Identifying your sub-type of Autism

Today’s post is very much a work in progress, so do not expect all the answers.

It has occurred to me and also some readers of this blog that you could produce a diagnostic decision tree that would narrow down each person’s sub-type of autism. This really does lend itself to a relatively simple computer model, meaning you could have a simple on-line diagnostic program/app. You do wonder why a tiny part of the hundreds of millions of dollars spent on autism research is not allocated in this direction.

A blank screen awaiting more case studies

A company called Verily, formerly Google Life Sciences, would be an appropriate partner for such a project.  Google is currently backing the approach that genetic testing will reveal all about autism, which looks unlikely.

The decision tree computing part of such a project could be done in an afternoon, what would like more time is creating the logical diagnostic steps.

One clever part, where Verily could help, would be the use of software to “read” the research and look for associations; this is after all what I do with the help of Google Scholar and Ctrl F. In this way you could quickly “read” many tens of thousands of research papers, books and case histories, if there were any.

Software can also be used to “read” all the personal data of any volunteer participants, such as genetic tests, MRIs, family history and all lab tests. As our reader Tyler pointed out, just relying on a pair of eyes to read the MRI means tiny variances go unnoticed and perhaps they do mean something.

You cannot automate everything, but technology certainly can help.

Even a primitive decision tree can help, because it pushes you to think logically and stops you wasting time potentially applying therapies that might help some biological dysfunctions, but clearly not yours.

Parent led initiatives have been successful in the past and have resulted in rare diseases or syndromes becoming treatable using so-called orphan drugs. Treating autism is a massive task and parent led initiatives are what exist today - they have not succeeded in making any impact on mainstream medicine. To make an impact in autism you need big money and big companies.


Start with severity

Ideally everyone would have autism diagnosed in early childhood.  In the case of mild autism this usually does not happen.  Ideally all children would be assessed using the same evaluation test, like CARS, but this also does not happen; most people have no evaluation test, just a subjective observational diagnosis.

So you would need unambiguous terminology to define how the person is affected by “autism”.  This would be how verbal they are; level of cognitive dysfunction and how “autistic” they are behaviorally.

Then you can add things like epilepsy, self-injury and adaptive behavior (toileting, feeding etc). 

Family History

While genetic testing is seen by many as the ultimate diagnostic test, in many cases family history tells you a great deal more. Similar family histories will very likely end up with similar sub-types of autism. This would include medical history of relatives, but also educational/job attainment. It would include health before and during pregnancy, type of delivery and health status at birth.

Genetic testing of your DNA can never be the holy grail of autism diagnosis; what matters is gene expression, when and where, and this is something much more complex.

Family history tells you what has happened in the past and most things happen for a reason.

Family history is by its nature very personal, but it is one of the richest areas to identify how people might be usefully grouped together. This may appear highly politically incorrect, but that does not stop it being useful. 

Physical Features

Until very recently even single gene types of disorder were actually diagnosed by their hallmark physical features. These are often facial, or on hands or feet, but can be anywhere.

One of the most useful physical markers is very simple, you just need to know at birth and for the next couple of years was there a tendency towards being big and/or muscular or small and more floppy?  The stronger the tendency to either extreme, the more important is the observation.

A recent study has even used 3D modeling to identify autism by analyzing people's faces. This apparently works particularly well in females with autism, who apparently tend to have more male features. I have no doubt Googlers could improve this.

Hypermasculinised facial morphology in boys and girls with Autism Spectrum Disorder and its association with symptomatology

Comorbidities

Other medical conditions in the child and also in the parents, and in particular in the mother during pregnancy, can help assign people to subgroups. 

In mothers thyroid disorders and diabetes during pregnancy look particularly relevant.

In the child, epilepsy, allergy and GI issues are important. There are many types of GI issue, some of which overlap with allergy and some do not.

Then you have sleep disorders, eating disorders, sensory disorders etc.  Some are only an issue when very young and then fade away, some may remain. 

Biological Markers

There are hundreds of possibly relevant biomarkers and many more that are likely totally irrelevant.  The most reliable tests will use samples taken from spinal fluid, which in effect is part of the central nervous system, and so tell you what is going on inside the blood brain barrier. Blood tests can be useful but often do not tell you what is going on inside the brain. 

