Sense, Missense or Nonsense - Interpreting Genetic Research in Autism (TCF4, TSC2 , Shank3 and Wnt)




Some clever autism researchers pin their hopes on genetics, while some equally clever ones are not convinced.

One big problem is that genetic testing is still not very rigorous, it is fine if you know what you are looking for, like a specific single gene defect, but if it is a case of find any possible defect in any of the 700+ autism genes it can be hopeless.

Most of the single gene types of autism can be diagnosed based on known physical differences and then that specific gene can be analyzed to confirm the diagnosis.

Today�s post includes some recent examples from the research, and they highlight what is often lacking - some common sense.

There are numerous known single gene conditions that lead to a cascade of dysfunctions that can result in behaviors people associate with autism.  However in most of these single gene conditions, like Fragile X or Pitt-Hopkins, there is a wide spectrum, from mildly affected to severely affected.

There are various different ways in which a gene can be disturbed and so within a single gene condition there can be a variety of sub-dysfunctions.  A perfect example was recently forwarded to me, a study showing how a partial deletion of the Pitt Hopkins gene (TCF4) produced no physical features of the syndrome, but did unfortunately produce intellectual disability.

The study goes on to suggest that �screening for mutations in TCF4 could be considered in the investigation of NSID (non-syndromic intellectual disability)�

Partial deletion of TCF4 in three generation family with non-syndromic intellectual disability, without features of Pitt-Hopkins syndrome



This all matters because one day when therapies for Pitt Hopkins are available, they would very likely be effective on the cognitive impairment of those with undiagnosed partial-Pitt Hopkins.



Another reader sent me links to the studies showing:-


Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex.

Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis.


But isn�t that Tuberous sclerosis (TSC) extremely rare? like Pitt Hopkins.  Is it really relevant?

Tuberous sclerosis (TSC)  is indeed a rare multisystem genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, and lung and kidney disease. TSC is caused by a mutation of either of two genes, TSC1 and TSC2, 

About 60% of people with TSC have autism (biased to TSC2 mutations) and many have epilepsy.

How rare is TSC?  According to research between seven and 12 cases per 100,000, with more than half of these cases undetected.  

Call it 0.01%, rare indeed.

How rare is partial TSC?  What is partial TSC?  That is just my name for what happens when you have just a minor missense mutation, you have a mutation in TSC2 but have none of the characteristic traits of tuberous sclerosis, except autism.
In a recent study of children with autism 20% has a missense mutation of TSC2. 

Not so rare after all.


Mutations in tuberous sclerosis gene may be rife in autism


Mutations in TSC2, a gene typically associated with a syndrome called tuberous sclerosis, are found in many children with autism, suggests a genetic analysis presented yesterday at the 2016 International Meeting for Autism Research in Baltimore.
The findings support the theory that autism results from multiple �hits� to the genome.
Tuberous sclerosis is characterized by benign tumors and skin growths called macules. Autism symptoms show up in about half of all people with tuberous sclerosis, perhaps due to abnormal wiring of neurons in the brain. Tuberous sclerosis is thought to result from mutations in either of two genes: TSC1 or TSC2.
The new analysis finds that mutations in TSC2 can also be silent, as far as symptoms of the syndrome go: Researchers found the missense mutations in 18 of 87 people with autism, none of whom have any of the characteristic traits of tuberous sclerosis.
�They had no macules, no seizure history,� says senior researcher Louisa Kalsner, assistant professor of pediatrics and neurology at the University of Connecticut School of Medicine in Farmington, who presented the results. �We were surprised.�
The researchers stumbled across the finding while searching for genetic variants that could account for signs of autism in children with no known cause of the condition. They performed genetic testing on blood samples from 87 children with autism.

Combined risk:

To see whether silent TSC2 mutations are equally prevalent in the general population, the researchers scanned data from 53,599 people in the Exome Aggregation Consortium database. They found the mutation in 10 percent of the individuals.
The researchers looked more closely at the children with autism, comparing the 18 children who have the mutation with the 69 who do not.
Children with TSC2 mutations were diagnosed about 10 months earlier than those without a mutation, suggesting the TSC2 mutations increase the severity of autism features. But in her small sample, Kalsner says, the groups show no differences in autism severity or cognitive skills. The researchers also found that 6 of the 18 children with TSC2 mutations are girls, compared with 12 of 69 children who don�t have the mutation.
TSC2 variants may combine with other genetic variants to increase the risk of autism. �We don�t think TSC is the sole cause of autism in these kids, but there�s a significant chance that it increases their risk,� Kalsner says.


"hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) is a consequence of tuberous sclerosis complex (TSC) 1/2 inactivation."

"the combination of rapamycin and resveratrol may be an effective clinical strategy for treatment of diseases with mTORC1 hyperactivation."


So for the 20% of autism with partial TSC, so-called Rapalogs and other mTOR inhibitors could be helpful, but Rapalogs all have side effects.

One interesting option that arose in my earlier post on Type 3 diabetes and intranasal insulin is Metformin. The common drug used for type 2 diabetes.

 








Metformin regulates mTORC1 signaling (but so does insulin).

'Metformin activates AMPK by inhibiting oxidative phosphorylation, which in turn negatively regulates mTORC1 signaling via activation of TSC2 and inhibitory phosphorylation of raptor. In parallel, metformin inhibits mTORC1 signaling by suppressing the activity of the Rag GTPases and upregulating REDD1."

Source:  Rapalogs and mTOR inhibitors as anti-aging therapeutics



Clearly you could also just use intranasal insulin.  It might be less potent but should have less side effects because it acting only within the CNS (Metfornin would be given orally).



The Shank protein and the Wnt protein family

Mutations in a gene called Shank3 occur in about 0.5 percent of people with autism.  
But what about partial Shank3 dysfunction?

