The de-diagnosis of autism begins? And calcium channel blockers considered for ADHD, which type of ADHD and which blocker?

Stockholm – an autism diagnosis hotspot according to the psychologist Sebastian Lundström

Nordic countries often lead the way and after apparently over-diagnosing autism and ADHD they are now eager to de-diagnose it.

I received an article from the British Medical Journal which drew my attention.

Autism and ADHD de-diagnosing services could be rolled out in Sweden—should the US and UK follow suit?

Swedish authorities are considering requests for “de-diagnosis services” for autism and attention deficit/hyperactivity disorder (ADHD) from a new patient group: adults who no longer want their diagnosis.

The proposals come against the backdrop of an ongoing study on around 100 patients, all of whom joined the trial with the hope of getting their diagnostic labels removed. It could see de-diagnosis services rolled out in several of Sweden’s clinics in a matter of months, the study authors told The BMJ.

While “de-diagnosis” is gaining traction in Sweden, clinicians and patient groups who spoke to The BMJ were divided as to whether similar services should be set up in the UK or the US.

What is a de-diagnosis service?

The psychologist Sebastian Lundström, one of the study’s researchers, told The BMJ that his work on this new patient group was prompted by “the sheer number of people with these diagnoses who now are turning into adult age and being told that they can’t join the military services [or] the draft.”

Historically, Swedish citizens with an ADHD or autism diagnosis have been barred from joining the military or working as train drivers without a specific doctor’s note. They must also provide a medical certificate when applying for a driving licence.

At the Preventing Overdiagnosis Conference in Oxford earlier this month, Lundström said that diagnoses had been “assigned by well meaning clinicians” to an increasing number of Swedish children in recent years but that the label could often be “sticky.”

 

Preventing Overdiagnosis Conference in Oxford

In September 2025 there was a conference about overdiagnosis across a wide range of conditions, it was not just about autism and ADHD.

https://www.cebm.ox.ac.uk/preventing-overdiagnosis

But, it did have presentations like:

THE TIDAL WAVE OF ADHD AND AUTISM: INSIGHTS FROM PATIENTS, PROFESSIONALS AND PUBLIC HEALTH

 

Sebastian Lundström’s presentation is available on YouTube. It is very interesting for anyone interested in the skyrocketing level of autism diagnosis.

I have mentioned previously that since in schools in many Western countries more than 20% of kids are now seen as having special educational needs, do not be surprised if autism/ADHD rates eventually hit 20%.  ADHD does look like autism-lite to me and the genetic studies also back this up. So, expect that autism/ADHD reaches 20% of boys.

Now look at Stockholm.

It turns out that in Stockholm 5.9% of teenage boys now have an autism diagnosis and 15% have an ADHD diagnosis. Some will have both.

 

 

Here is the full video for those who think this must be a mistake, or that doctors in Stockholm have gone insane.

 

Now, much to psychiatrists' surprise, adult Swedes are coming forward and trying to delete their autism/ADHD diagnosis from their records. Being Sweden, everything is recorded centrally. In the first 100 cases that were re-evaluated 90% were found to have no symptoms of autism/ADHD. In the video Professor Lundström gives the reasons for the misdiagnosis. It ranges from the parents insisting to have one, to the doctor giving one so that the child can access extra help at school. In many European countries the diagnosis qualifies the child/parents for various social security payments.

There are some downsides in Sweden to be an adult with an autism/ADHD diagnosis. It can affect employment, driving, or securing insurance.

The subject of ADHD leads to the second half of this post. Here we reconnect with the theme of treatable ion channel dysfunctions that have become somewhat a hallmark of this blog.

  

Calcium channel blockers now considered for ADHD treatment

 Blood pressure drug could be a safer alternative for treating ADHD symptoms, finds study

Repurposing amlodipine, a commonly used blood pressure medicine, could help manage attention-deficit/ hyperactivity disorder (ADHD) symptoms, according to an international study involving the University of Surrey.

