Monday, 22 May 2017

Green Tea Catechin EGCG in Down Syndrome, but Autism? and Cerebrolysin

In a recent comment a reader from Poland highlighted the popularity there of a drug called cerebrolysin to treat autism and Down syndrome.  It turns out that this treatment in also widespread in the former Soviet Union.

Green tea as a source of Epigallocatechin gallate (EGCG)

Cerebrolysin is a mixture of peptides purified from pig brains, including  brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF).

While cerebrolysin is used for stroke and vascular dementia, it is used by some as a nootropic. 

There are two Russian studies supporting the use of Cerebrolysin:

I was informed that cerebrolysin is prescribed off-label in Poland to treat autism, with some good results.
Three other substances were then mentioned.
MemoProve, an oral OTC product made by the same Austrian company that produces cerebrolysin, and then two research compounds P6 and P21. The P21 research is also part funded by the same Austrians. People in the US are using intranasal P21 as a nootropic.
It does seem that some people with autism do indeed benefit from cerebrolysin. 
As we have seen in previous posts the various growth factors (BDNF, NGF, IGF-1 etc) are disturbed in autism and they play a key role in various signaling cascades. There certainly is logic in using growth factors as autism therapies, but it would be important to use the right ones. In Rett syndrome there is almost no nerve growth factor (NGF), whereas in much autism there are elevated levels. Insulin-like growth factor IGF-1 already is a target autism therapy.
The disadvantage of cerebrolysin is that it is made from pigs’ brains and you need to inject it every day.
Unless you live in Poland, Russia or Romania, I doubt you will be able to try cerebrolysin, even if you want to.
Another therapy I am told is used in Poland is EGCG, which stands for Epigallocatechin gallate, or just green tea. 

Epigallocatechin gallate (EGCG)

EGCG is another natural substance like resveratrol, curcumin and indeed quercetin that has potent properties in lab, but never quite makes it in the human world.
The normal problem is low bioavailability and the lack of funding to do conclusive clinical trials.
In the case of EGCG there are now some serious studies being done in Spain. 

There is a mounting evidence of the modulation properties of the major catechin in green tea, epigallocatechin-3-gallate (EGCG), on dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene overexpression in the brains of DS mouse models. The aims are to investigate the clinical benefits and safety of EGCG administration in young adults with DS, to establish short-term EGCG effects (three months) on neurocognitive performance, and to determine the persistency or reversibility of EGCG related effects after three months of discontinued use. 

The flavonoid epigallocatechin gallate (EGCG) is a modulator of neuronal plasticity useful in other neurodevelopmental diseases. A recent study showed that EGCG is a promising tool for cognitive and health related quality of life improvement in Down's syndrome.

The objective is to determine the efficacy of EGCG as a therapeutic candidate for the improvement of cognitive performance in FAS patients  

Fragile X syndrome (FXS) present alterations in synaptic plasticity that produce intellectual disability. can produce improvement. Estrogens (targeting Estrogen Receptors beta (ER-β) can act as neuroprotective agents, promoting synaptic plasticity and neurite outgrowth, and health benefits derived from flavonoids, as the flavonol epigallocatechin gallate (EGCG), phytoestrogens of natural origin are partially explained by their interaction with membrane ER. Selective ER-β flavonoids are thus good candidates for their therapeutic evaluation in intellectual disabilities. EGCG also targets central intracellular transduction signals altered in FXS and improves memory recognition in a FXS animal model(adenosine triphosphate (ATP)-inhibitor of phosphatidylinositol 3-kinase (PI3K)and mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK1/2). This study targets the synaptic plasticity alterations that underlie the learning and memory impairment but also the computational disability in FXS. The hypothesis is that EGCG can act by favoring the physiological processes involved in cognition. 

The Spanish Science.

You might wonder why a hospital in Barcelona is doing all this research into a green tea extract.

EGCG has numerous biological effects and in the three trials they are not claiming the same mode of action.  In the fragile X trial it is the effect on Estrogen receptor beta, while in Down syndrome it is the effect on DYRK1A gene overexpression. 

Trial results

The only trial to have yet published results is the one on Down Syndrome.  Here the results were pretty good, given that this is a cheap supplement and the dose was modest.

The easy reading version:-

What were the basic results?

For most of the tests (21 of 24) there were no differences between the groups.