Shank proteins also play a role in synapse formation and dendritic spine maturation.

Mutations in this gene are associated with autism spectrum disorder. This gene is often missing in patients with 22q13.3 deletion syndrome

Researchers at MIT have just shown, for the first time, that loss of Shank3 affects a well-known set of proteins that comprise the Wnt signaling pathway.  Without Shank3, Wnt signaling is impaired and the synapses do not fully mature.



�The finding raises the possibility of treating autism with drugs that promote Wnt signaling, if the same connection is found in humans�

I have news for MIT, people already do use drugs that promote Wnt signaling, FRAX486 and Ivermectin for example.  All without any genetic testing, most likely.


Reactivating Shank3, or just promote Wnt signaling

The study below showed that in mice, aspects of autism were reversible by reactivating the Shank3 gene.  You might expect that in humans with a partial Shank3 dysfunction you might jump forward to the Wnt signaling pathway and intervene there.


Mouse study offers promise of reversing autism symptoms


One reader of this blog finds FRAX486 very helpful and to be without harmful side effects.  FRAX 486 was recently acquired by Roche and is sitting over there on a shelf gathering dust.



Where from here?

I think we should continue to look at the single gene syndromes but realize that very many more people may be partially affected by them.

Today�s genetic testing gives many false negatives, unless people know what they are looking for; so many dysfunctions go unnoticed.

This area of science is far from mature and there may be many things undetected in the 97% of the genome that is usually ignored that affect expression of the 3% that is the exome.

So best not to expect all the answers, just yet, from genetic testing; maybe in another 50 years.

Understanding and treating multiple-hit-autism, which is the majority of all autism, will require more detailed consideration of which signaling pathways have been disturbed by these hits.  There are 700 autism genes but there a far fewer signaling pathways, so it is not a gargantuan task.  For now a few people are figuring this out at home.   Good for them.

I hope someone does trials of metformin and intranasal insulin in autism.  Intranasal insulin looks very interesting and I was surprised to see in those earlier posts is apparently without side effects.

The odd thing is that metformin is indeed being trialed in autism, but not for its effect on autism, but its possible effect in countering the obesity caused by the usual psychiatric drugs widely prescribed in the US to people with autism.

My suggestion would be to ban the use of drugs like Risperdal, Abilify, Seroquel, Zyprexa etc.

Vanderbilt enrolling children with autism in medication-related weight gain study



Here are details of the trial.


Metformin will be dispensed in a liquid suspension of 100 mg/mL. For children 6-9 years of age, metformin will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if metformin is well-tolerated, the dose will be increased to 500 mg twice daily. For children from 10-17 years of age, metformin will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if metformin is well-tolerated, the dose will be increased to 500 mg twice daily. At the Week 4 visit, if metformin is well-tolerated, the dose will be increased to 850 mg twice daily.







More Melatonin!




  Older people, those with autism, those with reflux, IBS/IBD and other GI problems generally have low levels of melatonin.  Poor sleep is but one consequence.



I have previously written about the potential for melatonin in autism and I do not just mean to improve sleeping disorders.  Melatonin does a great deal more than that.

Melatonin for Kids with Autism, and indeed their Parents


MitoE, MitoQ and Melatonin as possible therapies for Mitochondrial Dysfunction in Autism. Or Dimebon (Latrepirdine) from Russia?




Most substances I write about in this blog are either prescription drugs or quite expensive supplements.

Other than in a small number of countries like the United Kingdom, melatonin is widely available as a cheap supplement, but that does not mean it is not a drug.

In humans melatonin is produced in two different places and it appears in two orders of magnitude.  Traditionally melatonin is considered to be a hormone produced by the pineal gland in the brain, but far more melatonin is actually produced in your intestines, where it has completely different functions.

Many people have low levels of melatonin, for example people with autism/schizophrenia/bipolar, older people and people with intestinal problems ranging from reflux/GERD/GORD to ulcerative colitis.

We know that melatonin is a potent antioxidant, but there are numerous other antioxidants.  Damaging oxidants vary both by type, but also by their location and so if you are clever you would match your antioxidant(s) very specifically to the oxidant(s).  

So if you have elevated risk of prostate cancer, take lycopene, it accumulates in fatty tissue and the prostate is surrounded by a fatty deposit called periprostatic adipose tissue (PPAT).  It is not agreed whether lycopene can cross the blood brain barrier in humans; it does for sure in rats.  

It seems that in people with type 2 diabetes there is oxidative stress in the mitochondria of the beta cells in their pancreas.  Beta cells make insulin and in type 2 diabetes there is often a gradual loss in beta cells resulting in type 1 diabetes.  Numerous cancer studies have shown the potential of different antioxidants in different cancers, NAC in breast cancer, Sulforaphane is esophageal cancer etc.  It seems to be agreed that antioxidants are most helpful in disease prevention, rather than cure.  
  
We know that melatonin is potent at combatting oxidants in the mitochondria, so logically people with mitochondrial dysfunction might well benefit from melatonin.  It is vastly cheaper than the antioxidant drugs that target the mitochondria (MitoE, MitoQ etc).

An interesting recent study has linked low levels of melatonin in the parents of those with autism.


