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?

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 (19–21). 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 (22–28). Some studies have anecdotally noted the occurrence of SIB with this drug (23–25, 27), 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) Ca_v1.2 and Ca_v1.3, 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 Ca_v1.2- and Ca_v1.3-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.

Pioglitazone for Autism and Specifically Summertime Raging and Verapamil-responsive Autism?

 

Adult-sized people with autism can cause property damage and much worse.

I am told that summertime raging is a common problem encountered by neurologists, but it remains poorly understood and usually remains untreated.

The most common worry for parents of toddlers diagnosed with severe autism is their lack of speech.

By the time these children reach adulthood, the biggest worry for parents is often aggression and self-injury. Often it is the mother who faces the worst episodes of aggression, which is a really cruel turn of events.

Aggression is usually not present in young children with autism, in some people it never develops, but in others it later becomes established as a learned behavior and then you are stuck with how to deal with it.

One of my own therapy targets has long been to improve cognitive function; this can indeed be achieved and then you can improve important daily living skills (adaptive function). Some steps that you can take to improve cognition, and indeed speech, have a downside in that they increase anxiety, which may lead to aggression. Calcium Folinate (Leucovorin) does cause aggression in a significant minority of people.  I think that low dose Roflumilast (60mcg) is cognitive enhancing, as proposed by the researchers at 100mcg, but it does seem to increase edginess/anxiety. DMF (Dimethyl fumarate) increases alertness, which is a good thing, but too much alertness will make you anxious.

When dealing with a full sized adult, which is more important, increased cognition/speech or avoiding explosive aggression?

Clearly there is a need for a compromise.

In adults with severe autism, living at home, entirely extinguishing aggressive behavior looks like the number one treatment goal.

For children in mainstream school, following the regular curriculum, cognitive function has to be a top priority.  Fortunately, this is our case, but only after starting Bumetanide therapy in 2012.

It looks like you can potentially have the best of both worlds - increased IQ and adaptive function, but without aggressive behavior. That is my own experience, but it was not simple.

Pioglitazone has been covered quite extensively in this blog and it is again featuring in the research. Pioglitazone is an interesting old drug used to treat people with type 2 diabetes; the phase 2 trial for autism has been completed.  I doubt there will be a phase 3 trial due to the high costs. Pioglitazone is broadly anti-inflammatory; it reduces the pro-inflammatory cytokine IL-6 and increases the anti-inflammatory cytokine IL-10.

We have seen in early posts how important is IL-6 and that it plays a key role in both allergy and even how milk teeth roots “dissolve” and then permanent teeth erupt. This transition to permanent teeth is another common cause of raging in autism, in our case it was mostly wintertime raging. 

IL-6, either directly or indirectly, seems to negatively affect behavior.

 

PPAR gamma

In earlier posts there was a lot about the various PPARs. These are used in medicine as targets to treat conditions like high cholesterol and type 2 diabetes.

Resveratrol and Pterostilbene are the OTC supplements that some readers are using. Sytrinol is another such supplement, but its cognitive benefit unfortunately just lasts a few days.

Here is a relatively recent paper on the subject, for those seeking the details. 

 

Nuclear Peroxisome Proliferator-Activated Receptors (PPARs) as Therapeutic Targets of Resveratrol for Autism Spectrum Disorder

 

Or just look up the old posts in this blog:- 

https://epiphanyasd.blogspot.com/search/label/PPAR%CE%B3

PPARs are rather complicated, but do seem to be very relevant.  For example, the master regulator of mitochondrial biogenesis, something called PGC-1 alpha, is activated by PPAR gamma. If you have mitochondrial dysfunction that included a reduced number of mitochondria, you might want to make more mitochondria. A PPAR gamma agonist might be beneficial.

Dysregulation of PGC-1 alpha is associated with neurodegenerative and metabolic disorders including Parkinson's, Alzheimer's and Huntington's.

Outside this blog, there is some interest in PGC-1 alpha and autism, particularly in connection with oxidative stress and mitochondrial dysfunction.

