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Showing posts with label Cav1.3. Show all posts
Showing posts with label Cav1.3. Show all posts

Sunday 23 October 2022

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, CACNA1CCACNA1I, CACNA1H, CACNA1DCACNA2D1CACNA2D2CACNA1ECACNA1F, 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. CACNA1ECACNA1GCACNA1FCACNA2D2 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 CACNA1CCACNA1A, 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. CACNA1ECACNA1GCACNA1FCACNA2D2 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?






Tuesday 19 May 2015

ASD variants - (mis and missed) diagnoses. Calcium ion channel dysfunctions Cav1.1, 1.2, 1.3 and 1.4


This post serves to introduce some ideas relevant to a post that is will shortly arrive on calcium ion channel dysfunctions (Cav1.1, 1.2, 1.3 and 1.4).

As we have seen, nearly all behavioral and psychiatric disorders are just diagnosed based on observation.  Only in very rare cases is the underlying biological problem diagnosed.  So it is fair to say that these are not accurate medical diagnoses.

Under the wide umbrella term of ASD are likely hundreds of thousands of  discrete variants, since ASD generally results from the combination of multiple hits/dysfunctions.  A single one of these dysfunctions is usually not enough to trigger autism, but some may indeed trigger something else noticeable.  A small number of individual hits, like Fragile-X and Retts can trigger autism, but these are the exception.


Mis and Missed diagnoses

One reader of this blog received a diagnosis for his child as “late onset regressive autism or possible childhood disintegrative disorder”.  Neither of these options is very good, since you are talking about an entirely typical child who, after the age of four, begins to regress and lose his acquired skills.

After a long struggle, he found the biological diagnosis, which is mitochondrial disease.  After a few months of the Richard Kelley (from Johns Hopkins), therapy the regression was halted and now new skills are again being acquired.

This is another example of how unacceptable simple observational diagnoses are.  What would have happened if the reader had not stumbled upon this blog and then later sought out help from the leading experts (just look on my Dean’s list)?



Attention Deficit Disorder (ADHD)

ADHD is very commonly diagnosed in the US, much more so than in other countries.  More severe cases of ADHD look much like ASD, which is why I call them autism-lite.

Another group of ADHD may indeed be purely behavioral – too much time with smart phones, iPads and video games.  This is supported by the fact that the data on incidence of ADHD shows that a large group of children with ADHD, “grow out of it”, or were misdiagnosed in the first place.

However, it does look like there is another group of ADHD which is biological, but may be different to autism.  On this subject I will bring you the comments of Dr. Manuel Casanova, a neurologist and along with that, thoughtful and knowledgeable about autism. 

Then we have the recurring clinical trials on high EPA/DHA fish oil, which really do show an effect in most trials in ADHD, but fail in most trials in autism.  This will be developed further in the later post on calcium channels.  The suggested view is that either the vitamin A, or the omega 3 oil, is somehow helping and even perhaps some people have a problem absorbing some types of vitamin A.  I was always unconvinced by this. 

However, it has now been shown that the EPA in fish oil has an effect on certain L-type calcium channels.  If you had a mild dysfunction (channelopathy) of one of the L-type calcium channels, then a big enough dose of EPA might have an effect on them.  This becomes more interesting when you learn that some doctors in the US think that dyslexia is another autism-lite.

One suggested cause of dyslexia is visual deficit that makes reading difficult, but it also accompanied by a difficulty seeing in the dark.  This night blindness is known to be caused by vitamin A deficiency (or an inability to absorb it properly) and also by an ion channel dysfunction in Cav1.4.

It appears that the high EPA fish oil would increase vitamin A and also affect the function of Cav1.4.  The calcium ion channel Ca1.4 is widely expressed in your eyes.