 

Here is the full study

 

Validation of L-type calcium channel blocker amlodipine as a novel ADHD treatment through cross-species analysis, drug-target Mendelian randomization, and clinical evidence from medical records

ADHD is a chronic neurodevelopmental disorder that significantly affects life outcomes, and current treatments often have adverse side effects, high abuse potential, and a 25% non-response rate, highlighting the need for new therapeutics. This study investigates amlodipine, an L-type calcium channel blocker, as a potential foundation for developing a novel ADHD treatment by integrating findings from animal models and human genetic data. Amlodipine reduced hyperactivity in SHR rats and decreased both hyperactivity and impulsivity in adgrl3.1−/− zebrafish. It also crosses the blood-brain barrier, reducing telencephalic activation. Crucially, Mendelian Randomization analysis linked ADHD to genetic variations in L-type calcium channel subunits (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3) targeted by amlodipine, while polygenic risk score analysis showed symptom mitigation in individuals with high ADHD genetic liability. With its well-tolerated profile and efficacy across species, supported by genetic evidence, amlodipine shows potential to be refined and developed into a novel treatment for ADHD.

 

This is not an entirely new finding, but prior research shows that crossing the blood barrier is a key factor. Drugs like Verapamil win over Amlodipine.

 

Brain-penetrant calcium channel blockers are associated with a reduced incidence of neuropsychiatric disorders 

Calcium channel blockers (CCBs) differ in their ability to penetrate into the brain. Pharmacoepidemiological studies suggest that CCBs as a class may have beneficial effects on the risks and outcomes of some psychiatric and neurological disorders. It is plausible but unknown whether this effect relates to their brain penetrance. To address this, we used the TriNetX electronic health records network to identify people prescribed a brain-penetrant CCB (BP-CCB), or those given amlodipine, a CCB with low brain penetrability. We created cohorts of patients who, prior to first CCB exposure, either had to have, or could not have had, a recorded ICD-10 diagnosis in any of the following categories: psychotic disorder; affective disorder (including bipolar disorder and major depressive disorder); anxiety disorder; substance use disorder; sleep disorder; delirium; dementia, or movement disorder. Cohort pairs were propensity score matched for age, sex, race, blood pressure, body mass index, and a range of other variables. The outcomes were the incidence of these disorders measured over a two-year exposure period. Matched cohort sizes ranged from 17,896 to 49,987. In people with no prior history of psychiatric or neurodegenerative disorder, there was a significantly lower incidence of most disorders with BP-CCBs compared to amlodipine, with risk ratios ranging from 0.64 to 0.88 and an overall risk ratio of 0.88, i.e. a risk reduction of 12%. In people who did have a prior psychiatric or neurodegenerative diagnosis, differences were much smaller, but again showed lower risks for several disorders with BP-CCBs compared to amlodipine. The differences were somewhat more marked in women and in people less than 60 years old. Results were similar when comparing BP-CCBs with verapamil and diltiazem. We also compared BP-CCBs with angiotensin receptor blockers, and found an overall risk ratio of 0.94 in favour of BP-CCBs, but with differential effects across disorders including a higher risk of psychotic disorder and dementia, but a lower risk for anxiety and sleep disorders. In some analyses, there was evidence of residual confounding even after the extensive matching, in that negative control outcomes showed a reduced incidence with BP-CCBs relative to the comparator cohort. In summary, CCBs that readily penetrate the brain are associated with a lower incidence of neuropsychiatric disorders, especially first diagnoses, compared to CCBs which do not. This may reflect their blockade of neuronal voltage-gated calcium channels. The findings encourage repurposing trials using existing BP-CCBs, and suggest that novel BP-CCBs with enhanced and more selective central actions might have greater therapeutic potential for psychiatric and neurodegenerative disorders.

  

Conclusion

I do not think de-diagnosis of autism/ADHD will catch on in the UK or US. Few countries have a centralized register of who has autism/ADHD and in general there are few downsides to adults holding a diagnosis, unlike in Sweden. If it affected your rights to drive a car and what you pay for insurance, there would be a long queue for de-diagnosis.

In the Swedish military conscription/assessment medical guidelines, autism spectrum disorders are listed among psychiatric/neurological conditions that can lead to exemption from service. Some patriotic young Swedes with autism/ADHD actually want to serve.

As conscription may return to other less patriotic European countries, you can expect an additional demand for adult autism diagnosis to avoid the draft!

When it comes to calcium channels, I think all bases have already been well covered in this blog.

