Scientists find way to silence extra chromosome that causes Down syndrome

Scientists find way to silence extra chromosome that causes Down syndrome

For patients suffering from Down syndrome, the source of their condition can be traced back to just one extra chromosome inherited during development – chromosome 21.

While it is still unclear exactly how this extra copy causes the symptoms of Down syndrome – also known as trisomy 21, its presence in a person’s genetic code is associated with delayed cognitive ability, slowed physical development and a whole host of health conditions, including congenital heart disease, cancer and early on-set Alzheimer’s.

But now, researchers say they have found a way to turn off the extra copy of chromosome 21.

In a new study published online in the journal Nature, scientists from University of Massachusetts Medical School (UMMS) harnessed the abilities of a naturally occurring gene called XIST that acts as an “off switch” in X chromosomes.  In a culture of stem cells, the researchers were able to repurpose the XIST gene so that instead of silencing X chromosomes, it silenced the extra chromosome 21 instead.

Though the research only shows proof-of-principle for turning off the chromosome – meaning the method is a long way from being utilized in humans – the findings have huge implications for the future of Down syndrome research. Researchers hope this study will pave the way for a better understanding of the disorder’s pathology and potentially help to create new therapeutic targets for therapies.

“This is the beginning of this idea, and we’re hoping more investigators get interested,” lead researcher Jeanne Lawrence, professor of cell and developmental biology at UMMS, told FoxNews.com. “… We used epigenetics, a new concept, to change the way the DNA is expressed, not changing the DNA itself. This could have a lot of promise in other ways for Down syndrome and other disorders.”

Each human inherits 23 chromosomes from their mother and 23 from their father, equaling 46 chromosomes in each cell.  Individuals with Down syndrome inherit three (instead of two) copies of chromosome 21, which ultimately causes their “trisomy 21.” 

According to Lawrence, the team’s method for silencing this chromosome was inspired by a naturally occurring process that occurs in women every day.

“What’s important in biology is not that you have the right sequence to your DNA, but you have the right balance of DNA,” Lawrence said.  “Women have two X chromosomes and men have one X and Y.  Since the Y chromosome lacks a lot of the genes in the X chromosomes, women have more expression of X chromosome genes than men – well that wouldn’t work biologically.  So nature had to devise a mechanism to equalize that.”

Lawrence had contributed to a previous study, which had identified that mechanism as the XIST gene, a piece of DNA located in the X chromosome that controls whether or not the chromosome can be silenced.  The XIST gene makes a unique non-coding RNA, which accumulates in the nucleus of the cell of the chromosome, triggering changes to the way the chromosome is packaged within the cell.  This ultimately renders the chromosome inactive – preventing its DNA from producing proteins and other components.

Hoping to recreate this effect, Lawrence and first author Dr. Jun Jiang, along with UMMS colleague Dr. Lisa Hall, devised a way to insert the XIST gene into the extra chromosome 21 of trisomic cells.  In a culture of pluripotent stem cells derived from the skin cells of a Down syndrome patient, the XIST gene was inserted into the chromosomes through the use of zinc finger nuclease (ZFN) technology. The technique ultimately allowed them to cut each chromosome at a specific location in its sequence and then paste the gene into that cut site.

“(Once the gene was inserted), we split the cultures, and took half the cells and turned on the XIST gene to silence the chromosome and (in) the other half we didn’t do that,” Lawrence said.  “Then we directly compared how the cell behavior changes…and the neural progenitor cells formed much more quickly in the (cultures) that we had silenced. So you can quickly start to say, ‘What are the pathologies of the different cells and the different organs?’”

According to Lawrence, the success of their findings will ultimately help researchers better understand the different cell pathologies in patients and how the disorder progresses during development.  She also noted the more significant implication of their research: that it could ultimately lead to the utilization of chromosome therapies in Down syndrome patients.  However, it may be many years before these treatments are realized.

Approximately 6,000 babies with Down syndrome are born each year in the United States, according to the Centers for Disease Control and Prevention.  Risk factors for Down syndrome include having a parent with a chromosomal disorder or having a sibling with Down syndrome or another chromosomal disorder. However, the mechanisms behind the condition are still largely unknown. Lawrence hopes that her lab’s findings will help get more people interested in better understanding the disorder.

“Down syndrome hasn’t received as much attention for therapeutics, partly because it’s so complex and there (are) other procedures people use to treat it,” Lawrence said.  “Also, people think Down syndrome is going away, but it’s not going away.  I think it’s good if this can help draw attention to research (for the disorder).”



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Drug Improves Cognitive Function in Mouse Model of Down Syndrome

This was posted on the DSTNI listserv by Richard and I thought I'd share here:

Drug Improves Cognitive Function in Mouse Model of Down Syndrome

July 2, 2013 — An existing FDA-approved drug improves cognitive function in a mouse model of Down syndrome, according to a new study by researchers at the Stanford University School of Medicine.

The drug, an asthma medication called formoterol, strengthened nerve connections in the hippocampus, a brain center used for spatial navigation, paying attention and forming new memories, the study said. It also improved contextual learning, in which the brain integrates spatial and sensory information.

Both hippocampal function and contextual learning, which are impaired in Down syndrome, depend on the brain having a good supply of the neurotransmitter norepinephrine. This neurotransmitter sends its signal via several types of receptors on the neurons, including a group called beta-2 adrenergic receptors.

"This study provides the initial proof-of-concept that targeting beta-2 adrenergic receptors for treatment of cognitive dysfunction in Down syndrome could be an effective strategy," said Ahmed Salehi, MD, PhD, the study's senior author and a clinical associate professor of psychiatry and behavioral sciences. The study will be published online July 2 in Biological Psychiatry.