The most immediately relevant biomarkers relate to treatable in-born errors of metabolism, each one of these syndromes may indeed be rare, but there are many of them and you would think it worth ruling them all out. 

The risk here is getting lost in hundreds of tests, rather like with genetic testing.

There will be some useful markers like for oxidative stress, inflammatory biomarkers, mitochondrial function etc. 

MRI

It does make sense for everyone with autism to have an MRI, including those with Asperger’s. People who break their arm get an X-ray by default, is an MRI for autism too much to expect?

The brain may appear entirely normal, but there is a significant chance of identifying a relevant variation, albeit small.

There are also some specific tests that can be carried by Functional Magnetic Resonance Imaging (fMRI) at the same time as the basic MRI.  

EEG

Many people with autism, but without epilepsy, do have an abnormal EEG, with so-called epileptiform activity.  Medicine does not have a consensus opinion regarding what to do, but some neurologists, like Dr Chez, believe it should be treated and can reduce the severity of autism.  Detailed knowledge of such epileptiform activity might be useful when defining sub-groups of autism.

Genetic Testing

The tests usually offered are microarray, whole exome and whole genome sequencing.  These tests may reveal something useful or may just reveal a list of variances that do not seem to have any relation to autism.

If funds are unlimited, then whole genome sequencing of the child and both parents is the best choice.  Then you need someone very methodical to review and interpret the results.

What matters is gene expression locally and even whole genome sequencing does not tell you this, it is however a part of the picture.

Nature of Onset

People tend to consider autism as either early onset or regressive. Here it is important to extract the group who were born entirely neurotypical, met all their milestones and then regressed.

Most people’s autism started long before birth but it manifests itself differently over time. This is like the progression of a disease. Indeed one therapeutic idea is that by very early pharmacological intervention you can affect this progression and improve the final outcome.

The point here is that you can have early onset autism that appears to “get worse”, this is not regressive autism.

People with regressive autism need to split into those who profoundly regressed and those who were always different and then became more so.

For people with mild autism the time/nature of onset is likely much less of an issue. 

Variability of Symptoms

Some people with autism exhibit the same severity of symptoms every day, but many do not.  In people with highly variable autism it is very useful to understand what makes it worse.  Many lay people refer to autism as being the result of the brain being "wired-up" differently, as if it was static condition. In those with highly variable autism, the condition is clearly not fixed. Something is making autism worse, you just have to find out what it is. It could very likely be allergy, but could potentially be many things even microorganisms affecting gene expression.

The Goal - Why would you want to collect all this personal data?

As I have noted in this blog, there clearly are groups of people who respond to the same therapies. It is remarkable and it is not a matter of chance.  I do not just mean one therapy, like NAC or bumetanide, but a whole string of them, even the ones that may appear odd to some readers.

If you could predict who fits into which subgroup of autism based on answering a long list of questions on an app on your smartphone and sending some data to Google, widespread treatment of autism would become a reality.

You do need a lot of data and most of it does not yet exist.

I know a lot about one subtype of autism and there is a substantial overlap with the son of one regular commenter. Bumetanide, Potassium, NAC, Atorvastatin, Verapamil, Potassium Bromide etc all appear to have the same (beneficial) effect.

Once you have more data, you look what all these children have in common and then you can try and predict which other people will have a similar drug response. 

You just need a lot of well documented case studies and a lot of experimentation with possible therapies. In other words not just Peter’s Polypill, Tyler’s Polypill, Alli’s Polypill or Dr Kelley’s mito-cocktail,  but very much more.

There does seem to be an effective therapy for regressive autism caused by mitochondrial disease, which is likely to be one of the larger subgroups. Given all the attention given to PANDAS/PANS, I cannot understand why the mitochondrial sub-group has not been similarly “mainstreamed”. The therapy is Dr Kelley’s (from Johns Hopkins) plus add-ons.  One potential add-on being calcium folinate (Leucoverin) to reduce peroxynitrite (ONOO⁻) from nitrosative stress, but there are undoubtedly other add-ons waiting to be discovered, or perhaps just documented.


Conclusion

Trying to match effective drugs to a long list of markers and other criteria, does have something in common with tracking individuals web browsing to generate personalized relevant advertising. So I do think that the likes of Google/Verily would do a much better job than medical researchers alone. They would of course automate the process, which is not what many doctors are going to like. 

