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.

Tardive Dyskinesia Exacerbated after Ingestion of Phenylalanine by Schizophrenic Patients

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.

   Alanine
   Arginine *
   Asparagine
   Aspartic acid
   Cysteine
   Glutamic acid
   Glutamine
   Glycine
   Histidine * Aromatic
   Isoleucine * BCAA
   Leucine * BCAA
   Lysine *
   Methionine *
   Phenylalanine *  Aromatic
   Proline
   Serine
   Threonine *
   Tryptophan * Aromatic
   Tyrosine  Aromatic
   Valine *  BCAA

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.

BRANCHED-CHAIN AMINO ACIDS AND THE BRAIN

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 actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes

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.

Dexamethasone and BCAA Failed to Modulate Muscle Mass and mTOR Signaling in GH-Deficient Rats

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

Metabolic and Physiological Roles of Branched-Chain Amino Acids

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

Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.

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 IBD Adults and Healthy Adult Controls

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. 

Dietary Threonine Restriction Specifically Reduces Intestinal Mucin Synthesis in Rats

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.

  

Mucin glycan foragingin the human gut microbiome

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.

Low Relative Abundances of the Mucolytic Bacterium Akkermansia muciniphila and Bifidobacteriumspp. in Feces of Children with Autism

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.

Conclusion

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.

http://www.prweb.com/releases/2017/02/prweb14088362.htm

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:-

Dietary interventions that reduce mTOR activity rescue autistic-like behavioral deficits in mice 

·        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:

Histidine for Allergy, but as an effective MTOR inhibitor?

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

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.  



P.S.

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.

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.

Predicting the long-term risk of tardive dyskinesia in outpatients maintained on neuroleptic medications.

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.

Inflammatory Response to GAS (Group A Strep) and Dysmaturational Syndrome (Tourette’s Syndrome with Autism “Recovery” by 6 Years Old)

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. 

Treatment of tardive dyskinesia: A systematic review (1997-2011)

  

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

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. 

Conclusion

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.

Pan-agonists of PPARs and PGC-1α in Mitochondrial Disease, Autism and Sport

Today’s post should be of interest to those concerned about mitochondrial disease and mTOR.

mTOR is a very important signaling cascade that often dysfunctional in autism. Many aspects of autism and its comorbidities can be traced back to mTOR.

The going is easier with a PPAR pan-agonist 

mTOR integrates the input from upstream pathways, including insulin, growth, and amino acids.   mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of metabolism and physiology, with important roles in the function of tissues including liver, muscle, adipose tissue, and the brain.  It is dysregulated in human diseases, such as diabetes, obesity, certain cancers and indeed autism.

One important process affected by mTOR is the creation of new mitochondria in your cells.  Each cell has many mitochondria, but in some people there are not enough and/or they may not work properly.  

Mitochondrial Disease and Autism

In the above post we saw that Oxidative phosphorylation (or OXPHOS in short) is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing energy.  This takes place inside mitochondria.

The five enzymes required have simplified names: complex I, complex II, complex III, complex IV, and complex V.

The most common problem in autism is a lack of complex 1, this leads to a lack in the production of energy (ATP) in cells.  In your muscles this will appear as a lack of exercise endurance and in your brain as a lack of cognitive function.

On that rather intimidating chart (below), all about mTOR, tucked away at the bottom right is PGC-1α.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is the master regulator of mitochondrial biogenesis.

PGC-1α may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.

PGC-1α is thought to be a master integrator of external signals. It is known to be activated by a many factors, including:-

·         Exercise  (gradual endurance training)

·         PPARδ , PPARγ and it was thought PPARα

·         AMPK (Metformin, or AICAR)

·         Sirt-1 (resveratrol and other polyphenolic ‎compounds)

Interestingly, massage therapy appears to increase the amount of PGC-1α which leads to the production of new mitochondria. Many autism parents believe in various massage therapies. 

Metformin is a very old drug to treat diabetes, it does activate AMPK but unfortunately it also inhibits the Complex 1 mitochondrial enzyme. This might explain why one reader of this blog found it had a negative effect in her son.  In some types of cancer metformin can be used to “starve” the cancer cells of energy and stop them proliferating.

Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

AICAR was thought to have been used by cyclists in the 2009 Tour de France, it is a heart drug from the 1980s. It activates AMPK and increases nitric oxide production from endothelial nitric oxide synthase.

Here is the lower right part enlarged:-

  

The above chart, while complex does not give the complete picture regarding PPAR.

It appears that the type of PPAR that is needed to activate PGC-1α  is actually PPARδ  (PPAR delta). For a long time researchers thought it was PPAR α (PPAR alpha).