 

“In conclusion, we demonstrated mitochondrial oxidative stress may affect a significant subgroup of ASD children and that the SIRT1/PGC-1α signaling pathway may be a promising medical treatment for ASD.”

Source: Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder

It does look like PPARs can be targeted and provide a benefit for at least some types of autism. My choice is Pioglitazone.

 

Dumber in the Summer

In parallel with summertime raging comes the phenomenon I called “Dumber in the Summer”, where cognitive function regresses.

Monty’s assistant told me recently there is no “Dumber in the Summer” this year, and I opened my medicine cupboard and explained why this is indeed the case.

At least in our case, when you resolve summertime raging, you also protect against cognitive regression. That therapy involves Verapamil, Pioglitazone and allergy therapies, Dymista spray (azelastine + fluticasone) plus Ceterizine and Clemastine. Clemastine also has the pro-myelination effect and stabilizes microglia.

 

Pioglitazone Side effects

In the stage 2 trials for autism doses of 0.25 mg/kg, 0.5 mg/kg and 0.75 mg/kg were all found to be safe and well tolerated.

As a summertime add-on therapy it appears very well tolerated.

In adults with type 2 diabetes, who will tend to be overweight and not so healthy, there are common side effects.  At one point, it was thought that there was an association between this drug and bladder cancer. Now this is thought not to be the case.

For adults with severe untreated autism, who are aggressive and self-injure, these behaviors very much limit where they can live and what they can do during the day. Life expectancy is also severely reduced. If Pioglitazone can help control these behaviors, some side effects are likely a price worth paying. 

 

Conclusion

Pioglitazone, by the standards of autism drugs, has plenty of evidence in the literature, regarding both mouse models and humans, to support an n=1 trial.  It addresses neuro-inflammation, one key feature of autism and it has beneficial effects on mitochondria.

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway

In a small cohort of autistic children, daily treatment with pioglitazone eased some autistic behaviors, such as irritability, lethargy, stereotypy, and hyperactivity, without significant side effects

 pioglitazone treatment inhibits the secretion of proinflammatory factors, such as nitric oxide and IL-6, and enhances the levels of the secretion of anti-inflammatory factors IL-4 and IL-10. Therefore, considering the results of Qiu and Li and our present findings, pioglitazone acted to benefit autistic-like behaviors possibly via the inhibition of IL-6 secretion in astrocytes stimulated by LPS, which inhibited the neuroinflammatory response.

 

I think for people whose child with autism has a behavioural or cognitive regression in summer, there is good reason to expect a benefit.  They very likely have allergies or other autoimmune conditions.

For people who deal with aggression and self-injury in a person who responds partially, but not 100%, to Verapamil, they may find that Pioglitazone helps to complete their anti-aggression therapy.

Our doctor reader Agnieszka did her best to collect case studies of people with autism responsive to Verapamil, but not enough parents wanted to participate.

Based on the comments section in this blog, it would look like our reader George in Romania has a son whose son’s aggression is reduced by Verapamil.  If some aggression persists in summer, I think there is a very good chance that Pioglitazone will help reduce it.  George did recently share with us the the anti-inflammatory Probiotic Lactobacillus Plantarum 299v, from the previous post and widely used for irritable bowel syndrome (IBS), improved his son's speech.  

Note that the research clearly shows that most autism has an "inflammatory" element, but the exact nature varies (for details read the work of Paul Ashwood at the MIND Institute).  There are very many different anti-inflammatory therapies that are reported to benefit specific people, but there are no unifying therapies that work for all. Some will inevitably make non-responders worse and potentially dramatically so, like L.reuteri ATCC PTA 6475, found in Biogaia Gastrus. Trial and error seems unavoidable if you want to find an effective therapy.

The research proposes Pioglitazone as a year round therapy for idiopathic autism.  In the phase 2 trial almost half of the children were deemed to be responders to the treatment; not a bad result. I think it also has potential as just a summertime add-on therapy. We used it last summer and now again this summer.

People with a diagnosis of mitochondrial disease, who also present with lethargy, might be another target group because of PGC-1 alpha.

