Ethosuximide to increase speech in some autism? and PTHS?

I have previously proposed the use of calcium T channel blockers to treat some types of autism. I did suggest that language might be a good target.

Time for T? Targeting language-associated gene Cntnap2 with a T-type calcium channel blocker corrects hyperexcitability driving sensory abnormalities, repetitive behaviors, and other ASD symptoms, but will it improve language? Will it also benefit Pitt Hopkins syndrome (PTHS) and broader autism?

I recently received a question from a reader who read an abstract from a paper presented to the Brain Foundation, that suggested Ethosuximide can increase speech in autism. She also asked what the effective dosage might be.

This subject has come up before in this blog. Ethosuximide is a very specific T channel blocker, commonly used to treat absence seizures. Some readers of this blog have already trialed it. The other interesting one is Zonisamide, which blocks T channels but also has other effects. We have reports that the starting low dose of Zonisamide had some interesting beneficial effects that were lost at the regular higher doses.

I did not expect to find much new information, but that changed when I found the patent document submitted by Charles Niesen. So here is a blog post dedicated to this specific subject.

Here is the full patent:

Method of treating expressive language deficit in autistic humans

Here is an easy-to-read summary:

 

A New Patent Claims an Unusual Approach to Autism Language Deficits

A recent patent proposes a novel pharmacological method for improving expressive language in individuals with autism. Rather than introducing a new drug, the invention repurposes a class of existing anticonvulsant medications—specifically succinimides such as ethosuximide, methsuximide, and phensuximide.

These drugs have long been used to treat epilepsy, particularly absence seizures. However, the patent suggests they may also address one of the most challenging aspects of autism: the inability to initiate and sustain meaningful verbal communication.

 

Understanding the Problem

Autism is often characterized by difficulties in social interaction, but a core feature—especially in more severe cases—is expressive language impairment. Many individuals with autism may speak only in short phrases or single words. Others may respond to questions but rarely initiate conversation or engage in back-and-forth dialogue.

This is distinct from related conditions like Asperger syndrome, where language is typically intact but social communication is impaired. In classic autism, the issue is not just how language is used—but whether it emerges spontaneously at all.

Currently, there are no FDA-approved medications specifically designed to improve expressive language in autism. Most available treatments focus on associated symptoms such as irritability, seizures, or attention deficits.

 

The Core Idea Behind the Patent

The patent proposes that daily administration of a succinimide anticonvulsant—most notably ethosuximide—over an extended period (typically several months) can significantly improve expressive language abilities.

Patients are treated for at least one month, with stronger effects reported after three to six months or longer. The goal is not just increased vocabulary, but a progression toward spontaneous speech and true conversational ability.

 

How Might This Work?

Ethosuximide works by blocking T-type calcium channels in the brain. These channels play a role in regulating neuronal activity and rhythmic signaling.

While the exact mechanism in autism is unknown, the patent speculates that modulating these channels may help normalize communication between brain regions involved in language. Another hypothesis is that the drug may “activate” previously underused or dormant neural circuits.

These ideas remain theoretical and are not yet confirmed by broader research.

 

Dosage and Treatment Approach

The proposed dosing follows standard epilepsy guidelines, typically ranging from 10 to 60 mg per kilogram of body weight per day. In many cases, a range of 20–40 mg/kg/day is used for children, while adolescents and adults may receive fixed doses between 150 mg and 1000 mg twice daily.

Treatment is administered consistently over months, with periodic evaluation of language and behavioral progress.

 

How Speech Was Measured

To evaluate improvement, the patent uses a simple but structured 7-point expressive language scale. This scale attempts to quantify how advanced a person’s spoken communication is, ranging from no speech at all to full conversational ability.

The scale is defined as follows:

• 0 — Nonverbal: No meaningful spoken language
• 1 — Echolalic: Repeats words or phrases (echoing others)
• 2 — Single words: Uses isolated words to communicate
• 3 — Phrases: Combines words into short phrases
• 4 — Sentences: Forms complete, understandable sentences
• 5 — Spontaneous speech: Initiates speech independently
• 6 — Mutual speech: Engages in true back-and-forth conversation

This scale is central to the patent’s claims. Improvements are measured as movement upward along these stages—for example, progressing from single words (2) to phrases (3), or from sentences (4) to spontaneous speech (5).