If you happen to know Larry Page or Sergey Brin from Google, you can suggest it. Brin's former wife incidentally is the founder of 23andMe. I am sure both companies employ plenty of people with Asperger's and so likely have some kids with autism. Brin apparently is interested to find a Parkinson's cure, he has a mutation in the gene LRRK2; since this gene is also associated with Crohn's disease, he might want to fund that too. Why does Brin have a LRRK2 mutation? You only need a glance at his family history.

Verapamil still working after 3+ years, for SIB in Autism

There are numerous ideas about how to treat self injurious behavior (SIB) associated with autism. ARI (the former home of Defeat Autism Now) have just had their take on the subject published.

https://www.autism.com/sib_book

In this blog we have seen that Tyler has developed a BCAA (branch chained amino acid) therapy, based on the idea of Acute Tryptophan Depletion, to control his son’s type of self injury.

The silver bullet for my son’s summer time raging and self-injury continues to be the L-type calcium channel blocker Verapamil.

I think many people will be skeptical of both BCAAs and Verapamil, which is entirely understandable. Unlike other aspects of autism, which are hard to measure, self-injury is really easy to measure and so you know when you have cracked the problem; what other people think tends not to matter.  

Now that Monty, aged 14 with ASD, has moved to secondary/high school the routine has changed a little and his assistant forgets to give him his midday dose of verapamil.

On the days she forgets, between 4.00pm and 4.30pm Monty starts to punch himself. On all other days and during the entire summer there has been no sign of self injury.

So when asked is it really necessary Monty keeps taking his pills, my answer remains yes.  In the case of verapamil I now have further evidence that after more than three years of use, his pollen allergy driven self injury continues to be entirely controllable using this therapy.

I do not know what ARI have put forward in their book. If your child has SIB that does not respond to whatever therapies you have tried, it might well be a helpful read. 

Other readers have noted GI and behavioral improvement from Verapamil and our doctor reader Agnieszka did try and collect case reports, but it seems parents are more interested in reading reports than writing them.
           

 Verapamil use in Autism – Request for Case Reports from Parents

Autism Drugs and Supplements A to Z

Today’s post is a draft list of about 130 drugs and supplements that are used by some people with autism. It is not a list of recommendations, just a list of what gets mentioned either in this blog, or is widely known to be used elsewhere.  I did not include bleach, but I did include potent drugs used by some psychiatrists, that may also be ill-advised.

If any item is interesting, you can use Google to find out about its use in autism. With more obscure ideas, Google will direct you back to this blog. 

To add items I have omitted, just send me a comment.

Click on the link below and the list should open in a spreadsheet:-

https://drive.google.com/open?id=0ByJafEi2YA2JM1pMYTIwaGphcGs

Autism MRI

Source: Brain MR Imaging Findings and Associated Outcomes in Carriers of the Reciprocal Copy Number Variation at 16p11.2

In the early days of this blog, one medical reader told me that in cases of autism an MRI scan of the brain should appear normal.

This also fits with the idea that once you have a biological diagnosis, you no longer have a case of “autism”. It is only Autism, when it is of unknown origin.  

People who have a single gene type of autism actually can have significant variations in brain structure that appear clearly on an MRI.  This was the subject of a recent study and the source of the MRI in this post.

MRI reveals striking brain differences in people with genetic autism

Brain MR Imaging Findings and Associated Outcomes in Carriers of the Reciprocal Copy Number Variation at 16p11.2

Many people with autism have abnormalities at a specific site on the 16th chromosome known as 16p11.2. Deletion or duplication of a small piece of chromosome at this site is one of the most common genetic causes of autism spectrum disorder.

People with deletions tend to have brain overgrowth, developmental delays and a higher risk of obesity.

Those with duplications are born with smaller brains and tend to have lower body weight, but also developmental delays. 

For regular readers of this blog there are some interesting points to note.

Agenesis of the Corpus Callosum

The corpus callosum is a wide, flat bundle of fibers about 10 cm long that connects the left and right sides of the brain.  It facilitates communication between the two sides of the brain.

Agenesis of the corpus callosum (ACC) is a birth defect in which there is a complete or partial absence of the corpus callosum.

