A Deep Dive into Closely Interacting Genes/Proteins that Account for Numerous Autism/Epilepsy Syndromes – (all Calcium or Sodium ion channels)

Even I thought this post was rather a long slog, but I kept finding more and more evidence to support the basic premise, so I covered all the genes that came up for completeness.

I have been going on about the relevance of calcium channels in autism for years. I have also pointed out that while you can have severe autism for a single mutated gene, you can also “just” have a miss-expression of that same gene, without any error in the code in your DNA. You can have a little bit of that severe autism phenotype.  You can even have the opposite dysfunction, which would usually be over-expression of that gene. 

Once you have miss-expression of a gene it will cause a cascade of other effects.

This means that while you may not be able to correct the initial genetic dysfunction, you may well be able to treat what comes further down the cascade.

I like to look for associations, so I skip quickly through the research papers, but take note when I see links to things like:- 

·        Epilepsy / seizures

·        Headaches, particularly episodic

·        Mental retardation / intellectual disability

·        Mathematical ability

·        High educational attainment

·        Big Heads

·        Epilepsy / seizures

·        Pain threshold

·        Speech development (or lack thereof)

·        Sleep disturbance

·        IBD (Inflammatory Bowel Disease)

It is very easy to look up the significance of any gene.

Open the site below and just type in the name of the gene.

https://www.genecards.org/

Today’s post does touch on complex subjects, but you can happily read it on a superficial level and get the key insights.

You have about 20,000 genes in your DNA and each gene encodes a protein.  That protein could be something important like an ion channel or a transcription factor.  Today we are mainly looking at ion channels, the plumbing of the brain.

These 20,000 genes/proteins interact with each other and clever people called Bioinformaticians collect and map this data.  These maps can then show you the cascade of events that might happen if one gene/protein is miss-expressed, perhaps due to a mutation.

Today I start with 2 genes CACNB1 and CACNA1C.

CACNB1 was only recently identified as an autism gene

Genome-wide detection of tandem DNA repeats that are expanded in autism

CACNA1C is the gene that encode the calcium ion channel Cav1.2.  It is the gene behind Timothy Syndrome and the gene that I followed to Verapamil, a key part of my son’s PolyPill therapy.

The reason the gene/protein interactions are important is that the same therapy can be applied to different dysfunctional genes/proteins. A person with a genetic defect in a sodium ion channel might get a therapeutic benefit from a drug targeting a calcium ion channel.

 

The top 5 interactions with CACNA1C (in red):

 Note CACNB1 (in blue) 

There is already  lot in this blog about the calcium channel Cav1.2 (encodeded by CACNA1C).

CACNA1C is associated with Autism, schizophrenia, anorexia nervosa, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), Tourette syndrome, unipolar depression and bipolar disorder. 

Today we look at the “new” autism gene CACNB1. 

It is actually much more interesting that you might imagine, especially if you have to deal with epilepsy or periodic headaches at home.  You also might also have some Math Whizz back there in your family tree.

We know that brainy people, particularly mathematicians, have elevated risk of autism in their family.  Having a maths protégé in the family may not be good for your kids.

We also know that bright mathematicians are very likely to have some feature’s of Asperger’s.

The chart below expresses the top 25 interactions with the gene CACNB1 which encodes voltage-dependent L-type calcium channel subunit beta-1. It is the pink circle in the middle.

Click on the link for a higher resolution image, or on the image itself.

https://version11.string-db.org/cgi/network.pl?taskId=KBcDrcBSd4X6

 

If you look at the above chart you can spot the genes that relate to calcium channels, they start with CAC.

At the top of the chart we 6 genes starting with SCN. These genes relate to sodium ion channels.

 

SCN9A

It was interesting to me that the gene SCN9A, which encodes the ion channel Na_v1.7 is associated with insensitivity to pain.  Reduced sensitivity to pain is very common in autism.  This is a feature of Monty’s autism.

A mutation in SCN9A can also cause epilepsy. Often these seizures are fever associated.

Local anesthetics such as lidocaine, but also the anticonvulsant phenytoin, mediate their analgesic effects by non-selectively blocking voltage-gated sodium channels. Na_v1.7.

Other sodium channels involved in pain signalling are Na_v1.3, Na_v1.8, and Na_v1.9.

