Low dose Clonazepam for MIA Autism, Ponstan and TRPM3 in Intellectual Disability, Clemastine to restore myelination in Pitt Hopkins, Improving Oxytocin therapy with Maca, Lamotrigine for some autism

 

Monty in Ginza, Tokyo

Today’s post comes from Tokyo and looks at 5 therapies already discussed in previous posts and follows up on recent coverage in the research. They all came up in recent conversations I have been having.

·      Low dose Clonazepam  – Maternal Immune Activation model of autism

·      Ponstan – TRPM3 causing intellectual disability  (ID/MR)

·      Clemastine – improving myelination in Pitt Hopkins syndrome model

·      Oxytocin – Maca supplement to boost effect

·      Lamotrigine (an anti-epilepsy drug) to moderate autism

The good news is that many of same therapies keep coming up.

Ponstan and TRPM3 caused ID/MR

There is a lot in this blog about improving cognition, which is how I called treating ID/MR.  There are very many causes of ID and some of them are treatable.

ID/MR was always a part of classic autism and in the new jargon is part of what they want to call profound autism.

I was recently sent a paper showing how the cheap pain reliever Ponstan blocks the TRMP3 channel and that this channel when mutated can lead to intellectual disability and epilepsy.

Mefenamic acid selectively inhibits TRPM3-mediated calcium entry.

My own research has established that mefenamic acid seems to improve speech and cognition, as well as sound sensitivity.  The latter effect I am putting down to its effect on potassium channels. 

De novo substitutions of TRPM3 cause intellectual disability and epilepsy

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3’s S4–S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3’s flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.

 

Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3

This study reveals that mefenamic acid selectively inhibits TRPM3-mediated calcium entry. This selectivity was further confirmed using insulin-secreting cells. K_ATP channel-dependent increases in cytosolic Ca²⁺ and insulin secretion were not blocked by mefenamic acid, but the selective stimulation of TRPM3-dependent Ca²⁺ entry and insulin secretion induced by pregnenolone sulphate were inhibited. However, the physiological regulator of TRPM3 in insulin-secreting cells remains to be elucidated, as well as the conditions under which the inhibition of TRPM3 can impair pancreatic β-cell function. Our results strongly suggest mefenamic acid is the most selective fenamate to interfere with TRPM3 function. 

Here, we examined the inhibitory effect of several available fenamates (DCDPC, flufenamic acid, mefenamic acid, meclofenamic acid, niflumic acid, S645648, tolfenamic acid) on the TRPM3 and TRPV4 channels using fluorescence-based FLIPR Ca²⁺ measurements. To further substantiate the selectivity, we tested the potencies of these fenamates on two other TRP channels from different subfamilies, TRPC6 and TRPM2. In addition, single-cell Ca²⁺ imaging, whole-cell voltage clamp and insulin secretion experiments revealed mefenamic acid as a selective blocker of TRPM3.

  

Oxytocin

 Oxytocin does increase how emotional you feel; the difficulty is how to administer it in a way that provides a long lasting effect.  The half-life of oxytocin is a just minutes. The traditional method uses a nose spray.

I favour the use of a gut bacteria that stimulates the release of oxytocin in the brain.  The effect should be much longer lasting. Even then the effect is more cute than dramatic.

The supplement Maca does not itself produce oxytocin, but “it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways”.

So Maca looks like an interesting potential add-on therapy to boost the effect of oxytocin.

One reader wrote to me with a positive report on using Maca by itself, without any oxytocin.

 

Oral Supplementation with Maca Improves Social Recognition Deficits in the Valproic Acid Animal Model of Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a congenital, lifelong neurodevelopmental disorder whose main symptom is impaired social communication and interaction. However, no drug can treat social deficits in patients with ASD, and treatments to alleviate social behavioral deficits are sorely needed. Here, we examined the effect of oral supplementation of maca (Lepidium meyenii) on social deficits of in utero-exposed valproic acid (VPA) mice, widely used as an ASD model. Although maca is widely consumed as a fertility enhancer and aphrodisiac, it possesses multiple beneficial activities. Additionally, it benefits learning and memory in experimental animal models. Therefore, the effect of maca supplementation on the social behavioral deficit of VPA mice was assessed using a social interaction test, a three-stage open field test, and a five-trial social memory test. The oral supplementation of maca attenuated social interaction behavior deficit and social memory impairment. The number of c-Fos-positive cells and the percentage of c-Fos-positive oxytocin neurons increased in supraoptic and paraventricular neurons of maca-treated VPA mice. These results reveal for the first time that maca is beneficial to social memory and that it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways, which play an essential role in diverse social behaviors.