ACC leads to behaviors compatible with a diagnosis of autism or Asperger’s in about half of cases.

Symptoms of ACC vary greatly among individuals, as they do in all types of autism.  Seizures are common, some people have poor motor coordination, and some people are non-verbal.  My original post on the subject:-

Agenesis of the Corpus Callosum (ACC)                                                                                 

You may recall that in the film Rain Man, Dustin Hoffman’s character was inspired by a man with ACC called Kim Peak.  It is now thought that Peak had FG Syndrome and this is what caused his ACC. It appears that his brain adapted and made unusual connections leading to his remarkable memory.

The Corpus Callosum is clearly visible on an MRI.

In 16p11.2. deletion you end up with an overgrown (thick) corpus callosum, while in 16p11.2. duplication you end up with a thin corpus callosum, which equates to a partial Agenesis of the Corpus Callosum.                                

At least one reader of this blog has a case of partial Agenesis of the Corpus Callosum and as he told me, it is not autism it is ACC.

Chiari 1 “brain hernia”

Another point of interest on the above MRI has been highlighted as Cerebellar Ectopia. Now if they had called it a Chiari malformation, you might have linked it to an old post on this blog.

Treatable Chiari 1“brain hernia” present in 7% of Autism

In people with brain overgrowth and/or a small skull, what happens when there is no space left for a growing brain? Well it appears that pressure builds up and you get a kind of hernia with the brain expanding downwards into the spine.

This is called a Chiari 1 malformation and it seems to be quite common in the types of autism associated with over active pro-growth signalling pathways.

Since 16p11.2 deletion is associated with too much growth (thick corpus callosum, brain overgrowth and obesity) we should not be surprised that they often present with Chiari 1 “brain hernia”, which is treatable and this should improve symptoms. 

Conclusion

An MRI can sometimes tell you a lot, when you know what to look for and clearly should be carried out on anyone diagnosed with disabling autism.

Undoubtedly there are other areas of the brain where important variances occur.

This would provide useful data to assign individuals with autism into subgroups and hence improve the chance of finding effective therapy.  What works for Peter may help Paul, but what works for Zach probably will not help Amber.

Acid-sensing Ion Channels (ASICs) and Autism – Acid in the Brain

Acid sensing ion channels (ASICs) are another emerging area of science where much remains known.  It would seem that ASICs have evolved for a good reason, when pH levels fall they trigger a reaction to compensate.  (The lower the pH the higher is the acidity)  In some cases, like seizures, this seems to work, but in other cases the reaction produced actually makes a bad situation worse.

Research is ongoing to find inhibitors of ASICs to treat specific conditions raging from MS (Multiple Sclerosis), Parkinson’s and Huntington’s to depression and anxiety. Perhaps autism should be added to the list.

NSAIDs like ibuprofen are inhibitors of ASICs.

The complicated-looking chart below explains the mechanism.  The ASIC is on the left, also present is a voltage-gated calcium channel (VGCC) and an NMDA receptor. We already know that VGCCs can play a key role in autism and mast cell degranulation. Similarly we know that in autism there is very often either too much or too little NMDA signaling. Here we have all three together.

  

The role of ASICs is to sense reduced levels of extracellular pH (i.e. acidity outside the cell) and result in a response from the neuron. Under increased acidic conditions, a proton (H+) binds to the channel in the extracellular region, activating the ion channel and opening transmembrane domain 2 (TMD2). This results in the influx of sodium ions.

All ASICs are specifically permeable to sodium ions. The only variant is ASIC1a which also has a low permeability to calcium ions. The influx of these cations results in membrane depolarization.

Voltage-gated Ca²⁺ channels are then activated resulting in an influx of calcium into the cell. This causes depolarization of the neuron and an excitatory response released.

NMDA receptors are also activated and this results in more influx of calcium into the cell.

This calcium inflow then triggers further reactions via CaMKII (calmodulin-dependent protein kinase II).

The overall effect is likely to damage the cell.

There is also an important effect on dendritic spines:-

“ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca²⁺]_i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures”

In general the research is looking to inhibit ASICs to improve a variety of neurological conditions.

Acid in the Brain

ASICs only become activated when there is acidity (low pH).  When the pH is more than 6.9 they do nothing at all.

Unfortunately, in many neurological disorders pH is found to be abnormally low and that includes autism.