Down syndrome, which is caused by an extra copy of chromosome 21, results in both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function. As a result, children with Down syndrome fall behind their peers' cognitive development. In addition, adults with Down syndrome develop Alzheimer's-type pathology in their brains by age 40. Down syndrome affects about 400,000 people in the United States and 6 million worldwide.

In prior Down syndrome research, scientists have seen deterioration of the brain center that manufactures norepinephrine in both people with Down syndrome and its mouse model. Earlier work by Salehi's team found that giving a norepinephrine precursor could improve cognitive function in a mouse model genetically engineered to mimic Down syndrome.

The new study refined this work by targeting only one group of receptors that respond to norepinephrine: the beta-2 adrenergic receptors in the brain. The researchers began by giving mice a compound that blocks the action of beta-2 adrenergic receptors outside the brain. They then gave the mice formoterol, a drug that can partially cross the blood-brain barrier and that was already known to activate beta-2 adrenergic receptors. Because people with Down syndrome are prone to heart problems, the researchers avoided activating a different group of norepinephrine-sensitive receptors, the beta-1 adrenergic receptors, which predominate in the heart.

The scientists saw improvement on a standard test of contextual learning in mice. In contextual learning, the brain integrates sensory and spatial information to remember the layout of a complex environment: for instance, a person using sounds, smells and sights to remember the location of a store in a shopping mall is using contextual learning. The researchers also saw more synapses and a more complex structure of dendrites, the nerves' outgoing ends, in the hippocampus after the affected mice received formoterol.

"The fact that such a short period of giving medication can make these neurons much more complex is very interesting," Salehi said, noting that mice in the study received the drug for a maximum of two weeks.

Further tests will be needed to determine whether formoterol might be an appropriate treatment for people with Down syndrome or whether to use another drug that activates the same receptors, Salehi said. The dose used in this study was many times higher than that used for asthma treatment, he cautioned, so it is not known whether it is safe. A lower dose might work, or other drugs that affect beta-2 adrenergic receptors might be safer and more effective in humans. Researchers also want to explore what parts of learning -- taking in new information, remembering it or both -- are affected by the drug treatment.

Prior research to improve cognitive function in children with Down syndrome has sometimes raised concerns from families that cognitive treatments would alter positive attributes of these children's personalities, but Salehi said that is not the goal of his team's research.

"Our aim is to enable these children to do better in school," Salehi said. "It is absolutely not to change their personalities or the way they react to society." Changing a child's personality would be much more complicated than activating a subgroup of receptors in the brain, he said.

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DYRK1A Overexpression Linked to Hypothyroidism

Green Tea Extract, EGCG, is a safe DYRK1A inhibitor. Which is one of the many reasons EGCG is so beneficial for people with DS.

Well, a new study is out which shows the overexpressed DYRK1A gene being linked to hypothyroidism in Down syndrome. Read below:

Dyrk1A (dual-specificity thyrosine (Y)-phosphorylation regulated kinase 1A) overexpression is linked to congenital hypothyroidism in Down syndrome

http://www.endocrine-abstracts.org/ea/0029/ea0029p1609.htm



D. Kariyawasam1, M. Martin-Pena1, L. Rachdi1, A. Carré5, M. Houlier1, C. Dupuy5, N. Janel4, J. Delabar4 & M. Polak1,2,3

Introduction: Trisomy 21 or Down Syndrome (DS) patients have a predisposition for Congenital Hypothyroidism which can aggravate their mental status.

Hypothesis: The presence of three copy of Dyrk1a gene, localized in chromosome 21 in Humans, is responsible for a thyroidal dysgenesis.

Our aim is to understand the molecular mechanisms underlying this condition.
Methods: The transgenic Dyrk1a (TgDyrk1a) mouse, our DS murine model, contains three copies of the Dyrk1a gene and was obtained through electroporation of a Bacterial Artificial Chromosome containing the entire gene with its own regulatory sequences. We studied their thyroidal phenotype in young adults (8–13 weeks old) by histology, immunohistochemistry and blood T4 hormonal dosages, reflecting the thyroidal function. We compared the thyroidal molecular phenotype of the TgDyrk1a and wild type mice: RNA levels of molecules involved in the thyroidogenesis were studied by qRT-PCR at different embryonic stages.

Results: The average surface of thyroidal follicles in young adult TgDyrk1a mice is smaller (TgDyrk1a: 2164 μm2 versus wild type: 1420 μm2; P=0.005; n=6). They presented also a lower plasmatic T4 (TgDyrk1a: 2.4 ng/ml versus wild type: 3.7 ng/ml; P=0.019; n=14). The overexpression of Dyrk1a in the thyroids leads to an elevation of RNA level expression of Nkx2-1, Foxe1, Thyroperoxidase and Thyroglobulin, involved in thyroidogenesis, at E13.5 and E17.5.
Conclusion: Our first results show an abnormal thyroid function and histology in young adult TgDyrk1a mice and an overexpression of thyroidal developmental molecules. To further understand the molecular mechanism linking Dyrk1a overexpression to altered thyroid folliculogenesis and function we are studying some candidates as direct targets of Dyrk1a using thyroidal cell lines.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported. Supported by Sandoz SAS, EDF and the Fondation Lejeune. T4 dosage courtesy of Pr S Refetoff, Chicago.