However, in three tests people who'd taken EGCG did better. This improvement lasted for six months after the study ended.

These were:

·         remembering and recognizing patterns

·         inhibitory control – the ability to override instinct to follow instructions; for example; in this test, to say "cat" when shown a picture of a dog, and vice versa

·         ability to carry out everyday living tasks (adaptive behaviour)   

I am very surprised that the benefit lasted six months after the study ended.  It would be great if they could validate that in their phase 3 trial. 

The full study:- 

We enrolled adults (aged 16–34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with, number NCT01699711.


The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: −4·58 s [–8·54 to −0·62], p=0·024; d −0·27 [–0·72 to −0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [–0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups.


EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training.  

The science behind EGCG

An expanding body of preclinical evidence suggests EGCG, the major catechin found in green tea (Camellia sinensis), has the potential to impact a variety of human diseases. Apparently, EGCG functions as a powerful antioxidant, preventing oxidative damage in healthy cells, but also as an antiangiogenic and antitumor agent and as a modulator of tumor cell response to chemotherapy. Much of the cancer chemopreventive properties of green tea are mediated by EGCG that induces apoptosis and promotes cell growth arrest by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing oncogenic transcription factors and pluripotency maintain factors. In vitro studies have demonstrated that EGCG blocks carcinogenesis by affecting a wide array of signal transduction pathways including JAK/STAT, MAPK, PI3K/AKT, Wnt and Notch. EGCG stimulates telomere fragmentation through inhibiting telomerase activity. Various clinical studies have revealed that treatment by EGCG inhibits tumor incidence and multiplicity in different organ sites such as liver, stomach, skin, lung, mammary gland and colon. Recent work demonstrated that EGCG reduced DNMTs, proteases, and DHFR activities, which would affect transcription of TSGs and protein synthesis. EGCG has great potential in cancer prevention because of it’s safety, low cost and bioavailability. In this review, we discuss its cancer preventive properties and it’s mechanism of action at numerous points regulating cancer cell growth, survival, angiogenesis and metastasis. Therefore, non-toxic natural agent could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies.

Mast Cells and EGCG
One interesting effect of EGCG, at least in the lab, is that it can stabilize mast cells. This would mean that it might he helpful in treating allergy and some types of GI problems, if you have enough of it.

Epigallocatechin-3-gallate Reduces Mast Cells Activity TNF-α and NFKB in Colitis by Interrupting an Inflammatory Cascade (MUC2P.827)

Epigallocatechin-3-gallate inhibits mast cell degranulation, leukotriene C4 secretion, and calcium influx via mitochondrial calcium dysfunction.

The green tea extract EGCG is inexpensive and widely available. It is often taken for its antioxidant properties. In most trials so-called phytoestrogens like EGCG have almost no estrogen-like effect in humans, so I doubt this mode of action.
The trials all used a dosage of 9mg/kg of EGCG which is easy to achieve with OTC supplements.
Given the positive results from the small trial in Down Syndrome (DS), it would fall into the “no-brainer” category to make a home trial, if you have a child with DS.
This is quite different to injecting your child with Cerebrolysin from pig’s brains, where there are some drawbacks.
Will EGCG help in Fragile-X or Fetal Alcohol Syndrome? I have no idea; but being having well established antioxidant properties, I expect it is almost guaranteed to help a least marginally.
Will EGCG help in autism? Given its safety profile, price and availability, it really should have a place on your to-do list. It is an antioxidant with numerous other possible effects, some of which hopefully may be evident in humans.  Compared to some exotic antioxidants that people buy, it is cheap.
With no great expectations, I will see if EGCG has any effect. It might help an as antioxidant, it might help stabilize mast cells and, if has enough potency as an estrogen, it would help via RORa. As you can see in the chart above it actually has dozens of potential effects.
Some natural substances like quercetin have undoubted positive effects, but after continued usage can give side effects.  The EGCG trial was 12 months long and they did not find adverse effects compared to the placebo.
The amount of EGCG in green tea varies wildly, making standardized supplements a safer bet.  Apparently, Lipton Green Tea bags contain about 70mg of EGCG per serving. So my son would need to drink 6 cups of green tea a day to match the trial dose.