I know of several different calcium and other channel blockers being used by readers, the latest being Journavx/suzetrigine, a new one approved in 2025, which blocks Nav1.8. Nicardipine is more likely to block Nav1.8 in the brain. Journavx was developed specifically to have poor CNS penetration to avoid central side effects. It targets acute pain situations where short-term opioid use would normally be considered. It all depends which Nav1.8 channels you want to block. But, if the blood brain barrier is impaired (as we know it is in certain types of autism) then more of the drug will enter the brain than expected.

An impaired blood brain barrier would also help Amlodipine to cross.

 

Regular readers of this blog will already know that calcium channels are dysfunctional across a wide range of disorders from bipolar, schizophrenia, autism, intellectual disability to epilepsy.

I was nonetheless surprised that a university in the United Kingdom would propose repurposing Amlodipine (an L type calcium channel blocker) to treat ADHD. Even if they are mistaken, at least they are showing signs of curiosity!

There is no single perfect calcium channel blocker for the brain.

If you want to target Cav1.2 you have a great option in Verapamil, because it is relatively selective for this channel and it crosses the blood brain barrier easily.

If you want to target Cav1.2 and Cav1.3 then Amlodipine appears the best drug, but it does not cross the blood brain barrier as well as Verapamil.

I think the ADHD researchers should start with Cav1.2, because we know 100% it can be blocked in the brain using Verapamil. Then compare the result with taking Amlodipine.

 

Pleiotropic Association of CACNA1C Variants With Neuropsychiatric Disorders

 

From this blog we know that both verapamil and amlodipine can be safely used in autism. A small number of people do have side effects and discontinue, but most do not have issues.

The effect of the two drugs overlap but are not identical. This matches what we know about what channels they block. Verapamil also has other effects:

·        Verapamil partially blocks Cav1.3

·        Verapamil partially blocks T-type channels (Cav3.1–3.3) particularly at higher doses.

·        Verapamil partially blocks potassium Kv channels.

The big advantage of Amlodipine is that it has a long half-life, so you take it once a day.

Verapamil needs to be taken 3 times a day, or in the extended release version.

I did look on Reddit and plenty of people with ADHD were commenting that taking Amlodipine for high blood pressure had not improved their ADHD symptoms.

Note that ADHD is another umbrella diagnosis and there will be many sub-types. For some people Amlodipine might well help. For some people ADHD is just a consequence of being glued to a smartphone all day, every day, for years on end. Guess what, 60% of adults with ADHD report chronic sleep problems.

The over liberal diagnosis of autism in Stockholm does look crazy. Maybe it is the Greta effect?

It is as if Stockholm has developed a new version of the old “Stockholm syndrome” — an emotional loyalty to the very diagnostic culture now being questioned. When 90% of adults seeking de-diagnosis are found not to have autism or ADHD, it suggests that what began as a well-meaning effort to help children may have trapped an entire system in its own narrative. Fancy that.

 

(The term “Stockholm syndrome” comes from a 1973 bank robbery in Stockholm, when hostages ended up sympathising with their captors — a classic case of misplaced loyalty.)

 

Is it safe to treat autism in very young children? Plus, the impact of impaired autophagy on cognition and treating SIB

This blog is full of clinical trials that use existing drugs that are repurposed to treat autism. One constant issue is whether the trial drug is free from side effects. Generally speaking side effects tend not to be a problem, but there always can be exceptions.

I was recently contacted by the parents of a two year old with a single gene (monogenic) type of autism and they want to treat their child to improve his outcome.  This is the youngest case I have encountered.

With monogenic autisms you often have clear indications from a very early age that something unusual is present. Once you have a diagnosis you quickly discover what issues the child is going to face. You therefore have a good idea of what will happen if you do nothing. Some other two year olds have delayed speech and other signs of autism, but within a couple of years develop normally – it was a case of delayed maturation.

I noted long ago that American autism doctors tend to want to treat younger patients with supplements rather than drugs.

The reality is that the sooner you start to correct a severe biological dysfunction the better the outcome will be. We even see that some treatments are only effective if given to toddlers. This makes perfect sense although it may be uncomfortable to accept.

I was looking for supporting evidence for very early intervention. I found a glowing report of the treatment of a 2 year old with Fragile X syndrome using Metformin. I am amazed Fragile X still remains untreated in most cases.