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Full Text of EGCG Study on Mitochondrial Biogenesis in Individuals with Down Syndrome

Remember the study that prompted my big post on EGCG a few months back? The one that showed EGCG can actually create Mitochondrial Biogenesis in individuals with Down syndrome? Yeah, that was huge news!

Epigallocatechin-3-gallate prevents oxidative phosphorylation deficit and promotes mitochondrial biogenesis in human cells from subjects with Down's syndrome

The abstract of that study is below:

A critical role for mitochondrial dysfunction has been proposed in the pathogenesis of Down's syndrome (DS), a human multifactorial disorder caused by trisomy of chromosome 21, associated with mental retardation and early neurodegeneration. Previous studies from our group demonstrated in DS cells a decreased capacity of the mitochondrial ATP production system and overproduction of reactive oxygen species (ROS) in mitochondria. In this study we have tested the potential of epigallocatechin-3-gallate (EGCG) – a natural polyphenol component of green tea – to counteract the mitochondrial energy deficit found in DS cells. We found that EGCG, incubated with cultured lymphoblasts and fibroblasts from DS subjects, rescued mitochondrial complex I and ATP synthase catalytic activities, restored oxidative phosphorylation efficiency and counteracted oxidative stress. These effects were associated with EGCG-induced promotion of PKA activity, related to increased cellular levels of cAMP and PKA-dependent phosphorylation of the NDUFS4 subunit of complex I. In addition, EGCG strongly promoted mitochondrial biogenesis in DS cells, as associated with increase in Sirt1-dependent PGC-1α deacetylation, NRF-1 and T-FAM protein levels and mitochondrial DNA content.

In conclusion, this study shows that EGCG is a promoting effector of oxidative phosphorylation and mitochondrial biogenesis in DS cells, acting through modulation of the cAMP/PKA- and sirtuin-dependent pathways. EGCG treatment promises thus to be a therapeutic approach to counteract mitochondrial energy deficit and oxidative stress in DS.

Well, we have the full text in PDF format of that study, which is always a helpful resource to have. You can download the PDF here.



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New Randomized Double-Blind Trial in the Works With EGCG

Richard over at the DSTNI listserv, shared the following:

I just found out that a second and larger clinical trial has started in Spain. The dosage remains the same as in the pilot study, but this time the duration was set for 12 instead of only 3 months, and there are 100 participants ages 14 to 29yrs. First results are expected for December 2013.

The name of the clinical trial is: Normalization of dyrk1A and APP Function as an Approach to Improve Cognitive Performance and Decelerate AD Progression in DS Subjects: Epigallocatechin Gallate as Therapeutic Tool.

This is the brief summary and the goal of the study:

Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, is postulated to modulate dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and amyloid beta precursor protein (APP) gene overexpression in the brains of Down syndrome mouse models. The clinical study is aimed at demonstrating that normalization of Dyrk1A and APP functions is a therapeutic approach to improve cognitive performance and decelerate AD (Alzheimer's disease) like progression.

You can see the full clinical trial page at http://clinicaltrials.gov/ct2/show/record/NCT01699711.


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EGCG - Green Tea Extract - and Bones

First off, I didn't realize it had been so long since the last blog post! Oops! Time flies by, doesn't it?!

A couple parents of kids with DS that I know shared this recent study on EGCG, so I thought I'd share it up here.

The final conclusion of this: EGCG seems to help improve bone mineral density and skeletal problems in individuals with Down syndrome. Pretty cool.

Evaluation of the Effects of Green Tea Extracts on Bone Homeostasis in the Ts65Dn Down Syndrome Mouse Model

Irushi S. Abeysekera1, Jared R. Thomas2, Joshua D. Blazek1, and Randall J. Roper1 1Department of Biology, Indiana-University-Purdue-University, Indianapolis; 2 Ivy Tech Community
College- Central Indiana

Down Syndrome (DS) is a genetic disorder that affects ~1 in 700 live births, caused by trisomy of human chromosome 21 (Hsa21), and results in cognitive impairment, craniofacial abnormalities, low muscle tone, and skeletal deficiencies. To study these phenotypes, we utilized the Ts65Dn mouse model, which contains three copies of approximately half the orthologous found on Hsa21 and exhibits similar phenotypes as found in humans with DS. Individuals with DS and Ts65Dn mice have deficits in bone mineral density (BMD), architecture, and bone strength. Over-expression of DYRK1A, a serine-threonine kinase encoded on Hsa21, has been linked to deficiencies in DS bone homeostasis. Epigallocatechin-3- gallate (EGCG), an aromatic polyphenol found in high concentrations in green tea, is a known inhibitor of Dyrk1a activity. Normalization of Dyrk1a activity by EGCG may have the potential to regulate bone homeostasis and increase BMD and bone strength in individuals with DS. In this study, we hypothesized that EGCG obtained from different sources would have differential effects in correcting bone deficits associated with DS. To test our hypothesis, we performed on EGCG and related compounds from different sources. The LC-MS analysis determined the amount of EGCG and the degradation in our stock solution. Next, we treated three-week- old Ts65Dn and control male mice with EGCG for three weeks. At six weeks of age, mice were sacrificed. DXA and micro CT analysis were performed on the femurs and skulls of the mice to assess trabecular and cortical bone structure and BMD. Our results indicate the ability of EGCG to ameliorate skeletal deficiencies and compared pure EGCG with EGCG purchased from commercial vendors in correcting skeletal deficits associated with DS.

Mentors: Randall J. Roper, Department of Biology, Indiana-University-Purdue-University, Indianapolis



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New Decreased Protein Found in Down Syndrome - Treatment is Promising

There's some new research out by scientists at the Sanford-Burnham Medical Research Institute.

