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Showing posts with label Ion channels. Show all posts
Showing posts with label Ion channels. Show all posts

Thursday, 6 October 2022

Different L-type Calcium Channel Blockers Repurposed for Different Types of Autism

 

 A Purkinje Neuron, home of P-type calcium channels

Today’s post was prompted by a reader who saw a very positive response from the L-type calcium channel blocker, Amlodipine.

So we return to the subject of calcium channels.

The good news about calcium channel defects is that many are easy to treat.

In most single gene autisms (Rett, Fragile-X, Pitt Hopkins etc) the underlying problem is that a faulty gene does not do its job of producing the expected protein.  This is a problem of too little.

In many ion channel dysfunctions the problem is not too little, it is too much expression. For example, in Timothy Syndrome the mutation in the gene produces too much of the protein, in this case the L-type calcium channel Cav1.2.

Ion channel dysfunctions can be the result of a faulty gene, or just that the on/off switch for that gene is faulty.  Fortunately, the problem is usually that it is stuck “on”.

In people who develop Type-1 diabetes we have seen how the disease process can be halted by blocking Cav1.2 in the pancreas.  This halts the decline in the beta cells that produce insulin.

Once all the beta cells are dead, the person cannot produce insulin and has type-1 diabetes. Treating the person after this point with a Cav1.2 blocker will provide no benefit; the damage has already been done

Something similar happens in Parkinson’s disease, but this time you need to block Cav1.3.  In the early stages of the disease Cav1.3 is over-expressed in a key part of the brain, which triggers a slow process of degeneration. Treating a person with all the visible symptoms of Parkinson’s with a Cav1.3 blocker will provide no benefit; the damage has already been done.

 

Calcium channel blockers are not very specific

The current drugs used to block calcium channels were mainly developed to treat heart conditions.

When treating neurological disorders like autism we are primarily focused on the brain, what goes on elsewhere can also be very relevant, but in an indirect way.

In the brain the important calcium channels are: -

L type

N type

P type

R type

T type

Plus, Inositol trisphosphate receptor (IP3R) and Ryanodine receptors. IP3R has been covered in previous posts.


Verapamil (a Phenylalkylamine class drug)

Verapamil blocks L type channels and T type channels, plus some potassium ion channels.

When it comes to specific L type channels there are 4, Cav1.1, Cav1.2, Cav1.3, and Cav1.4.

In the brain we have just Cav1.2 and Cav1.3. Verapamil mainly affects Cav1.2.

 

Amlodipine (a Dihydropyridine class drug)

Amlodipine blocks L type channels and N type channels.

Amlodipine mainly affects Cav1.3.

 

Nicardipine (a Dihydropyridine class drug)

Nicardipine blocks L type channels and N type channels.

As a Dihydropyridine, it should mainly affect Cav1.3.

In addition, it blocks the sodium ion channel Nav1.8.

The effect on Nav1.8 is why it has been proposed as a therapy for Pitt Hopkins. In this syndrome Nav1.8 is over expressed as a downstream consequence of a mutation in the TCF4 gene.

 

Effect on P channels

To some extent Verapamil, Amlodipine and Nicardipine all block P channels.

P channels are called P after the Purkinje neurons, where they are located. These Purkinje cells likely define some aspects of autism, because of their absence. Purkinje neurons are among the largest in the brain, with elaborate dendritic arbor.  I imagine this makes them vulnerable.




In the people with severe autism most of the Purkinje cells appear to have died.

Blocking P channels might have protected Purkinje cells from death.

 

The effect of too much L-type calcium channel signaling on behavior 

You can both turn on self-injury via activating L type calcium channels and extinguish it by blocking the same channels.  It is proven in mice and seems to apply to at least some humans.

Calcium channel activation and self-biting in mice

The L type calcium channel agonist (±)Bay K 8644 has been reported to cause characteristic motor abnormalities in adult mice. The current study shows that administration of this drug can also cause the unusual phenomenon of self-injurious biting, particularly when given to young mice.

The self-biting provoked by (±)Bay K 8644 can be inhibited by pretreating the mice with dihydropyridine L type calcium channel antagonists such as nifedipine, nimodipine, or nitrendipine. However, self-biting is not inhibited by nondihydropyridine antagonists including diltiazem, flunarizine, or verapamil.