Maca (Lepidium meyenii) belongs to the cruciferous family and grows at high altitudes in Peru. In 2002, it was transplanted from Peru to the Yunnan Province of China. It is rich in dietary fiber; has many essential amino acids and nutrients including vitamin C, copper, and iron; and its root contains bioactive compounds. It is globally consumed and is popularly used as a fertility enhancer and aphrodisiac. On the other hand, with its potential to possess multi-nutritious components, it is reported to have diverse functions, including immunomodulation, antioxidant, antidepressant, antirheumatic, UV radiation protection, hepatoprotective, anti-fatigue, and neuroprotective effects. Interestingly, although the mechanism of the neuronal effect of maca is unclear, the uptake of maca extract improves learning and memory in memory-impaired model mice induced by either ethanol, ovariectomy, or scopolamine. However, the effects of maca on social memory impairment in neurodevelopmental disorders, including ASD, have not yet been tested.

In this study, the effects of maca on ASD animal models, in utero VPA-exposed mice, were investigated. The effect on social recognition by maca uptake with gavage was assessed using the social interaction test, a three-stage open field test, and the five-trail social recognition test. We also explored whether maca intake affects oxytocinergic signaling pathways, which play an important role in various social behaviors.

In this study, we showed that maca uptake rescues the deficits of social behavior and social recognition memory in VPA mice, a mouse model of autism. The c-Fos immunoreactivity of oxytocinergic neurons in SON and PVN increased significantly after maca treatment in VPA mice. Following previous studies indicating that OT administration ameliorates the impairment of social behavior in VPA mice, maca may also have improving effects on the deficit of social behavior and social recognition memory of VPA mice, probably by activating the OT neuronal pathway. Previous studies showed that maca could improve cognitive function in the mice model of impaired cognitive memory induced by either ovariectomy, ethanol, or scopolamine. Further studies are necessary to elucidate the potential link between maca and OT and to determine which components are involved in improving social recognition memory.

We have shown that maca improves the impairment of social memory and social behavioral deficits through oxytocinergic system modulation in this study. Although maca may not have an immediate effect on social behavioral deficits and takes days or weeks to demonstrate the effects, behavioral improvements, were visible regardless of the time of oral intake. The time between the very last oral intake of maca and the start of the social behavioral experiments in this study was more than 16 h. The duration of the maca’s effect on social behavioral deficits after the supplementation period is being investigated in our follow-up experiments. The possibility of the persistent effect of maca is very appealing, given that OT does not have a sustained effect due to its rapid metabolism, despite its immediate effects. Therefore, taking maca as a supplement while also receiving repeated OT treatment may have a synergistic, sustainable effect on improving social impairment in patients with ASD. Maca is already being used as a dietary supplement worldwide and has a high potential for practical applications.

 

This study showed for the first time that maca supplementation improves the impairment of social recognition memory in ASD model mice. We added the mechanism that social memory improvement may occur through the upregulation of oxytocinergic pathways. Maca highlights the possibility of treating social deficits sustainably in individuals with ASDs.

 

Low dose clonazepam

Professor Catterall was the brains behind low dose clonazepam for mice, I just translated it across to humans. It is one way to modify the E/I (excitatory/inhibitory) imbalance in autism.

I found that it gave a boost to cognition. Not as big as bumetanide, but worth having nonetheless.

I do not believe you have to be a bumetanide responder to respond well to low dose clonazepam.

Several people have written to me recently to say it works for their child.

Our reader Tanya is interested in the Maternal Immune Activation (MIA) trigger to autism. She highlighted a recent study showing how and why clonazepam can reverse autism in the MIA mouse model of autism. 