The reduced protein is SNX27. The article states,

Near-normal brain function can be restored in mouse models by increasing levels of this protein, called SNX27

One of the researchers says,

"It's hard to say in humans (how much brain function can be repaired), but in those particular mice, the mouse model of Down syndrome, we were able to pretty much rescue all the pathology," according to cognitive tests given to the rodents, Xu said. 

The research showed the following,

Lack of SNX27 decreases the number of certain molecules on the surface of mouse neurons, the study found. These molecules, called glutamate receptors, are important for learning. Researchers studied brain samples collected after death from people with Down syndrome, and found lower levels of SNX27 than in control samples of those without the condition. In addition, neurons have abnormal dendrites, the long filaments that help transmit signals from cell to cell. 

If the mouse model is a good guide, such therapy should work in children almost up until puberty. 

The mice were treated using gene therapy.

The mice were treated with gene therapy to deliver a human version of the gene that makes the SNX27 protein. A common virus was given the gene, then delivered to the mouse brains. Such an approach is now considered too risky for human use, Xu said, so researchers are looking for a drug that produces the same effect.

The beginning of the article linked above states,

Moreover, the study points the way to a possible therapy to improve brain function in children with the genetic abnormality. No such therapy now exists.

I would have to disagree with this. There is nutritional therapy that exists right now which improves brain function in children with Down syndrome. Namely Longvida Curcumin, Ginkgo Biloba and EGCG. Some families even use Prozac with their children with Down syndrome to improve brain function.

It would be nice if Down syndrome was easily "solved" with just one therapy. But, it's not. It's so complex, due to the triplicated chromosome, that so many different genes are "turned on," "turned off," underexpressed, overexpressed and so on. While I am excited for every new research find and every new possible therapy to help individuals with DS, it's a complicated puzzle. Ultimately, at this point, we have to use as many researched aspects of treatment as are available to us (which are safe), to address the concerns in Down syndrome. It's an every changing journey though and something that has to be looked at as a marathon, not a sprint.


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Green Tea Extract: EGCG & The Benefits It Has for Down Syndrome

EGCG, which stands for Epigallocatechin-3-gallate, is an extract from Green Tea. EGCG is the major polyphenolic compound found in green tea. Green Tea has been known to have lots of health benefits for awhile, but about two years ago it came to the attention of people in the Down syndrome world.

I’ve been watching it over the last couple years. But, when I saw some new research come out about EGCG a couple weeks ago, I decided it was time to jump on the bandwagon and start supplementing with EGCG. As usual though, I needed to have all my ducks in a row, so to speak, have all the research and facts lined up, so I can definitively know why we are using EGCG. Of course, this helps others as well, which is also why I’ve typed it all up.

Original research with EGCG that sparked the attention of those in the DS world was research for Alzheimer’s disease. Let’s look at some of this initial research to lay the groundwork.

EGCG prevents certain apoptotic (pre-programmed) cell death through inhibiting the elevation of Abeta (a protein involved with Alzheimer’s and also involved with DS) via inhibition of beta and gamma-secretases. This, therefore, reduces neuroinflammation that’s associated with the progression of Alzheimer’s disease (1). We also know that neuroinflammation is involved with DS.

Alzheimer’s Disease & Down syndrome have the increased amyloid-beta protein (Abeta), which causes plaques & tangles in the brain. The processes & increases which Abeta cause are reduced by EGCG. EGCG improves memory function, as well as reducing harmful levels of increased Abeta and its associated functions (2).

So, we have EGCG which prevents cell death, reduces the elevated levels of amyloid beta, reduces Beta Secretase expression, reduces APP (Amyloid Precursor Protein – overexpressed in DS) and reduces neuroinflammation. All of this will help improve neurogenesis. That’s all great stuff, but there’s still more amazing benefits to EGCG – specifically for Down syndrome.

There’s an annoying little gene that is over expressed in Down syndrome called – get ready for this long word - dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A, also known as DYRK1A. We’ll use the abbreviated word, since it’s a lot easier to say and remember! DYRK1A causes cognitive & learning impairments in DS and is highly involved in the neurodegenerative process in the Down syndrome brain (3-6). It also plays a role in the Alzheimer-like pathway that is seen in Down syndrome (3).
The good thing about DYRK1A is research has shown that it can be inhibited. If DYRK1A is inhibited, then the harmful effects of the gene won’t be able to function.  Remember, the over expressed aspect of this gene is what is the problem – not just the gene in and of itself.

EGCG is a safe DYRK1A inhibitor and there has been very successful research done in individuals with Down syndrome. The Jerome Lejeune Foundation has a program designed to research what will inhibit this gene. Professor Mara Dierssen, from the Jerome Lejeune Foundation, has had a very successful clinical trial (10) with individuals with Down syndrome using EGCG. Professor Dierssen is also now recruiting for a second clinical trial (11).

EGCG is also a GABA antagonist (7-9). An antagonist is a substance that acts within the body to reduce the physiological activity of another substance. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter.

Now that we have the definitions down, let’s get on to the problem with GABA. GABA is a good thing when it is not in excess, because it creates the perfect balance between neuronal excitation and inhibition to allow for efficient learning. But, there appears to be too much GABA-related inhibition in Down syndrome and therefore it “turns off” too many neurons in the brain and makes it more difficult to process information.

So, EGCG being a GABA antagonist, namely blocking the GABA(A) receptor (recombinant alpha1beta2gamma2L GABA(A) receptor), is a very beneficial thing for individuals with DS.  Having an antagonist which can reduce GABA, will greatly help the brain and learning in Down syndrome.