(±)Bay K 8644 functions as an L type calcium channel activator that increases calcium fluxes in response to depolarizing stimuli (). In rodents, this drug has been reported to produce characteristic motor abnormalities including impaired ambulation, twisting and stretching movements, transient limb extension, back arching, spasticity, ataxia, or catatonia (). Some studies have anecdotally noted the occurrence of SIB with this drug (), though this phenomenon has received little attention. The current study shows that (±)Bay K 8644 will reliably provoke SB and SIB under certain conditions in mice, providing a tool to study the neurobiology of this unusual behavior.

 

When I first encountered the above study, I did wonder why Verapamil did not extinguish the self-injury.

It turns out that Bay K 8644 is a modified version of the common drug nifedipine, which is a Cav1.3 blocker.  Verapamil is mainly a Cav1.2 blocker.  Bay K 8644 is like the opposite of nifedipine.

In the trial they have activated Cav1.3 causing excess calcium inside neurons. The only way to block this process is to block Cav1.3. Blocking Cav1.2 with Verapamil could not solve the problem. 

Note that activation of Cav1.3 can cause motor abnormities in mice and this might be seen as ataxia in a human. One particular reader of this blog will see the relevance of this. 

I did write extensively in earlier posts about the large amount of research that links L type calcium channels to neuropsychiatric disorders.

I did mainly focus on Cav1.2 using Verapamil, but the evidence for the role of Cav1.3 is clear as day. 

L-type calcium channels as drug targets in CNS disorders

 L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases such as Parkinson disease, febrile seizures and neuropsychiatric disorders. Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value.

 

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms.

The L-type calcium channels (LTCCs) Cav1.2 and Cav1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder.

Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Cav1.2- and Cav1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

 

Was I surprised that Amlodipine, that targets Cav1.3 rather than Cav1.2, was very beneficial in someone with severe autism?  Not at all.

I was interested that the effect was more pro-cognitive than anti-anxiety.  Is that the effect on Cav1.3 or is it via that N channel Cav2.2?

N-type calcium channels are important in neurotransmitter release because they are localized at the synaptic terminals. Piracetam, the original cognitive enhancing drug, is also a N type channel blocker.

  

Statins and L type calcium channels blockers – it matters which one you choose

We previously saw how the statin class of drugs can be beneficial in autism, but it depends which one you chose. For example, in SLOS (Smith-Lemli-Opitz syndrome), where both copies of the gene DHCR7 are mutated, you need to push the gene to work. To increase expression of this gene you need Simvastatin. This is hard for people to understand because SLOS features very low cholesterol and statins are thought of as cholesterol lowering drugs. The body needs the enzyme DHCR7 to make cholesterol and Simvastatin increases DHCR7 expression.

In the case of L type channel blockers, the selection is very important.  The effect will not be the same.

If you have a mutation in Cav1.2, you would expect Verapamil to be a good choice.  If the mutation is in Cav1.3, you would expect Amlodipine to be better.

If you have over expression of T channels (Cav3.1, Cav3.2 or Cav3.3) then you would expect a benefit from Verapamil and none from Amlodipine.

If you have over expression of the N channel (Cav2.2) then you would want Amlodipine

If you have over expression of the sodium channel Nav1.8 then you would want Nicardipine

  

Conclusion

It is likely that many people with autism, bipolar, ADHD or schizophrenia might benefit from treating their ion channel dysfunctions.  The required drugs are cheap generics that have been in your local pharmacy for a few decades.

Back in 2019 I wrote the post below:

Cheap common drugs may help mental illness

I highlighted a new study, using historic data from Sweden, that looked at the secondary effects of statins, calcium channel blockers and metformin on psychiatric hospitalization.

 

Association of Hydroxylmethyl Glutaryl Coenzyme A Reductase Inhibitors, L-Type Calcium Channel Antagonists, and Biguanides With Rates of Psychiatric Hospitalization and Self-Harm in Individuals With Serious Mental Illness

 

Question  Are drugs in common use for physical health problems (hydroxylmethyl glutaryl coenzyme A reductase inhibitors, L-type calcium channel antagonists, and biguanides) associated with reduced rates of psychiatric hospitalization and self-harm in individuals with serious mental illness?

