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.

Calcium channelopathies and intellectual disability

 

Changsha, another big city in China you probably have not heard of

 

Today’s post follows up on the use of calcium channel blockers to treat autism.  This is a subject that I first looked at in this blog several years ago.  One of our readers even wrote a book entirely about this subject.

There has been plenty of research going back a decade or more, but no effort to translate it into common therapy.

By coincidence, one reader recently sent me a list of about 20 suspect genes from her daughter’s tests. 7 are related to just a pair of L-type calcium channels, the suggested action was to take magnesium sulfate. I referred her back to my old posts, particularly since her main concern is self-injury. I have written a great deal about Cav1.2 and self-injury, since it is treatable using Verapamil. 

I think a better interpretation of the genetic testing results would have been to say possible channelopathies in Cav1.2 and Cav1.3.  Given that mutations usually lead to over expression of ion channels, a likely effective therapy would be to block these channels.

Magnesium does act as a calcium channel blocker, among its very many other effects.

Is magnesium sulfate the best choice of Cav1.2 and Cav1.3 blocker?  I doubt it, but at least it is OTC. 

 

Treating Intellectual Disability (ID) rather than Autism

I do often think that we should be talking more about treating ID rather than autism.

Who would object to treating ID? Hopefully nobody.

Today’s paper is about treating intellectual disability (ID) and global developmental delay (GDD).

Almost all people with level 3 autism could also be described as ID + GDD.

Level 3 autism = ID + GDD

We also have IDD which is Intellectual and Developmental Disability.

Too many names for the same thing, if you ask me.

The paper below from Changsha, China starts with the hypothesis that:-

Calcium Channels play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD.

The paper is published in the  Orphanet Journal of Rare Diseases.

2.3% of the general population have an IQ less than 70 and so have intellectual disability (ID).  ID is not really rare. More than 1 million people in the United States have intellectual disability (ID). 

There are many different processes involved in intellectual disability (ID).  On the one hand that makes it complicated, but on the other hand that means there are many options beyond just L-type calcium channels blockers.

The paper below is really only looking and at Cav1.2 and Cav1.3.  As I pointed out in my previous post, there is much more to it than just this pair.

On the bright side, at least some people in China are looking at this.

  

Calcium channelopathies and intellectual disability: a systematic review

Background

Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel.

 

Main body

A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro.

 

Conclusion

Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

 

Discussion

Overall, this condition seems to be progressive, however, most primary authors provided less information on the course of the disease. Many of the reported cases with electrophysiological studies had gain-of- function variants. Severe to profound ID/GDD was more predominant for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. The possible reasons as why these genes associated with more severe phenotype include (1) the neuronal location of the genes; all of them are located in the pre-synaptic membrane, (2) brain distribution; most of them are distributed in the brain cortex and/or hippocampus and/or cerebellum, (3) function of the genes; they all regulate the release of neurotransmitter, and (4) the effect of the variants; most of the reported variants in these genes had gain-of-function property. This review has also revealed some hotspots for future research.

  

Conclusion

Gain of function of Cav1.2 and Cav1.3 continues to be well documented in the literature.  That means too much calcium (Ca²⁺ ) entering neurons, from outside.

Note that inside cells/neurons you have a store of Ca²⁺ in something called the Endoplasmic Reticulum (ER). There is supposed to be a high level of Ca²⁺ inside the ER.  When things go wrong, there can be ER stress and Ca²⁺ may get pushed out, or too much Ca²⁺ may be let in. ER stress plays a role in many diseases including autism. In autism the channel implicated is called IP3R. ER stress ultimately leads to cell death. This is the mechanism behind how people with diabetes stop producing insulin. ER stress in the beta cells in their pancreas caused the beta cells to die. No beta cells means no insulin. In such people very prompt treatment by blocking Cav1.2 stops the beta cells dying.

The people seeing a benefit from blocking Cav1.2 and/or Cav1.3 in someone with autism, ID, IDD, GDD, ADHD, epilepsy, SIB, or chronic headaches etc, have science on their side.  It is not just Chinese science; it is science from everywhere.

Note that ion channel dysfunctions can be genetic (they show up on genetic tests) or they can be acquired (they do not show up on testing).

The open issue is what is the most effective therapy.  This is going to vary from person to person, but it is unlikely to be magnesium sulfate.

Magnesium is an important mineral to get from a healthy diet, but it has many effects including blocking NMDA receptors.  This effect might be good or it might be bad. High doses of magnesium supplements will cause GI problems. Most people lack magnesium so a little extra would seem fine, but using enough to block calcium channels may not be wise.

Blocking Cav1.3 will Amlodipine should be the subject of a clinical trial.

Blocking Cav1.2 with Verapamil should be the subject of a clinical trial.

Maybe in China?

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.