Mitochondrial dysfunction has been well established in Down syndrome. EGCG prevents oxidative deficit in the mitochondria, reduces oxidative stress and actually promotes mitochondrial biogenesis in Down syndrome (12).  This is amazing, because there has never before, to my knowledge, been a way to efficiently combat the mitochondrial dysfunction in Down syndrome.

EGCG is also an iron-chelator, which can be beneficial for individuals with DS, due to the oxidation issues that come with high levels of iron. Now, if an individual with DS already has low levels of iron, this would be something to keep in mind and monitor the iron levels while supplementing with EGCG.
So, to recap, EGCG helps improve memory, reduce the learning impairment seen in individuals with DS, reduce oxidative stress, is a potent antioxidant, promotes mitochondrial biogenesis, is a GABA antagonist, is an iron-chelator, inhibit DYRK1A, prevents cell death, reduces neuroinflammation, reduces Beta Secretase & APP expression, and causes a reduction in Abeta and the problems it causes.

With all this, one may ask, is there anything negative about EGCG? There is one thing to keep an eye on, but I wouldn’t necessarily call it a “negative.”

EGCG inhibits or reduces DHFR, which is an enzyme involved in the methylation and folate cycle. So, ultimately, it may reduce folate. We already know that folate is reduced in Down syndrome and many people use additional supplements to increase folate in Down syndrome. As long as a sufficient amount of folate or folinic acid is supplemented, I would not be too concerned about this aspect of EGCG. There are some other questions regarding DHFR and some genes that it is involved in regulating – whether it is good to stop that or not.

But, for now, look at all the benefits for EGCG above and think about all the problems which DYRK1A (and others) cause. The answer is simple for me, at the moment: Supplement with additional folate/folinic acid, or supplements to support the methylation cycle, as you are using EGCG.

Now, the question comes down to, what is the recommended dosage and what are the best brands.

The recommended dosage is 9mg/kg (kg=2.5lbs) of EGCG. This is the dosage that the clinical trials in Down syndrome are using. This is also the dosage that many parents are using with their children.

One important note on the dosage: that is NOT 9mg/kg of Green Tea. This is important to note, as most products will be Green Tea that you are giving. You will have to calculate the amount of EGCG in the product to give the correct amount. You will be giving more Green Tea, but the recommended dosage of 9mg/kg.

Because EGCG is still in the early stages of use and development, it can be a little tricky to get a brand that is bioavailable. A good brand of just EGCG is Teavigo. The problem with Teavigo is that it is not in a liposomal encapsulation (a fatty acid), to make it bioavailable enough to cross the blood-brain-barrier (which is where it is needed).

GreenSelect Phytosomes made by a company named Indena, has been found by some to be a good bioavailable form of EGCG. This has the phospholipid bound to it. There are several companies which use GreenSelect as their base. One example is VitaCost GreenSelect. Another example is Swanson's Ultra GreenSelect Green Tea Phytosome.

Another liposomal brand which some families use with their children is Enzymatic Therapy Green Tea Elite with EGCG. You can view it here and here.

We will be using the Swanson's Ultra GreenSelect Green Tea Phytosome, as is mentioned above. The cost is $14.99 for 60 capsules. Each capsule contains the following:

GreenSelect® Phytosome™

(green tea extract Camellia sinensis leaves/ Glycine max soybeans) -600 mg

Standardized to:  

19-25% polyphenols - 114-150 mg  

13% epigallocatechin 3-0 gallate (EGCG) - 78 mg

The dosage can be a little tricky with the GreenSelect Green Tea. VitaCost's GreenSelect Extract which is mentioned above contains the following per 1 capsule:

“Green Tea Extract (Camellia sinensis leaves/Glycine max soybeans) [standardized to 60% polyphenols 180mg, 40% epigallocatechin 3-0 gallate (EGCG) 120 mg]”

Originally we were going to use the VitaCost brand. But, Richard on the DSTNI list pointed out that VitaCost doesn't calculate the dosage accurately. Yes, it can be a little confusing. But, they miss the dosage part of the fatty acids in the mix. So, the dosage above for Swanson's GreenSelect is accurate and not as confusing. The VitaCost dosage is not accurate.

For a child that is O’s weight – 50 lbs – that would calculate out to 180mg/day of EGCG. With the Swanson GreenSelect EGCG, that would mean approximately 2 & 1/2 capsules. With the VitaCost brand, the dosage is almost doubled.

So, there’s a LONG explanation of why EGCG is good and everything that goes with it. I will keep notes of how O does on the EGCG and any changes we see.

*Note (Update 8/20/15): I realized that it is not mentioned about giving the child the 9mg/kg dosage of EGCG twice a day. That IS the recommended thing to do. It is best to give the 9mg/kg dosage TWICE a day, as then it is in child's body at all times. We do this with O. Some have had problems giving the dosage at night, because it has kept their child awake. Others have not had this problem. We have not experienced this problem at all.