You would think that SCN9A would encode Nav1.9, but it seems to really be Nav1.7.  Nav1.9 is encoded by the gene SCN11A, just to see who is paying attention.

 

SCN8A

The SCN8A gene encodes the sodium ion channel Nav1.6. It is the primary voltage-gated sodium channel at the nodes of Ranvier. 

The channels are highly concentrated in sensory and motor axons in the peripheral nervous system and cluster at the nodes in the central nervous system.

If you have a mutation is in SCN8A you may face Cute syndrome.  You will have some severe challenges including treatment resistant epilepsy and may include autism and intellectual disability.

 https://www.thecutesyndrome.com/about-scn8a.html

Not such a cute syndrome.

 

SCN4A

The Na_v1.4 voltage-gated sodium channel is encoded by the SCN4A gene. Mutations in the gene are associated with hypokalemic periodic paralysis, hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia.

I have covered hypokalemic periodic paralysis and hypokalemic sensory overload previously in this blog.  I showed that I could reduce Monty’s sensitivity to the sound of a baby crying by giving a modest potassium supplement. 

Mutations in SCN4A are also associated with abnormal height and abnormalities of the head, mouth or neck.

 

SCN3A

The Na_v1.3 voltage-gated sodium channel is encoded by the SCN3A gene

It has recently been shown that speech development is affected by this ion channel.  Many people with severe autism never fully develop speech.

  

Sodium channel SCN3A (Na_V1.3) regulation of human cerebral cortical folding and oral motor development

Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel Na_V1.3. Pathogenic Na_V1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (Na_V1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.

 

 SCN2A

The Na_v1.2 sodium ion channel is encoded by the SCN2A gene.

Mutations in this gene have been implicated in cases of autism, infantile spasms bitemporal glucose hypometabolism, and bipolar disorder and epilepsy.

  

SCN1A

 The Na_v1.1 sodium ion channel is encoded by the SCN1A gene.

Mutations to the SCN1A gene most often results in different forms of seizure disorders, the most common forms of seizure disorders are Dravet Syndrome (DS), Intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), and severe myoclonic epilepsy borderline (SMEB).

Mutations are also associate with

·        Febrile seizures up to 6 years of age

·        MMR-related febrile seizures

·        Sleep duration

·        Educational attainment

 

 

Now the Calcium ion channels:-

CACNB1

The gene CACNB1 encodes the Voltage-dependent L-type calcium channel subunit beta-1.

CACNB1 regulates the activity of L-type calcium channels that contain CACNA1A, CACNA1C or CACNA1B.  Required for functional expression L-type calcium channels that contain CACNA1D.

The gene is associated with headaches, asthma, mathematical ability and acute myeloid leukemia

CACNB2

The gene CACNB2 encodes the Voltage-dependent L-type calcium channel subunit beta-2.

Mutation in the CACNB2 gene are associated with Brugada syndrome, autism, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia.

 

CACNB3

The gene CACNB3 encodes the Voltage-dependent L-type calcium channel subunit beta-3.

Diseases associated with CACNB3 include Headache and Lambert-Eaton Myasthenic Syndrome.

Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs.

CACNA1A

The Ca_v2.1 P/Q voltage-dependent calcium channel is encoded by the CACNA1A gene.

Mutations in this gene are associated with multiple neurologic disorders, many of which are episodic, such as familial hemiplegic migraine, movement disorders such as episodic ataxia, and epilepsy with multiple seizure types.

 

CACNA1B

The voltage-dependent N-type calcium channel subunit alpha-1B is encoded by the CACNA1B gene. Diseases associated with CACNA1B include Neurodevelopmental Disorder With Seizures And Nonepileptic Hyperkinetic Movements and Undetermined Early-Onset Epileptic Encephalopathy.

 

CACNA1C (covered earlier in this blog)

The CACNA1C gene encodes the calcium channel Ca_v1.2.   Ca_v1.2 is a subunit of the L-type voltage-dependent calcium channel.

 

CACNA1S

The CACNA1S gene encodes Ca_v1.1 also known as the calcium channel, voltage-dependent, L type, alpha 1S subunit.

This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility.

Mutations are associated with inflammatory bowel disease (IBD) and ulcerative colitis.

Note that Rezular or R-Verapamil was a drug developed to treat IBD.

 

CACNA1D

The CACNA1D gene encodes Ca_v1.3.

Ca_v1.3 is required for proper hearing.