  
Background: Low melatonin levels are a frequent finding in autism spectrum disorder (ASD) patients. Melatonin is also important for normal neurodevelopment and embryonic growth. As a free radical scavenger and antioxidant melatonin is highly effective in protecting DNA from oxidative damage. Melatonin deficiency, possibly due to low CYP1A2 activity, could be a major factor, and well a common heritable variation. ASD is already present at birth. As the fetus does not produce melatonin, low maternal melatonin levels should be involved. Methods: We measured 6-sulfatoxymelatonin in urine of mothers of a child with ASD that attended our sleep clinic for people with an intellectual disability (ID), and asked for parental coffee consumption habits, as these are known to be related to CYP1A2 activity. Results: 6-Sulfatoxymelatonin levels were significantly lower in mothers than in controls (p = 0.005), as well as evening coffee consumption (p = 0.034). In mothers with a second child with ASD and/or ID, 6-sulfatoxymelatonin levels were lower compared to mothers with one child with ASD (p = 0.084), 

Conclusions: Low parental melatonin levels, likely caused by low CYP1A2 activity, seem to be a major contributor to ASD and possibly ID etiology.


I think you would also find, more generally, high levels of oxidative stress in parents of those with autism, and more importantly oxidative stress during pregnancy would have negative effects.  I think autism produces stress and stress helps produce autism.

  

Potency of pre�post treatment of coenzyme Q10 and melatoninsupplement in ameliorating the impaired fatty acid profile in rodent model ofautism


  

  
"It is now almost 60 years since the discovery of melatonin and new physiological functions of the indole continuously appear in the most recent studies worldwide. Besides the pineal gland, the existence and value of other sources of synthesis force us to rethink the established premises about the biological role of this molecule, such as the well-known regulation of circadian and reproductive cycles (Hardeland et al., 2008). In the last few years, other properties of melatonin such as antioxidant power, immunoregulatory capacity, and oncostatic action have enriched our knowledge about the pleiotropic nature of the hormone.

The role of melatonin in mitochondrial homeostasis has gained strength in the scientific community. Experimental evidence emphasizes its importance as a stabilizer of organular bioenergetics, which could be related to the             prevention of development of aging and several diseases.

  
Role of melatonin on mitochondrial dysfunction and diseases

The idea that mitochondrial dysfunction is implicated in the etiology of various diseases has been strengthened after several years of research. Initially, studies of mitochondrial diseases have focused on mitochondrial respiratory-chain diseases associated with mutations of mtDNA. However, more recent evidence shows that oxidative damage is responsible for the impairment of mitochondrial function, leading to a self-induced vicious cycle that finally culminates in necrosis and apoptosis of cells and organ failure. We are now starting to understand the mechanisms of a large list of mitochondrial-related diseases (cancer, diabetes, obesity, cardiovascular and neurodegenerative diseases, and aging); all of them seem to share the common features of disturbances of mitochondrial Ca2+, ATP, or ROS metabolism (Sheu et al., 2006). Therefore, selective prevention of such phenomena should be an effective therapy in a wide range of human diseases (Smith et al., 1999; Sheu et al., 2006). Melatonin, as was described in the previous section, has many of the characteristics of a perfect candidate for the treatment of these kinds of illnesses.

  
Conclusion

Mitochondrial dyshomeostasis and related events have begun to reveal themselves as possible etiologies of several diseases of unknown origin. In the next years, conscientious investigation about this topic should be undertaken by scientists of different research areas to achieve a better understanding of the molecular mechanisms implied, which will ultimately allow the development and clinical application of efficacious treatments."


Recent posts looked at disturbed calcium homeostasis in autism, particularly low bone density.  Melatonin may play a role here as well.



Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women.


Abstract


The purpose of this double-blind study was to assess the effects of nightly melatonin supplementation on bone health and quality of life in perimenopausal women. A total of 18 women (ages 45-54) were randomized to receive melatonin (3mg, p.o., n=13) or placebo (n=5) nightly for 6months. Bone density was measured by calcaneal ultrasound. Bone turnover marker (osteocalcin, OC for bone formation and NTX for bone resorption) levels were measured bimonthly in serum. Participants completed Menopause-Specific Quality of Life-Intervention (MENQOL) and Pittsburgh Sleep Quality Index (PSQI) questionnaires before and after treatment. Subjects also kept daily diaries recording menstrual cycling, well-being, and sleep patterns. The results from this study showed no significant change (6-month-baseline) in bone density, NTX, or OC between groups; however, the ratio of NTX:OC trended downward over time toward a ratio of 1:1 in the melatonin group. Melatonin had no effect on vasomotor, psychosocial, or sexual MENQOL domain scores; however, it did improve physical domain scores compared to placebo (mean change melatonin: -0.6 versus placebo: 0.1, P<0.05). Menstrual cycling was reduced in women taking melatonin (mean cycles melatonin: 4.3 versus placebo: 6.5, P<0.05), and days between cycles were longer (mean days melatonin: 51.2 versus placebo: 24.1, P<0.05). No differences in duration of menses occurred between groups. The overall PSQI score and average number of hours slept were similar between groups. These findings show that melatonin supplementation was well tolerated, improved physical symptoms associated with perimenopause, and may restore imbalances in bone remodeling to prevent bone loss. Further investigation is warranted.

           Melatonin Effects on Hard Tissues: Bone and Tooth


Melatonin, as an endogenous hormone, participates in many physiological and pharmacological processes. The above analyzed data indicate that melatonin may be involved in the development of the hard tissues bone and teeth. Decreased melatonin levels may be related to bone disease and abnormality. Due to its ability of regulating bone metabolism, enhancing bone formation, promoting osseointegration of dental plant and cell and tissue protection, melatonin may used as a novel mode of therapy for augmenting bone mass in bone diseases characterized by low bone mass and increased fragility, bone defect/fracture repair and dental implant surgery. The investigation of melatonin on tooth still insufficient and requires further research.

The following very interesting study, looking at the broader effects of high dose melatonin in autism, has been completed, but the results have yet to be published

Melatonin Dose-effect Relation in Childhood Autism (MELADOSE)

the objective of this clinical trial is to study the relation between the melatonin dose administered and its effect on severity of autistic impairments especially in verbal communication and play.