Findings  In this series of within-individual cohort studies of 142 691 patients with bipolar disorder, schizophrenia, or nonaffective psychosis, exposure to any of the study drugs was associated with reduced rates of psychiatric hospitalization compared with unexposed periods. Self-harm was reduced in patients with bipolar disorder and schizophrenia during exposure to all study drugs and in patients with nonaffective psychosis taking L-type calcium channel antagonists. 

We found that periods of HMG-CoA RI (statin) exposure were associated with reduced psychiatric hospitalization in all subgroups of SMI (Serious Mental Illness) and with reduced self-harm in BPD and schizophrenia.

Exposure to LTCC (L type calcium channel) antagonists was associated with reduced rates of psychiatric hospitalization and self-harm.

Periods of metformin (a type 2 diabetes drug) exposure were associated with reduced psychiatric and nonpsychiatric hospitalization across all SMI subgroups.

 

Use of L type calcium channel blockers reduces self-harm.

How much more evidence is needed?

I took an educated guess several years ago that Verapamil would tame summertime raging in my son.  It was the only calcium channel blocker I tried and it worked. This year we had the emergence of extreme sound sensitivity. My educated guess was that blocking potassium channels with Ponstan (Mefenamic acid) would resolve the problem, and it did.  

Treating ion channel dysfunctions (channelopathies) in autism clearly is not rocket science; it is just waiting to be attempted.







Monday, 1 March 2021

Medicinal Psychedelics for Neuroinflammatory conditions - Depression, Severe Headaches, OCD, Addiction and Autism

 

62 clinical trials with Psilocybin are registered


Today’s post is about treating a wide range of conditions that share neuroinflammation in common, by targeting the serotonin receptor 5-HT2A.

Severely disabling cluster headaches, that were seen as untreatable, have been resolved by monthly micro dosing with psilocybin.

Psilocybin is a naturally occurring prodrug compound produced by more than 200 species of fungus, including magic mushrooms. Psilocybin is quickly converted by the body into Psilocin.

 

Psilocin Binding Profile

Target

Affinity

Species

 

Ki (nM)

 

SERT

3,801.0

Human

 

5-HT1A

567.4

Human

 

5-HT1B

219.6

Human

 

5-HT1D

36.4

Human

 

5-HT1E

52.2

Human

 

5-HT2A

107.2

Human

 

5-HT2B

4.6

Human

 

5-HT2C

97.3

Rat

 

5-HT3

> 10,000

Human

 

5-HT5

83.7

Human

 

5-HT6

57.0

Human

 

5-HT7

3.5

Human

 

 

 

“The neurotransmitter serotonin is structurally similar to psilocybin.

Psilocybin is rapidly dephosphorylated in the body to psilocin, which is an agonist for several serotonin receptors, which are also known as 5-hydroxytryptamine (5-HT) receptors. Psilocin binds with high affinity to 5-HT2A receptors and low affinity to 5-HT1 receptors, including 5-HT1A and 5-HT1D; effects are also mediated via 5-HT2C receptors.

Various lines of evidence have shown that interactions with non-5-HT2 receptors also contribute to the subjective and behavioral effects of the drug. For example, psilocin indirectly increases the concentration of the neurotransmitter dopamine in the basal ganglia, and some psychotomimetic symptoms of psilocin are reduced by haloperidol, a non-selective dopamine receptor antagonist.

Taken together, these suggest that there may be an indirect dopaminergic contribution to psilocin's psychotomimetic effects. Psilocybin and psilocin have no affinity for dopamine receptor D2, unlike another common 5-HT receptor agonist, LSD. Psilocin antagonizes H1 receptors with moderate affinity, compared to LSD which has a lower affinity.”

  

A Canadian company, Pilz Bioscience, is trialing its version of psilocybin to treat autism.

We already know that micro dosing of Lysergic acid diethylamide (LSD) promotes social behavior via 5-HT2A/AMPA receptors and mTOR signaling.

  

The FDA is already onside

For those worrying about the law, the FDA is well aware of the therapeutic potential of low dose psychedelics like Psilocybin, and indeed LSD. 

FDA Grants Psilocybin Second Breakthrough Therapy Designation for Resistant Depression

The US Food and Drug Administration (FDA) has granted the Usona Institute breakthrough therapy designation for psilocybin for the treatment of major depressive disorder (MDD).