Some mutations in CACNA1D) cause excessive aldosterone production in aldosterone-producing adenomas (APA) resulting in primary aldosteronism, which causes treatment - resistant arterial hypertension. These mutations allow increased Ca²⁺ influx through Cav1.3, which in turn triggers Ca²⁺ - dependent aldosterone production. The number of validated APA mutations is constantly growing. In rare cases, APA mutations have also been found as germline mutations in individuals with neurodevelopmental disorders of different severity, including autism spectrum disorder.

Recent evidence suggests that L-type Ca_v1.3 Ca²⁺ channels contribute to the death of dopaminergic neurones in patients with Parkinson's disease

Inhibition of L-type channels, in particular Ca_v1.3 is protective against the pathogenesis of Parkinson's in some animal models

CACNA1D is highly expressed in prostate cancers compared with benign prostate tissues. Blocking L-type channels or knocking down gene expression of CACNA1D significantly suppressed cell-growth in prostate cancer cells

 

CACNA1E

CACNA1E encodes the calcium channel Cav_2.3 , also known as the calcium channel, voltage-dependent, R type, alpha 1E subunit.

These channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death.

Mutations are associated with epilepsy, acute myeloid leukemia, mathematical ability and having a big head.

 

CACNA1F

The gene CACNA1F encodes Ca_v1.4.

Mutations in this gene can cause X-linked eye disorders, including congenital stationary night blindness type 2A, cone-rod dystropy, and Aland Island eye disease

Mutations are associated with astigmatism and other eye conditions.

 

CACNA2D1

The CACNA2D1 gene encodes the voltage-dependent calcium channel subunit alpha-2/delta-1.

Alpha2/delta proteins are believed to be the molecular target of the gabapentinoids gabapentin and pregabalin, which are used to treat epilepsy and neuropathic pain. 

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

CACNA2D2

The CACNA2D2 gene encodes the voltage-dependent calcium channel subunit alpha2delta-2 is a protein that in humans is encoded by.

The Calcium Channel Subunit Alpha2delta2 Suppresses Axon Regeneration in the Adult CNS

CACNA2D3

The CACNA2D3 gene encodes the Calcium channel alpha2/delta subunit 3.

Cacna2d3 has been associated with CNS disorders including autism.

Synaptic, transcriptional and chromatin genes disrupted in autism

CACNA2D4

Calcium channel, voltage-dependent, alpha 2/delta subunit 4 is a protein that is encoded by the CACNA2D4 gene.

Mutations in CACNA2D4 are associated with mathematical ability and educational attainment.

 

CACHD1

CACHD1 (Cache Domain Containing 1) is not well researched, it may regulate voltage-dependent calcium channels.  It is moderately associated with anxiety.

 

CACNG1

The CACNG1 gene encodes the Voltage-dependent calcium channel gamma-1 subunit

Diseases associated with CACNG1 include hypokalemic periodic paralysis, type 1 and Malignant Hyperthermia.

 

REM1

The protein encoded by this gene is a GTPase and member of the RAS-like GTP-binding protein family. The encoded protein is expressed in endothelial cells, where it promotes reorganization of the actin cytoskeleton and morphological changes in the cells.

Recall my posts about RASopathies and MR/ID.

Diseases associated with REM1 include Mental Retardation and late onset Parkinson’s disease.

 

NALCN

NALCN (Sodium Leak Channel, Non-Selective) gene encodes a voltage-independent, nonselective cation channel which belongs to a family of voltage-gated sodium and calcium channels that regulates the resting membrane potential and excitability of neurons.

It is highly associated with an abnormality in the process of focusing of light by the eye in order to produce a sharp image on the retina.

It is associated with mental or behavioral disorders and unusual body height.

 

GEM

GEM encodes a protein that belongs to the RAD/GEM family of GTP-binding proteins.

It is associated with heart disease.

 

Conclusion

I was really surprised just how many autism/epilepsy genes are so closely related to the newly recognised autism gene CACNB1.

I hope you can see that a child without a mutation in CACNB1 can be affected by several of today's genes.  What matters is differentially expressed genes (DEGS).

In my simplification of autism, I have a category called channelopathies and differentially expressed genes (DEGS).  I did add the DEG part a while back, but this chart has stood the test of time.

I think many people with severe autism are affected by the genes in today’s post.