Experimental: 2 mg melatonin
1 tablet of 2mg melatonin and 4 tablets of its placebo once a day, an hour before falling asleep, for 6 weeks.
Experimental: 4 mg melatonin
2 tablets of 2mg melatonin and 3 tablets of its placebo once a day, an hour before falling asleep, for 6 weeks.
Experimental: 10 mg melatonin
5 tablets of 2mg melatonin once a day, an hour before falling asleep, for 6 weeks.




The science part

The following is an extract from an excellent paper about the use of melatonin to treat ulcerative colitis:-







Melatonin was first described as a secretion from the pineal gland with multiple neurohormonal functions, including regulation of the circadian rhythm, reproductive physiology, and body temperature, but has since also been found to inhibit the Cox-2 and NF-_B pathways and several aging processes. The multifactorial role of this hormone, however, has only relatively recently been appreciated (Fig. 1) as it circulates unimpeded across anatomical barriers, the blood� brain barrier included, and exhibits both receptor-dependent and receptor-independent effects.

Furthermore, melatonin exhibits a high degree of conservation across the evolutionary ladder, pointing to a critical function in various forms of life, even in organisms devoid of a pineal gland. In fact, the analysis of extrapineal sources of melatonin have highlighted the GI tract as a major source of this factor, with concentrations of melatonin as much as 100 times that found in blood and 400 times that found in the pineal gland.40 GI melatonin comes from both pineal melatonin and de novo synthesis in the GI tract and may have a direct effect on many GI tissues, serving as an endocrine, paracrine, or autocrine hormone, influencing the regeneration and function of epithelium, modulating the immune milieu in the gut, and reducing the tone of GI muscles by targeting smooth muscle cells.40 Melatonin may also influence the GI tract indirectly, through the central nervous system and the mucosa, by a receptor-independent scavenging of free radicals leading to reduction of inflammation, reduction of secretion
of hydrochloric acid, stimulation of the immune system, COX-2 fostering tissue repair and epithelial regeneration, and increasing microcirculation. Human intestinal motility follows a circadian rhythm with reduced nocturnal activity. Abnormalities in colonic motor function in patients with UC have been well documented.

Melatonin appears to be involved in the regulation of GI motility, exerting both excitatory and inhibitory effects on the smooth musculature of the gut.  The precise mechanism through which melatonin regulates GI motility is not clear, although some studies suggest that this may be related to blockade of nicotonic channels by melatonin and/or the interaction between melatonin and Ca2+ activated K channels.

Melatonin may also function as a physiological antagonist of serotonin. In a recent rodent model, melatonin administration was shown to reverse lipopolysaccharide-induced GI motility disturbances through the inhibition of oxidative stress. The net motor regulation by melatonin is, therefore, likely multifactorial.

In addition, several lines of in vitro studies as well as animal studies, have reported that melatonin regulates the extensive gut immune system and has important general antiinflammatory and immunomodulatory effects. Given its
presence in GI tissue and its suggested importance in GI tract physiology, it is reasonable to hypothesize that melatonin could influence inflammation-related GI disorders, including UC. In various animal experiments, melatonin administration was (among other immunomodulatory effects) shown to increase
IL-10 production and inhibit production of IFN-_, TNF-_, IL-6, and NO, suggesting that melatonin may exert benefits in UC by reducing or controlling inflammation.

Melatonin administration has also inhibited the TNF-_-induced mucosal addressin cell adhesion molecule (MAd-CAM)-1 in vitro, and intercellular adhesion molecule (ICAM)-1 in vivo, limiting the influx of activated _4_7_ and LFA-1_ leukocytes to the mucosal environment. During inflammation, the mucosal microvasculature controls the selection and magnitude of influx of T-cell subsets into the gut through cell adhesion molecules expression and chemokine secretion, which further amplify the communication with other leukocytes and cells. In animal experiments neutralization of MAdCAM-1 and ICAM-1 led to attenuation of mucosal damage in colitis.


If you made your way through the above section, and regularly read this blog you will appreciate the multiple possible beneficial actions for many types of autism.

I was going to have a post about GI issues, but I will put some of the melatonin part in this post.  In summary, very many GI problems are associated with low levels and melatonin and numerous studies have shown that giving oral melatonin is an effective treatment to varying degrees. Melatonin is a useful adjunct (add-on) therapy in these conditions. 

Not only does melatonin appears to promote healing of the esophagus but also the tightening of the LES (The lower esophagealsphincter)

Failure of this sphincter to close is why people get reflux/GERD/GORD.

One possibility is that the night time spike in melatonin signals your brain that it is time to sleep and also signals your LES to shut tightly, so that during the night acid does not rise up your esophagus while you are horizontal.



The potential therapeutic effect of melatonin in gastro-esophageal reflux disease


Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and aminoacids: comparison with omeprazole.   




Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases





Conclusion

Melatonin may already be the most widely used drug to treat autism, but generally at the lower sleep-inducing doses.

It would seem that those with GI problems, mitochondrial problems or more general oxidative stress may very well benefit from the higher doses of melatonin already used by some.

Older people, people with esophagitis/duodenitis or IBS/IBD, people with type 1 or 2 diabetes and even people with osteoporosis may also want to look into melatonin supplementation.

Given the supplement is ending up in your intestines, where much melatonin should already be being produced, the impact on pineal melatonin production becomes less of an issue.  People giving thyroid hormones T3 and T4 to children who are euthyroid (ie normal thyroid function) should be aware of the consequences (thyroid shutdown).

For various reasons, production of ROS (reactive oxygen species) that are the oxidants varies throughout the day, the morning is the worst time supposedly.  Ideally you would match this with your antioxidant intake.  One combination would be melatonin before bed, a larger dose of NAC at breakfast and then NAC throughout the day.  As highlighted in an earlier post, sustained release NAC is also interesting, but it would help if there was a more potent version. 