Clonazepam attenuates neurobehavioral abnormalities in offspring exposed to maternal immune activation by enhancing GABAergic neurotransmission

Ample evidence indicates that maternal immune activation (MIA) during gestation is linked to an increased risk for neurodevelopmental and psychiatric disorders, such as autism spectrum disorder (ASD), anxiety and depression, in offspring. However, the underlying mechanism for such a link remains largely elusive. Here, we performed RNA sequencing (RNA-seq) to examine the transcriptional profiles changes in mice in response to MIA and identified that the expression of Scn1a gene, encoding the pore-forming α-subunit of the brain voltage-gated sodium channel type-1 (Na_V1.1) primarily in fast-spiking inhibitory interneurons, was significantly decreased in the medial prefrontal cortex (mPFC) of juvenile offspring after MIA. Moreover, diminished excitatory drive onto interneurons causes reduction of spontaneous gamma-aminobutyric acid (GABA)ergic neurotransmission in the mPFC of MIA offspring, leading to hyperactivity in this brain region. Remarkably, treatment with low-dose benzodiazepines clonazepam, an agonist of GABA_A receptors, completely prevented the behavioral abnormalities, including stereotypies, social deficits, anxiety- and depression-like behavior, via increasing inhibitory neurotransmission as well as decreasing neural activity in the mPFC of MIA offspring. Our results demonstrate that decreased expression of Na_V1.1 in the mPFC leads to abnormalities in maternal inflammation-related behaviors and provides a potential therapeutic strategy for the abnormal behavioral phenotypes observed in the offspring exposed to MIA.

 

Pitt Hopkins – Clemastine and Sobetirome

Poor myelination is a feature of much autism and is a known problem in Pitt Hopkins syndrome.

I did cover a paper a while back where the Pitt Hopkins researchers showed that genes involved in myelination are down-regulated not only in Pitt Hopkins, but in several other popular models of autism.

From the multiple sclerosis (MS) research we have assembled a long list of therapies to improve different processes involved in myelination. Today we can add to that list sobetirome (and the related Sob-AM2). Sobetirome shares some of its effects with thyroid hormone (TH), it is a thyroid hormone receptor isoform beta-1 (THRβ-1) liver-selective analog.

Some people do use thyroid hormones to treat autism, and indeed US psychiatrists have long used T3 to treat depression.

The problem with giving T3 or T4 hormones is that it has body-wide effects and if you give too much the thyroid gland will just produce less.

One proposed mechanism I wrote about long ago is central hypothyroidism, that is a lack of the active T3 hormone just within the brain. One possible cause proposed was that oxidative stress reduces the enzyme D2 that is used to convert circulating prohormone T4 to T3. The result is that your blood test says your thyoid function is great, but in your brain you lack T3.

It looks like using sobetirome you can spice up myelination in the brain, without causing any negative effects to your thyroid gland.

Rather surprisingly, sobetirome is already sold as a supplement, but it is not cheap like Clemastine, the other drug used in the successful study below.

 

Promyelinating drugs promote functional recovery in an autism spectrum disorder mouse model of Pitt–Hopkins syndrome

Pitt–Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and myelination. In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt–Hopkins syndrome mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells and normalized oligodendrocyte density. In vivo, 2-week intraperitoneal administration of clemastine also normalized oligodendrocyte precursor cell and oligodendrocyte density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in the proportion of uncompacted myelin and an overall reduction in the g-ratio. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behaviour. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt–Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt–Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination.

 

Sobetirome  (also called GC-1)

Sobetirome is a thyroid hormone receptor isoform beta-1 (THRβ-1) liver-selective analog.

In humans, sobetirome lowers plasma LDL cholesterol and reduced plasma triglycerides, while its liver-selective activity helped avoid the side effects seen with many other thyromimetic agents.

 

Myelin repair stimulated by CNS-selective thyroid hormone action

Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.

 

Compound protects myelin, nerve fibers

 

Research could be important in treating, preventing progression of multiple sclerosis, other neurodegenerative diseases

A compound appears to protect nerve fibers and the fatty sheath, called myelin, that covers nerve cells in the brain and spinal cord. The new research in a mouse model advances earlier work to develop the compound - known as sobetirome - that has already showed promise in stimulating the repair of myelin.

Lead author Priya Chaudhary, M.D., assistant professor of neurology in the OHSU School of Medicine who is focused on developing therapies for neurodegenerative diseases, said that the technique is a common step in drug discovery.

"It is important to show the effectiveness of potential drugs in a model that is most commonly used for developing new therapies," Chaudhary said.

The researchers discovered that they were able to prevent damage to myelin and nerve fibers from occurring, by stimulating a protective response in the cells that make and maintain myelin. They also reduced the activity of migroglia, a type of inflammatory cell in the brain and spinal cord that's involved in causing damage in multiple sclerosis and other diseases.