Another interesting point is that it is thought that a dysfunction in one type of Calcium channel will often affect the function of others.  This is important because when you look at the effect of dysfunctions in these channels you will a listing including:-

·        Autism (Timothy Sydrome)
·        Mood disorder
·        Depression
·        Bipolar

As well as things like

·        Night blindness
·        Heart defects (Timothy Sydrome)

We also should note that many people (without autism) with sight problems claim improvement from taking high EPA fish oil.



Dyslexia

Dyslexia is the most common learning disability. It affects about 3 to 7 percent of people. While it is diagnosed more often in males, some believed it affects males and females equally. Up to 20 percent of the population may have some degree of symptoms

Dyslexia and attention deficit hyperactivity disorder (ADHD) commonly occur together; about 15 percent of people with dyslexia also have ADHD and 35 percent of those with ADHD have dyslexia.

The causes appear to be genetic and epigenetic. For example the gene KIAA0319


People usually think of dyslexia only in children, but that may be because many adults do not read very much.  Or do they "grow out of it".



ADHD

“It affects about 6–7% of children when diagnosed via the DSM-IV criteria and 1–2% when diagnosed via the ICD-10 criteria.  Rates are similar between countries and depend mostly on how it is diagnosed. ADHD is diagnosed approximately three times more in boys than in girls. About 30–50% of people diagnosed in childhood continue to have symptoms into adulthood.”

So it would seem that most people “grow out” of ADHD 



Dr. Manuel Casanova

Dr. Manuel Casanova is a neurologist and along with that is clever, thoughtful and knowledagable about autism.  He looks at measurable anatomical differences and how these may be related to behaviour.  So he is more into the consequences of unchangeable differences in brains.

If you start looking at ion channels and transporters as being key drivers in behaviour then you have the chance to make alterations.  We saw that the same applies to fine tuning the function and indeed structure of key neurotransmitter receptors.

In lay terms, Manuel is showing how brains are indeed “hardwired” differently in many cases of autism, ADHD and even dyslexia.  This might reinforce the old view that really it is “case closed” and nothing more can be done.

However the really clever scientists looking in greater depth show us that notwithstanding some structural variation, much of the problem lies in the aspects of the brain that can be modified and indeed some are constantly in a state of change, for example the shape of dendritric spines and indeed the very substructure of those  GABAA receptors.

He groups dyslexia with ADHD and sees them as fundamentally different to autsim.  Having said that, Manuel tells us that attention disorders may be found in close to 30% of autistic individuals


 He has his own blog.



I suggest you read his full article, but here are some excerpts:-


“Claiming that there is comorbidity across neurodevelopmental disorders based on a single behavioral symptom negates many aspects of the individuality of each condition. In this regard, there are marked differences in the cognitive styles of dyslexic or ADHD individuals and those within the autism spectrum. Dyslexics enjoy a top-down cognitive style, tend to be holistically-oriented and have a gestalt processing bias (e.g., they see the forest but lose track of the individual trees). They are considered to have strong central coherence and excel in synthesizing sensory or cognitive experiences. Individuals within the autism spectrum enjoy a bottom-up cognitive style which makes them detail-oriented. Thus, contrary to dyslexic/ADHD subjects, ASD individuals see the tree but tend to lose sight of the forrest. In addition, they have a local processing bias with weak central coherence and appear to be good analyzers.”






“The above related differences in cognitive style appear to have anatomical correlates. As compared to neurotypicals, dyslexics tend to have smaller brain volumes with a concomitant striking increase in the size of their corpus callosum (the white matter projections that join homologous areas in both cerebral hemispheres). In addition, they have a simplification of their convolutional pattern and their cortical modules for information processing (minicolumns) are wider than expected. We find completely the opposite in patients within the autism spectrum.”



Yet more labels

Since we will be looking at calcium channels and one thing that does affect them is EPA, we should look at another label, dyspraxia, which also is reportedy  affected by fatty acids.
  
Fatty Acids in Dyslexia, Dyspraxia, ADHD and the Autistic Spectrum





What is Dyspraxia, also known as Developmental Coordination Disorder (DCD) ?