Hopefully Dr Tordjman will publish the results of her high dose melatonin in autism study soon.
  
Most people struggle to access the really effective autism drugs, but antioxidants are available in abundance.

Oxidative stress is not a cause of autism, but it is a common side effect.  Treating oxidative stress does indeed seem to help many people with autism, but since the source of those oxidants may vary so should the most effective therapy.  Melatonin may be a useful part of that antioxidant mix, particularly if there are GI, mitochondrial or sleep issues.

Melatonin has a half-life of less than an hour, people who respond well might consider sustained release versions, which are available quite cheaply (5 and 10 mg sustained release forms look interesting).  There are even some clinical trials measuring the resulting plasma levels.











Talents and Savants





Today�s post does not have much to do with science, just a little about genes. 

Several years ago at school, a teacher asked me what Monty�s special skill is; as she understood autism, people always have one.

Recently, at the same mainstream school, a teacher was explaining to the assembled now older kids why it was that she had decided to establish a talent show.  Did the kids really know what talent means?  Her point was that everyone has a special ability, something that they are surprisingly good at.  You just have to find it and develop it.  The key is what you do with those talents, do they grow or not?


�Talent� came ultimately from Greek talanton, and referred originally to a unit of weight used by the Babylonians, Assyrians, Romans, and Greeks. The use of talent to mean �natural aptitude or skill� comes from the biblical parable of the talents in the Gospel of Matthew. In this story a master gives one, two, and ten talents of silver to each of three servants. Two of them use their talents well and double the value of what they have been given, but the third buries his coin and fails to benefit from it.


The teacher in kindergarten was assuming Monty, now aged 12, would have some savant skills that are apparently nearly always connected to memory.  The study below finds that 10% of people really do fit this description.


Savant syndrome is a rare, but extraordinary, condition in which persons with serious mental disabilities, including autistic disorder, have some �island of genius� which stands in marked, incongruous contrast to overall handicap. As many as one in 10 persons with autistic disorder have such remarkable abilities in varying degrees, although savant syndrome occurs in other developmental disabilities or in other types of central nervous system injury or disease as well. Whatever the particular savant skill, it is always linked to massive memory. This paper presents a brief review of the phenomenology of savant skills, the history of the concept and implications for education and future research.


The science part of the post is to highlight the overlap between some autism genes and some of the genes that make you clever; we should not be surprised that some people with severe autism do indeed have some areas of intellectual excellence.

Autism risk genes also linked to higher intelligence

"Our findings show that genetic variation which increases risk for autism is associated with better cognitive ability in non-autistic individuals�

I was thinking back to my one and only ever �autism lunch�, talking with former university classmates who now have a child with autism. At least six out of 200 have a child with serious autism, this continues to surprise me since this kind of autism has an incidence of about 0.3%, so you would expect one or two cases not six. More anecdotal evidence to link autism incidence with IQ perhaps? 

One is preparing his non-verbal son for the 2020 Tokyo Paralympics.  This boy has great athletic talents.  I could not picture Monty sprinting round the Olympic stadium.

One has son with a photographic memory, who seems to have instant recall of underground/metro travel maps.  Monty has yet to memorize any maps. 

One Australian lady, who could not make that lunch, has a son diagnosed with autism and MR/ID, who ended up great at fencing (sword fighting).  I remember being surprised to hear this, since I could not imagine Monty doing this, although his typical big brother did do this.  

Not to paint an unrealistic picture, one child was non-verbal, then developed self-injury and aggression, improved somewhat but at puberty developed epilepsy and then began a spiral downwards to institutionalization.  This is a case where the right pharmacological intervention at the right time might have been a game changer.
My son�s special skill is music, I just had not realized this yet when asked several years ago by that kindergarten teacher.

So based on my unscientific review of the people I have come across with more severe autism, I would have to say that many do indeed have special talents and some are indeed savants.
But just as in the biblical tale, it really is a case of nurturing those talents.

Monty�s musical talents where nurtured by years of music and dance with his Assistant.  All I did was provide the piano later on.
Adults with autism generally have a lot of time on their hands and so it will be very useful to have those interests/talents.   


Golf, sailing, swimming, running, trampolining, horseback riding are all good candidates.
Since many people with autism really do have unusually good memory and can recognize patterns, there is potential for everything from chess to poker.
Monty�s other talent could be diving, he is very competent underwater and down there you do not need to speak, so perhaps a pearl diver somewhere warm?


Parental Involvement

Whereas for typical children being a pushy parent is usually counter-productive, children with autism actually like the repetition and routine of training and do not have conflicting social engagements that mean training is a burden.  Even a trace of talent can be the foundation of something impressive later.

I think many talents in autistic teenagers are indeed the result of a great deal of parental nurture over the previous decade. 
When Monty won the talent show at school with his piano recital, I was amazed at how much of a big deal people made. His after-school assistant immediately called her mother who then bought him a present.  The other kids are school were genuinely happy for him. Days later, other parents were congratulating him.

Imagine what would happen if you won a medal at the 2020 Tokyo Paralympics?

So it looks like what is your talent is indeed a better question, than do you have a talent.





Combatting Brain Calcification in Some Autism (and Bipolar and Schizophrenia) and Osteoprotegerin (OPG) as a potential biomarker, implicating Cav1.2


In today�s post there is more supposition than normal, but plenty of anecdotal evidence.  It follows on from the previous post that suggested calcification might be an issue in some types of autism.  As we know, many unrelated biological dysfunctions can lead to autism, but there do seem to be some commonly affected pathways.