Thursday, 18 May 2017

Amino Acids in Autism

Amino Acids (AAs) are very important to health and it is important that all 20 are within the reference ranges, or there can be serious consequences.  Inborn errors of amino acid metabolism do exist and there are metabolic disorders which impair either the synthesis and/or degradation of amino acids.
It has been suggested that a lack of certain amino acids might underlie some people’s autism. This seems to be the basis of one new autism drug, CM-AT, being developed in the US, but this idea remains somewhat controversial.

In those people who have normal levels of amino acids, potential does exist to modify their level for some therapeutic effect. 

Examples include:-

·        Using histidine to inhibit mast cells de-granulating and so reducing symptoms of allergy

·       Using the 3 branch chained AAs to reduce the level of the AA, phenylanine, which can drive movement disorders/tics

·       Methionine seems to promote speech in regressive autism, but for no known reason.

·        Some AAs, such as leucine, activate mTOR. It is suggested that others (histidine, lysine and threonine) can inhibit it, which might have a therapeutic benefit in those with too much mTOR signaling.

·        D-Serine, synthesized in the brain by from L-serine, serves as a neuromodulator by co-activating NMDA receptors.  D-serine has been suggested for the treatment of negative symptoms of schizophrenia

·        Aspartic acid is an NMDA agonist

·       Threonine is being studied as a possible therapy for Inflammatory Bowel Disease (IBD), because it may increase intestinal mucin synthesis.

Amino acids, the building blocks for proteins

To make a protein, a cell must put a chain of amino acids together in the right order. It makes a copy of the relevant DNA instruction in the cell nucleus, and takes it into the cytoplasm, where the cell decodes the instruction and makes many copies of the protein, which fold into shape as they are produced.

There are 20 standard or “canonical” amino acids, which can be thought of as protein building blocks.
Humans can produce 10 of the 20 amino acids; the others must be supplied in the food and are called “essential”. The human body does not store excess amino acids for later use, so these amino acids must be in your food every day.

The 10 amino acids that we can produce are alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine and tyrosine. Tyrosine is produced from phenylalanine, so if the diet is deficient in phenylalanine, tyrosine will be required as well.

The essential amino acids (marked * below) are arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.

The three so-called branched-chain amino acids (BCAAs) are leucine, isoleucine and valine

The so-called aromatic amino acids (AAAs) are histidine, phenylanine, tryptophan and tyrosine

When plasma levels of BCAAs increase, this reduces the absorption of aromatic AAs; so the level of tryptophan, tyrosine, and phenylalanine will fall and this directly affects the synthesis and release of serotonin and catecholamines.
Many sportsmen, and indeed soldiers, take BCAA supplements in an attempt to build stronger muscles, but within the brain this will cause a cascade of other effects.
In people with tardive dyskinesia, which is a quite common tic disorder found in schizophrenia and autism, taking phenylalanine may make their tics worse.  It seems that taking BCAA supplements may make their tics reduce, because reducing the level of phenylalanine will impact dopamine (a catecholamine). Most movement disorders ultimately relate to dopamine.

In effect, BCAA supplements affect the synthesis and release of serotonin and catecholamines.  This might be good for you, or might be bad for you; it all depends where you started from.

   Arginine *
   Aspartic acid
   Glutamic acid
   Histidine * Aromatic
   Isoleucine * BCAA
   Leucine * BCAA
   Lysine *
   Methionine *
   Phenylalanine *  Aromatic
   Threonine *
   Tryptophan * Aromatic
   Tyrosine  Aromatic

Blood levels of the BCAAs are elevated in people with obesity and those with insulin resistance, suggesting the possibility that BCAAs contribute to the pathogenesis of obesity and diabetes.  BCAA-restricted diets improve glucose tolerance and promote leanness in mice.

In the brain, BCAAs have two important influences on the production of neurotransmitters. As nitrogen donors, they contribute to the synthesis of excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) They also compete for transport across the blood-brain barrier (BBB) with tryptophan (the precursor to serotonin), as well as tyrosine and phenylalanine (precursors for catecholamines)Ingestion of BCAAs therefore causes rapid elevation of the plasma concentrations and increases uptake of BCAAs to the brain, but diminishes tryptophan, tyrosine, and phenylalanine uptake. The decrease in these aromatic amino acids directly affects the synthesis and release of serotonin and catecholamines. The reader is referred to Fernstrom (2005) for a review of the biochemistry of BCAA transportation to the brain. Oral BCAAs have been examined as treatment for neurological diseases such as mania, motor malfunction, amyotrophic lateral sclerosis, and spinocerebral degeneration. Excitotoxicity as a result of excessive stimulation by neurotransmitters such as glutamate results in cellular damage after traumatic brain injury (TBI). However, because BCAAs also contribute to the synthesis of inhibitory neurotransmitters, it is unclear to what extent the role of BCAAs in synthesis of both excitatory and inhibitory neurotransmitters might contribute to their potential effects in outcomes of TBI.