"The effects are impressive and are at least in part consistent with a neuroprotective effect with particular inhibition of myelin and axon degeneration, and oligodendrocyte loss," the authors write.

The discovery, if proven in clinical trials involving people, could be especially useful for people who are diagnosed with multiple sclerosis early in the disease's progression.

"The drug could protect the nervous system from damage and reduce the severity of the disease," Bourdette said.

 

Does Lamotrigine have the potential to 'cure' Autism?

Recently headlines appeared like this one:-

Scientists 'CURE autism' in mice using $3 epilepsy drug

It referred to the use of the epilepsy drug Lamotrigine to treat a mouse model of autism, caused by reduced expression of the gene MYT1L.

What the tabloid journalists failed to notice was that there has already been a human trial of Lamotrigine in autism.  That trial was viewed as unsuccessful by the clinicians, although the parents did not agree.

There were many comments in the media from parents whose child already takes this drug for their epilepsy and they saw no reduction in autism. There were some who found it made autism worse.

 

MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention

 

Lamotrigine therapy for autistic disorder: a randomized, double-blind, placebo-controlled trial

In autism, glutamate may be increased or its receptors up-regulated as part of an excitotoxic process that damages neural networks and subsequently contributes to behavioral and cognitive deficits seen in the disorder. This was a double-blind, placebo-controlled, parallel group study of lamotrigine, an agent that modulates glutamate release. Twenty-eight children (27 boys) ages 3 to 11 years (M = 5.8) with a primary diagnosis of autistic disorder received either placebo or lamotrigine twice daily. In children on lamotrigine, the drug was titrated upward over 8 weeks to reach a mean maintenance dose of 5.0 mg/kg per day. This dose was then maintained for 4 weeks. Following maintenance evaluations, the drug was tapered down over 2 weeks. The trial ended with a 4-week drug-free period. Outcome measures included improvements in severity and behavioral features of autistic disorder (stereotypies, lethargy, irritability, hyperactivity, emotional reciprocity, sharing pleasures) and improvements in language and communication, socialization, and daily living skills noted after 12 weeks (the end of a 4-week maintenance phase). We did not find any significant differences in improvements between lamotrigine or placebo groups on the Autism Behavior Checklist, the Aberrant Behavior Checklist, the Vineland Adaptive Behavior scales, the PL-ADOS, or the CARS. Parent rating scales showed marked improvements, presumably due to expectations of benefits.

One reader of this blog who heard all about the news and was sceptical, since after all it is a mouse model. Her 8 year old non-verbal child was not happy taking the drug Keppra and was already scheduled to try Lamotrigine. 

“Within a week his teacher called to say he was saying his ABCs, the next week he was counting out loud, the following month he’s attempting to repeat words of interest and this week he’s spelling animals by memory, dolphin, duck, wolf, chicken, pig, etc.

We are 2 months in and at 50mg, our target dose is 100mg bid. Obviously with our success, I’ve been working with his doctor and will continue to.”

 

Conclusion

Even though every day new autism research is published, there is so much already in this blog that not much appearing is totally new to regular readers.

We saw several years ago that low dose clonazepam should be beneficial to some people with autism, in particular Dravet syndrome. Today we learnt a little more about why Nav1.1 might be disturbed beyond those with Dravet syndrome. In the maternal immune activation model it seems to be a winner. It seems to benefit many of those who have trialed it.

Treating myelination deficits has been well covered in this blog. In previous posts we saw how Pitt Hopkins syndrome researchers showed how myelination gene expression was disturbed in a wide range of autisms. Today we saw evidence to support such therapy and we discovered a new drug.

Oxytocin does help some people with autism, but not as much as you might expect. Today we learnt of a potential add on therapy, a supplement called Maca.

The idea that anti-epilepsy drugs might help some autism has been well covered. From low dose valproate to low dose phenytoin from Dr Philip Bird in Australia.

Treatment of Autism with low-dose Phenytoin, yet another AED

Recent research suggested that Lamotrigine should help some with autism and today you learned that it really does help in one case. The fact that a tiny study a few years ago suggested no responders just tells us that only a small subgroup are likely to benefit.

We already know that some people's autism is made worse by their epilepsy therapy. This is just what you would expect. Time to find a different epilepsy therapy.