ASIC1a channels specifically open in response to pH 5.0-6.9 and contribute to the pathology of ischemic brain injury because their activation causes a small increase in Ca²⁺permeability and an inward flow of Ca²⁺. ASIC1a channels additionally facilitate the activation of voltage-gated Ca2+ channels and NMDA receptor channels upon initial depolarization, contributing to the major increase in intracellular calcium that results in cell death.

However in the case of epilepsy, ASIC1a channels can be helpful.  Seizures cause increased, uncontrolled neuronal activity in the brain that releases large quantities of acidic vesicles. ASIC1a channels open in response and have shown to protect against seizures by reducing their progression. Studies researching this phenomenon have found that deleting the ASIC1a gene resulted in amplified seizure activity. 

Increased brain acidity in psychiatric disorders

Changes in the brain pH level have been considered an artifact, therefore substantial effort has been made to match the tissue pH among study participants and to control the effect of pH on molecular changes in the postmortem brain. However, given that decreased brain pH is a pathophysiological trait of psychiatric disorders, these efforts could have unwittingly obscured the specific pathophysiological signatures that are potentially associated with changes in pH, such as neuronal hyper-excitation and inflammation, both of which have been implicated in the etiology of psychiatric disorders. Therefore, the present study highlighting that decreased brain pH is a shared endophenotype of psychiatric disorders has significant implications on the entire field of studies on the pathophysiology of mental disorders.

This research raises new questions about changes in brain pH. For example, what are the mechanisms through which lactate is increased and pH is decreased? Are specific brain regions responsible for the decrease in pH? Is there functional significance to the decrease in brain pH observed in psychiatric disorders, and if so, is it a cause or result of the onset of the disorder?. Further studies are needed to address these issues.

The following paper is mainly by Japanese researchers and is very thorough; it will likely make you consider brain acidosis as almost inevitable in your case of autism. 

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders

Lower pH is a well-replicated finding in the post-mortem brains of patients with schizophrenia and bipolar disorder. Interpretation of the data, however, is controversial as to whether this finding  reflects a primary feature of the diseases or is a result of confounding factors such as medication, post-mortem interval, and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models, which can be studied without confounds inherent in human studies.  In the present study, we first confirmed that the brains of patients with schizophrenia and bipolar  disorder exhibit lower pH values by conducting a meta-analysis of existing datasets. We then  utilized neurodevelopmental mouse models of psychiatric disorders in order to test the hypothesis  that lower brain pH exists in these brains compared to controls due to the underlying pathophysiology of the disorders. We measured pH, lactate levels, and related metabolite levels in brain homogenates from three mouse models of schizophrenia (Schnurri-2 KO, forebrain-specific  calcineurin KO, and neurogranin KO mice) and one of bipolar disorder (Camk2a HKO mice), and  one of autism spectrum disorders (Chd8 HKO mice). All mice were drug-naïve with the same post-mortem interval and agonal state at death. Upon post-mortem examination, we observed  significantly lower pH and higher lactate levels in the brains of model mice relative to controls. There was a significant negative correlation between pH and lactate levels. These results suggest that lower pH associated with increased lactate levels is a pathophysiology of such diseases rather than mere artefacts.

A number of postmortem studies have indicated that pH is lower in the brains of patients with schizophrenia and bipolar disorder. Lower brain pH has also been observed in patients with ASD. In general, pH balance is considered critical for maintaining optimal health, and low pH has been associated with a number of somatic disorders. Therefore, it is reasonable to assume that lower pH may exert a negative impact on brain function and play a key role in the pathogenesis of various psychiatric disorders.            

Researches have revealed that brain acidosis influences a number of brain functions, such as anxiety, mood, and cognition. Acidosis may affect the structure and function of several types of brain cells, including the electrophysiological functioning of GABAergic  neurons and morphological properties of oligodendrocytes. Alterations in these types of cells have been well-documented in the brains of patients with schizophrenia, bipolar disorder, and ASD and may underlie some of the cognitive deficits associated with these disorders. Deficits in GABAergic neurons and oligodendrocytes have been identified in the mouse models of the disorders, including Shn2 KO mice. Brain acidosis may therefore be associated with deficits in such cell types in schizophrenia, bipolar disorder, and ASD.