A list of human studies (years 1990 and beyond) evaluating the effectiveness of BCAAs in providing resilience or treating TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy) in the acute phase is presented in Table 8-1; this also includes supporting evidence from animal models of TBI. The occurrence or absence of adverse effects in humans is included if reported by the authors.

Cell Signaling

Leucine indirectly activates p70 S6 kinase as well as stimulates assembly of the eIF4F complex, which are essential for mRNA binding in translational initiation. P70 S6 kinase is part of the mammalian target of rapamycin complex (mTOR) signaling pathway.

The present study provides the first evidence that mTOR signalling is enhanced in response to an acute stimulation with the proteinogenic amino acid, leucine, within cultured human myotubes. While these actions appear transient at the leucine dose utilised, activation of mTOR and p70S6K occurred at physiologically relevant concentrations independently of insulin stimulation. Interestingly, activation of mTOR signalling by leucine occurred in the absence of changes in the expression of genes encoding both the system A and system L carriers, which are responsible for amino acid transport. Thus, additional analyses are required to investigate the molecular mechanisms controlling amino acid transporter expression within skeletal muscle. Of note was the increased protein expression of hVps34, a putative leucine-sensitive kinase which intersects with mTOR. These results demonstrate the need for further clinical analysis to be performed specifically investigating the role of hVps34 as a nutrient sensing protein for mTOR signalling.

Skeletal muscle mass is determined by the balance between the synthesis and degradation of muscle proteins. Several hormones and nutrients, such as branched-chain amino acids (BCAAs), stimulate protein synthesis via the activation of the mammalian target of rapamycin (mTOR).
BCAAs (i.e., leucine, isoleucine, and valine) also exert a protective effect against muscle atrophy. We have previously reported that orally administered BCAA increases the muscle weight and cross-sectional area (CSA) of the muscle in rats

3.4. BCAAs in Brain Functions
BCAAs may also play important roles in brain function. BCAAs may influence brain protein synthesis and production of energy and may influence synthesis of different neurotransmitters, that is, serotonin, dopamine, norepinephrine, and so forth, directly or indirectly. Major portion of dietary BCAAs is not metabolized by liver and comes into systemic circulation after a meal. BCAAs and aromatic AA, such as tryptophan (Trp), tyrosine (Tyr), and phenylalanine (Phe), share the same transporter protein to transport into brain. Trp is the precursor of neurotransmitter serotonin; Tyr and Phe are precursors of catecholamines (dopamine, norepinephrine, and epinephrine). When plasma concentration of BCAAs increases, the brain absorption of BCAAs also increases with subsequent reduction of aromatic AA absorption. That may lead to decrease in synthesis of these related neurotransmitters [3]. Catecholamines are important in lowering blood pressure. When hypertensive rats were injected with Tyr, their blood pressure dropped markedly and injection with equimolar amount of valine blocks that action [49]. In vigorous working persons, such as in athletes, depletion of muscle and plasma BCAAs is normal. And that depletion of muscle and plasma BCAAs may lead to increase in Trp uptake by brain and release of serotonin. Serotonin on the other hand leads to central fatigue. So, supplementation of BCAAs to vigorously working person may be beneficial for their performance and body maintenance

Example of a treatable Amino Acid variant of Autism

Autism Spectrum Disorders (ASD) are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy and intellectual disability (ID). The encoded protein is responsible for phosphorylation-mediated inactivation of the E1-alpha subunit of branched chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK mRNA and protein, E1-alpha phosphorylation and plasma branched chain amino acids (BCAAs). Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.