 

For really motivated readers, click on the link below to read the details of Psilocybin


https://www.usonainstitute.org/wp-content/uploads/2020/08/Usona_Psilocybin_IB_V3.0_08.31.2020_cc.pdf

   

Nova (Pilz Bioscience) Launches Preclinical Autism Spectrum Disorder Therapeutic Study

 

A treatment phase with its proprietary psilocybin compound is scheduled to begin in February 2021.    


https://pilzbioscience.com/

 

PILZ BIOSCIENCE

INNOVATION IN ASD

Though ASD symptoms are diverse, underlying causes converge on common biological mechanisms, priming development of a new approach to diagnostics and treatment. Scientific studies suggest a strong association between ASD and inflammation, as well as ASD and microbiota in the gut. Likewise, parallels exist between social cognition in autism and some of the key behavioral elements already being treated with psychedelic therapy.

 

 


 


 

Micro dose LSD for Autism? via activation of 5-HT2A/AMPA/mTORC1

  

LSD may offer viable treatment for certain mental disorders

Researchers from McGill University have discovered, for the first time, one of the possible mechanisms that contributes to the ability of lysergic acid diethylamide (LSD) to increase social interaction. The findings, which could help unlock potential therapeutic applications in treating certain psychiatric diseases, including anxiety and alcohol use disorders, are published in the journal PNAS.

Psychedelic drugs, including LSD, were popular in the 1970s and have been gaining popularity over the past decade, with reports of young professionals claiming to regularly take small non-hallucinogenic micro-doses of LSD to boost their productivity and creativity and to increase their empathy. The mechanism of action of LSD on the brain, however, has remained a mystery.

The researchers note that the main outcome of their study is the ability to describe, at least in rodents, the underlying mechanism for the behavioural effect that results in LSD increasing feelings of empathy, including a greater connection to the world and sense of being part of a large community. "The fact that LSD binds the 5-HT2A receptor was previously known. The novelty of this research is to have identified that the prosocial effects of LSD activate the 5-HT2 receptors, which in-turn activate the excitatory synapses of the AMPA receptor as well as the protein complex mTORC1, which has been demonstrated to be dysregulated in diseases with social deficits such as autism spectrum disorder,” as specified by Prof. Nahum Sonenberg, Professor at the Department of Biochemistry of McGill University, world renowned expert in the molecular biology of diseases and co-lead author of the study.

  

Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission


Significance

Social behavior (SB) is a fundamental hallmark of human interaction. Repeated administration of low doses of the 5-HT2A agonist lysergic acid diethylamide (LSD) in mice enhances SB by potentiating 5-HT2A and AMPA receptor neurotransmission in the mPFC via an increasing phosphorylation of the mTORC1, a protein involved in the modulation of SB. Moreover, the inactivation of mPFC glutamate neurotransmission impairs SB and nullifies the prosocial effects of LSD. Finally, LSD requires the integrity of mTORC1 in excitatory glutamatergic, but not in inhibitory neurons, to produce prosocial effects. This study unveils a mechanism contributing to the role of 5-HT2A agonism in the modulation of SB.

Abstract

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptorf/f:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptorf/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

   

D-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology


Figure 1. D-Lysergic Acid Diethylamide (LSD) acts at different brain regions with a pleiotropic mechanism of action involving serotonin 5-HT1A, 5-HT2A, 5-HT2C, and dopamine D2 receptors in the Dorsal Raphe (DR); dopamine D2 receptor and Trace Amine Associate (TAAR1) receptors in the Ventral Tegmental area (VTA); and 5-HT2A in the Locus Coerules (LC). These three nuclei project to the prefrontal cortex (PFC), enhancing or inhibiting the release of neurotransmitters and ultimately medicating the psychotic-like effects and cognitive changes. mPFC: medial prefrontal cortex (mPFC); NMDA(NR2B): N-methyl-D-aspartate (NMDA) receptor subunit NR2B.

  

LSD vs Psilocybin

LSD and psilocybin have effects that overlap, but they are not identical.  Both are used by sufferers to treat cluster headaches. 

