are continuing an extensive study of brain histamine but in the meantime, it certainly cannot be harmful to add these foods to your child’s daily diet and it may be beneficial.
FOODS THAT CONTAIN TCTP (HFR) DESIGNATED IN HUMAN BEINGS AS HISTAMINE LIBERATORS
TOMATOES
MANGO
PINEAPPLE
PAPAYA

NOTE: The fruit powders are more concentrated than fresh fruit. Green mango powder contains higher levels of TCTP than ripe. Mango seed powder also contains sufficient amounts of TCTP. Papaya powder contains higher levels of TCTP than fresh fruit.

At this point let’s not alter the diet other than to introduce histamine liberators as we are just not certain if exogenous histamine will reduce HRF further though one study indicated that it may.
We must be careful with excess use of antihistamines.

LONG TERM ANTIHISTAMINE USAGE AND AD
http://www.webmd.com/…/use-of-certain-allergy-depression-me…

H3 RECEPTORS IN DS AND AD
https://www.ncbi.nlm.nih.gov/pubmed/10511950

FOXP2 EXPRESSES DURING ADULTHOOD
http://onlinelibrary.wiley.com/d…/10.1002/cne.10654/abstract

TCTP IN EMBRYONIC VISUAL DEVELOPMENT
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852495/

LOW HMT IN DS
https://www.ncbi.nlm.nih.gov/pubmed/11880199

HISTAMINE AND FOXP2
http://neuraldevelopment.biomedcentral.com/…/…/1749-8104-8-4

BELOW ARE SUGGESTIONS FROM PARENTS, AND POSTS FROM DELETED THREADS:

Make sure fresh fruit papaya is ORGANIC- as it is one of the top genetically modified foods!!! If you have a 23andme on your child, look for the PON snp- that is the one responsible for detoxifying pesticides- if that is mutated, organic is much more crucial. The others are not GMO like papaya is. AVOID ‘SUNRISE’ Papaya…a good way to tell if your papaya is GMO is that it will be pinker in color vs. orange..the pink varieties are GMO.
Papaya enzymes WILL NOT HELP.
Lycopene has been isolated from tomatoes so it is unlikely to contain TCTP. What we really want to do us extract TCTP.

CONTINUING WITH INFORMATION ON THIS TOPIC BY DIXIE LAWRENCE
It looks like the number of histamine receptors is equal the amount of available histamine. In cases like DS and AD where there is low histamine there are studies showing low numbers of receptors as well but again we just don’t know.
The bottom line is not so much the production of speech as it is to determine how we can increase this neurotransmitter in the brain. If HRF is the big boy in getting histamine levels to rise in the brain, then I’d say that is where we start. Especially when you consider the relationship between artificially low levels of brain histamine in AD possibly linked to antihistamine use and that 100% of all person with DS (untreated) will develop AD.
If we are correct and it is true in AD then antihistamine usage could make this worse. Sometimes antihistamines are used when they are unnecessary as in cases of mucous but excess mucous in DS may have nothing at all to do with histamine but with the over expression of IL-10 and the best way to deal with it is a Curcumin.

(Great speech) it doesn’t have much to do with speech therapy. If the neurons aren’t there the child will have difficulty with speech. Madison benefited from speech therapy but not your average therapy. She is deaf. Her ability to speak is definitely the result of her being taught to use her lips and tongue to make sounds and speak without hearing.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601999/

Giving your child foods high in histamine or it’s precursor, histadine, may not be helpful and could result in lowering the already low levels of HRF in the brain. If you are using one of the histamine liberators and speech has not improved, try raising the dose or removing foods high in histamine/histadine from your child’s diet.
http://www.sciencedirect.com/…/art…/pii/0306452285902337

GREEN MANGO FROM AMAZON
https://www.amazon.com/…/B01…/ref=oh_aui_detailpage_o06_s00…

The use of Resveratrol and EGCG in Trisomy 21/ Down syndrome

Resveratrol (from grapeskins or Knotweed) and EGCG (from Green tea) have multiple benefits, including supporting cell health, anti-aging benefits, immune response support, healthy inflammatory function, anti-oxidant effects, and brain and neurological support. However,  Resveratrol and EGCG are two phytochemicals with very important roles in TNI (targeted nutritional intervention- the name for the protocol to address gene over-expression caused by Trisomy 21/ Down syndrome.)