Summertime Autism Raging and Dumber in the Summer

By far the most read post in this blog is one about histamine and allergies, which means many people are searching on Google for “histamine, allergy and autism”.

Our reader Kei recently commented that his daughter, without allergy, was again showing signs of summertime raging and that his neurologist confirmed that summertime raging does indeed happen and nobody knows why.

I did figure out how to deal with our version of “summertime raging” and the post-bumetanide “dumber in the summer” phenomena.  There were several posts on this subject.  The lasting solution was to treat the raging as if it was caused by inflammation driven by pollen allergy and to note that inflammation will further worsen the KCC2/NKCC1 imbalance in Bumetanide-responsive autism, making those people appear “dumber in the summer”.  This also accounts for the “Bumetanide has stopped working” phenomenon, reported by some parents.  You need to minimize inflammation from allergy and increase Bumetanide (or add Azosemide).  My discovery was that Verapamil was actually more effective than anti-histamines and actual mast cell stabilizers. Mast cells degranulate via a process dependent of the L-type calcium channels that Verapamil blocks. Mast cells release histamine and inflammatory cytokines like IL-6.

This spring when Monty’s brother asked why Monty was acting dumber, it was time to implement the “dumber in the summer” therapies.  Add a morning tablet of cetirizine (Zyrtec) and a nasal spray of Dymista (Azelastine + Fluticasone).

Dymista is inexpensive and OTC where we live, but I see in the US it is quite an expensive prescription drug.  It is a favourite of Monty’s pediatrician and his ENT doctor. 

Summertime Regression in the Research Literature

I recently came across two very relevant papers on this subject by a proactive American immunologist called Dr Marvin Boris.  If you live in New York, he looks like a useful person to know.

In his first study he investigated whether the onset of the allergy season caused a deterioration in behavior of children with autism or ADHD; in more than half of the trial subjects, it did.

In his second study he went on to make a double‐blind crossover study with nasal inhalation of a pollen extract or placebo on alternate weeks during the winter.  This was his way to recreate the pollen season during winter.

Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms.

In other words, half of children with autism regress when exposed to pollen, even though they may not show any symptoms of allergy, or test positive for allergy.  This should be of interest to Kei and his neurologist.

Pollen Exposure as a Cause for the Deterioration of Neurobehavioral Function in Children with Autism and Attention Deficit Hyperactive Disorder

Purpose: To determine whether children with autistic spectrum disorders (ASD) or attention deficit hyperactive disorder (ADHD) exhibit neurobehavioral regressive changes during pollen seasons.

Design: A behavioral questionnaire‐based survey, with results matched to pollen counts; an uncontrolled, open non‐intervention study.

Materials and Methods: Twenty‐nine children identified with ASD and 18 children with ADHD comprised the study population. The parents of the study children completed the Allergic Symptom Screen for 2 weeks during the winter prior to the pollen allergy season under investigation. The parents of the ASD children also completed the Aberrant Behavior Checklist and the parents of the ADHD children completed Conners' Revised Parent Short Form for the same periods. The parents completed the respective forms weekly from 1 March to 31 October 2002. Pollen counts from the geographical area of study were recorded on a daily basis during this period.

Results: During natural pollen exposure, 15 of 29 (52%) children with ASD and 10 of 18 (56%) children with ADHD demonstrated neurobehavioral regression. There was no correlation with the child's allergic status (IgE, skin tests and RAST) or allergy symptoms.

Conclusions: Pollen exposure can produce neurobehavioral regression in the majority of children with ASD or ADHD on a non‐IgE‐mediated mechanism. Psychological dysfunction can be potentiated by environmental exposures. 

Pollen Exposure as a Cause for the Deterioration of Neurobehavioral Function in Children with Autism and Attention Deficit Hyperactive Disorder: Nasal Pollen Challenge 

Purpose: In a previous study it was established that children with attention deficit hyperactive disorder (ADHD) and autistic spectrum disorders (ASD) had regressed during pollen seasons. The purpose of this study was to determine if these children regressed on direct nasal pollen challenge. 