My favorite new therapy, low dose mefenemic acid / ponstan has numerous effects. One reader without autism, but with an unusual visual dysfunction (visual snow syndrome) and a sound sensitivity problem contacted me a while to see if NKCC1 might be the root of his problem. I suggested he try Ponstan, which did actually work for him and is easy to buy where he lives. Now he sends me research into all its possible modes of action. One mode of action relates to a cause of intellectual disability (ID/MR). Is this a factor in why Ponstan seems to improve speech and cognition in some autism? I really don't mind why it works - I just got lucky again, that is how I look at it. The more I read the luckier I seem to get.

Doom Scrolling vs Taking Action - more Game Changers

 

Arnie (in the brown jacket) fixing a local pothole

Source: https://twitter.com/Schwarzenegger/status/1645886847342743552

  

Some actors can act and some cannot

I recently went to see Keanu Reeves in John Wick Chapter 4 with both of my sons. Big brother thought it was great, like a three-hour non-stop video game with Keanu Reeves laying waste to hundreds of villains. My view was that there was almost no dialogue. I have more dialogue with Monty, aged 19 with classic autism, than Reeves has in this film. It was rather like watching a film with Sylvester Stallone or indeed Arnold Schwarzenegger. For Monty I think the best part was probably the popcorn.

Big brother told me that Arnie can act, that is why he also made films like Kindergarten Cop.  That apparently is acting.

There is no doubt though that Arnie is a man of action, as well as being an action man.

I just got a link to him fixing a local pothole.  It is on his twitter feed. Not quite sure why I received it.

I forwarded the link to Monty’s Big Brother.

What does Dad have in common with Arnie?  We both go out and fix the pothole outside our house – the one that nobody wants to come and fix.

In our case I brought several bucket loads of steaming hot asphalt to fix the road. Arnie and his helpers used a few bags of cold repair asphalt – which looks a lot less bother.

When I went twice in search of asphalt, I explained to the road crews laying asphalt with a big machine that I just wanted a few bucket loads to repair an annoying hole in the road in front of our house. Both times the initial story was “you can’t do that ... you cannot fix the road yourself”. My approach, like Arnie’s, was “just watch me”.  The second time one of the road crew actually came to help.  Since then the whole road has been resurfaced, so my asphalting days are likely over.

 

Doom Scrolling

Even if you are not aware of the term "doom scrolling", if you have a smartphone you are probably already doing it.

 

Doom scrolling

The practice of obsessively checking online news for updates, especially on social media feeds, with the expectation that the news will be bad, such that the feeling of dread from this negative expectation fuels a compulsion to continue looking for updates in a self-perpetuating cycle.

 

It is similar to the echo chamber

In news media and social media, an echo chamber is an environment or ecosystem in which participants encounter beliefs that amplify or reinforce their pre-existing beliefs by communication and repetition inside a closed system and insulated from rebuttal.

 

These days many people have got hooked on reading about problems, rather than solving them. Severe autism being one such problem.

 

Taking action in Autism

I recently was contacted by a Dad who has been treating his child with autism for a few years.  He probably does not fix potholes like me and Arnie, but he does like to fix autism.  He is doing rather well.

He read my book and contacted me.  His very extensive investigation and trials resulted in his personalized therapy.  These were his game changers:-

 

SSRIs

Fluvoxamine         to treat OCD and improve cognition

(Luvox)

 

Antifungals

Fluconazole          The single most effective intervention. 

 (Diflucan)            It just lifted the fog.

Itraconazole 

          
Nystatin  

Antiviral

Valaciclovir (Valtrex)   

       

Antibiotics
Rifaximin               used extensively

 

Bumetanide             Improves cognition.

The antifungals and Rifaximin have the similar effect in terms of more situational awareness, “presence” and ability to interact.  Bumetanide improves cognition.

 

Vitamins

B1 (Sulbutiamine)   high doses (800mg) quickly solved the longstanding feeding problems like chewing and swallowing, the stubbornness (e.g. refusing to go through a door)

Another form of B1 has been covered in this blog. Benfotiamine was proposed by our reader Seth in 2016 and he wrote a guest post about it.

Benfotiamine for Autism

A researcher/clinician called Derek Lonsdale wrote about the potential to treat autism with vitamin B1. 

B6  high doses (> 150 mg a day) are essential to avoid explosive rages. 

Vitamin B6 with magnesium is an old autism therapy that was made popular by the late Bernie Rimland. Rimland founded and directed two advocacy groups: the Autism Society of America (ASA) and the Autism Research Institute. He was the force behind Defeat Autism Now! (DAN). 

