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?