Design: A double‐blind crossover placebo‐controlled nasal challenge study. Materials and Methods: Twenty‐nine children with ASD and 18 with ADHD comprised the population. The study was a double‐blind crossover with nasal instillation of a pollen extract or placebo on alternate weeks during the winter. The pollens used were oak tree, timothy grass and ragweed. The dose insufflated into each nostril was 25 mg (±15%) of each pollen. 

Results: Sixteen of 29 (55%) children with ASD and 12 of 18 (67%) children with ADHD or a total of 28 of 47 (60%) children regressed significantly from their baseline. 

Nasal pollen challenge produced significant neurobehavioral regression in these children. This regression occurred in both allergic and non‐allergic children and was not associated with respiratory symptoms. There was no correlation to the child's IgE level, positive RAST pollen tests, or skin tests.

Conclusion

When I was figuring out Monty’s summertime raging and cognitive decline, several years ago, there were no significant signs of allergy present.  Nowadays there are far more visible signs of allergy.

Dr Boris does not suggest any therapy for summertime raging, but he did show that it can be driven by pollen in half of those with autism, even children who have no signs of having any allergy.

His studies were published more than a decade ago and seem to have been forgotten.  This seems a pity, but it says a lot.

I only stumbled upon his papers because I was reading another of his decade old papers.  That paper is based on his early use of Pioglitazone in autism, which resulted in several hundred children being successfully prescribed this drug.  Pioglitazone selectively stimulates the peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α.

There was a bladder cancer scare, lots of hungry lawyers and I suppose people stopped prescribing Pioglitazone for autism a decade ago.  The numerous subsequent safety studies and meta-analysis show either a small increased risk, or no increased risk, very much dependent on who financed the research.  Pioglitazone is given to people with type 2 diabetes, and they are already at an increased risk of bladder cancer.  In those people, that risk increases between 0 and about 20%, depending on the study.  We are talking about 0.07% to 0.1% of people with T2 diabetes taking Pioglitazone later developing bladder cancer.

A decade later and Pioglitazone is again back in fashion with trials in humans with autism and studies in mouse models of autism. The current autism research does not see cancer risk as reason not to use Pioglitazone.  I agree with them. 

It looks like a minority of people taking Pioglitazone are more likely to suffer upper respiratory tract infections.  That is the risk that I consider relevant.  I also note that in trials even the placebo can appear to cause upper respiratory tract infections.

Pioglitazone was covered in earlier posts, 

https://epiphanyasd.blogspot.com/search/label/pioglitazone

but there will soon be a new post.  For most people I think histamine, allergy and summertime raging will continue to be of more interest.

Bumetanide for TSC-type Autism, Verapamil now for sinusitis, Lower dose Folinic Acid looks interesting for Autism in France, Roche cuts Balovaptan and Basmisanil; Stanford continue repurposing Vasopressin for Autism

 Repurposing what already exists – cheap, safe, effective and sometimes colourful

Today’s post is nice and simple.

Yet another sub-type of autism is shown in a clinical trial to respond to the cheap drug bumetanide, this time it is children diagnosed with TSC (tuberous sclerosis complex); TSC is a leading genetic cause of autism often used in research.

In France researchers repurposed Folinoral, a lower dose equivalent of Dr Frye’s, and our reader Roger’s, Leucovorin to treat autism with a positive result.  Folinoral is Calcium Folinate, but the dose was just 5mg twice a day, much less than the dose used in the US research.

The potential off-label uses for Verapamil, the old calcium channel blocker helpful in some autism, continue to grow.