Why does low dose psilocybin provide long lasting protection from cluster headaches?  These headaches are often thought to be driven by ion channel dysfunctions (channelopathic).  Does psilocybin, or indeed LSD, directly or indirectly affect ion channels?  Nobody knows.

Regular readers will know that certain calcium/sodium channels are implicated in autism, epilepsy and MR/ID.  Some of these same ion channels are also associated with headaches.  So no surprise that some people with a mutation in one of these genes have additional problems to autism. 

 

Are all types of migraine channelopathies?

Familial hemiplegic migraine (FHM) is characterized by migraine attacks, which is with transient, unilateral motor weakness as its episodic aura. FHM is an autosomal dominant migraine, three encoding protein genes have been identified: CACNA1A encodes α1 subunit of calcium channel Cav2.1, ATP1A2 encodes α2 subunit of Na+/ K+-ATPase pump, and SCN1A encodes α subunit of sodium channel Nav1.1. All these proteins are specially expressed on nervous system, and all the mutations mainly cause brain dysfunction. Series studies on FHM indicated that mutations on Cav2.1 and ATP1A2 increased the concentration of glutamate in synapses and disturbed the excitatory and inhibitory balance, which induced the brain dysfunction. Although the same result has not yet been concluded firmly enough from the functional studies on sodium channels (Nav1.1) owe to the more perplexed expression and structure of Nav1.1 and its encoding gene SCN1A, it firmly concluded that all the mutations of the three genes cause brain dysfunction. All above indicate that FHM is a definitely channelopathy. Are other types of migraine channelopathies?

  

Conclusion

Tiny doses of psilocybin (magic mushrooms) have been used for years by a small number of people with severe headaches.  These headaches are not your typical migraine, they are totally disabling. Note that large doses of Psilocybin frequently cause headaches.

It appears that the same therapy has an effect on other neurological conditions ranging from depression to autism.  Take a look at all the trials to date:


https://clinicaltrials.gov/ct2/results?recrs=&cond=&term=psilocybin&cntry=&state=&city=&dist=


We know from anecdotes that many Aspies feel better when they activate the serotonin receptor 5-HT2A, but I suspect that may “overshoot” with dosing. It is a non-hallucinogenic effect that we are looking for.  The dose can be as little as a micro dose once a month.

Genuinely effective micro dosing is very attractive, because it is likely to be very safe and indeed very cheap.  Intermittent micro dosing, if therapeutic, would be even better.  

Clearly, a standardized drug like PLZ-1013 from Pilz Bioscience is what many people will want.  It is very encouraging that these researchers and those at McGill University and the Usona Institute have engaged themselves.  But, prepare to wait a decade or two.

It is a pity we have to wait so long; LSD was first used as an autism therapy before I was born. LSD was then made a banned substance.  Clearly back in the days that Professor Lovaas was giving LSD to people with autism at UCLA in the 1960s, he was using the “wrong” dose, but he might have eventually stumbled upon the micro dose.  Here we are almost 60 years later, still with anecdotes.  Roll on the clinical trial of PLZ-1013.












Friday, 9 October 2020

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 Nav1.7 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. Nav1.7.

Other sodium channels involved in pain signalling are Nav1.3, Nav1.8, and Nav1.9.

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 Nav1.4 voltage-gated sodium channel is encoded by the SCN4A gene. Mutations in the gene are associated with hypokalemic periodic paralysishyperkalemic periodic paralysisparamyotonia 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 Nav1.3 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 (NaV1.3) 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 NaV1.3. Pathogenic NaV1.3 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 (NaV1.1) 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 Nav1.2 sodium ion channel is encoded by the SCN2A gene.

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

  

SCN1A

 The Nav1.1 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 syndromeautismattention deficit-hyperactivity disorder (ADHD), bipolar disordermajor 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 Cav2.1 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 Cav1.2.   Cav1.2 is a subunit of the L-type voltage-dependent calcium channel.

 

CACNA1S

The CACNA1S gene encodes Cav1.1 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 paralysisthyrotoxic 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 Cav1.3.

Cav1.3 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 Cav1.3 Ca2+ channels contribute to the death of dopaminergic neurones in patients with Parkinson's disease

Inhibition of L-type channels, in particular Cav1.3 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 Cav2.3 , 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 Cav1.4.

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.