Dyspraxia, also known as Developmental coordination disorder (DCD), is is a chronic neurological disorder beginning in childhood that can affect planning of movements and co-ordination as a result of brain messages not being accurately transmitted to the body.

People with developmental coordination disorder sometimes have difficulty moderating the amount of sensory information that their body is constantly sending them, so as a result dyspraxics are prone to sensory overload and panic attacks.
Many dyspraxics struggle to distinguish left from right, even as adults, and have extremely poor sense of direction generally.

Moderate to extreme difficulty doing physical tasks is experienced by some dyspraxics, and fatigue is common because so much extra energy is expended while trying to execute physical movements correctly. Some (but not all) dyspraxics suffer from hypotonia, low muscle tone, which like DCD can detrimentally affect balance.


Gross motor control

Whole body movement, motor coordination, and body image issues mean that major developmental targets including walking, running, climbing and jumping can be affected. The difficulties vary from person to person and can include the following:


  • Poor timing
  • Poor balance (sometimes even falling over in mid-step). Tripping over one's own feet is also common.
  • Difficulty combining movements into a controlled sequence.
  • Difficulty remembering the next movement in a sequence.
  • Problems with spatial awareness, or proprioception.
  • Some people with developmental coordination disorder have trouble picking up and holding onto simple objects such as pencils, owing to poor muscle tone and/or proprioception.
  • This disorder can cause an individual to be clumsy to the point of knocking things over and bumping into people accidentally.
  • Some people with developmental coordination disorder have difficulty in determining left from right.
  • Cross-laterality, ambidexterity, and a shift in the preferred hand are also common in people with developmental coordination disorder.
  • Problems with chewing foods.

Fine motor control


Fine-motor problems can cause difficulty with a wide variety of other tasks such as using a knife and fork, fastening buttons and shoelaces, cooking, brushing one's teeth, styling one's hair, shaving, applying cosmetics, opening jars and packets, locking and unlocking doors, and doing housework.

Difficulties with fine motor co-ordination lead to problems with handwriting, which may be due to either ideational or ideo-motor difficulties. Problems associated with this area may include:
  • Learning basic movement patterns.
  • Developing a desired writing speed.
  • Establishing the correct pencil grip
  • The acquisition of graphemes – e.g. the letters of the Latin alphabet, as well as numbers.

Associated disorders


People who have developmental coordination disorder may also have one or more of these co-morbid problems:




Dysjustabouteverything (DJE)

If you consider the early years of classic autism, you will see that, in many cases, it includes all of the above disorders, even hypertonia.

But some people are otherwise pretty much typical/normal, are diagnosed with a single disorder like dyscalculia.

The problem is that these are all just observational diagnoses.  Does something biological underlie and connect them?  I think it does.

An autistic person’s struggles with mathematics may be more to do with a problem of understanding the language used to explain it.  This is why, in many cases, they struggle to move beyond counting.  Special methods of teaching maths have been created for such people, but they only take you to an elementary level.

If you have Asperger’s, you have no problem with the language used to explain the concepts or to frame the questions.  Some people with Asperger’s excel at mathematics.

The same is true for dysgraphia, autistic people tend to have very scruffy handwriting, but does this mean that they have dysgraphia? 

Hypotonia is an interesting one.  Many parents report low muscle tone and indeed DAN doctors actually treat it (apparently with Creatine).  I think hypotonia, if present in autism, is likely to be connected to the disruption in the various growth factors that has occurred and this itself may related to GABAB dysfunctions. (I mentioned this connection in an earlier post).  In Monty, aged 11 with ASD, when he was a baby he had Hypertonia.  He was big and all muscle.  As he got older he slid down from the 80-90Th percentile to the 20th percentile.  This fits one very distinct pattern of classic autism.