Original purpose:  

Lower blood pressure by blocking L-type calcium channels

Alternative uses:

·        Treating bipolar disorder

·        Treating cluster headaches and some migraine

·        Halting the loss of insulin production in people with diabetes

·        Treating diarrhea-predominant irritable bowel syndrome (IBS-D)

·        Treating aggression/anxiety in some autism

We can now add, as our reader Lisa discovered by chance,

·        Treating chronic sinusitis

Patients with severe chronic rhinosinusitis show improvement with Verapamil treatment

"Recently, we became aware that some of the inflammation in chronic rhinosinusitis (CRS) with nasal polyps is generated by the nasal lining itself, when a particular protein pump (P-glycoprotein) is overexpressed and leads to the hyper-secretion of inflammatory cytokines," said senior author Benjamin S. Bleier, M.D., a sinus surgeon at Mass. Eye and Ear and an assistant professor of otolaryngology at Harvard Medical School. "Verapamil is a first-generation inhibitor that is well-established in blocking P-glycoprotein. In some patients with CRS with nasal polyps, we saw dramatic improvement in their symptom scores."

Roche ditching experimental autism drugs

Basmisanil which targets the alpha 5 sub-unit of GABA_A receptors was originally being developed to improve cognition in Down Syndrome; those clinical trials failed. Now Roche have pulled the plug on the trials to improve cognition in Schizophrenia.

Balovaptan was Roche’s expensive bet on Vasopressin to treat autism, covered in earlier posts; it blocks the activity of the V1a vasopressin receptor.  The Balovaptan phase 3 clinical trials have also been cancelled.

Roche culls key phase 3 drug trials, including a cancer med and an autism 'breakthrough'therapy

Stanford still pursuing Vasopressin for autism

Stanford’s bet on Vasopressin for autism is still ongoing.  They had the much simpler idea of just putting some pharmaceutical-grade vasopressin in a nasal spray and trialling that.

Intranasal delivery of drugs to target the brain appeals to me, as do eye drops.  Your eyes are part of the central nervous system, in the case of your nose it appears that drugs are transported directly to the brain from the nasal cavity along the olfactory and trigeminal nerves. 

Mechanism of intranasal drug delivery directly to the brain

One feature of this blog is a belief that central hormonal dysfunction is a core feature of much autism.  The big problem is that you cannot easily measure hormone levels in the central nervous system (CNS) and you may get quite contradictory results measuring hormone levels in blood samples.

Plasma oxytocin and vasopressin do not predict neuropeptide concentrations in human cerebrospinal fluid.

I was encouraged to see that the Stanford vasopressin researchers measured vasopressin in samples from spinal fluid.  They found that children who went on to be diagnosed with autism has very low levels of vasopressin in their brains early in life. Making it a potential biomarker.

Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder

Autism spectrum disorder (ASD) is a brain disorder characterized by social impairments. ASD is currently diagnosed on the basis of behavioral criteria because no robust biomarkers have been identified. However, we recently found that cerebrospinal fluid (CSF) concentration of the “social” neuropeptide arginine vasopressin (AVP) is significantly lower in pediatric ASD cases vs. controls. As an initial step in establishing the direction of causation for this association, we capitalized upon a rare biomaterials collection of newborn CSF samples to conduct a quasi-prospective test of whether this association held before the developmental period when ASD first manifests. CSF samples had been collected in the course of medical care of 0- to 3-mo-old febrile infants (n = 913) and subsequently archived at −70 °C. We identified a subset of CSF samples from individuals later diagnosed with ASD, matched them 1:2 with appropriate controls (n = 33 total), and quantified their AVP and oxytocin (OXT) concentrations. Neonatal CSF AVP concentrations were significantly lower among ASD cases than controls and individually predicted case status, with highest precision when cases with comorbid attention-deficit/hyperactivity disorder were removed from the analysis. The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT. These preliminary findings suggest that a neurochemical marker of ASD may be present very early in life, and if replicated in a larger, prospective study, this approach could transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.

  

Easy to read version: -

Potential autism biomarker found in babies

Cerebrospinal fluid levels of a hormone called vasopressin were lower in babies who went on to develop autism than in those who did not, a study found. 

Cerebrospinal Fluid Vasopressin and Symptom Severity in Children with Autism

 

Cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration differs between children with and without autism (AUT), predicts AUT diagnosis, and predicts symptom severity. (A) CSF AVP concentration is lower in children with AUT (n = 36) compared to control children (n = 36), whereas (B) CSF oxytocin (OXT) concentration does not differ between groups. 