The data suggest that the neurological phenotype may be treated by dietary supplementation with BCAAs. To test this hypothesis, we studied the effect of a chow diet containing 2% BCAAs or a BCAA-enriched diet, consisting of 7% BCAAs, on the neurological phenotypes of the Bckdk−/− mice. Mice raised on the BCAA-enriched diet were phenotypically normal. On the 2% BCAA diet, however, Bckdk−/− mice had clear neurological abnormalities not seen in wild-type mice, such as seizures and hindlimb clasping, that appeared within 4 days of instituting the 2% BCAA diet (Fig. 3B). These neurological deficits were completely abolished within a week of the Bckdk−/− mice starting the BCAA-enriched diet, which suggests that they have an inducible yet reversible phenotype (Fig. 3C).

Our experiments have identified a Mendelian form of autism with comorbid ID and epilepsy that is associated with low plasma BCAAs. Although the incidence of this disease among patients with autism and epilepsy remains to be determined, it is probably quite a rare cause of this condition. We have shown that murine Bckdk−/− brain has a disrupted amino acid profile, suggesting a role for the BBB in the pathophysiology of this disorder. The mechanism by which abnormal brain amino acid levels lead to autism, ID, and epilepsy remains to be investigated. We have shown that dietary supplementation with BCAAs reverses some of the neurological phenotypes in mice. Finally, by supplementing the diet of human cases with BCAAs, we have been able to normalize their plasma BCAA levels (table S10), which suggests that it may be possible to treat patients with mutations in BCKDK with BCAA supplementation.

(Look at the three red rows, the BCAAs, all lower than the reference range, before supplementation)

Threonine, Mucin and Akkermansia muciniphila in Autism
Mucins are secreted as principal components of mucus by mucous membranes, like the lining of the intestines.  People with Inflammatory Bowel Disease (IBD) have mucus barrier changes.

The low levels of the mucolytic bacterium Akkermansia muciniphila found in children with autism, apparently suggests mucus barrier changes.

The amino acid Threonine is a component of mucin and Nestle have been researching for some time the idea of a threonine supplement to treat Inflammatory Bowel Disease (IBD), being a serious Swiss company they publish their research.      

Threonine Requirement in Healthy Adult Subjects and in Patients With Crohn's Disease and With Ulcerative Colitis Using the Indicator Amino Acid Oxidation (IAAO) Methodology

Threonine is an essential amino acid which must be obtained from the diet. It is a component of mucin. Mucin, in turn, is a key protein in the mucous membrane that protects the lining of the intestine.

Inflammatory bowel disease (IBD) is a group of inflammatory conditions that affect the colon and small intestine. IBD primarily includes ulcerative colitis (UC) and Crohn's disease (CD). In UC, the inflammation is usually in the colon whereas in CD inflammation may occur anywhere along the digestive tract. Studies in animals have shown that more threonine is used when there is inflammation in the intestine.

The threonine requirement in healthy participants and in IBD patients will be determined using the indicator amino acid oxidation method. The requirement derived in healthy participants will be compared to that derived in patients with IBD.

Each participant will take part in two x 3 day study periods. The first two days are called adaptation days where the subjects will consume a liquid diet specially designed for him. The diet will be consumed at home. It contains all vitamins, minerals, protein and all other nutrients required. On the third day, the participant will come to the Hospital for Sick Children in Toronto. Subjects will consume hourly meals for a total of 8 meals and a stable isotope 13C-phenylalanine. Breath and urine samples will be collected to measure the oxidation of phenylalanine from which the threonine requirement will be determined. 

We determined whether the steady-state levels of intestinal mucins are more sensitive than total proteins to dietary threonine intake. For 14 d, male Sprague-Dawley rats (158 ± 1 g, n = 32) were fed isonitrogenous diets (12.5% protein) containing 30% (group 30), 60% (group 60), 100% (control group), or 150% (group 150) of the theoretical threonine requirement for growth. All groups were pair-fed to the mean intake of group 30. The mucin and mucosal protein fractional synthesis rates (FSR) did not differ from controls in group 60. By contrast, the mucin FSR was significantly lower in the duodenum, ileum, and colon of group 30 compared with group 100, whereas the corresponding mucosal protein FSR did not differ. Because mucin mRNA levels did not differ between these 2 groups, mucin production in group 30 likely was impaired at the translational level. Our results clearly indicate that restriction of dietary threonine significantly and specifically impairs intestinal mucin synthesis. In clinical situations associated with increased threonine utilization, threonine availability may limit intestinal mucin synthesis and consequently reduce gut barrier function.