PPAR delta, but not PPAR alpha,activates PGC-l alpha gene transcription in muscle

PGC-1 alpha induces mitochondrial biogenesis in muscle and its activity has been related to insulin sensitization. Here, we report that fibrates induce PGC-1 alpha gene expression in muscle both in vivo and in vitro. However, only activation via PPAR delta but not PPAR alpha underlies this effect. PPAR delta induces PGC-1 alpha gene transcription through a PPAR-response element in the PGC-1 alpha promoter. Moreover, PGC-1 alpha coactivates the PPAR delta-responsiveness of its own gene. A further positive autoregulatory loop of control relies on the induction of PPAR6 expression by PGC-1 alpha. These data point to a distinct value of PPARdelta rather than PPAR alpha agonists in the improvement of oxidative metabolism in muscle.

Peroxisome proliferator-activated receptors (PPARs)

There was a post in this blog a long time ago about all the PPARs. There are three types (alpha, delta and gamma) just to confuse us, sometimes delta is called beta.

• α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others
• β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin
• γ (gamma) - although transcribed by the same gene, this PPAR through is expressed in three forms:
• γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen
• γ2 - expressed mainly in adipose tissue
• γ3 - expressed in macrophages, large intestine, white adipose tissue.

It does seem that activating alpha, gamma and delta has potential benefit.

The PPAR alpha agonist PEA is available as a supplement and as food for medical purposes In Italy and Spain.  It has been proposed for various inflammatory and pain syndromes. A large trial at a Skoda car factory in 1972 showed that PEA was protective against flu and the common cold.

Palmitoylethanolamide:A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold 

Fibrate drugs are PPAR alpha agonist drugs used to lower cholesterol. A key point here is that these drugs also activate other types of PPAR as well.

PPAR gamma agonists are widely used to treat diabetes.  They improve insulin sensitivity and decrease some inflammatory responses. They lower cholesterol.

PPAR delta has various antidiabetic effects and agonism of PPAR delta changes the body's fuel preference from glucose to lipids. Recently it was shown that PPAR delta can be activated to promote biogenesis of mitochondria.

It does appear likely that there is some interaction between the PPARs.

Using the mild PPAR gamma agonist, Sytrinol, which gives a long term cholesterol lowering effect, gives a short term cognitive and behavioral improvement in autism.

Pioglitazone is used to lower glucose levels in type 2 diabetes and is a PPAR gamma agonist.  It has been shown to have a positive effect in autism and more trials are in progress. It also binds to a lesser extent to PPAR alpha.

Our reader Maja is investigating whether Sytrinol will maintain its initial good effect when combined with a mild PPAR alpha agonist, like PEA. 

Pan-agonists of PPAR

Bezafibrate appears to be the best known “pan-agonist” of PPAR alpha, gamma and delta.

The PPARpan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome 

   
Bezafibrate as treatment option in patients with mitochondrial complex I (CI) deficiency

These results support bezafibrate as a promising treatment option for specific subgroups of patients with CI deficiency.

Less well known is the natural substance Berberine. 

Berberine Is a Potent Agonist of Peroxisome Proliferator Activated Receptor Alpha

Berberine activates peroxisome proliferator-activated receptor gamma to increase atherosclerotic plaque stability in Apoe-/- mice with hyperhomocysteinemia. 

Effect of berberine on PPAR alpha/delta/gamma expression in type 2 diabetic rat retinae.

The multifaceted drug Telmisartan, from a recent post, is also a pan-agonist of PPARs. It is usually quoted as being a PPAR delta agonist. 

Telmisartan increases lipoprotein lipase expression via peroxisome proliferator-activated receptor-alpha in HepG2 cells.

Telmisartan is a promising cardiometabolic sartan due to its unique PPAR-gamma-inducing property

Angiotensin II receptor blockertelmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway.

AICAR

The drug AICAR is thought of as an AMPK activator rather than a PPAR agonist, but it does affect all three types of PPAR.

AICAR Protects against High Palmitate/High Insulin-Induced Intramyocellular Lipid Accumulation and Insulin Resistance in HL-1 Cardiac Cells by Inducing PPAR-Target Gene Expression

Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK.

Conclusion

It looks like some athletes, seeking an advantage, are already using the above strategies to improve their exercise endurance; having more mitochondria is of course a competitive advantage.  A list of all the substances banned in sport might be another good source of therapies not only for autism, but also dementia.

Since mitochondrial dysfunction is a feature of Parkinson’s, Huntington’s and Alzheimer’s there are some investigations ongoing. There is even a trial to perk up the mitochondria in people with Bipolar using Bezafibrate.

It is odd that Sytrinol has only a short term positive effect in most people with autism, although our reader RG’s daughter has a long term benefit. I suspect some people may need a pan-agonist, there may be some interaction/crosstalk/ feedback that we are not aware of.

It would be nice to have some data on the relative potency of Bezafibrate,  Telmisartan and Berberine across alpha, delta and gamma receptors, otherwise we are left with trial and error.

The advantage of Berberine is that it is an OTC supplement.

AICAR is also interesting.