Bupropion is transformative, but the effect unfortunately fades in 5 days. 

 The mechanism of action of bupropion in the treatment of depression and for other indications is unclear. However, it is thought to be related to the fact that bupropion is a norepinephrine–dopamine reuptake inhibitor (NDRI) and antagonist of several nicotinic acetylcholine receptors. It is uncertain whether bupropion is a norepinephrine–dopamine releasing agent. 

L type calcium channel blockers helped but Nimodipine caused side effects with gum inflammation; this is a well-known possible side effect.

 * * *

Fluconazole and Rifaximin are quite popular therapies in autism and certainly tell that something is amiss in the intestines.  In the US Rifaximin is very expensive and so you will see Vancomycin used.

In Singapore one of the US-trained MAPS (autism) doctors recently got in trouble prescribing Fluconazole/ Diflucan and Vancomycin to young children with autism. The kids' pediatricians heard what he was prescribing and complained to the medical regulator. 

 

Doctor ordered to temporarily stop prescribing antibiotics, antifungal medication to children after specialists complain

Dr Erwin Kay Aih Boon, a general practitioner in private practice at Healthwerkz Medical Centre, had prescribed antibiotic Vancomycin and antifungal medication Fluconazole – trade name Diflucan – to children with autism.

It comes after four paediatricians in a hospital, which was unnamed in the grounds, complained to the Singapore Medical Council (SMC) about Dr Kay’s management of children with autism.

They said his management of the children were “not based on evidence”, the grounds read.

“Hospital A’s paediatricians were of the view the use of antibiotics and antifungal agents for the treatment of children with (autism spectrum disorders) was unnecessary and had the potential for harm,” said the committee in its grounds.

 

Conclusion

It is rather addictive reading the news that appears on your phone.

Making your own news, even if you choose not to share it with the wider world, looks like a better option.

I was asked by one person who reviewed a draft of my book, why do I not include a collection of autism treatment case studies. I explained that most people who have been successful do not want to publicly share their results.  That is a pity, but it is human nature – why take an unnecessary risk? Even Dr Kay in Singapore gets himself into trouble, just trying to help other people.

In spite of there being no autism treatment gazette with hundreds of detailed case histories for parents to look through, there are nonetheless many clues in the published research.

The key point is that therapy needs to be personalized. Antifungals, antibiotics and antivirals might do wonders for one person, but do absolutely nothing for your child.    

The worst problem of all can be aggression and self-injurious behavior; vitamin B6 clearly works for some, but most people will need one of the numerous other therapies.

 

A virus as a trigger for some Cancer, most Multiple Sclerosis (MS) and perhaps some Autism

 

Mexico is the world's largest exporter of beer, and it's not just Corona

Not many years ago you would have been considered mad to suggest that a virus could trigger cancer, MS or some autism.

We now have a vaccine to prevent cancers triggered by the human papillomavirus (HPV). Young people aged 9 - 26 are offered this vaccine in many wealthy countries.

It is believed that the Epstein-Barr virus (EBV) contributes to about 1.5% of all cases of human cancer.

 

Epstein-Barr Virus and Cancer

 

EBV causes mononucleosis (IM, mono), also known as glandular fever. A commercial vaccine does not yet exist but is thought to be achievable.

Multiple sclerosis (MS) has long been thought to have a viral trigger. I have been reading about impaired myelination for 10 years and it takes a very long time for ideas to get confirmed.  In the case of MS it is again the Epstein-Barr virus. Almost all adults have been exposed to this virus and most people do not develop MS.  The science suggests that multiple events are needed to trigger MS, but that a required one is the presence of this virus.  That would suggest that if children were vaccinated against EBV, they could not go on to develop MS later in life.

 

Epstein-Barr virus may be leading cause of multiple sclerosis

 “The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality,” said Alberto Ascherio, professor of epidemiology and nutrition at Harvard Chan School and senior author of the study. “This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.”

 

Recall that MS is one of those diseases that is very much more prevalent in females than men.  It is the opposite of autism.

The science is moving on and now has got the point of explaining why EBV can cause cancer.  The actual biological pathways have been proposed.

 

Signaling pathways of EBV-induced oncogenesis

 

One of several examples is EBV-induced oncogenesis through the PI3K/AKT signaling pathway.