Headaches and epilepsy are an integral part of autism and better not considered as comorbidities. The same is true with big/small heads and indeed high/low IQ.

 

If you do invest in genetic testing, you would be well advised to look up any affected genes yourself. From what I have seen, do not rely on your DAN Doctor to do this thoroughly.

Is the Door about to Close on Alternative Medical Treatments for Autism in France? Plus, more on Dravet Syndrome and RIP Charlotte Figi

 

I was talking to the organizers of an autism conference in the US and one question that came up was, do I know a clinician who prescribes potassium bromide (KBr).

It is a question that illustrates the problem in treating autism. In Germany, Austria and some neighbouring countries KBr is an established treatment for pediatric epilepsy and particularly some specific conditions like Dravet sydrome. Dravet syndrome is a rare, catastrophic, lifelong form of epilepsy which begins in the first year of life.  It is one of those conditions where parents in the UK are begging to use cannabis. Dravet syndrome may be accompanied by an autism diagnosis.  In the US KBr is currently only used for canine epilepsy.

Regular readers of this blog may recall that Dravet syndrome responds to potassium bromide (KBr) and should respond to low dose clonazepam (it works in the mouse model).

I proposed KBr as an autism therapy and even found an “autism” case history from 150 years ago. KBr was the only effective therapy for epilepsy back then, so a child with epilepsy and severe autism might be lucky and get KBr prescribed, as in the case history I highlighted.  It worked well for that little girl and she developed the ability to play appropriately with a doll - that is what caught my attention.

Is KBr a widely used autism therapy in Europe?  Definitely not.  Only a handful of people use it for autism, but it is an approved safe therapy for pediatric epilepsy.

KBr will have a similar effect on GABA as bumetanide, but via a different mechanism, (some Cl^- gets replaced by Br^- inside neurons, this lowers the Cl^- concentration and so changes the effect of GABA).

The drawback with KBr is bromo-acne, or spots.  I suppose if your child has Dravet Syndrome, or very severe autism, you will not be bothered by some spots. 

150 years ago they used a potion containing arsenic to treat the spots, this was a very bad idea. Arsenic is poisonous.

Charlotte Figi, who was the inspiration for the popular medical cannabis strain called Charlotte's Web, had Dravet syndrome. She died this year, aged 13. 

I am told that you actually need some THC, rather than just CBD (cannabidiol), to be effective, but over time Charlotte’s commercial product contained less THC and I am told lost its effect.

Stiripentol, a positive allosteric modulator of GABA_A receptors, is an approved therapy to treat Dravet Syndrome. 

Dravet syndrome is usually caused by the ion channel Na_v1.1

You might wonder why does a sodium ion channel cause a defect in GABA signalling.

 

Delayed maturation of GABAergic signaling in the Scn1a and Scn1b mouse models of Dravet Syndrome

We found that GABAergic signaling remains immature in both DS models, with a depolarized reversal potential for GABA_A-evoked currents compared to wildtype in the third postnatal week. Treatment of Scn1b^−/− mice with bumetanide resulted in a delay in SUDEP onset compared to controls in a subset of mice, without prevention of seizure activity or amelioration of failure to thrive. We propose that delayed maturation of GABAergic signaling may contribute to epileptogenesis in SCN1B- and SCN1A-linked DS. Thus, targeting the polarity of GABAergic signaling in brain may be an effective therapeutic strategy to reduce SUDEP risk in DS.

 

SUDEP is Sudden Unexpected Death in Epilepsy and this is what is likely to occur in about 1 in 5 children with Dravet Syndrome. These deaths would appear to be, to some extent, preventable if you read the science and apply it.

This takes me to France where well-intentioned Autism Moms/Mamans are seeking to rein in 50 French doctors thought to be prescribing autism therapies off-label to 5,000 children.

Are these crazy therapies? or beneficial therapies? or perhaps a mixture of both?  For sure they are unorthodox therapies.

Olivia Cattan thinks French Moms/Mamans should be using behavioral methods (ABA, TEACCH etc) because they worked well for her young son.  Her charity, SOS Autisme, is trying to stop French doctors treating other people’s children with autism. 

The same thing happened a few years ago in the UK. A lone UK doctor was prescribing drugs to children with autism, word spread and other doctors reported him the medical regulator, who banned him from seeing patients with autism.