It has been proposed that excessive mucin degradation by intestinal bacteria may contribute to intestinal disorders, as access of luminal antigens to the intestinal immune system is facilitated. However, it is not known whether all mucin-degraders have the same effect. For example A. muciniphila may possess anti-inflammatory properties, as a high proportion of the bacteria has been correlated to protection against inflammation in diseases such as type 1 diabetes mellitus, IBD, atopic dermatitis, autism , type 2 diabetes mellitus, and.

Gastrointestinal disturbance is frequently reported for individuals with autism. We used quantitative real-time PCR analysis to quantify fecal bacteria that could influence gastrointestinal health in children with and without autism. Lower relative abundances of Bifidobacteria species and the mucolytic bacterium Akkermansia muciniphila were found in children with autism, the latter suggesting mucus barrier changes. 

Previous studies in rats by MacFabe et al. have shown that intraventricular administration of propionate induces behaviors resembling autism (e.g., repetitive dystonic behaviors, retropulsion, seizures, and social avoidance) (12, 13). We have also reported increased fecal propionate concentrations in ASD children compared with that in controls in the same fecal samples (25). However, the abundance of a key propionate-producing bacterium, Prevotella sp., was not significantly different between the study groups. This suggests that other untargeted bacteria, such as those from Clostridium cluster IX, which also includes major propionate producers (24), may be responsible for the observed differences in fecal propionate concentrations. Moreover, it is possible that the activities of the bacteria responsible for producing propionate, rather than bacterial numbers, have been altered. Other factors, such as differences in GI function that change GI transit time in ASD children, should also be considered.
In summary, the current findings of depleted populations of A. muciniphila and Bifidobacterium spp. add to our knowledge of the changes in the GI tracts of ASD children. These findings could potentially guide implementation of dietary/probiotic interventions that impact the gut microbiota and improve GI health in individuals with ASD.

I think that modifying levels of amino acids can have merit for some people, but it looks like another case for personalized medicine, rather than the same mix of powders given to everyone.
Threonine is interesting given the incidence of Inflammatory Bowel Disease (IBD) in autism.  IBD mainly describes ulcerative colitis and Crohn's disease.
The research into Threonine, is being funded by Nestle, the giant Swiss food company, who fortunately do publish their research.
The trial in the US of CM-AT is unusual because no results have ever been published in the literature, so we just have press releases. It likely that CM-AT is a mixture of pancreatic enzymes from pigs and perhaps some added amino acids.

This 14-week, double-blind, randomized, placebo-controlled Phase 3 study is being conducted to determine if CM-AT may help improve core and non-core symptoms of Autism. CM-AT, which has been granted Fast Track designation by FDA, is designed to enhance protein digestion thereby potentially restoring the pool of essential amino acids. Essential amino acids play a critical role in the expression of several genes important to neurological function and serve as precursors to key neurotransmitters such as serotonin and dopamine.

Based on the study I referred to early this year:-

·        Amino acids, his, lys and thr, inhibited mTOR pathway in antigen-activated mast cells

·     Amino acids, his, lys and thr inhibited degranulation and cytokine production of mast cells

·     Amino acid diet reversed mTOR activity in the brain and behavioral deficits in allergic and BTBR mice.

in my post:

I for one will be evaluating both lysine and threonine, having already found a modest dose histidine very beneficial in allergy (stabilizing mast cells).