 

 

EBV-induced oncogenesis through the PI3K/AKT signaling pathway. LMP1 and LMP2A promote angiogenesis through the PI3K/AKT/HIF-1α/CCL5 signaling axis and the PI3K/AKT/mTOR/HIF-1α signaling axis, respectively. LMP1 inhibits PTEN through miRNA-21 and enhances the PI3K/AKT signaling pathway to promote the formation and proliferation of CSCs. EBV-miRNA-BART7-3P can also promote the high expression of β-catenin by inhibiting PTEN, leading to EMT

 

Regular readers may notice overlaps with what we have seen in autism. The same pathway can lead to autism.

Here is a recent autism paper on this same pathway.

Targeting PI3K-AKT/mTOR signaling in the prevention of autism

 The role of viruses in autism

Now we have established that medicine accepts that a virus can play a role in triggering cancer and that science points a finger at a virus being a trigger for MS, it is not so crazy to think about the role viruses might play in some autism. 

 

The easy part – Maternal Immune Activation (MIA)

We have clear evidence that if a pregnant mother’s immune system is activated during pregnancy the incidence of autism rises.  In this case it is the immune response that causes the problem, rather than the specific virus.

 

Virus specific

One very damaging virus, spread by mosquitos, is Zika. If a mother is infected  during pregnancy it may lead to microcephaly (small head), brain damage and joint/muscle malformation in her child.

 

Endogenous retroviruses

It has been suggested in the research for many years that endogenous retroviruses play a role in autism.

Human endogenous retroviruses (HERVs) are DNA sequences within human chromosomes; they comprise 1 to 8% of the human genome.  HERVs represent footprints of previous retroviral infection and have been termed “fossil viruses”.

 

Demystified . . . Human endogenous retroviruses

Human endogenous retroviruses (HERVs) are a family of viruses within our genome with similarities to present day exogenous retroviruses. HERVs have been inherited by successive generations and it is possible that some have conferred biological benefits. However, several HERVs have been implicated in certain cancers and autoimmune diseases. This article demystifies these retroviruses by providing an insight into HERVs, their means of classification, and a synopsis of HERVs implicated in cancer and autoimmunity. Furthermore, the biological roles of HERVs are explored.

Take home messages

o   Human endogenous retroviruses (HERVs) make up part of our genome and represent footprints of previous retroviral infection

o   HERVs possess a similar genomic organisation (gag–pol–env) to present day exogenous retroviruses but are not infectious

o   The HERV-K superfamily represents one of the most active HERVs and is capable of producing retroviral particles

o   HERVs may be of benefit to the host but could also be harmful, and may be involved in certain autoimmune diseases and cancers

 

I came across this article recently: 

Could an Ancient Virus Be a Genetic Driver of Autism?

Genome and transcriptome analysis revealed BTBR autism mouse models have increased levels of endogenous retrovirus genes. BTBR/R models of ASD showed differences in the expression of a variety of genes that are indicative of endogenous retrovirus activation. BTBR/R mice exhibit autistic-like behaviors without reduced learning abilities. 

Overall, the study revealed that retrovirus activation causes the copy number variants in BTBR mice to increase, which leads to the differences in behavior and brain structure seen in BTBR/J and BTBR/R mice. 

Further Developments 

BTBR/J mice are widely used by researchers as a mouse model of autism. However, the results of this study highlight the usefulness of the other lineage of BTBR/R mice because they exhibit autistic-like behavior without compromised spatial learning ability. The results also suggest that it may be possible to develop new treatments for autism that suppress ERV activation. 

Furthermore, it is necessary to classify autism subtypes according to their onset mechanism, which is a vital first step towards opening up new avenues of treatment for autism.

 

Here is the full paper, which comes from the RIKEN Brain Science Institute in Japan, which has been mentioned in a previous post.

 

An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development

The BTBR T+Itpr3tf/J (BTBR/J) strain is one of the most valid models of idiopathic autism, serving as a potent forward genetics tool to dissect the complexity of autism. We found that a sister strain with an intact corpus callosum, BTBR TF/ArtRbrc (BTBR/R), showed more prominent autism core symptoms but moderate ultrasonic communication/normal hippocampus-dependent memory, which may mimic autism in the high functioning spectrum. Intriguingly, disturbed epigenetic silencing mechanism leads to hyperactive endogenous retrovirus (ERV), a mobile genetic element of ancient retroviral infection, which increases de novo copy number variation (CNV) formation in the two BTBR strains. This feature makes the BTBR strain a still evolving multiple-loci model toward higher ASD susceptibility. Furthermore, active ERV, analogous to virus infection, evades the integrated stress response (ISR) of host defense and hijacks the transcriptional machinery during embryonic development in the BTBR strains. These results suggest dual roles of ERV in the pathogenesis of ASD, driving host genome evolution at a long-term scale and managing cellular pathways in response to viral infection, which has immediate effects on embryonic development. The wild-type Draxin expression in BTBR/R also makes this substrain a more precise model to investigate the core etiology of autism without the interference of impaired forebrain bundles as in BTBR/J.