On examination at age 2 years, typical physical features of FXS were observed, and baseline laboratory findings were normal (see Table Table1).1). He was started on metformin at 25 mg of the liquid form that is 100 mg/ml at dinner, and his dose was gradually increased to 200 mg twice a day (bid) over 1 year (see Table Table1).1). After initiation of metformin, his sleep disturbance resolved, only occasionally awakening once for roughly 30 min. Two weeks after initiation, he went from stacking 3–4 blocks to stacking a tower of 11 or more blocks; within a few more weeks, he began building more complex structures comprised of different size blocks. He showed marked improvement in self‐help and motor activities, including toilet training, clearing the table and loading the dishwasher, brushing his own teeth, dressing independently, and learning how to make toast. His preschool teachers, who were unaware of metformin treatment, told his mother that “it's like something just clicked or he just woke up. He's a whole different kid.”

Source: Metformin treatment in young children with fragile X syndrome

Some drugs including bumetanide are already safely given to babies.

Nonetheless, it is a brave step to start treatment in a two year old. I did connect the parents to a reader of this blog whose child has the same syndrome but is a few years older.

Today’s post was prompted by the news that the child is already showing improvements from the first therapy, which is a small dose of clemastine. In this syndrome there is a mutation in TCF4 and there is impaired myelination and very likely activated microglia (the brain’s immune cells). The near immediate beneficial effect cannot be on myelination, but it could be resetting microglia to the resting state.

Other genes very recently raised have been TRIT1 and PSMB9; neither of these are classed as autism genes, but evidently can cause it. Mutations in TRIT1 cause a problem in the mitochondria and PSMB9 mutations cause the immune system to misbehave.  It looks like both can lead to an autism diagnosis.

A common issue parents encounter is that often the interest shown by researchers and clinicians stops at the point of diagnosis. What really matters is what to do next. Only very rarely will such “experts” suggest what to do next. 

It looks like there nearly always are therapeutic avenues to pursue after such a diagnosis. It should be noted that even in single gene (monogenic) autisms there are varying levels of response to the same therapy. We saw this a while back with the new FDA approved therapy for Rett syndrome – it works for some, but not for others.

 

Treating self injurious behavior (SIB) in idiopathic autism

I recently received feedback from several parents who have had success in treating SIB based on ideas in this blog.

Verapamil came up again as successful.

Pioglitazone, at a low dose of 7.5mg, was the game changer for one child.

Ibuprofen worked in another case, but this cannot be used long term. Celecoxib should be better tolerated and in theory should be as effective. Time will tell.

More people are trying the add-on therapy of a small dose of taurine.

 

Macroautophagy as a cause of impaired cognition

Impaired autophagy came up recently in two people’s genetic testing results. There is a lot in this blog about autophagy and dementia/mild cognitive impairment.

Today we have a paper that links impaired autophagy with impaired cognition.

Twenty years ago severe autism generally also meant impaired cognition. Nowadays it does not; you can have severe autism with normal cognition.

There are various different types of autophagy but in general it is all about collecting bits of cellular garbage that might clog things up. As we get older this intracellular garbage collection process works less well and then diseases like Alzheimer’s follow decades later.

Impaired autophagy may contribute to impaired cognition at any age. Most research concerns dementia treatment, or other conditions affecting older people like Huntington’s disease.

There is little focus on younger populations, even though we know that children with Down syndrome are prone to get early onset Alzheimer’s. Treating young people with Down syndrome to improve autophagy might bring both short and long term benefits. 

Here is the recent paper on this subject. 

Impaired macroautophagy confers substantial risk for intellectual disability in children with autism spectrum disorders