(C) The effect of CSF AVP concentration on predicted (line) and observed (symbols) group is plotted, corrected for the other variables in the analysis. Children with AUT plotted above, and control children plotted beneath, the dashed line (which represents 50% probability) are correctly classified. Specifically, across the range of observed CSF AVP concentrations, the likelihood of AUT increased over 1,000-fold, corresponding to nearly a 500-fold increase in risk with each 10-fold decrease in CSF AVP concentration (range odds ratio = 1,080, unit odds ratio = 494, β1 ± SE = −6.202 ± 1.898). (D) CSF AVP concentration predicts Autism Diagnostic Observation Schedule (ADOS)–Calibrated Severity Score (CSS) in male but not in female children with AUT.

I think many hormones are likely disturbed in autism and that modifying them is one potential method of treating autism.

At Stanford they have already had success by squirting vasopressin up kids’ noses:-

Hormone reduces social impairment in kids with autism

In a Stanford study of 30 children with autism, intranasal vasopressin improved social skills more than a placebo, suggesting that the hormone may treat core features of the disorder.

A RANDOMIZED CONTROLLED TRIAL OF INTRANASAL VASOPRESSIN TREATMENT FOR SOCIAL DEFICITS IN CHILDREN WITH AUTISM

Stanford University, Department of Comparative Medicine, Stanford Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments and restricted, repetitive behaviors. Despite ASD’s prevalence, there are currently no medications that effectively treat its core features. Accumulating preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in mammalian social functioning, may be a possible treatment for ASD. Objective: The goal of this investigation is to examine the safety and efficacy of AVP in the treatment of social deficits in children with ASD. Material and Methods: Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-week intranasal AVP treatment in a sample of N=30 children with ASD aged 6-12 years. Results: AVP compared to Placebo treatment significantly enhanced social abilities in children with ASD as measured by change from baseline in the trial’s primary outcome measure, the Social Responsiveness Scale (a parent-report measure). AVP-related social improvements were likewise evident on clinician impression and child performance-based measures. AVP treatment also diminished anxiety symptoms and some restricted/repetitive behaviors. An endogenous blood AVP concentration by treatment group interaction was also observed, such that participants with the highest pre-treatment blood AVP concentrations benefitted the most from AVP (but not Placebo) treatment. AVP was well tolerated with minimal side-effects. No AVP-treated participant dropped out of the trial, and there were no differences in adverse event rates reported between the AVP and Placebo groups. Finally, no significant changes from baseline were observed in electrocardiogram, vital signs, height and weight, or clinical chemistry measurements after 4-week AVP treatment. Conclusions: These findings suggest that intranasally administered AVP is a well-tolerated and promising medication for the treatment of social impairments in children with ASD.

Using a double-blind, randomized, placebo-controlled, parallel clinical trial design, we found that the 4-week intranasal AVP treatment enhanced social abilities in children with ASD as assessed by the trial’s primary outcome measure, the SRS-2 T score. The robustness of this parent-reported social improvement score was corroborated by convergent evidence from clinician evaluation of the social communication abilities of trial participants and by performance of trial participants on laboratory tests of social cognition. These preliminary findings suggest that intranasally administered AVP may be a promising medication for treatment of core social impairments in children with ASD.

We also sought to investigate whether pretreatment neuropeptide concentrations in blood could predict AVP treatment response. We found that participants with the highest pretreatment AVP concentrations in blood benefitted the most from intranasal AVP treatment. This finding may seem counterintuitive, particularly in light of our recent studies showing that low AVP concentrations in CSF could be used to differentiate ASD cases from non-ASD control individuals (13, 14). One might therefore expect that it would be those children with the lowest endogenous AVP concentrations that stood to benefit the most from intranasal AVP treatment. However, being mindful of safety in this pediatric population, our pilot study used a conservative dose escalation regimen in which children were treated with fairly low doses of AVP throughout much of the trial. Assuming that blood AVP concentrations are related, in some manner, to brain AVP activity—a notion about which there is debate (14, 22–25)—it is possible that participants with lower endogenous AVP concentrations at the trial’s outset were “underdosed” in terms of drug amount or duration of treatment and, therefore, would not benefit as fully from AVP administration as those with higher endogenous AVP concentrations. This interpretation is consistent with our finding that AVP treatment enhanced simple social perceptual abilities independent of pretreatment AVP concentrations in blood, whereas it was only those AVP-treated individuals with higher pretreatment blood AVP concentrations who showed gains in complex social behaviors and a reduction in repetitive behaviors.