Sunday, 14 May 2017

A Visit to Secondary School and Piano Recitals

Today’s post is science free, since for some of the original readers this blog it has become heavy going at times.
Monty, now aged 13 with autism, is about to move up to mainstream secondary/high school.  While this might sound quite a normal transition I really doubt his kindergarten teacher ever thought he would make it that far, in a meaningful way. Even I thought that finishing mainstream primary/junior school would be quite a challenge.
One reader of this blog is Monty’s kindergarten teacher who has known him from before his diagnosis, a decade ago. Outside of the North America people tend not to want to diagnose autism in three year olds and parents do not want to hear reports from kindergarten that things may not be so good. Even being non-verbal may not ring alarm bells with pediatricians; where we live it is put down as “dysphasia”.
In spite of the tell-tale signs, the differences at the age of three between classic autism and typical are not so big.  We do not have great expectations of three year olds, even though some are already very talented.
Monty’s kindergarten teacher requested he have a 1:1 assistant before he was diagnosed with autism at the age of three and a half; he has had one ever since.
Having started kindergarten quite young it was no big deal to spend an extra year there before moving to primary/junior school. 
For the next four years Monty went to mainstream school in the morning and had 1:1 tuition at home in the afternoon. Very slowly some academic skills were acquired, but mainly as the result of the home program. Not surprisingly, a gulf had opened up between Monty’s skills and that of his peer group. 
As is often the case with little boys with autism, he did get “adopted” by nicer little girls in primary. So you would see him walking hand in hand around the school playground.
At this point, aged 8, Monty had a big regression involving both self-injury and aggression to others.  This lasted about 9 months and was associated with a loss of some of the recently acquired skills.
We never had an assessment using the Childhood Autism Rating Scale (CARS), which is a pity because at least it tells you, at one point in time, where you stand. At the age of 9, Monty had mastered the skills in the very detailed ABLLS assessment, which is an excellent list of all the very basic skills you need; these are skills big brother had at 3 years old.
Shortly thereafter I started my autism science research and instigated a trial of bumetanide.  The rate of skill acquisition then accelerated and the severity of autism faded.
Even though the violent behavior had subsided, at the end of that school year I decided to move him down one school year.  In effect his peer group changed to one which was 2-3 years younger than him.  In subsequent years he moved forward with this new peer group, so he has been in the same peer group for 5 years.
Each year I said to the class teacher that if at the end of the school year Monty had not mastered the year we could repeat it, because there is no point deluding yourself and moving to a higher level when you are clueless about the previous level.  So as long as there are 10+% of the class with lower grades in each subject, I think it is fine to move ahead.  It does surprise me how badly some neurotypical kids do at school, because they should all be ahead of Monty, but some are not. From time to time, Monty is actually closer to the top of the class, which is remarkable.
Since big brother has only one more year to finish secondary/high school, he was rather expecting little brother to wait another year in primary/junior school.
As his classmates started talking about the move to secondary school, Monty naturally assumed he would be moving too.  Having been told by Monty “in September we go to secondary school” so many times, this is of course what is happening.
Recently Monty and his class had a half day visit to their new school and everybody had a great time.
Plenty of the younger kids in secondary already know Monty and as do some of the big ones who are friends of Monty’s big brother.
So big brother realized it was not going to be embarrassing after all.
Siblings going to the same school often have issues, in part because teachers feel the need to compare them to see who is better/cleverer. The fair comparison is the progress you make from where you started, as I keep telling big brother's maths teacher; so not to accept that you have A, B and C grade students and be happy they get their predicted grade, but to try and improve them.
The secondary school is small, but has had some boys with Asperger’s in the past. In theory it should be much easier for them to fit into school, but often it is not. Most of the issues that I get to hear about were entirely preventable.  Having an assistant who the other kids like and respect solves most of these issues.
How far Monty goes through the standard secondary program remains to be seen. He cannot do the high level things that his big brother can do but, as I have learned, neither can 20% of the class and nobody diagnoses them with MR/ID.

Music Recitals

One area where people with Asperger’s can excel is music. There is research to show that people with autism/Asperger’s are far more likely to have perfect pitch than other people. Another big difference is that the Asperger’s child may be happy to practice at home three hours a day.
We recently had a visit from a girl with Asperger’s and she played the piano amazingly, but as Monty’s big brother pointed out, so would he if he practiced 20 hours a week.  It appears to be a case of social life or music practice.
Monty does not play his piano 20 hours a week, for him it is more like 3 hours a week.
Monty recently had two concerts, one at school with typical peers and an autism/Asperger’s concert.
Who plays the best? Well in this unscientific sample, it is clear that the Asperger’s kids play the best, followed by the typical kids and then the autism kids.
Where does Monty fit in? Well he started out as an autism kid, but after nearly five years of pharmacotherapy he is well up there with the more talented typical kids, but not yet up there with the star Asperger’s kids who practice 3 hours a day.

Monty's piano teacher, who has seen him twice a week for five years and only teaches kids with special needs has pretty much the same opinion. Monty is not her best pupil, but he is the only one to progress so far, from where he started. He started his piano before he started his PolyPill. Her comment a while back was, whatever it is he is taking, keep giving it to him.  


Monty goes to an International school using the English curriculum, where high school starts at the age of 11; he will start aged 14.  Most of the spelling I use is American English, except for some words that look really odd, since this blog's audience is 70% American and spelling was never my strong point.