The US is the Wild West by comparison – anything goes.  A doctor can tweet "vaccines DO cause autism" and there are no consequences. Today, governments around the world are buying up future Covid-19 vaccines for their citizens and one factor in agreeing the price is whether the government indemnifies the producer for legal claims due to vaccine side effects. Rare side effects are possible even with a "good" vaccine.

I did ask Dr Frye about MAPS doctors getting into trouble with the authorities.  He told me the big issue is the occasional divorced spouse who objects to a child’s therapy.

France probes doctors prescribing antibiotics for autism

French prosecutors said Thursday that they had opened an inquiry into dozens of doctors prescribing antibiotics and other drugs as a purported treatment for autism in children, potentially endangering their health.

French prosecutors said Thursday that they had opened an inquiry into dozens of doctors prescribing antibiotics and other drugs as a purported treatment for autism in children, potentially endangering their health. The investigation comes after an alert by France's ANSM medicines watchdog that doctors were prescribing long-term courses of antibiotics and drugs against metal poisoning to autistic children. According to Olivia Cattan, who heads the help group SOS Autisme and has written a book on the practice, some 50 doctors in France are thought to be treating up to 5,000 children this way. Such prescriptions have been linked to controversial ideas from Nobel Medicine Prize laureate Luc Montagnier, honored in 2008 for his co-discovery of the virus that causes AIDS, but frequently dismissed by the medical community for his unconventional ideas in recent years.

The Paris prosecutor's office said its public health department has been entrusted with the probe into charges of "endangering the lives of others" and "offences related to research involving human beings." On Tuesday, the ANSM said it had referred the matter, flagged by Cattan, to prosecutors after collecting evidence including parents' testimony and prescription sheets. The watchdog said the children were prescribed antibiotics, anti-fungal, anti-parasitic or anti-viral drugs, as well as treatments for heavy metal ingestion that are normally reserved for use in case of poisoning. The ANSM "formally advises against these uses, for which these drugs have not shown to be effective and which put these children at risk, particularly with prolonged use." Effects can include digestive, cardiovascular and skin disorders, while misuse of antibiotics can lead to drug resistance that undermines the effectiveness of future treatments. The ANSM has also alerted French doctors' and pharmacists' associations. 

According to SOS Autisme:-

L’autisme n’est pas une déficience mentale, ce n’est pas une maladie, ce n’est pas une fatalité, et cela peut toucher tout le monde.

Aujourd’hui, grâce aux méthodes cognitives (ABA, Teach, Feuerstein, Pecs…). tous nos enfants peuvent progresser et devenir des êtres autonomes, des citoyens qui fondent une famille et qui travaillent.

 

Autism is not a mental disability, it is not a disease, it is not a destiny, and it can affect anyone.

Today, thanks to cognitive methods (ABA, TEACCH, Feuerstein, PECS ...). all our children can progress and become independent, people who start a family and who work.

 

The highlighted part in yellow would be great if this was true, but it is not.  Tell that to the Paris Prosecutor.

All these behavioral therapies can help, but go and look at autistic people born in the 1990s in the US, who had rich parents and who used ABA, TEACCH, PECS etc, for two decades.

Are they all now independent people who started a family and who hold down a meaningful job?  No.

Sadly, they are either still living at home with Mom and Dad, or they got packed off to live in a group home, or some other sheltered living accommodation. Life expectancy is short and parents are likely to outlive their child.

If you want to know autism reality to adulthood, go and talk to old hands with no vested interest like Catherine Lord, Bryna Siegel or even Manuel Casanova. 

 

Conclusion

There are many obstacles to treating and educating a child with severe autism and this is clearly reflected in the outcome in adulthood.  

Where you live can matter much more than how much money you have.

Yes, there are some crazy sounding autism therapies.

Yes, there are some people seeking to make a lot of money out of gullible parents.

Yes, there are labs overcharging for "special" diagnostic tests.

But, that is not the complete picture.

There are also some therapies that might look bizarre to a lay person, but if you read the science, they are very well founded.  They are experimental therapies.

The risks of not treating severe autism are huge; death due to seizures, drowning and accidents are very common and according to the Karolinska Institute such people have a life expectancy of under 40 years.   Too many continue to die in childhood. 

I am no fan of DAN doctors, but it looks like only one death has ever been associated with their treatment.  In 2005 a British boy was given intravenous chelation in a clinic near Pittsburgh; he went into cardiac arrest and died.