In the case of Monty, almost all the earlier signs of Dysjustabouteverything have now vanished.  Is this always the case?  Why would that happen in some people and not others?  Did his Polypill interventions play a role?



To investigate

What we need to know is whether there is a common link between all these various “dys-disorders”.

Probably in some (mis/over-diagnosed) people there is no link; but in others there may well be.

In some people there really is a link.  I did not tell you that my old “favourite”, hypokalemic periodic paralysis (HPP), can be caused by a Cav1.1 dysfunction.  HPP-lite is something called hypokalemic sensory overload.  In a little experiment I demonstrated that autistic sensory overload can be just hypokalemic sensory overload.  You just need 250 mg of potassium and a disturbing noise or light to illustrate it.  This is also a symptom of what they call Dyspraxia.

So Cav1.1 associates with HPP (hypokalemic periodic paralysis) and by my inference, sensory overload and some hypotonia;  Cav1.2 associates directly with autism (Timothy Syndrome) and bipolar; Cav1.3 associates with mood disorders, depression, bipolar; Cav1.4 associates with night blindness and perhaps some dyslexia.
A dysfunction in one L-type channel (Cav1.1, Cav1.2, Cav1.3 and Cav1.4) can apparently cause dysfunction in the others.  This surprised me.

So if you have autism, is not surprising if you appear afraid of the dark, feel depressed, experience sensory overload and are not very muscular.

The good news is that much of this appears to be treatable.

For the scientists among you:-

CACNB2    

Voltage-dependent L-type calcium channel subunit beta-2 is a protein that in humans is encoded by the CACNB2 gene
http://www.ebi.ac.uk/interpro/entry/IPR005444


I did forget to remind readers that I see the label schizophrenia as just another name for adult onset autism.

So it is no surprise that adults with autism have a 22 times higher chance of also being diagnosed with schizophrenia compared to non-ASD people.  Note bipolar, OCD etc; and this does not include all those adults with autism who get forgotten.









Conclusion

I am not suggesting “medicalizing” people with dyslexia, or indeed most with ADHD. 
However, it might be useful for somebody affected to know if Cav1.1 to 1.4 were dysfunctional, then at critical moments, like exam time at school, you could indeed give them some extra help.

People with dyslexia, and I presume other “dys-disorders” do often get given extra time at school for exams.  People with ADHD are often entitled to financial benefits in developed countries, and it has been suggested that these countries are the ones with high incidence of diagnosis.  In the US 11% of children and 4.4% of adults have a diagnosis.   ADHD has been medicalized in the U.S. since the 1960s.  In the UK, 3.62% of boys and 0.85% of girls have an ADHD diagnosis.  In France less than 0.5% of children are taking medication for ADHD.

Here is a nice quote:-

Why Are ADHD Rates 20 Times Higher in the U.S. Than in  France?

“it makes perfect sense to me that French children don't need medications to control their behavior because they learn self-control early in their lives. The children grow up in families in which the rules are well-understood, and a clear family hierarchy is firmly in place.

In French families, as Druckerman describes them, parents are firmly in charge of their kids—instead of the American family style, in which the situation is all too often vice versa.”



In the case of ADHD, it looks like the French have got it right; but not sadly for autism.

Knowing many different nationalities, I can certainly confirm that French parenting is much tougher than the UK or US variety.  The UK variety is very similar to the US, but without the liberal use of drugs for ADHD or indeed autism.

In tough cases of ADHD, that even French parenting cannot control, perhaps it really is a calcium channelopathy.  Perhaps in these cases a mild calcium channel blocker like fish oil, or indeed Olive Leaf Extract may be potent enough, so you could use these daily without the need for any prescription medication.

In any case, Verapamil, if shown effective, looks a much safer bet than the usual ADHD stimulants like Ritalin.  If your ADHD was caused by calcium channel dysfunction, it would likely later appear elsewhere in your body; all those years on stimulants would not have helped you.

Recall that Verapamil can also be effective in bipolar.