Most people diagnosed today with autism have mild autism, often without a speech delay or cognitive loss and should be able to complete the standard school curriculum. People with more severe autism do not normally progress far with academic learning and many "graduate" aged 18 with the skills of a 7 to 8 year old. This does not have to be the case, as some readers of this blog have also discovered.

Thursday, 11 May 2017

Tardive Dyskinesia (TD)  - Amino Acids, VMAT2, Diamox, B6 etc

Today’s post is about Tardive Dyskinesia which is a side effect eventually experienced by about 30% of people taking antipsychotic drugs, like risperidone, widely prescribed in both autism and schizophrenia.

Enough money for your lifetime supply of a VMAT2 inhibitor?

Tardive Dyskinesia (TD) is a disorder resulting in involuntary, repetitive body movements, which might think of as tics or grimaces.

It appears that the longer the drug is taken the greater the chance of developing Tardive Dyskinesia.

Tics are quite common in autism and not just in those taking psychiatric drugs.

Tourette’s syndrome is a well-known tic disorder that does overlap with autism, it used to be considered rare, but now 1% of children are thought to be affected.  Some common Tourette’s tics are eye blinking, coughing, throat clearing, sniffing, and facial movements.

People diagnosed with Tourette’s might also be diagnosed with ADHD, OCD or indeed autism.  

We saw in some Italian research that young children with Tourette’s type autism have a fair chance of seeing their symptoms of autism substantially fade away. It was called Dysmaturational Syndrome.

The part of the brain that is thought to be affected in  Tardive Dyskinesia is that same part suspected in Tourette’s and indeed PANDAS/PANS; it is the basal ganglia.  

Avoiding Tardive Dyskinesia

The best way to avoid Tardive Dyskinesia is not to use antipsychotic/ neuroleptic drugs.

It appears that high doses of melatonin and other antioxidants may give a protective effect from developing Tardive Dyskinesia. 

Treating Tardive Dyskinesia

Much is written about treating Tardive Dyskinesia (TD), because nobody yet has found a cure for it, nonetheless there is a long list of partially effective therapies.

Given that the underlying basis of TD may very likely to overlap to some extent with Tourette’s and PANDAS/PANS it is over broader interest.  

A Review of off-label Treatments  for Tardive Dyskinesia 

The Spanish study below gives a good overview of most therapies, but exclude the very recent therapies based on VMAT2. 

All of the studies in the review were small, but you can see that some therapies did seem to help, including:-

·        Vitamin E

·        Vitamin B6

·        Acetazolamide/Diamox

·        Amino Acids

·        Piracetam

I proposed Acetazolamide/Diamox to potentially treat some autism a while back and some readers of this blog do find it effective.

Piracetam is the world’s first cognitive enhancing (nootropic) drug.  It was discovered by mistake when trying to make a cure for motion sickness.

Amino acids may look an odd choice, but in males, and only males, branched chain  amino acids (BCAAs) valine, isoleucine, and leucine in a 3:3:4 ratio appears to be beneficial.  Another amino acid called Phenylalanine is associated with tardive dyskinesia in men but not in women. It is an established fact that an increase in BCAAs will cause a reduction in phenylalanine in the brain, among a range of other effects.

Phenylalanine is a precursor for dopamine (as well as  tyrosine, norepinephrine, and epinephrine). 

One theory is that tardive dyskinesia results primarily from neuroleptic-induced dopamine supersensitivity. So if the BCAAs reduce the amount of dopamine produced, this might explain their effect.


VMAT2 transports monoamines - particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine - from cellular cytosol into synaptic vesicles. Inhibiting VMAT2 will reduce the release of dopamine. 

In some circumstances VMAT2 is necessary for the release of the neurotransmitter GABA. 

Drugs that inhibit VMAT2 appear to help treat Tardive Dyskinesia and one drug Valbenazine/Ingrezza was FDA approved for this purpose in April 2017. Not surprisingly, it is now being investigated to treat Tourette’s syndrome. 

Valbenazine is known to cause a reversible reduction of dopamine release by selectively inhibiting VMAT2. 


Since our regular reader Valentina is dealing with Tardive Dyskinesia, she will probably be very interested in Valbenazine.

The problem is the price. The drug will apparently cost $60,000 a year in the US.

So for the time being it is best to work through the list of very cheap interventions that do seem to be partially effective, at least in some people.