 

Hyper-activation of ancient retroviral infection accelerates host genome evolution toward ASD susceptibility by increasing the chance of CNV formation. The accumulated genetic variations lead to the divergence of autistic-like behaviors in both BTBR strains. Active ERV also recapitulates the viral infection process of ISR pathway invasion and IRES-mediated translation, which changes the global transcriptome during embryonic development in BTBR mice. BTBR/R has severer core symptoms of autism and wildtype Draxin expression, which suggests BTBR/R is a valid autism model with unaffected forebrain bundles.

 

There have been previous studies looking into ERVs and autism.

 

Children With Autism Spectrum Disorder and Their Mothers Share Abnormal Expression of Selected Endogenous Retroviruses Families and Cytokines

 

Human Endogenous Retroviruses in Autism Spectrum Disorders: Recent Advances and New Perspectives at the Gene-Environment Interface

Human endogenous retroviruses (HERVs) are genetic elements, derived from their exogenous retroviral counterpart by a process of germline infection and proliferation within the human genome, and their integration as proviruses led to the fixation and the vertical transmission, following Mendelian laws. HERVs currently make up ~8% of the genetic material, and some of them have been cooped for physiological functions. Otherwise, their activation in response to environmental factors has been associated with human pathological conditions. In the setting of neurodevelopmental disorders, HERVs have been proposed as contributing factors involved in Autism Spectrum Disorders (ASD), spanning the bridge between genetic susceptibility, environmental risk factors and immune response. We described a distinct expression profile of some HERV families and cytokines in lymphocytes from autistic children and in their mothers suggesting a close mother-child association in ASD. Moreover, in vitro treatment with an antiretroviral drug was able to restore the expression level of HERVs and cytokines providing new insights into the potential role of HERVs as biomarkers of ASD and raising the possibility of using HERVs expression as a therapeutic target for a tailored approach to patient care.

  

Conclusion 

We know that some cancer is preventable via a vaccine blocking the progress of a virus, hopefully more types of cancer will be prevented in future.

Some of the suggested modes of action for the Epstein-Barr virus (EBV) to cause cancer do involve pathways that are very relevant to autism.

It appears that an effective EBV vaccine might protect women (and some men) from developing multiple sclerosis (MS).  Will it also have the effect of reducing their chance of giving birth to a child with autism?  Time will tell.

Any kind of illness, viral or other, may trigger an exaggerated immune response during pregnancy and increase the incidence of autism.  This is the basis of one of the common animal models of autism, called Maternal Immune Activation (MIA).

The human endogenous retroviruses  (ERVs) accumulated as junk in our DNA do appear to be able to affect gene expression leading to cancer, autoimmune disease and indeed some autism.

The Japanese researchers from RIKEN suggest that it may be possible to develop new treatments for autism that suppress ERV activation.

One logical question is whether viruses are relevant just to causing autism or its ongoing level of severity.

In the case of cancer and MS it looks like the virus is primarily involved in triggering the disease.  Once the process has started, the benefit from suppressing the virus may have passed. 

Can existing antiviral drugs treat some autism?  Antiviral drugs work just for specific viruses and they just suppress them, rather than eliminating them.

The antiviral drug Valtrex has long been used by some doctors to treat autism in the US. Just Google it and you will find enthusiasts like parent Jenny McCarthy -- “when we started him on Valtrex, speech started pouring out of him”.  There have been no clinical trials.

This is an area where more research genuinely is needed. Hopefully the RIKEN Brain Science Institute will translate their ERV findings into approved therapies.  That is what is supposed to happen, but usually does not when it comes to autism.

Autism is nowadays such a broadly defined diagnosis, just about anything might have caused it. Autistic behaviors have been caused by a bacterium, a fungus/mold and very possibly a virus.  If only it was as straightforward as understanding and treating MS.