Pharmacological intervention

Commercially available injectable sterile AVP was used in this study. It was initially purchased from JHP Pharmaceuticals (Rochester, MI), which was subsequently acquired by Par Sterile Products (Chestnut Ridge, NY) in 2014. The placebo solution was prepared by Koshland Pharm (San Francisco, CA) and consisted of ingredients used in the active solution except for the AVP compound. A pharmacist transferred 25 ml of AVP (20 International Units (IU)/ml) or placebo solutions into standard sterile amber glass bottles with metered (0.1 ml per puff) nasal spray applicators to ensure that the AVP and placebo applicators were visually indistinguishable to the research team. These applicators were coded and given to the Stanford Health Care’s Investigational Drug Service for refrigerated storage (2°C to 8°C) and subsequent dispensing. After the first AVP dose (see below), the dose-escalation regimen at home for all participants involved administration of 4 IU twice daily (or BID) of AVP during week 1 and 8 IU BID of AVP during week 2. Participants aged 6 to 9.5 years then received 12 IU BID of AVP during weeks 3 and 4, whereas participants aged 9.6 to 12.9 years received 16 IU BID of AVP during weeks 3 and 4. A range of possible AVP doses was identified by review of the published literature; the final study doses were then determined in close consultation with the FDA.

A few years ago I did write about the hormone TRH as a potential means of improving autism.  TRH can also be squirted up your nose, although I favoured an oral TRH super-agonist called Taltirelin/Ceredist.

I also suggested that DHED, an orally active, centrally selective prodrug of estradiol, could well be a therapeutic in autism. DHED should give all the benefits of the female hormone estradiol, without any side-effects outside the CNS.  Many of the benefits are via ROR alpha.

Without having samples of spinal fluid, identifying, let alone treating, central hormonal dysfunction is rather a matter of guesswork.

Hormones are very much interrelated and perform different functions in different parts of the body, so it would be easy to get unwanted effects, as with estradiol, if taken orally.

  

Bumetanide for TSC (Tuberous Sclerosis Complex)

A small trial in children with TSC (Tuberous sclerosis complex) has shown that bumetanide improved their features of autism (social behavior, irritability and hyperactivity) but did not reduce seizures.

Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study

Conclusion

This pilot study indicates the potential efficacy of bumetanide on behavioral problems in young patients with TSC. Bumetanide improved irritable, explosive, and social behavior in the majority of patients in this sample and treatment was well tolerated.

Folinic Acid for Autism, but at a lower dose than Dr Frye

I did recently complete my trial of generic Calcium Folinate at something like Dr Frye’s Leucovorin dose.

I found that it did indeed have a positive effect on the use of expressive language.  It prompted the use of more complex sentences.

The downside was that it did also cause aggressive/violent outbursts, so I put it in my “rejected” pile of therapies.  

I was interested to see that in France a trial has been carried out using a lower dose than that proposed by Dr Frye.  Is it possible to get benefits without the side effects? 

Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial  

Highlights 

Folinic acid treatment is well tolerated in children with Autism spectrum disorders.

Folinic acid treatment shows improvement in Autism Diagnostic Observation Schedule score.

Effect of 10 mg/d folinic acid should be confirmed by a larger a multi-center trial.

Autism spectrum disorders (ASD) are influenced by interacting maternal and environmental risk factors. High-dose folinic acid has shown improvement in verbal communication in ASD children. The EFFET randomized placebo-controlled trial (NCT02551380) aimed to evaluate the efficacy of folinic acid (FOLINORAL®) at a lower dose of 5 mg twice daily.