Plant polyphenols as natural drugs for the management of Down syndrome and related disorders.    https://www.ncbi.nlm.nih.gov/pubmed/27826066

The polyphenols resveratrol and epigallocatechin-3-gallate restore the severe impairment of mitochondria in hippocampal progenitor cells from a Down syndrome mouse model.  https://www.ncbi.nlm.nih.gov/pubmed/26964795

RESVERATOL

Resveratrol is used in T21 to address Micro RNA 155.An elevation of MicroRNA – 155 causes permeability in the Blood Brain Barrier (BBB), which allows toxins and other things to get to the brain and nervous system tissue.In Trisomy 21/ Down syndrome, people have a minimum of a 30% – 50% over expression. This results in constant access to the brain of toxins that might otherwise be filtered by this barrier. A damaged blood brain barrier will not let everything cross it to enter the brain but neither will it efficiently keep every harmful thing out of the brain. Studies have proven that it reduces 155 by upregulating MicroRNA-633. Since 633 is a tumor suppressor gene, this is a plus.

Studies have confirmed that Resveratrol heals the BBB in Alzheimer’s disease. The mechanism in AD and DS creating the permeable BBB is the same. There is every reason to believe that Resveratrol takes care of this, but it is not know to what degree.

“The homeostasis of the central nervous system (CNS) environment is maintained by the BBB, which separates the brain from the systemic blood circulation. The cerebral capillaries are organized such that the brain is protected from blood-borne compounds, since a strict homeostasis of the neuronal environment and an intact barrier are essential for optimal brain functioning. However, during various neurological diseases the permeability of the BBB may be changed. This review will discuss the role of the BBB and especially of the CEC in various neuroinflammatory diseases.”http://pharmrev.aspetjournals.org/content/49/2/143

Resveratrol also protects from hypoxia, an issue in Ds because of the high amount of sleep apnea in the Ds population.

Protective effect of resveratrol against chronic intermittent hypoxia-induced spatial memory deficits, hippocampal oxidative DNA damage and increased p47Phox NADPH oxidase expression in young rats. http://www.ncbi.nlm.nih.gov/m/pubmed/26940604/

Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer’s disease.  https://www.ncbi.nlm.nih.gov/pubmed/25024312

But there is another issue In Trisomy 21/ Down syndrome where resveratrol is particularly useful.

Resveratrol helps repair telomere shortening by upregulating telomerase. Studies suggest that it does not require large doses to effect telomere length.

Immortalization of epithelial progenitor cells mediated by resveratrohttp://www.nature.com/onc/journal/v27/n17/full/1210886a.html

SIRT1 prevents replicative senescence of normal human umbilical cord fibroblast through potentiating the transcription of human telomerase reverse transcriptase gene.   http://www.ncbi.nlm.nih.gov/pubmed/22197555

http://munews.missouri.edu/…/1119-natural-compound…/

What does this mean for people with Down syndrome?

It means Resveratrol may be an answer to yet another serious issue in DS.

“It is suggested that telomere repair is directly related to cell survival (fact) and human longevity (both fact and probability). In DS the telomeres are very short in comparison to normal controls and they simply do not repair at the rate seen in the non DS population. Giving our children the ability to repair the telomeres may help prevent rapid aging, Alzheimer’s disease, Leukemia, and other age related diseases, including autoimmune diseases associated in younger people and even small children with DS. One very important result may be giving our children an additional decade or more of healthy life.

The tips of chromosomes (think about the tips of a shoe string) are called telomeres. These prevent the destruction of DNA and serve other purposes. Every time a cell divides telomeres shorten. It’s as it the tips are chipped off during cell division. But the human body produces an enzyme called telomerase that activates and repairs the telomeres instantly. What a miracle. But not for our children. The telomeres shorten but are not easily repaired. In time, they are too short to sustain life and it may well be a major reason for premature death in DS. Remember, on average, our children’s lives are 20 years shorter than a non DS individual. That means that DS is a terminal disease by definition because death is directly related to it. But! Resveratrol upregulates telomerase and allows the repair of telomeres. You can see how critical Resveratrol is for our children.”

-Dixie Lawrence, T21 biochemist and Ds researcher

EGCG

EGCG is used to down regulate DyrK1a, and enhance learning, cognition and memory.

Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A.  https://www.ncbi.nlm.nih.gov/pubmed/19242551

Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome? https://www.ncbi.nlm.nih.gov/pubmed/28203607

Combined Treatment With Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits and Hippocampal Alterations in a Mouse Model of Down Syndrome. https://www.ncbi.nlm.nih.gov/pubmed/27844057

Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and degrades the amyloid beta peptide whose abnormal misfolding and aggregation in neural tissue has been implicated as a cause of Alzheimer’s disease.

Neprilysin is low in the brain of both AD and Down syndrome patients. A recent study found that a DYRK1a inhibitor, harmine, upregulated Neprilysin in both DS and AD.

Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts https://www.jstage.jst.go.jp/arti…/…/40/3/40_b16-00825/_html

Harmine, the compound utilized in the above study is not an option for use in DS as there are numerous issues involving both side effects and availability. However, EGCG is very similar in structure and also acts as a DYRK1a inhibitor and has the identical effect on Neprilysin, increasing its levels in the brain.

(-)-Epigallocatechin-3-gallate attenuates cognitive deterioration in Alzheimer’s disease model mice by upregulating neprilysin expression. https://www.ncbi.nlm.nih.gov/pubmed/…

DOSAGE RECOMMENDATIONS

Resveratrol- start with .5 – 1 mg/kg (1 mg of resveratrol per 1 kg of body weight).  Do this does 2 times a day, spaced at lest 8 hours apart.  Gradually increase the dose to 4-5 mg/kg.

EGCG- start with .5-1 mg of EGCG per kg of body weight.  Gradually increase the does anywhere from 3-5 mg.kg.  Some studies and protocols for much higher amounts.

ADDITIONAL CONSIDERATIONS

EGCG needs to be separated from folate (like in NuTriVene) by 4 hours, as EGCG can effect one of the enzymes in the folate pathway.

At doses much higher than we are using in T21, liver and kidney stress have bee noted.  If your child is low in ferritin, be sure to monitor it, and additional supplementation with a high quality iron and adding organ meats to the diet may be warranted- as EGCG can in some cases, have a chelating effect on iron.

NuTriVene Products

Nutrivene products- the foundation of Targeted Nutritional Intervention (TNI)

NUTRIVENE DAILY FORMULA

NuTriVene-D is the main supplement in the treatment of Down syndrome, and the one to start with. It was developed by a team of researchers and scientists.  It’s purpose is to provide nutritional agents, such as vitamins, minerals and amino acids, in specific forms and amounts to help offset or manage several of the genes over-expressing in Trisomy 21/ Down syndrome.

“The Daytime Formula targets all the aberrant nutritional needs of kids with DS. It corrects the damage to the folate/methyl cycle caused by the over expression of the CBS gene. It provides all of the missing precursors for normal thyroid function. It provides nutrients found in low quantities necessary for immune response. It targets oxidative stress caused by the over expression of SOD1. There are there antioxidant enzymes in the oxidative triad that must be in levels sufficient to work in synergy. When they do not work, the cells fill up with hydrogen peroxide. Hydrogen peroxide then becomes the most deadly free radical known to man, the hydroxyl free radical. So, in addition to providing other antioxidants, Nutrivene Daytime Formula upregulates the two antioxidant enzymes that are NOT located on chromosome 21, Catalase and Glutathione Peroxidase and therefore far too low for the triad to function. But by up regulating them as much as possible, this triad functions much better. The Daytime Formula normalizes the child’s biochemistry as much as possible in the exact levels required.”

– Dixie Lawrence, DS Biochemist and Researcher

To read the list of article about Nutrivene-D please go here http://www.nutrivene.com/educational_information.php

http://www.nutrivene.com/faqs.php

 

If you have an infant, start with the NuTriVene Daily Formula.  It comes with dosage information, as dosage is based on the weight of your child.  I recommend starting at 1/4 of the dose for your child, and gradually work up to the full dose.  The full dose split into 2 doses a day ensures your child has better blood saturation of the product.

There are 2 other parts of NuTriVene,  the NuTriVene Daily Enzymes and the NuTriVene NightTime Formula.

NUTRIVENE ENZYMES

The NuTriVene enzymes are digestive enzymes.  These help to break down food so that it is more easily digested, and nutrients are better absorbed and assimilated by the body.  For infants, do not start this product until solids are introduced….however infants on formula may benefit from this product.  Infants with acid reflux  may have a worsening of reflux with this product.  Dosage recommendations come with this product.

To use, you can open up the capsule and sprinkle into or onto food, until your child is old enough to swallow pills.  Our webstore also carries some other digestive enzyme options, including a chewable one!

NUTRIVENE NIGHTTIME

NuTriVene NightTime formula helps provide nutrients to support growth hormone and serotonin production.

Growth hormone can be deficient in people with T21.  This product makes sure the nutrients are available for the pituitary gland to make growth hormone.  The nutrients also help the body make serotonin, a neurotransmitter that can help with sleep, which is often low in children with T21/Ds.  Tis will better aid children with Ds to get into REM sleep- which is crucial for growth and development.  Dosage recommendations come with the product.

Please note that while all people with Trisomy 21 have genes that are over-expressing, each person still has an individual and unique biochemistry, and may be best served by working with a practitioner who specializes in TNI, to customize a specific protocol.