The French lady behind SOS Autisme is a big fan of ABA and I hope her son is fully functional when he reaches adulthood. Most children with severe autism become adults with severe autism, regardless of how much ABA therapy they receive, they are just more functional. Their life has no fairy tale ending.

For a transformative effect on outcome, you have to address the biological problems.  By all means, combine this with whatever educational therapy works for the child.   I am also a fan of ABA, but a realistic one; I continue to see its benefits. But, no amount of ABA could teach my son even basic mathematics, I know, I tried it to the age of 9.  Now he can do algebra and solve equations, sometimes better than his NT classmates. I am delighted to contradict SOS Autisme - autism is a mental disability and it is a disease, but it is treatable. 

Personalized therapy / precision medicine does not lend itself to clinical trials with thousands of participants, by definition you are treating a rare combination of dysfunctions. 

The important thing is that personalized therapy must be both safe and effective.

No progress without some ruffled feathers.

 

 

 

Betahistine is in the Pipeline for ADHD, but will it help Autism? Maybe for some, but not for others

 Will Betahistine provide a benefit?

Today’s post is the logical follow on from the post showing that the new drug compound E-100 gives a benefit in two models of autism.

Another Potential Autism Therapy - novel compound E100 from Krakow, a combined histamine H3 receptor blocker (H3R antagonist) and an acetylcholine esterase inhibitor (AChEI)

We saw that E-100 has two modes of action, thought to be complementary:-

·        Acetylcholinesterase inhibitor (AChEI)

·        Histamine H3 antagonists (H3R antagonist)

I think our reader Rene is thinking along the lines I suggested that you might achieve the same effects with existing generic drugs.  One combination would be Donepezil plus Betahistine.

Donepezil has long been studied in autism, a recent example is here:

Improvement of Language in Children with Autism with Combined Donepezil and Choline Treatment

The safety and efficacy of a novel combination treatment of AChE inhibitors and choline supplement was initiated and evaluated in children and adolescents with autism spectrum disorder (ASD). Safety and efficacy were evaluated on 60 children and adolescents with ASD during a 9-month randomized, double-blind, placebo-controlled trial comprising 12 weeks of treatment preceded by baseline evaluation, and followed by 6 months of washout, with subsequent follow-up evaluations. The primary exploratory measure was language, and secondary measures included core autism symptoms, sleep and behavior. Significant improvement was found in receptive language skills 6 months after the end of treatment as compared to placebo. The percentage of gastrointestinal disturbance reported as a side effect during treatment was higher in the treatment group as compared to placebo. The treatment effect was enhanced in the younger subgroup (younger than 10 years), occurred already at the end of the treatment phase, and was sustained at 6 months post treatment. No significant side effects were found in the younger subgroup. In the adolescent subgroup, no significant improvement was found, and irritability was reported statistically more often in the adolescent subgroup as compared to placebo. Combined treatment of donepezil hydrochloride with choline supplement demonstrates a sustainable effect on receptive language skills in children with ASD for 6 months after treatment, with a more significant effect in those under the age of 10 years.

I was not aware that a lot of money is being spent preparing to bring Betahistine to the US as a treatment for ADHD (Attention Deficit Hyperactivity Disorder).

Outside the US, Betahistine is cheap generic drug that is widely available.  It is used in adults for vertigo and tinnitus etc.  It is not approved for use in children, but that just means its use was never studied in children.  It was envisaged as a drug for older people.

In the US, Betahistine is not an approved drug, so if the promoter gets it approved for ADHD they will not have any cheap competition.  They might even make it in the form of nasal spray, which they say makes Betahistine much more bioavailable.  It would also make it look like a modern drug, rather than just an old drug sold for a high price.

48 mg Oral dose vs varying intranasal doses

Source: https://ir.aurismedical.com/static-files/093ed1ec-9744-4144-92d3-7f6faca3a18a

The promoter’s idea is to use a lower dose of Betahistine intranasally and yet be more potent/effective than the oral tablet now used to treat vertigo.  They also want to use it to treat antipsychotic-induced weight gain, which seems to be a huge problem and a $600 million a year market they suggest.  It appears after this they want to use Betahistine to treat ADHD and depression.