References:
1. Brain Res. 2009 Jan 23;1250:164-74 (-)-Epigallocatechin-3-gallate prevents lipopolysaccharide-induced elevation of beta-amyloid generation and memory deficiency. Lee YK, Yuk DY, Lee JW, Lee SY, Ha TY, Oh KW, Yun YP, Hong JT.
2. Nutr. 2009 Oct;139(10):1987-93. Green tea (-)-epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-kappaB pathways in mice. Lee JW, Lee YK, Ban JO, Ha TY, Yun YP, Han SB, Oh KW, Hong JT.
3. Ageing in Down Syndrome: DYRK1A As a Candidate Gene for Cognitive Decline
http://www.sciencedirect.com/science/article/pii/S2171974808700394
4. Dyrk1A Overexpression Inhibits Proliferation and Induces Premature Neuronal Differentiation of Neural Progenitor Cells. http://www.jneurosci.org/content/30/11/4004.full
5. DYRK1A in normal brain development and Down syndrome. http://www.nature.com/nrn/journal/v13/n12/fig_tab/nrn3314_F2.html 
6. Green Tea Polyphenols Rescue of Brain Defects Induced by Overexpression of DYRK1A http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004606
7. http://sydney.edu.au/medicine/pharmacology/adrien-albert/images/pdfs/RefsPDFs/367.pdf 
8. Reducing GABAA α5 Receptor-Mediated Inhibition Rescues Functional and Neuromorphological Deficits in a Mouse Model of Down Syndrome. http://www.jneurosci.org/content/33/9/3953.full
9. Implications for treatment: GABAA receptors in aging, Down syndrome and Alzheimer's disease. http://www.ncbi.nlm.nih.gov/pubmed/21388375
10. http://clinicaltrials.gov/ct2/show/NCT01394796?term=EGCG+and+down+syndrome&rank=1
11. http://clinicaltrials.gov/ct2/show/NCT01699711?term=EGCG+and+down+syndrome&rank=2
12. Epigallocatechin-3-gallate prevents oxidative phosphorylation deficit and promotes mitochondrial biogenesis in human cells from subjects with Down's syndrome http://www.sciencedirect.com/science/article/pii/S092544391200302X
13.  A few helpful websites:
https://sites.google.com/site/superdownsyndrome/supplements/green-tea-extract
http://changingmindsaboutdownsyndrome.blogspot.com (search EGCG)
http://dsdaytoday.blogspot.com/2011/03/egcg-green-tea-extract.html
http://dstoner.net/Math_Science/Downs.html

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SimplyThick - Warning With It's Use in Infants - Causes Death

My friend forwarded this news article to me. While some of it may be old news, I thought this was important and I would share it. I know SimplyThick has been recommended and used with babies who have Down syndrome to help with reflux and feeding issues.

Warning Too Late for Some Babies
By CATHERINE SAINT LOUIS

Six weeks after Jack Mahoney was born prematurely on Feb. 3, 2011, the neonatal staff at WakeMed Hospital in Raleigh, N.C., noticed that his heart rate slowed slightly when he ate. They figured he was having difficulty feeding, and they added a thickener to help.

When Jack was discharged, his parents were given the thickener, SimplyThick, to mix into his formula. Two weeks later, Jack was back in the hospital, with a swollen belly and in inconsolable pain. By then, most of his small intestine had stopped working. He died soon after, at 66 days old.

A month later, the Food and Drug Administration issued a caution that SimplyThick should not be fed to premature infants because it may cause necrotizing enterocolitis, or NEC, a life-threatening condition that damages intestinal tissue.

Experts do not know how the product may be linked to the condition, but Jack is not the only child to die after receiving SimplyThick. An F.D.A. investigation of 84 cases, published in The Journal of Pediatrics in 2012, found a "distinct illness pattern" in 22 instances that suggested a possible link between SimplyThick and NEC. Seven deaths were cited; 14 infants required surgery.

Last September, after more adverse events were reported, the F.D.A. warned that the thickener should not be given to any infants. But the fact that SimplyThick was widely used at all in neonatal intensive care units has spawned a spate of lawsuits and raised questions about regulatory oversight of food additives for infants.

SimplyThick is made from xanthan gum, a widely-used food additive on the F.D.A.'s list of substances "generally recognized as safe." SimplyThick is classified as a food and the F.D.A. did not assess it for safety.

John Holahan, president of SimplyThick, which is based in St. Louis, acknowledged that the company marketed the product to speech language pathologists who in turn recommended it to infants. The patent touted its effectiveness in breast milk.

However, Mr. Holahan said, "There was no need to conduct studies, as the use of thickeners overall was already well established. In addition, the safety of xanthan gum was already well established."

Since 2001, SimplyThick has been widely used by adults with swallowing difficulties. A liquid thickened to about the consistency of honey allows the drinker more time to close his airway and prevent aspiration.

Doctors in newborn intensive care units often ask non-physician colleagues like speech pathologists to determine whether an infant has a swallowing problem. And those auxiliary feeding specialists often recommended SimplyThick for neonates with swallowing troubles or acid reflux.

The thickener became popular because it was easy to mix, could be used with breast milk, and maintained its consistency, unlike alternatives like rice cereal.

"It was word of mouth, then neonatologists got used to using it. It became adopted," said Dr. Steven Abrams, a neonatologist at Texas Children's Hospital in Houston. "At any given time, several babies in our nursery - and in any neonatal unit - would be on it."

But in early 2011, Dr. Benson Silverman, the director of the F.D.A.'s infant formula section, was alerted to an online forum where doctors had reported 15 cases of NEC among infants given SimplyThick. The agency issued its first warning about its use in babies that May. "We can only do something with the information we are provided with," he said. "If information is not provided, how would we know?"

Most infants who took SimplyThick did not fall ill, and NEC is not uncommon in premature infants. But most who develop NEC do so while still in the hospital. Some premature infants given SimplyThick developed NEC later than usual, a few after they went home, a pattern the F.D.A. found unusually worrisome.