Nineteen children were included in the EFFET trial. The primary efficacy outcome was improvement of Autism Diagnostic Observation Schedule (ADOS) score. The secondary outcomes were the improvement in ADOS sub scores communication, social interactions, Social Responsiveness Score (SRS) and treatment safety.

The global ADOS score and social interaction and communication sub scores were significantly improved at week 12 compared to baseline in the folinic acid group (P = 0.003, P = 0.004 and P = 0.022, respectively), but not in the placebo group (P = 0.574, P = 0.780, P = 0.269, respectively). We observed a greater change of ADOS global score (−2.78 vs. −0.4 points) and (−1.78 vs. 0.20 points) in the folinic acid group, compared to the placebo group. No serious adverse events were observed.

This pilot study showed significant efficacy of folinic acid with an oral formulation that is readily available. It opens a perspective of therapeutic intervention with folinic acid but needs to be confirmed by a multi-center trial on a larger number of children.

  

Covid-19

There was concern that people with severe autism might be at increased risk during the current pandemic and indeed the death rate among people with intellectual disability/learning disability/mental retardation did double from 240 a month to 480 a month in the UK.  The real scandal though was deaths in care homes for the elderly, in countries with advanced healthcare systems, where tens of thousands of extra deaths have occurred.

In “advanced” healthcare systems like the UK, early in the epidemic, elderly people caught Covid-19 in hospital and when they returned to their care home, they infected others.  Care workers who are allowed/forced to work in multiple care homes then caught the virus in one home and transmitted it to the others.  Nobody was tested until care homes had already become breeding grounds for the virus.

In Hong Kong they report zero covid-19 deaths in care homes.  Elderly people could not return to their care home from hospital without testing negative for the virus, and procedures were in place to release elderly patients from hospital first to repurposed hotels, where they stayed until negative for the virus. Due to their grim experience with the 2003 SARS epidemic, Hong Kong already had very strict measures in place to limit infections and they even had regular rehearsals in care homes of the procedures to implement in future pandemics.

Where we live there was an outbreak in a care home and the authorities’ reaction was to arrest the boss of the care home.  I suppose that is one way to get other care homes to take matters seriously. We even had soldiers posted outside care homes to stop people entering.  In New York, Cuomo’s threat to care homes was that you might eventually lose your license to operate if you flout the rules. If most care homes are flouting the rules, they cannot all lose their licenses.

Some rich Western countries apparently implemented their much-vaunted flu pandemic procedures.  It looks like they have much to learn from other places, from Hong Kong to Greece, who did very much better.  Greece implemented a draconian lock down, very early, and has had a tiny number of cases and just 166 deaths. When Greece re-opens in July to tourists from high risk countries (UK, France, Italy, Spain etc) we will see what happens.

I do wonder why so many people are living in care homes. In Sweden, I saw on TV, one lady complaining that her fit and healthy father, capable of walking a few miles/km had caught covid-19 in his care home, was refused transfer to hospital and later died.  Why was he sent to live a care home in the first place?

Milan has an old care home called Pio Albergio Trivulzia ("Baggina"), it had over a thousand residents and media reports 200+ covid deaths.

There are horrific cases in the UK of young adults being sent to live in small mental hospitals by their parents; they subsequently deteriorate and some have even died.  Why did the parents hand their children over in the first place?  They thought they could not cope at home, but clearly some dedicated institutions have even less capacity to care. 

Conclusion

Re-purposing existing cheap drugs to treat a different medical condition makes a lot of sense, but it is not going to make the inventor or the drug firm much money.  It is not popular with drug producers.

Developing new drugs to treat any neurological condition looks great in the early stages of research and then they all seem to fade way, wasting many tens of millions of dollars.  Don’t raise your hopes.

Is intranasal vasopressin the smartest hormone to choose to modify?  It is possible today, using existing products and appears to be safe, which are the most important issues. I think there is more potential beyond this single hormone.

Treat autism and intellectual disability/mental retardation medically, so those people can live more normally, be more fulfilled and do not later need such expensive care home provision. It is a win-win strategy.