Life on an anti-psychotic, without Betahistine

Betahistine might start as a drug for young adults with ADHD, but ADHD is normally seen as a childhood disorder (something like 7% of US school children have taken ADHD drugs) the promoter will have to carry out studies to show it is safe for pediatric use.  They are actually trialing quite high doses orally for ADHD.

Betahistine in autism, without ADHD

I am not sure that Betahistine, or E-100, is going to have a good overall effect in autism in humans.  E-100 does look good in two mouse models of autism.

Acting via the histamine H3 receptor, Betahistine will increase the levels of neurotransmitters histamine, acetylcholine, norepinephrine, serotonin, and GABA.  In any specific case of idiopathic autism, some of these effects may be beneficial, but quite possibly not all.

If you have GABA still working in reverse, as in some Bumetanide-responsive autism, increasing the level of GABA will cause agitation and aggression, just like taking Valium does.

The active metabolite of Betahistine is something called 2-PAA and the level peaks in your blood about an hour after taking the pill. There certainly is potential for a negative reaction, but it would fade gradually over the next few hours.  The half-life is 3.5 hours.

In the ADHD trials of Betahistine agitation was listed as a possible side effect. The promoter does say that overall the drug is very well tolerated.

Auris Medical Announces Closing of Two US Patent Acquisitions Related to the Use of Betahistine for the Treatment of Depression and ADHD

 Betahistine is a small molecule structural analog of histamine, which acts as an agonist at the H1 and as an antagonist at the H3 histamine receptors. Unlike histamine, it crosses the blood-brain-barrier. It is known to enhance inner ear and cerebral blood flow, increase histamine turnover and enhance histamine release in the brain, increase release of acetylcholine, dopamine and norepinephrine in the brain and to result in general brain arousal. Betahistine for oral administration is approved in about 115 countries, with the US being a notable exception, for the treatment of vertigo and Meniere’s disease. The compound has a very good safety profile, yet it is also known that its clinical utility is held back by poor bioavailability. Intranasal administration of betahistine has been shown to result in 4 to 26 times higher bioavailability.

Safety first

Safety, tolerability and pharmacokinetics of 2-pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD

Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with the betahistine dose (R2 0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for the power model were 0.8684 (Cmax) and 1.007 (AUC0-4). A population pharmacokinetic model with first-order absorption of betahistine and metabolism to 2-PAA, followed by a first-order elimination of 2-PAA provides estimates of clearance that underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested.

Pharmacokinetics and Dose Proportionality of Betahistine in Healthy Individuals

Betahistine dihydrochloride is widely used to reduce the severity and frequency of vertigo attacks associated with Ménière’s disease. Betahistine is an analogue of histamine, and is a weak histamine H1 receptor agonist and potent histamine H3 receptor antagonist. The recommended therapeutic dose for adults ranges from 24 to 48 mg given in doses divided throughout the day. Betahistine undergoes extensive first-pass metabolism to the major inactive metabolite 2-pyridyl acetic acid (2PAA), which can be considered a surrogate index for quantitation of the parent drug due to extremely low plasma levels of betahistine. The aim of the present investigation was to assess the pharmacokinetics and dose proportionality of betahistine in Arabic healthy adult male subjects under fasting conditions. A single dose of betahistine in the form of a 8, 16, or 24 mg tablet was administered to 36 subjects in randomized, cross-over, three-period, three-sequence design separated by a one week washout period between dosing. The pharmacokinetic parameters C_max, AUC_0–t, AUC_0–∞, T_max, and T_half were calculated for each subject from concentrations of 2-PAA in plasma, applying non-compartmental analysis. The current study demonstrated that betahistine showed linear pharmacokinetics (dose proportionality) in an Arabic population over the investigated therapeutic dose range of 8–24 mg

Conclusion

I think Rene is right to be curious about whether the benefit of E-100 in autism models can be replicated today with cheap generic compounds.  Our readers who are doctors outside the US will be familiar with Betahistine, a cheap drug sitting on the shelf in their local pharmacy.

In my N=1 case of autism I am not so optimistic, because I did once follow up on another idea in the published literature.  That idea was to “fix” GABA_A receptors with bumetanide/bromide and then “increase GABA”, in lay-speak. It was in this post from 2015:  “More GABA” for Autism and Epilepsy? Not so Simple

Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures

GABA is not supposed to cross the blood brain barrier (BBB), but when combined with niacin the Russians discovered it does, the result was the prodrug Picamilon (until recently sold in the US as a supplement). Some people with autism do take Picamilon.