Interestingly, we observed that Wnt- and EGF-related pathways, which are highly implicated in somatic and brain cancers, are enriched in the genes whose expressions were altered among the  five mutant mouse strains.

These findings raise the possibility that elevated glycolysis underlies the increased lactate and pyruvate levels in the brains of the mouse models of schizophrenia, bipolar disorder, and ASD.

Dysregulation of the excitation-inhibition balance has been proposed as a candidate cause of schizophrenia, bipolar disorder, and ASD. A shift in the balance towards excitation would result in increased energy expenditure and may lead to increased glycolysis.

UI team develops new way to look at brain function

University of Iowa neuroscientist John Wemmie is interested in the effect of acid in the brain (not that kind of acid!). His studies suggest that increased acidity—or low pH—in the brain is linked to panic disorders, anxiety, and depression. But his work also indicates that changes in acidity are important for normal brain activity too.

“We are interested in the idea that pH might be changing in the functional brain because we’ve been hot on the trail of receptors that are activated by low pH,” says Wemmie, associate professor of psychiatry in the UI Carver College of Medicine. “The presence of these receptors implies the possibility that low pH might be playing a signaling role in normal brain function.”

Wemmie’s previous studies have suggested a role for pH changes in certain psychiatric diseases, including anxiety and depression. With the new method, he and his colleagues hope to explore how pH is involved in these conditions.

“Brain activity is likely different in people with brain disorders such as bipolar or depression, and that might be reflected in this measure,” Wemmie says. “And perhaps most important, at the end of the day: Could this signal be abnormal or perturbed in human psychiatric disease? And if so, might it be a target for manipulation and treatment?”

Panic attacks as a problem of pH

An easy to read article from the Scientific American

Dendritic Spines and ASICS

ASIC2 Subunits Target Acid-Sensing Ion Channels to the Synapse via an Association with PSD-95

The present results and previous studies suggest that ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca²⁺]_i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures (Xiong et al., 2004; Yermolaieva et al., 2004; Gao et al., 2005; Friese et al., 2007; Ziemann et al., 2008). Interestingly, one previous report suggested increased ASIC2a expression in neurons surviving ischemia, although the functional consequence of those changes are uncertain (Johnson et al., 2001). Moreover, recent studies suggest genetic associations between the ASIC2 locus and multiple sclerosis, autism and mental retardation (Bernardinelli et al., 2007; Girirajan et al., 2007; Stone et al., 2007). Thus, we speculate that ASIC1a and ASIC2, working in concert, may regulate neuronal function in a variety of disease states  

ASICs in neurologic disorders

Disease	Role of ASICs
Parkinson’s disease	Lactic acidosis occurs in the brains of patients with PD.
	Amiloride helps protect against substantia nigra neuronal degeneration, inhibiting apoptosis.
	Parkin gene mutations result in abnormal ASIC currents.
Huntington’s disease	ASIC1 inhibition enhances ubiquitin-proteasome system activity and reduces huntingtin-polyglutamine accumulation.
Pain	ASIC3 is involved in: 1) primary afferent gastrointestinal visceral pain, 2) chemical nociception of the upper gastrointestinal system, and 3) mechanical nociception of the colon.
	Blocking neuronal ASIC1a expression in dorsal root ganglia may confer analgesia.
	NSAIDs inhibit sensory neuronal ASIC expression.
Cerebral ischemia	Neuronal ASIC2 expression in the hypothalamus is upregulated after ischemia.
	Blockade of ASIC1a exerts a neuroprotective effect in a middle cerebral artery occlusion model.
Migraine	Most dural afferent nerves express ASICs.
Multiple sclerosis	ASIC1a is upregulated in oligodendrocytes and in axons of an acute autoimmune encephalomyelitis mouse model, as well as in brain tissue from patients with multiple sclerosis.
	Blockade of ASIC1a may attenuate myelin and neuronal damage in multiple sclerosis.
Seizure	Intraventricular injection of PcTX-1 increases the frequency of tonic-clonic seizures.
	Low-pH stimulation increases ASIC1a inhibitory neuronal currents.
Malignant glioma	ASIC1a is widely expressed in malignant glial cells.
	PcTx1 or ASIC1a knock-down inhibits cell migration and cell-cycle progression in gliomas.
	Amiloride analogue benzamil also produces cell-cycle arrest in glioblastoma.