This subject is definitely worthy of much more detailed study than my post, which is based on an initial review of the science.  Some leading researchers, like Persico and Courchesne are fully aware of the issue.  I am not sure who would undertake such a study.  There is no physician specialty dedicated solely to osteoporosis, so we are lacking experts.  The bone-vascular axis is worthy of more study, as much for heart disease as autism.

A variety of medical specialists treat people with osteoporosis, including internists, gynecologists, family physicians, endocrinologists, rheumatologists, physiatrists, orthopaedists, and geriatricians.  If you do not know what a physiatrist is, I also had to look it up.  Physical Medicine and Rehabilitation (PM&R) physicians, also known as physiatrists, treat a wide variety of medical conditions affecting the brain, spinal cord, nerves, bones, joints, ligaments, muscles, and tendons.
 

Overview

There is more support for the potential use of calcium channel blockers that affect Cav1.2, via its effect on calcification by modulating Osteoprotegerin (OPG).  OPG is known to be elevated in autism and its two older brothers schizophrenia and bipolar.

It appears that in some people with severe brain calcification, that shows up on CT scans, biphosphanate drugs can be helpful, but do not actually shrink the calcification, perhaps they stop it growing.

Biphosphanate drugs used to treat osteoporosis are not without side effects in some people.

Some people have disturbed calcium homeostasis as a result of drugs they are taking, for example antiepileptic drugs.

So-called �chelation� using powerful intravenous antioxidants has been shown in the TACT clinical trial to reduce future heart problems, but only in people with diabetes. Diabetics are known to have disturbed calcium homeostasis leading to calcification, heart disease and osteoporosis.

In some counties intravenous antioxidants have long been given to people with diabetes to treat its main side effects but not to clear calcification.  In those countries this is seen as perfectly safe and routine. Preventative care for diabetics is actually rather poor in the UK and US.

Vitamin K plays a key role in calcium homeostasis and in some people just giving large amounts of this vitamin has the required therapeutic effect.  Unless given alongside blood thinning drugs, it is claimed that high dose Vitamin K does not have side effects.

Perhaps the most common osteoporosis therapy, calcium plus vitamin D is shown in some trials to be of no value whatsoever.  This therapy would most likely be ill advised in autism.



Osteoprotegerin (OPG)

Osteoprotegerin (OPG) is a cytokine involved in calcification and inflammation.


Osteoprotegerin has been used experimentally to decrease bone resorption in women with postmenopausal osteoporosis.
 It has been particularly related to the increase in cardiovascular risk in patients suffering from diabetes

Interestingly it has been shown that the L type calcium channel Cav1.2 regulates Osteoprotegerin (OPG) expression and secretion.
A NASA space shuttle flight in 2001 tested the effects of osteoprotegerin on mice in microgravity, finding that it did prevent increase in resorption and maintained bone mineralization.  Space flight is not good for your bones.

Osteoprotegerin levels are elevated in people with bipolar and schizophrenia.


Osteoprotegerin levels in patients with severe mental disorders


Severe mental disorders are associated with elevated levels of inflammatory markers. In the present study, we investigated whether osteoprotegerin (OPG), a member of the tumour necrosis factor receptor family involved in calcification and inflammation, is elevated in patients with severe mental disorders.


Methods

We measured the plasma levels of OPG in patients with severe mental disorders (n = 312; 125 with bipolar disorder and 187 with schizophrenia) and healthy volunteers (n = 239).

The mean plasma levels of OPG were significantly higher in patients than in controls (t531 = 2.6, p = 0.01), with the same pattern in bipolar disorder and schizophrenia. The increase was significant after adjustment for possible confounding variables, including age, sex, ethnic background, alcohol consumption, liver and kidney function, diabetes, cardiovascular disease, autoimmune diseases and levels of cholesterol, glucose and C-reactive protein.


Conclusion

Our results indicate that elevated OPG levels are associated with severe mental disorders and suggest that mechanisms related to calcification and inflammation may play a role in disease development.



As shown in the study below, many inflammatory cytokines are elevated in autism, just look at those insulin-like growth factor binding proteins.  Osteoprotegerin is a modest 500% of what it might be expected to be in non autism.









Chelation

Because of the continuing non-debate in scientific terms about vaccines and autism, it is unlikely that there will ever be any study about calcium chelation and autism.  Rather than admit that in a small number of cases vaccination may trigger mitochondrial disease and result in autism, there is complete denial, at least in public. In private it is an open secret.

The planned chelation trial in autism was banned, on �safety grounds�.

It looks to me that the enemy is not mercury or other heavy metals, the problem is much less exotic. 


Oxidative Stress
Most people with autism have oxidative stress, which should be improved by any potent antioxidant.  Agents used to chelate metals have to be potent antioxidants.


Calcification
In some yet to be determined percentage of people they potentially have disturbed calcium homeostasis resulting in some calcium deposits in the brain.  Those chelating to remove, most likely non-existing, �toxins� may sometimes be reducing harmful calcification.



Fortunately there has been a very large study, called TACT, on de-calcification (calcium chelation) in Coronary Heart Disease.

One large group of people at risk from low bone density are those with diabetes.

Patients with diabetes, who made up approximately one third of the 1,708 TACT participants, had a 41 percent overall reduction in the risk of any cardiovascular event; a 40 percent reduction in the risk of death from heart disease, nonfatal stroke, or nonfatal heart attack; a 52 percent reduction in recurrent heart attacks; and a 43 percent reduction in death from any cause.

   

Chelation for Coronary Heart Disease


  Patients with diabetes, who made up approximately one third of the 1,708 TACT participants, had a 41 percent overall reduction in the risk of any cardiovascular event; a 40 percent reduction in the risk of death from heart disease, nonfatal stroke, or nonfatal heart attack; a 52 percent reduction in recurrent heart attacks; and a 43 percent reduction in death from any cause. In contrast, there was no significant benefit of EDTA treatment in participants who didn't have diabetes.