In my case of autism, a single small dose of Picamilon had a pronounced negative effect, which I interpreted as GABA still acting as excitatory (it should be inhibitory).  It is possible that the niacin part of Picamilon was the problem.

Taurine is an agonist of GABA_A receptors, so it will also act like “increasing GABA”

Taurine and GABA neurotransmitter receptors, a relationship with therapeutic potential?

Very many people with autism take Taurine. Some people with autism who take Leucovorin (calcium folinate) also take Taurine to reduce its side effects.

Some people take Bumetanide and Taurine, which is surprising.

The original intended use of Leucovorin is for people undergoing chemotherapy, to reduce its side effects. Taurine is also used to reduce the side effects of chemotherapy. So not a surprise to see that Leucovorin is often together prescribed with Taurine, but that is in people fighting cancer.

In autism, there is no chemotherapy and so what is the rational to prescribe Taurine with Leucoverin?

Perhaps, by chance more than anything else, Taurine does reduce the aggression that is a common side effect of Leucovorin.  I hope it does.

My conclusion is that for plenty of people with autism, and particularly those who tolerate/use Taurine or Picamilon,  Betahistine’s effect on GABA should not cause a problem. When Betahistine gets FDA approval for pediatric use in ADHD, parents in the US will likely have little difficult getting a prescription for their child with autism. ADHD is highly comorbid with autism.

If Betahistine gives a benefit and is well tolerated, all you have to do is add Donepezil or Galantamine and you have something very similar to the research drug E-100, that shines in those two mouse models of autism.

I think the effect of Betahistine  increasing the levels of neurotransmitters histamine, acetylcholine, norepinephrine, serotonin, and GABA released from the nerve endings is likely to be occur from the first dose. It makes sense that the effect on your inner ear takes weeks/months to develop.

I think the ADHD version of betahistine will be a much more potent dose than current generic tablets and it will be achieved intranasally.

Betahistine was withdrawn from sale in the US many years ago because it was thought not to be effective;  the chart further below shows otherwise. 

If you are an adult outside the US, with some hearing loss, it looks like you might want to ask your doctor for a trial of Betahistine.  It is safe and very cheap.  While researched for Ménière's disease, you can have sudden onset reduction in hearing caused by an inflammatory response due to a virus or bacteria, that produces something very similar in the inner ear to what gets diagnosed as Ménière's disease, as I discovered myself. 

Sudden onset hearing loss (SOHL) is a 30 dB or greater hearing loss over less than 72 hours, it is usually idiopathic (you never get to know what caused it).  It is thought that most people do not go to their doctor – big mistake. If you treat SOHL immediately with steroids, hearing loss should be temporary. For people with the inner ear disease Ménière's, it looks like they should benefit from Betahistine, and then be able to hear sounds 6 decibels quieter.  Is Betahistine going to benefit SOHL that was not treated in time?  It might be worth finding out.

 

 Hearing function after betahistine therapy inpatients with Ménière's disease

Betahistine, acting via H3 receptors, reduces the pressure of the fluid that fills the labyrinth in the inner ear; it also is thought to improve blood supply.  The diuretic acetazolamide, covered in this blog because of its effects on ion channels relevant to autism, is also used to reduce fluid build-up in the inner ear in Ménière's disease.

When I had sudden onset hearing loss (SOHL), it was initially misdiagnosed and steroid therapy started very late, so I added some acetazolamide from my autism stock pile.  It all worked out well.

If someone reading this post goes on to try Betahistine off-label for:-

·        ADHD

·        Depression

·        Autism

·        Weight gain associated with antipsychotics, particularly Olanzapine

·        Previously untreated, sudden onset hearing loss (SOHL)

it would be interesting to know your results.

Take note that Betahistine is also a mild agonist of H1 receptors, which explains why it may cause mild nausea (H1 blockers are used to reduce nausea) for a short while after taking it.  This side effect seems not to appear if Betahistine is taken with or after a meal. Betahistine may also reduce the H1 histamine receptor effect of any H1 antihistamine drugs being taken.

Ultimately the new E-100 drug may well be the best solution.  Hopefully the UAE researchers will persevere to human trials, but that is something that would need a lot of time and money and probably will not happen.