Propranolol, Autism and Sodium Ion Channels Nav1.1, Nav1.2, Nav1.3 and Nav1.5

When writing this blog I frequently wonder what happened to all the very clever people; why are these full-time paid researchers often missing the obvious?

Boy with severe headache and ASD, awaiting Propranolol

The answer is, with a few notable exceptions (Catterall, Ben-Ari etc), the clever ones do not study autism, they study things that are much better defined, rare things like Angelman Syndrome and, recently, Pitt-Hopkins Syndrome.  These researchers seem much more rigorous.  For example:-

David Sweatt (Pitt Hopkins)

Pitt–Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription

Edwin Weeber (Angelman syndrome)

http://weeberlab.com/as.html

So autism is left to what might be termed the Baron Cohen brigade.

Propranolol

Propranolol is a medication of the beta blocker type.  It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, performance anxiety, and essential tremors. It is used to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks.

It is a nonselective beta blocker which works by blocking β-adrenergic receptors.

While once a first-line treatment for hypertension, they do not perform as well as other drugs, particularly in the elderly, and evidence is increasing that the most frequently used beta blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.

Beta blockers block the action of endogenous catecholamines epinephrine (adrenaline) and norepinephrine(noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response. Some block all activation of β-adrenergic receptors and others are selective.

It is occasionally used to treat performance anxiety.   Given the effect (above) on the fight or flight response this is logical.

The sympathetic nervous system's primary process is to stimulate the body's fight-or-flight response. It is, however, constantly active at a basic level to maintain homeostasis.

Evidence to support the use in other anxiety disorders is poor.

But what the ever useful Wikipedia almost glosses over is the part I find more interesting:-

Propranolol blocks cardiac and neuronal voltage-gated sodium channels

  

Now we have to hope that cardiologists prescribing Propranolol are fully aware of the role of Nav1.5 in the heart and its role in heart rate.  This has nothing to do with it being a beta blocker.

Hopefully neurologists prescribing it for certain severe headaches understand the role of Nav1.1 in the brain.

It would not surprise me if they did not.

Propranolol earlier in this Blog

Earlier in this blog there are comments regarding the use of low doses of Propranolol to treat anxiety in autism.

Some people report it works wonders, while for others it did nothing.

  

Propranolol in Autism Research

A study was published recently and a reader drew my attention to it, but there have also been a few others.

Blood pressure medicine may improve conversational skills of individuals with autism

An hour after administration, the researchers had a structured conversation with the participants, scoring their performance on six social skills necessary to maintain a conversation: staying on topic, sharing information, reciprocity or shared conversation, transitions or interruptions, nonverbal communication and maintaining eye contact. The researchers found the total communication scores were significantly greater when the individual took propranolol compared to the placebo.

"Though more research is needed to study its effects after more than one dose, these preliminary results show a potential benefit of propranolol to improve the conversational and nonverbal skills of individuals with autism," said Beversdorf

  

Effect of propranolol on verbal problem solving in autism spectrum disorder

Effect of Propranolol on Functional Connectivity in Autism Spectrum Disorder—A Pilot Study

Back to Channelopathies

There are 24,000 human genes, but a much more manageable number of ion channels.  For each ion channel or transporter, there is a gene that expresses it.

When ion channels malfunction, it is called a channelopathy.  Channelopathies are quite well researched and very common in autism.  Early on in this blog I simplified idiopathic classic autism with the following chart.

I suspect that people with channelopathies (Nav1.1, Nav1,2, Nav1.3) caused by dysfunctions in the genes SCN1A, SCN2A, SCN3A are the ones that will most benefit from Propranolol.

I suspect those people will already suffer terrible headaches and/or seizures.

These three channelopathies have been known to be associated with autism for ten years.

Nav1.1 / SCN1A

http://ghr.nlm.nih.gov/gene/SCN1A

Migraine, other headaches

Epilepsy

Dravet syndrome

Regular readers will know that Professor Catterall is the expert on sodium channels and here he is again below

NaV1.1 channels and epilepsy

Nav1.2 / SCN2A

http://ghr.nlm.nih.gov/gene/SCN2A

Epileptic encephalopathy, early infantile, 11 (EIEE11): An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG

Nav1.3 / SCN3A

neuronal hyperexcitability and epilepsy 

         Novel SCN3A variants associated with focal epilepsy in             children.

Nav1.5 / SCN5A

http://ghr.nlm.nih.gov/gene/SCN5A

Mainly heart conditions, since this ion channel is expressed mainly in the heart.

Brugada syndrome  Romano-Ward syndrome  etc

Autism and Nav1.1, Nav1.2, Nav1.3

For many years it has been known that the hundreds of variations in the genes SCN1A, SCN2A and SCN3A are associated with autism.  So we can consider them pretty well established autism genes.

Clearly any drug affecting expression of those genes, or affecting the ion channels they express, should be a target autism drug.

Sodium channels SCN1A,SCN2A and SCN3A in familial autism

Conclusion

Some people with autism and severe headaches, or epilepsy, have an underlying sodium channelopathy.  Sodium channel blockers are not as well understood/ developed as calcium channel blockers.

In some cases, but maybe not all, this should be detectable by genetic testing of the genes SCN1A, SCN2A and SCN3A.

If you live in a country that does not bother with genetic testing, you might want to fall back on trial and error and discuss Propranolol with your doctor.

Did all the people with Asperger’s, in the recent study, who became more conversational after a single dose of Propranolol, have problems with Nav1.1, Nav1.2 or Nav1.3 ?  I doubt it.  The other commonly known effects of Propranolol should also play a role.

But for a sub-set of people with Strictly Defined Autism, Propranolol might be hugely beneficial.  Perhaps Professor Catterall should investigate?