The inventors argue that even a 1–2 point increase represents a meaningful functional gain in real-world communication.

 

Summary of the Reported Study

The patent describes a small observational study involving 24 patients with autism. Participants were treated with ethosuximide for periods ranging from one month to over six months.

Patients were grouped based on cognitive level, including normal IQ, borderline, mild impairment, and moderate impairment. Language ability was assessed using the 7-point scale described above.

 

Reported Outcomes

Across all groups, improvements in expressive language were observed. The most significant gains occurred in individuals with higher baseline cognitive function.

On average, patients improved by approximately two points on the language scale. This often meant progressing from single words to phrases, or from phrases to full sentences and occasional spontaneous speech.

In some documented cases, children who initially spoke only in isolated words were able to form sentences within six months and engage in basic conversation within a year.

 

Timeline of Improvement

Initial changes were sometimes observed within the first month of treatment. More consistent and substantial gains were reported after three months, with the most pronounced improvements occurring after six months or longer.

Interestingly, the progression of language development in treated patients appeared to mirror typical early childhood language acquisition—albeit delayed.

 

Persistence After Treatment

One of the more striking claims is that improvements persisted even after the medication was discontinued. In several cases, language abilities continued to develop beyond the treatment period.

This suggests the possibility of longer-term changes in neural function, rather than temporary symptom management.

 

Additional Observations

Beyond language, some patients also showed improvements in social interaction and mood. Increased engagement, better eye contact, and reduced irritability were noted in certain cases.

However, many participants were also receiving speech therapy and applied behavioral analysis (ABA), making it difficult to isolate the effects of the medication alone.

 

Safety Profile

Ethosuximide was generally well tolerated in the study. Known side effects include gastrointestinal discomfort, fatigue, and behavioral changes. Rare but serious risks—such as blood or liver abnormalities—are also associated with the drug and require medical supervision.

 

Age Range and Cognitive Profile of Participants

The patent provides limited but useful information about the participants’ ages and cognitive abilities.

Age Range

• The study included both young children and adolescents.
• Specific examples mention children as young as 3 years old and others up to around 12–15 years old.

Cognitive (IQ) Groups

Participants were divided into four categories based on cognitive level:

• Normal IQ (NIQ)
• Borderline IQ (BIQ)
• Mild intellectual impairment (mMR)
• Moderate intellectual impairment (moMR)

 

Key Takeaways

• The strongest language improvements were reported in children with normal IQ.
• Children with lower cognitive levels also improved, but to a lesser degree.
• The results suggest that baseline cognitive ability may influence response to treatment.

 

Final Thoughts

This patent presents an intriguing hypothesis: that a well-established epilepsy medication may have the potential to improve core language deficits in autism.

The reported results are promising, particularly the magnitude of language gains and their persistence after treatment. However, the evidence is limited by the small sample size, lack of a control group, and reliance on a subjective rating scale.

As it stands, this work should be viewed as exploratory rather than definitive. Larger, controlled clinical trials would be needed to determine whether this approach truly offers a reliable and reproducible benefit.

Still, the idea highlights an important direction for future research—targeting the underlying neural mechanisms of communication itself, rather than just managing associated symptoms.

 

Critical periods and CNTNAP2

Another factor to consider is the role of developmental “critical periods,” when brain circuits involved in language are particularly plastic. Disruption of CNTNAP2 has been linked to altered neuronal connectivity and delayed circuit maturation, which may extend or shift these windows of plasticity. If so, interventions that stabilize network activity—such as T-type calcium channel modulation—might help enable more effective language development during these periods. This could potentially explain why some improvements, once initiated, continue even after treatment is stopped.

This also raises the possibility that timing may be critical. If language development depends on sensitive developmental windows, and pathways involving CNTNAP2 alter the timing of circuit maturation, then the age at which a treatment is given could determine its effectiveness. Interventions such as T-type calcium channel modulation may be more beneficial when applied during periods of higher neural plasticity, and less effective once circuits have become more established. This could help explain why any signal of benefit has been difficult to detect in routine clinical use.

 

Conclusion

The study did not have a placebo group. We know from many previous small studies that in most cases everyone improved in autism studies, including those who were assigned the placebo.

Has Niesen identified a simple therapy that will improve speech in autism?