Autism spectrum disorder (ASD) represents a complex of neurological and developmental disabilities characterized by clinical and genetic heterogeneity. While the causes of ASD are still unknown, many ASD risk factors are found to converge on intracellular quality control mechanisms that are essential for cellular homeostasis, including the autophagy-lysosomal degradation pathway. Studies have reported impaired autophagy in ASD human brain and ASD-like synapse pathology and behaviors in mouse models of brain autophagy deficiency, highlighting an essential role for defective autophagy in ASD pathogenesis. To determine whether altered autophagy in the brain may also occur in peripheral cells that might provide useful biomarkers, we assessed activities of autophagy in lymphoblasts from ASD and control subjects. We find that lymphoblast autophagy is compromised in a subset of ASD participants due to impaired autophagy induction. Similar changes in autophagy are detected in postmortem human brains from ASD individuals and in brain and peripheral blood mononuclear cells from syndromic ASD mouse models. Remarkably, we find a strong correlation between impaired autophagy and intellectual disability in ASD participants. By depleting the key autophagy gene Atg7 from different brain cells, we provide further evidence that autophagy deficiency causes cognitive impairment in mice. Together, our findings suggest autophagy dysfunction as a convergent mechanism that can be detected in peripheral blood cells from a subset of autistic individuals, and that lymphoblast autophagy may serve as a biomarker to stratify ASD patients for the development of targeted interventions.

 

There are different types of autophagy and there are some overlaps. 

·      mTOR dependent (Fasting or Rapamycin)

·      AMPK dependent (Spermidine)

·      P53 dependent (no simple therapies)

·      Calcium signalling dependent (Verapamil)

The OTC way to increase autophagy is to use Spermidine, which is made from wheat germ or rice germ. Studies in humans are rather mixed and I think the dose is likely far too low. Supplements tend to contain about 1mg; I suspect you need much more to have an impact. You can indeed grow your own wheat sprouts which are highly nutritious and a rich source of spermidine. You can eat them raw or even in smoothies. 100 g of sprouts contains 10-15mg of spermidine.

The most researched calcium channel drug to induce autophagy is Verapamil, from my son’s original autism Polypill.

My takeaway continues to be to look for convergent mechanisms, like impaired autophagy, myelination, microglial activation etc that commonly occur in severe autism, of any origin. You then try and treat these likely dysfunctions rather than getting overly focused on individual genes.

 

Differential Diagnosis and Treatment in Autism – Verapamil & Curcumin for Williams Syndrome?

 

The face of Williams syndrome kids. Source: Figure 2.  GeneReviews® - NCBI Bookshelf

Continuing from the last post, today we look again at differential diagnosis and treatment, which I prefer to just call personalized medicine.

This is the subject of a conference for parents in the UK, that I agreed to draw to the attention of readers.

 

Click on the picture above to read about the upcoming event in London.

 

 

Williams syndrome

Williams syndrome: MedlinePlus Genetics (click for info)

Williams syndrome occurs when someone is missing a small piece of chromosome 7, resulting in them lacking 25 to 27 genes. Most people with Williams syndrome have not inherited the condition from a parent.

Williams syndrome can delay a child’s milestones including:

·         Learning (mild to moderate intellectual challenges)

·         Saying their first words and talking

·         Sitting and walking

Socializing is unusual – there is excessive empathy. A child will be outgoing and very friendly, but has difficulty identifying strangers. There may be attention problems, phobias, or anxiety.

Williams is another syndrome with distinct facial features that can help with diagnosis.

·         Large ears

·         Full cheeks

·         Small jaw

·         Wide mouth

·         Small teeth

·         Upturned nose

Williams syndrome is still viewed as untreatable.

In this blog we always start from the basis that all severe autism is potentially treatable.  Often some of the downstream effects of genetic mutations overlap with other types of autism and some of these effects actually are treatable.

There is a great deal in this blog about targeting both calcium channels and potassium channels to treat autism. Verapamil and Ponstan are the two drugs I have written most about.

Curcumin is an OTC therapy for autism that has been widely covered in this blog and people do regularly write to me to tell me that it is beneficial.  Just last week a reader told me that both Ponstan and Curcumin are beneficial in his specific case.

I was intrigued to read the paper from Spain below where the researchers found the combination of Verapamil + Curcumin to improve behaviors in Williams syndrome.  The mechanism was found to be by regulation of MAPK pathway and microglia overexpression.

 

Verapamil + Curcumin to treat the behavioral issues in Williams syndrome

One key takeaway is that in the model of Williams syndrome you need both verapamil (VER) and curcumin (CUR). Either intervention on its own provided no benefit – you need the combination (VERCUR). 