Source:   Acid-sensing ion channels: potential therapeutic targets for neurologic diseases

One logical question is whether the brain ASIC connection with autism connects to the common  gastrointestinal problems, some of which relate to acidity and are often treated with H2 antihistamines and proton pump inhibitors (PPIs).

Acid-Sensing Ion Channels in Gastrointestinal Function 

Gastric acid is of paramount importance for digestion and protection from pathogens but, at the same time, is a threat to the integrity of the mucosa in the upper gastrointestinal tract and may give rise to pain if inflammation or ulceration ensues. Luminal acidity in the colon is determined by lactate production and microbial transformation of carbohydrates to short chain fatty acids as well as formation of ammonia. The pH in the oesophagus, stomach and intestine is surveyed by a network of acid sensors among which acid-sensing ion channels (ASICs) and acid-sensitive members of transient receptor potential ion channels take a special place. In the gut, ASICs (ASIC1, ASIC2, ASIC3) are primarily expressed by the peripheral axons of vagal and spinal afferent neurons and are responsible for distinct proton-gated currents in these neurons. ASICs survey moderate decreases in extracellular pH and through these properties contribute to a protective blood flow increase in the face of mucosal acid challenge. Importantly, experimental studies provide increasing evidence that ASICs contribute to gastric acid hypersensitivity and pain under conditions of gastritis and peptic ulceration but also participate in colonic hypersensitivity to mechanical stimuli (distension) under conditions of irritation that are not necessarily associated with overt inflammation. These functional implications and their upregulation by inflammatory and non-inflammatory pathologies make ASICs potential targets to manage visceral hypersensitivity and pain associated with functional gastrointestinal disorders.

It looks like it is still early days in the research into ASICs and GI problems. Best look again in decade or two.  

Too Much Lactic Acid – Lactic Acidosis 

One theory is that panic attacks are cause by too much lactic acid.

In earlier posts of mitochondrial disease and OXPHOS, we saw that when the mitochondria have too little oxygen they can continue to produce ATP, but lactate accumulates and this leads to lactic acidosis.

So people with mitochondrial disease might have some degree of lactic acidosis that would reduce extracellular pH and activate ASICs.

So perhaps along with those prone to panic attacks, people with regressive autism and high lactate might benefit from an ASIC inhibitor?

Aerobic exercise is suggested to reduce excess lactate, although extreme exercise like running a marathon will actually make more.  Moderate exercise has the added advantage of stimulating the production of more mitochondria.

So moderate exercise for panic disorders and regressive autism (mitochondrial disease).   Moderate exercise is then an indirect ASIC inhibitor, because it should increase pH (less acidic). 

ASICs in panic and anxiety?

Localization and Behaviors in Null Mice Suggest that ASIC1 and ASIC2 Modulate Responses to Aversive Stimuli 

Acid sensing ion channels (ASICs) generate H⁺-gated Na⁺ currents that contribute to neuronal function and animal behavior. Like ASIC1, ASIC2 subunits are expressed in the brain and multimerize with ASIC1 to influence acid-evoked currents and facilitate ASIC1 localization to dendritic spines. To better understand how ASIC2 contributes to brain function, we localized the protein and tested the behavioral consequences of ASIC2 gene disruption. For comparison, we also localized ASIC1 and studied ASIC1^−/− mice. ASIC2 was prominently expressed in areas of high synaptic density, and with a few exceptions, ASIC1 and ASIC2 localization exhibited substantial overlap. Loss of ASIC1 or ASIC2 decreased freezing behavior in contextual and auditory cue fear conditioning assays, in response to predator odor, and in response to CO₂ inhalation. In addition, loss of ASIC1 or ASIC2 increased activity in a forced swim assay. These data suggest that ASIC2, like ASIC1, plays a key role in determining the defensive response to aversive stimuli. They also raise the question of whether gene variations in both ASIC1 and ASIC2 might affect fear and panic in humans.

Recent genome-wide studies have associated SNPs near ASIC2 with autism (Stone et al., 2007), panic disorder (Gregersen et al., 2012), response to lithium treatment in bipolar disorder (Squassina et al., 2011) and citalopram treatment in depressive disorder (Hunter et al., 2013), and have implicated a copy number variant of ASIC2 with dyslexia (Veerappa et al., 2013). However, little is currently understood about whether ASIC2 is required for normal behavior.