If ethosuximide strongly improves language, why has this not already been noticed?

Neurologists have used ethosuximide for decades for autistic children with absence seizures, but it is not widely recognized as a language-enhancing drug.

I expect there likely is a subgroup of responders, but it will not be a silver bullet for all.

Ethosuximide is cheap, but it can have some unusual side effects.

Zonisamide is more predictable than Ethosuximide, but still can have problematic side effects, more so than drugs like bumetanide or atorvastatin.

It may be the case that responders to Ethosuximide do not need to take it permanently and that has to be factored into the side effect assessment.

Any potential benefit is likely limited to a specific subgroup, such as children with subtle absence seizures, epileptiform activity, or abnormalities in calcium channel signaling. One candidate subgroup involves mutations in the CNTNAP2 gene, which are associated with language impairment, autism, and increased neuronal excitability. Preclinical studies suggest that targeting T-type calcium channels in such models can reduce hyperexcitability and improve behavioral features, raising the possibility that drugs like ethosuximide may be more effective in individuals with similar underlying biology.

CNTNAP2 is also regulated by TCF4, the gene mutated in Pitt-Hopkins syndrome, a condition marked by profound speech deficits. This points to overlapping biological pathways underlying language impairment across different neurodevelopmental disorders and reinforces the idea that identifying responders will be key to determining clinical value.

So, another idea for Pitt Hopkins parents is to consider is Ethosuximide. Maybe the parents’ organisation should contact Charles Niesen to make a small clinical trial, like the forthcoming Clemastine one.

pH and Neuronal Excitability - Therapy in Autism, Epilepsy, Mitochondrial Disease and ASIC mutations. Plus GPR89A

 

Diamox or Meldonium would make it easier

 

Several times recently the subject of pH (acidity/alkalinity) has come up in my discussions with fellow parents. It is not a subject that gets attention in the autism research, so here is my contribution to the subject.

If your child has a blood gas test a day after a seizure and it shows high pH, this is not the result of the seizure, but a likely cause of it. Treat the elevated pH to avoid another seizure and likely also improve autism symptoms. It may be respiratory alkalosis which is caused by hyperventilation, due to stress, anxiety etc.

The regulation of pH inside and outside brain cells is a delicate balance with far-reaching consequences. Subtle shifts toward acidity (low pH) or alkalinity (high pH) can alter calcium handling, neuronal excitability, and ultimately drive seizures, fatigue, or even inflammation. This interplay becomes especially important in conditions like autism, epilepsy, and mitochondrial disease, where metabolism and excitability are already dysregulated.

You can measure blood pH quite easily, but within cells different parts are maintained at very different levels of pH and this you will not be able to measure. Blood pH is about 7.4 (slightly alkaline) the gogli apparatus is slightly acidic, whereas the lysome is very acidic (pH about 4.7).

 

pH and Calcium Balance

Calcium (Ca²⁺) is central to neuronal excitability. Small pH changes shift the balance between intracellular and extracellular calcium:

• Alkalosis (↑ pH): reduces extracellular calcium availability, destabilizes neuronal membranes, and promotes hyperexcitability and seizures.
• Acidosis (↓ pH): activates acid-sensing ion channels (ASICs), leading to Na⁺ and Ca²⁺ influx and further excitability.

Thus, both too much acidity and too much alkalinity can increase seizure risk, though through different mechanisms.

Your body should tightly regulate its pH. You can only nudge it slightly up or down. Even small changes can be worthwhile in some cases.

When extracellular (ionized) calcium enters neurons through ion channels it can drive inflammation, excitability, and mitochondrial stress. Calcium needs to be in the right place and in autism it often is not, for a wide variety of reasons.

 

 

Mitochondrial Disease and pH

Mitochondria produce ATP through oxidative phosphorylation. Dysfunction can impair this process and lead to accumulation of lactate (acidosis) or, paradoxically, reduced proton flux (relative alkalosis). In autism, mitochondrial dysfunction is reported in a significant minority (10–20%) of cases.

 

Hyperventilation and Alkalosis

Another often-overlooked contributor is hyperventilation. By blowing off CO₂, blood pH rises (respiratory alkalosis), leading to reduced ionized calcium and increased excitability. This is the reason why hyperventilation is used during EEG testing to provoke seizures in susceptible individuals.