Even now it is not known how the thickener might have contributed to the infant deaths. One possibility is that xanthan gum itself is not suitable for the fragile digestive systems of newborns. The intestines of premature babies are "much more likely to have bacterial overgrowth" than adults', said Dr. Jeffrey Pietz, the chief of newborn medicine at Children's Hospital Central California in Madera.

"You try not to put anything in a baby's intestine that's not natural." If you do, he added, "you've got to have a good reason."

A second possibility is that batches of the thickener were contaminated with harmful bacteria. In late May 2011, the F.D.A. inspected the plants that make SimplyThick and found violations at one in Stone Mountain, Ga., including a failure to "thermally process" the product to destroy bacteria of a "public health significance."

The company, Thermo Pac, voluntarily withdrew certain batches. But it appears some children may have ingested potentially contaminated batches.

The parents of Jaden Santos, a preemie who died of NEC while on SimplyThick, still have unused packets of recalled lots, according to their lawyer, Joe Taraska.

The authors of the F.D.A. report theorized that the infants' intestinal membranes could have been damaged by bacteria breaking down the xanthan gum into too many toxic byproducts.

Dr. Qing Yang, a neonatologist at Wake Forest University, is a co-author of a case series in the Journal of Perinatology about three premature infants who took SimplyThick, developed NEC and were treated. The paper speculates that NEC was "most likely caused by the stimulation of the immature gut by xanthan gum."

Dr. Yang said she only belatedly realized "there's a lack of data" on xanthan gum's use in preemies. "The lesson I learned is not to be totally dependent on the speech pathologist."

Julie Mueller's daughter Addison was born full-term and given SimplyThick after a swallow test showed she was at risk of choking. It was recommended by a speech pathologist at the hospital.

Less than a month later, Addison was dead with multiple holes in her small intestine. "It was a nightmare," said Ms. Mueller, who has filed a lawsuit against SimplyThick. "I was astounded how a hospital and manufacturer was gearing this toward newborns when they never had to prove it would be safe for them. Basically we just did a research trial for the manufacturer."


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Interesting Research done at University of Washington

Extra chromosome 21 removed from Down syndrome cell line

University of Washington scientists have succeeded in removing the extra copy of chromosome 21 in cell cultures derived from a person with Down syndrome, a condition in which the body’s cells contain three copies of chromosome 21 rather than the usual pair.

A triplicate of any chromosome is a serious genetic abnormality called a trisomy. Trisomies account for almost one-quarter of pregnancy loss from spontaneous miscarriages, according to the research team. Besides Down syndrome (trisomy 21), some other human trisomies are extra Y or X chromosomes, and Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13), both of which have extremely high newborn fatality rates.

In their report appearing in the Nov. 2 edition of Cell Stem Cell, a team led by Dr. Li B. Li of the UW Department of Medicine described how they corrected trisomy 21 in human cell lines they grew in the lab.  The senior scientists on the project were gene therapy researchers Dr. David W. Russell, professor of medicine and biochemistry, and Dr. Thalia Papayannopoulou, professor of medicine.

The targeted removal of a human trisomy, they noted, could have both clinical and research applications.

In live births, Down syndrome is the most frequent trisomy. The condition has characteristic eye, facial and hand features, and can cause many medical problems, including heart defects, impaired intellect, premature aging and dementia, and certain forms of leukemia, a type of blood cancer.

“We are certainly not proposing that the method we describe would lead to a treatment for Down syndrome,” Russell said.  “What we are looking at is the possibility that medical scientists could create cell therapies for some of the blood-forming disorders that accompany Down syndrome.”

For example, he said, someday Down syndrome leukemia patients might have stem cells derived their own cells, and have the trisomy corrected in these lab-cultured cells.  They could then receive a transplant of their own stem cells – minus the extra chromosome – or healthy blood cells created from their fixed stem cells and that therefore don’t promote leukemia, as part of their cancer care.

He added that the ability to generate stem cells with and without trisomy 21 from the same person could lead to better understanding of how problems tied to Down syndrome originate.  The cell lines would be genetically identical, except for the extra chromosome. Researcher could contrast, for example how the two cell lines formed brain nerve cells, to learn the effects of trisomy 21 on neuron development, which might offer insights into the lifelong cognitive impairments and adulthood mental decline of Down syndrome. Similar comparative approaches could seek the underpinnings of untimely aging or defective heart tissue in this genetic condition.

The formation of trisomies is also a problem in regenerative medicine research using stem cells. Russell and his team observed that their approach could also be used to revert the unwanted trisomies that often arise in creating stem cell cultures.

Figuring out the exact techniques for removing the extra chromosome was tricky, Russell said, but his colleague Li worked hard to solve several challenges during his first attempts at deriving the engineered cell lines.

“Dr. Li’s achievement was a tour de force,” Russell said.

The researchers used an adeno-associated virus as a vehicle to deliver a foreign gene called TKNEO into a particular spot on chromosome 21, precisely within a gene called APP, which sits on the long arm of the chromosome.  The TKNEO transgene was chosen because of its predicted response to positive and negative selection in specific laboratory growth mediums.  When grown in conditions that selected against TKNEO, the most common reason for cells to survive was the spontaneous loss of the chromosome 21 harboring the transferred gene. Other survival tactics were point mutations, which are single, tiny alterations in DNA base pairs; gene silencing, which meant TKNEO was “turned off” by the cell; or deletion of the TKNEO.

Russell explained a key advantage of this technique for getting rid of the entire extra chromosome: Once it was gone, nothing was left behind.

“Gene therapy researchers have to be careful that their approaches do not cause gene toxicity,” he said. This means, for example, that removal of a chromosome must not break or rearrange the remaining genetic code. This method shouldn’t do that.”