The goals of this study were to better understand the role of ASIC2 in brain function. Thus our first aim was to localize ASIC2 subunits. Because ASIC2 subunits multimerize with ASIC1 subunits, we hypothesized that the distribution of the two subunits would show substantial overlap. In addition, given that ASIC channels in central neurons missing ASIC2 have altered trafficking and biophysical properties, we hypothesized that disrupting expression of ASIC2 would impact behavior. Therefore, we asked if mice missing ASIC2 would have altered behavioral phenotypes, and whether disrupting both ASIC1 and ASIC2 would have the same or greater behavioral effects than disrupting either gene alone. Because we found that ASIC2, like ASIC1, was highly expressed in brain regions that coordinate responses to threatening events, we focused on tests that evaluate defensive behaviors and reactions to stressful and aversive stimuli.

These results suggest that ASIC channels can influence synaptic transmission. We speculate that pH falls to the greatest extent with intense synaptic activity; the mechanism might involve release of the acidic contents of synaptic vesicles, transport of HCO₃⁻ or H⁺ across neuronal or glial cell membranes, and/or metabolism. The reduced pH could activate ASIC channels leading to an increased [Ca²⁺]_i (Xiong et al., 2004; Yermolaieva et al., 2004; Zha et al., 2006). In this scenario, the main function of ASIC channels would be to enhance synaptic transmission in response to intense activity. This would explain the pattern of abnormal behavior in ASIC null mice when the stimulus is very aversive.

Translating ASIC research into therapy

As you may have noticed in the first chart in this post, there already exist ways to inhibit ASICs, ranging from a diuretic called Amiloride to NSAIDs, like ibuprofen.  The process of translating science into medicine has already begun in multiple sclerosis, as you can see in the following study:-

Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. 

Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis. 

Agmatine and Spermine

In the graphic at the start of this post you might have noticed Agmatine and Spermine.  While ASICs are acid sensing and so activated by protons, they appear to be also activated by other substances.

The arginine metabolite agmatine may be an endogenous non-proton ligand for ASIC3 channels.

Extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction.

However, other research shows spermine promotes autophagy and has been shown to ameliorate ischemia/reperfusion injury  (IRI) and suggests its use in children to prevent IRI .  

So nothing is clear cut.

It looks like spermine, spermidine and agmatine all promote autophagy.            

Agmatine gets converted to a polyamine called putrescene.

Personally, I expect polyamines will generally be found beneficial in autism, but there will always be exceptions.  

Conclusion

There is a case to be made for the use of the diuretic amiloride to treat MS and indeed panic disorders.

Will amiloride help autism? You would not want to use it if there is comorbid epilepsy, since ASICs are “seizure protective”. 

If your genetic testing showed an anomaly with the ASIC2 gene, which is known to occur in both autism and MR/ID, then amiloride would seem a logical therapy.

I think we should not be surprised if people with neurological conditions have lower pH brains than NT people, just like we should expect them to show signs of oxidative stress.

If you do indeed happen to have a rather acidic brain, as seems to be quite often the case, damping down the response from ASICs might make things better or worse, or in indeed a mixture of the two. You would hope, at least in some people, that ASICs provide some beneficial response on sensing low pH.

It would be useful if a researcher did a trial of amiloride in different types of autism, then we might have some useful data. You would think the Japanese researchers would be the ones to do this.

One good thing about amiloride is that it increases the level of potassium in your blood and there even is a combined bumetanide/amiloride pill.  Bumetanide has the side effect of lowering potassium.

Many people with autism find NSAIDs beneficial, either long term or for flare-ups. NSAIDs have many beneficial effects; just how important is ASIC inhibition is an open question.

Is the anxiety that many people with autism seem to suffer, sometimes related to ASICs?  Perhaps it is just a minor panic disorder and it relates to ASIC1 and ASIC2.  I think there are numerous different dysfunctions that produce what we might term “anxiety”, among the long list one day you may well find ASICs.

Science has a long way to go before there is a complete understanding of this subject.

Moderate exercise again appears as a simple therapy with countless biological benefits, in this case reducing lactate and thus reducing acidity (increasing pH).