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?