From the Mayo Clinic:-

          Results of trial to assess chelation therapy (TACT) study presented



 A further review from TACT just looking at patients with diabetes:- 

The Effect of an EDTA-based Chelation Regimen on Patients with Diabetes and Prior Myocardial Infarction in TACT



Patients with diabetes:-









Patients without diabetes (no benefit over placebo):-





Treatment

The 10 component 500 mL intravenous solution in TACT consisted of 3 g of disodium EDTA, adjusted downward based on estimated glomerular filtration rate; 7 g of ascorbic acid; 2 g of magnesium chloride; B-vitamins, and other components (eTable 4). The placebo solution consisted of 500 mL of normal saline and 1.2% dextrose (2.5 g total). The solution was infused over at least 3 hours through a peripheral intravenous line weekly for 30 weeks and then biweekly to bimonthly to complete 40 infusions.



Background

The Trial to Assess Chelation Therapy (TACT) showed clinical benefit of an ethylene diamine tetraacetic acid (EDTA-based) infusion regimen in patients 50 years or older with prior myocardial infarction (MI). Diabetes prior to enrollment was a pre-specified subgroup.

Methods and Results

Patients received 40 infusions of EDTA chelation or placebo. 633 (37%) had diabetes (322 EDTA, 311 placebo). EDTA reduced the primary endpoint (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina) [25% vs 38%, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.44, 0.79), p<0.001] over 5 years. The result remained significant after Bonferroni adjustment for multiple subgroups (99.4% CI (0.39, 0.88), adjusted p=0.002). All-cause mortality was reduced by EDTA chelation [10% vs 16%, HR 0.57, 95% CI (0.36, 0.88) p=0.011], as was the secondary endpoint (cardiovascular death, reinfarction, or stroke) [11% vs 17% HR 0.60, 95% CI (0.39, 0.91), p=0.017]. After adjusting for multiple subgroups, however, those results were no longer significant. The number needed to treat to reduce one primary endpoint was 6.5 over 5 years (95% CI (4.4, 12.7). There was no reduction in events in non-diabetics (n=1075, p=0.877), resulting in a treatment by diabetes interaction (p=0.004).

Conclusions

Post-MI diabetic patients age 50 or older demonstrated a marked reduction in cardiovascular events with EDTA chelation. These findings support efforts to replicate these findings and define the mechanisms of benefit. They do not, however, constitute sufficient evidence to indicate the routine use of chelation therapy for all post-MI diabetic patients.





Effect of the Polypill on Calcification

Oral antioxidants like NAC and Alpha lipoic Acid given daily will have both a direct and indirect �chelating� effect.

Alpha-Lipoic Acid Promotes Osteoblastic Formation in H2O2 -Treated MC3T3-E1 Cells and Prevents Bone Lossin Ovariectomized Rats.

 

Alpha-lipoic acid (ALA), a naturally occurring compound and dietary supplement, has been established as a potent antioxidant that is a strong scavenger of free radicals. Recently, accumulating evidences has indicated the relationship between oxidative stress and osteoporosis (OP). Some studies have investigated the possible beneficial effects of ALA on OP both in vivo and in vitro; however, the precise mechanism(s) underlying the bone-protective action of ALA remains unclear. Considering this, we focused on the anti-oxidative capacity of ALA to exert bone-protective effects in vitro and in vivo. In the present study, the effects of ALA on osteoblastic formation in H(2)O(2) -treated MC3T3-E1 pre-osteoblasts and ovariectomy (OVX)-induced bone loss in rats were investigated. The results showed that ALA promoted osteoblast differentiation, mineralization and maturation and inhibited osteoblast apoptosis, thus increasing the OPG/receptor activator of nuclear factor-?B (NF-?B) ligand (RANKL) ratio and leading to enhanced bone formation in vitro and inhibited bone loss in vivo. Further study revealed that ALA exerted its bone-protective effects by inhibiting reactive oxygen species (ROS) generation by down-regulating Nox4 gene expression and protein synthesis and attenuating the transcriptional activation of NF-?B. In addition, ALA might exert its bone-protective effects by activating the Wnt/Lrp5/�-catenin signaling pathway. Taken together, the present study indicated that ALA promoted osteoblastic formation in H(2)O(2) -treated MC3T3-E1 cells and prevented OVX-induced bone loss in rats by regulating Nox4/ROS/NF-?B and Wnt/Lrp5/�-catenin signaling pathways, which provided possible mechanisms of bone-protective effects in regulating osteoblastic formation and preventing bone loss. Taken together, the results suggest that ALA may be a candidate for clinical OP treatment.



Statins are known to promote bone health.

Statins and osteoporosis:new role for old drugs.


Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case-control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted.



Verapamil via the effect on OPG should have positive effect on bones and reduce vascular calcification.



Use of Biphosphanate Drugs to Treat Brain Calcification



Brain calcification might be associated with various metabolic, infectious or vascular conditions. Clinically, brain calcification can include symptoms such as migraine, Parkinsonism, psychosis or dementia. The term Primary Brain Calcification was recently used for those patients without an obvious cause (formerly idiopathic) while Primary Familial Brain Calcifications was left for the cases with autosomal dominant inheritance. Recent studies found mutations in four genes (SLC20A2,PDGFRB, PDGFB and XPR1). However, these genes represent only 60% of all familial cases suggesting other genes remain to be elucidated. Studies evaluating treatments for such a devastating disease are scattered, usually appearing as single case reports. In the present study, we describe a case series of 7 patients treated with Alendronate, a widely prescribed biphosphanate. We observed good
tolerance and evidence of improvements and stability by some patients. No side effects were reported and no specific symptoms related to medication. Younger patients and one individual continuing a prescription (prior to study commencement) appeared to respond more positively with some referred improvements in symptoms. Biphosphanates may represent an excellent prospect for the treatment of brain calcifications due to their being well tolerated and easily available. Conversely, prospective and controlled studies should promptly address weaknesses found in the present analysis.