Other researchers on this study were Kai-Hsin Chang, Pei-Rong Wang and Roli K. Hirata. The project was supported by grants from Horizon Discovery and from the National Institutes of Health (DK55759, HL53750,GM086497, DK077864, and HL46557.)  The researchers declared no financial conflicts of interest.


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Dr. Julia Kinder & A Petition to Medical Schools

I received an email about 10 days ago and just kept forgetting to look at it with much detail. I took a look at it today and while it's not Down Syndrome Awareness Month still, thought it would be good to share nonetheless. 

Celebrate the UPside of Down™ during National Down Syndrome

Awareness Month: Dispelling Myths and Smashing Stereotypes

Dr. Julia Kinder is celebrating National Down Syndrome Awareness Month with a Sweepstakes,

Photo Contest, and a Petition to Medical School Faculty across the United States.

Cape Girardeau, MO – October 18, 2012 – Dr. Julia Kinder, practicing physician, national speaker, and an advocate for children with special needs, is celebrating National Down Syndrome Awareness Month with an online Photo Contest, Sweepstakes, and a very important Petition. These can be found on her website, www.JuliaKinder.com. The photo contest gives families of children with Down syndrome an avenue for showcasing their child’s abilities. The sweepstakes offers fun awareness products created by Dr. Kinder while drawing attention to dispelling the myths and stereotypes surrounding Down syndrome.  The newly launched petition calls upon medical schools to provide more training on Down syndrome.

“No parent should feel like their baby's life starts out with a death; the death of their dreams for the future, the end of their hope for a happy, healthy child,” said Dr. Kinder, owner of JuliaKinder.com. “But it happens every day, because physicians who deliver the diagnosis of Down syndrome often give inaccurate, incomplete, and negative information that intensifies the unfounded fear of this diagnosis.”

Currently physicians do not receive training on giving the diagnosis of Down syndrome in a productive way, according to Dr. Kinder. Nor do they learn of needed resources for parents and baby. Medical education focuses on the possible health and learning issues, which not every child will encounter. Physicians do not understand what a child with Down syndrome is like outside of the medical aspects. What is crucial to every baby with Down syndrome is that they begin receiving early intervention and therapy immediately. Medical education does not cover this topic, therefore, physicians are missing a crucial piece of information to pass along to new parents.

Dr. Kinder has been a practicing physician for the past decade. However, eight years ago when her daughter was born with Down syndrome, she discovered her medical training did nothing to prepare her for raising a child with Down syndrome.

“Ella is completely healthy and smart, which contradicts everything I learned about Down syndrome,” said Dr. Kinder. “Medical school taught me about a laundry list of health problems and mental retardation, none of which applied to my child. I had no practical information on how to take care of her. I didn’t know she needed to start therapy immediately. When she was born, the doctors and hospital gave me no information or resources. I left the hospital without so much as a pamphlet.”

According to Dr. Kinder, the information on Down syndrome that doctors give to new parents tends to focus on the potential medical and learning problems. Doctors have not been trained to explain to these new parents that a child with Down syndrome is more like other children than they are different, and that many of the medical issues never materialize. Parents leave the hospital with the impression that their child’s prospects for a happy, healthy, and fulfilled life are grim. Unfortunately, many parents admit they struggled to connect emotionally with their baby during those first few months, as if unconsciously attempting to prepare for some awful manifestation of the diagnosis.

“I have decided to tackle this issue head-on,” states Dr. Kinder. “It is unacceptable for the medical community to contribute to a new parent’s fear of their own baby. This negative emotional state can prevent parents from providing the appropriate care their newborn needs. Babies with Down syndrome must start early intervention and therapy immediately - it should not be delayed because doctors fail to give parents complete and accurate information, along with resources for support.”

Dr. Kinder has spent eight years speaking to the medical community, future teachers and therapists, and to the general public regarding Down syndrome, as well as counseled hundreds of new parents. In 2009 Dr. Kinder began blogging on the topic, giving new parents hope and direction. She has devised fun ways to dispel the myths and darkness by promoting positive phrases such as “My kid has more Chromosomes than yours” as well as the “UPside of Down” concept. She encourages others to proudly display the UPside of Down with car decals, shirts, bracelets, and other awareness products that she has developed. Dr. Kinder has created a tribe of families who support each other and spread awareness. Their motto is, “Go beyond just surviving [with Down syndrome] to Thriving - become a Thrivalist!”

“I want to show the world the UPside of Down syndrome and I want to improve the education medical students receive on helping new parents,” said Dr. Kinder. “My ultimate goal is for the birth of every baby with Down syndrome to be celebrated, and for every baby to receive the care required to maximize their developmental potential.”

To get involved and sign Dr. Kinder’s petition please go to www.JuliaKinder.com/petition/. To learn more about her website’s Down Syndrome Awareness Month activities and to participate in the celebration, please visit http://www.JuliaKinder.com/DownSyndromeCelebration/.

About Dr. Julia Kinder

Dr. Julia A. Pewitt Kinder is an accomplished national speaker, early childhood education advocate, author and practicing physician. She and husband Mitch reside in Cape Girardeau, Mo., with their three children, Ella and twin boys Paxton and Dexter.  Dr. Kinder is licensed to practice in both Missouri and Texas and is in private practice with her brother in Jackson, Missouri. She also serves as a hospice physician for Tri-County Hospice. In addition, Dr. Kinder is a certified fitness instructor and promotes easy ways to incorporate exercise into daily routines. More information about Dr. Kinder can be found on her website at www.JuliaKinder.com.

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