Co-Treatment With Verapamil and Curcumin Attenuates the Behavioral Alterations Observed in Williams–Beuren Syndrome Mice by Regulation of MAPK Pathway and Microglia Overexpression

Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there are currently no effective treatments. We investigated the progression of behavioral deficits present in WBS complete deletion (CD) mice, after chronic treatment with curcumin, verapamil, and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and, thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism. CD mice showed an increased density of activated microglia in the motor cortex and CA1 hippocampal region, which was prevented by co-treatment. Behavioral improvement correlated with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation to the control of synaptic transmission, and inflammation. Therefore, the results show that co-treatment prevented behavioral deficits by recovering altered gene expression in the cortex of CD mice and reducing activated microglia. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients.

Accumulated evidence has described that curcumin, the major constituent of turmeric (Curcuma longa), exerts a variety of pharmacological effects due to its antioxidant, anti-inflammatory, and neuroprotective properties. Recent studies have reported positive effects of curcumin over different cognitive aspects such as anxiety-like behaviors, memory deficits, and motor impairments of different murine models Many studies have described that its effects on the behavioral phenotype of mice models are mediated by upregulation of BDNF (brain-derived neurotrophic factor) expression BDNF has been described as a crucial molecule for neural development and plasticity processes and its mechanism of action is highly dependent on a proper maintenance of intracellular ionic homeostasis Moreover, it has also been described to prevent neuroinflammation by modulating pathways related to NRF2 and MAPK signaling.

Verapamil is a widely used medication, and its mechanism of action involves mainly the blocking of voltage-dependent calcium channels, but it has also been proven to directly bind and block voltage-gated potassium channels  and to inhibit drug efflux pump proteins like P-glycoprotein. Although it has been mainly studied for cardiovascular applications, it has also been associated with positive effects on anxiety and memory processing in murine models.

Given the properties of both compounds, we decided to explore the effects of each compound and a combinatorial treatment on the behavioral phenotype of CD mice. The results show that only the combined treatment with curcumin and verapamil improved the deficits. This improvement can be correlated with the normalization of the MAPK and inflammasome signaling pathways and with the concomitant reduction of activated microglia. 

·   The Increased Microglia Activation in Motor Cortex and Hippocampus Presented by CD Mice Is Prevented by VERCUR Co-Treatment

·    Combinatorial Treatment Prevents Hypersociability of CD Mice

·    Only VERCUR Co-Treatment Improves Motor Coordination in CD Mice

·    VERCUR Co-Treatment Prevents Gene Expression Changes in Cortex of CD Animals

·    Neuroanatomical Features of CD Mice Do Not Change After VERCUR Co-Treatment

In conclusion, we suggest that the hemizygous loss of WBSCR in the cerebral cortex of CD mice has a direct effect on the neuroinflammatory state of the brain, as well as on the expression of some genes related to synaptic signaling or extracellular matrix structure, which are crucial for a proper neural function. This may at least be partly responsible for the behavioral phenotype observed in CD animals. A treatment combining verapamil and curcumin is able to address different molecular targets and rescue some of those pathways, being a promising therapeutic approach for the cognitive phenotype of WBS patients.

  

Conclusion 

Today’s study was in a mouse model of William’s syndrome; clearly it would be more informative if the researchers had tried it on humans.  It does though raise the question as to what other treatments from idiopathic autism might be effective in this supposedly untreatable genetic condition.

The other perspective of course is to wonder what other types of autism might benefit from Verapamil plus curcumin (VERCUR). It was interesting to note that in the model neither Verapamil nor curcumin was effective by itself, they needed the combined therapy (VERCUR).

If you read the experiences that have been shared over the years in this blog you can see that some parents spend a lot of money on genetic testing, hoping to improve their child’s outcome.  It is only very rarely that you see any great success resulting.

The alternative approach is understand the commonly shared biological features of autism and try and treat those, to see whether the individual shows a benefit.  Where there is a positive response, it is a “keeper,” if there is no response, or a negative response, the therapy is dropped.  Essentially it is a process of trial and error.  Not as fancy as genetic testing, but it works.

Clearly if your child has Williams syndrome you would be well advised to look up the function of each of the 26 missing genes, to see if there are any obvious steps to take. One good tool to use is www.genecards.org.  

Old posts that refer to cucumin:

Epiphany: Curcumin (epiphanyasd.com)

 

Old posts that refer to verapamil

Epiphany: Verapamil (epiphanyasd.com)

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?