Patient 3. A 43-year-old man, one of seven children born to the same mother (described below as Patient 4), presented with rapid progression of parkinsonism. In the last 5 years, a progressive presentation of general bradykinesia, rigidity, and paresis in the right arm had developed. He had previously been an active individual with regular employment. Prior to recruitment, this patient had been on carbidopa/levodopa, which was continued throughout the duration of the present study. Genetic screening identified a SLC20A2 mutation (c.1483 G > A)3, and the patient was placed on alendronate therapy.

Patient 4. This 84-year-old woman presented with mild depression, late-stage parkinsonism, and large calcifications (10.85 cm3) in the basal ganglia and cerebellum. She is the mother of Patient 3 and carries the same SLC20A2 mutation. This patient had been taking alendronate for 10 years due to a diagnosis of osteoporosis. Intriguingly, she presented with fewer symptoms than her son, despite being 41 years old older.


We chose alendronate due to its availability, safety, and comfortable dosing schedule (oral administration, once a week). Etidronate probably works via a different mechanism (bulk action binding to hydroxyapatite) than
the newer amino bisphosphonate alendronate (inhibition of osteoclasts). This might explain why the effects seen in our series were less dramatic than those seen in patients treated with etidronate. Thus, while alendronate has a more convenient dosing schedule and, possibly, fewer side effects, a larger clinical trial should consider the choice of bisphosphonate carefully.

To date, there is no specific treatment for primary brain calcification; the main goal is symptom management.

Clinicians should make sure that the idiopathic/primary profile is accurately defined to rule out any underlying organic cause, e.g., in non-idiopathic basal ganglia calcification caused by abnormal calcium regulation, such as in primary endocrine disorders.

Bisphosphonates represent the only effective (although still anecdotal) treatment that could have wider applications in basal ganglia calcification. Prospective, controlled studies should be conducted to address the weaknesses of the present manuscript and establish a definitive analysis of bisphosphonate therapy for primary brain calcification. Furthermore, the excellent tolerability profile of alendronate in primary brain calcifications suggests that a trial in asymptomatic patients could help address the potential benefit of this strategy to control symptoms in younger patients.

Conclusion

Bisphosphonates may be applicable, safe and change the natural progression of primary brain calcifications, especially in younger patients and across prolonged periods. Nevertheless, future studies with adequate design should answer remaining questions.



Metabolic Bone Diseases

There are numerous things that can affect the bone-vascular axis including various  metabolic diseases.  This is rather beyond the scope of an autism blog, but if you are interested here is a link.

Imaging Findings and Evaluation of Metabolic Bone Disease





Conclusion

Unless you have evidence of osteoporosis, or a brain scan showing calcification, it might be rather extreme to take a biphosphanate drug like Fosamax.

If you already take oral NAC , ALA or L-carnitine you have a pretty potent therapy which would target any calcification, if indeed it existed.  Intravenous ALA, as used my Monty�s Grandad for years, should be even more effective as it is for diabetic neuropathy.

Those using verapamil appear to have another layer of protection against calcification. I did suggest to Agnieszka that elevated OMG might indeed be the biomarker needed for the use of verapamil in Autism. Remember to contact her to participate in her study.

Verapamil use in Autism � Request for Case Reports from Parents



Vitamin K2 is claimed to be extremely safe unless you are taking a blood thinning drug like Warfarin, that are Vitamin K antagonists.

Some studies claim great results from K2, while some others are more mixed.  It is likely that depending on what underlying dysfunction exists, high dose K2 may help or do nothing.  It is clear that low amounts of K2 are damaging.

So K2 would seem worthwhile trialing.  It is found in the not so pleasant tasting Natto.  Vitamin K (more K1 than K2) is found in broad-leafed vegetables.  The excellent Linus Pauling Institute reviewed all the vitamin K evidence and concluded people should:-

 �eat at least one cup of dark green leafy vegetables daily�


This brings me back to where I started the previous post with the Mediterranean diet, rich in dark green leafy vegetables.

Intravenous infusion of antioxidants looks like a very good idea for people with diabetes.  Where we live this has been standard practice for years, where Monty�s grandad goes twice a year for 10 days of ALA infusion, the rest of the year he is prescribed oral ALA.  This is given to control diabetic neuropathy, but clearly a side effect is that it will reduce the likelihood of a heart attack or stroke.

I have no doubt IV infusion of ALA would be beneficial for some with autism, but I think they might get sufficient benefit from oral ALA or indeed NAC.

I wish the FDA would permit the �chelation� autism trial in the US, I have no doubt it would show a positive effect, but not for the reasons put forward by DAN doctors and the chelation cults. 

The TACT chelation trial in older people showed that the therapy was very well tolerated.  IV ALA therapy is also well tolerated.

Public health officials should not fear the truth.  In the long run the truth is the best policy and when given all the facts the public are not stupid.  If vaccination is in the interest of their child, enough parents will happily cooperate. The Herd Immunity Threshold (HIT) is the percentage of people who need to be vaccinated.  HIT is 95% for measles.  Therapies used at Johns Hopkins exist to minimize the possible damaging effect on mitochondria and never give paracetamol/acetaminophen to children after a vaccination.













Ketones and Autism Part 4 � Inflammation, Activated Microglia, CtBP, the NLRP3 Inflammasome and IL-1�

This series of posts on ketones and the ketogenic diet (KD) is nearly finished and I am glad that I made favourable comments about the KD ea...