 

Therapeutic Approaches - Adjusting pH

Several therapies—old and new—intentionally alter pH balance:

1. Sodium and Potassium Bicarbonate

• Mechanism: Buffers acids, increases systemic pH (alkalinization).
• Applications: Beneficial in some cases of autism and epilepsy, as reported in blogs and small studies.
• Note: Raises extracellular pH, which can reduce ASIC activation but may increase excitability if alkalosis is excessive.
• Beyond buffering, sodium bicarbonate (baking soda) has been shown to trigger anti-inflammatory vagal nerve pathways. This effect may be especially valuable in neuroinflammation seen in autism and epilepsy.

 

2. Acetazolamide (Diamox)

• Mechanism: A carbonic anhydrase inhibitor that causes bicarbonate loss in the urine, lowering blood pH (mild acidosis).
• Neurological Effects: Used as an anti-seizure drug, especially in patients with channelopathies and mitochondrial disorders.
• In Climbers: At altitude, the body tends toward alkalosis due to hyperventilation (blowing off CO₂). Diamox counteracts this by inducing a mild metabolic acidosis, which stimulates ventilation, improves oxygenation, and prevents acute mountain sickness (AMS). This is why mountaineers often describe Diamox as helping them “breathe at night” in the mountains.

3. Zonisamide

• Mechanism: Another carbonic anhydrase inhibitor, with both anti-seizure and mild acidifying effects.
• Benefit: Often used in refractory epilepsy.

 

ASICs: Acid-Sensing Ion Channels

ASICs are neuronal ion channels directly gated by protons (H⁺). Their activity is pH-sensitive:

• Low pH (acidosis): Activates ASICs → Na⁺/Ca²⁺ influx → excitability and seizures.
• High pH (alkalosis): Reduces ASIC activity, but destabilizes calcium balance in other ways.

 

ASIC Mutations

Mutations in ASIC genes can alter how neurons respond to pH shifts. In theory, modest therapeutic modulation of pH (via bicarbonate or acetazolamide) could normalize excitability in patients with ASIC mutations.

 

ASIC2 is seen as a likely autism gene. There is even an ASIC2 loss of function mouse model.

Give that mouse Diamox!

 

Meldonium vs Diamox — Two Paths to Survive Altitude

During the Soviet–Afghan war in the 1980s, Russian troops were supplied with meldonium, while American soldiers and climbers commonly used acetazolamide (Diamox) for altitude adaptation. The Mujahideen and Taliban need neither, because they have already adapted to the low oxygen level.

Meldonium is a Latvian drug made famous by the tennis star Maria Sharapova who was found to be taking it for many years. It is a very plausible therapy to boost the performance of your mitochondria and so might help some autism. I know some people have tried it.

Although both drugs were used to improve performance under hypoxia, they worked in almost opposite ways:

 

At high altitude without Diamox

• You hyperventilate to compensate for low oxygen.
• Hyperventilation ↓ CO₂ in the blood → respiratory alkalosis (↑ pH).
• The alkalosis suppresses breathing (since the brainstem senses “too alkaline, slow down”), which is why people breathe shallowly at night, leading to periodic apnea and low oxygen saturation.

With Diamox

• Diamox blocks carbonic anhydrase in the kidneys → you excrete more bicarbonate (HCO₃⁻).
• This causes a metabolic acidosis (↓ pH).
• The brainstem now senses blood as “acidic,” which stimulates breathing.
• So, you hyperventilate more, but this time it’s sustained, because the metabolic acidosis counterbalances the respiratory alkalosis.

The net effect

• Without Diamox: hyperventilation → alkalosis → suppressed breathing → poor oxygenation.
• With Diamox: hyperventilation + mild metabolic acidosis → balanced pH → sustained ventilation and better oxygen delivery.

 So, the key is that Diamox shifts the body’s set point for breathing, letting climbers breathe harder without shutting down from alkalosis.

The Irony

• Meldonium - indirect alkalinization to reduce stress on cells.
• Diamox - deliberate acidification to stimulate respiration.
• Both approaches improved function under low oxygen, but they pulled physiology in opposite pH directions.

 

Another irony is that not only is Meldonium banned in sport, but so is Diamox. Diamox is banned because it is a diuretic and so can be used to mask the use of other drugs.

Now an example showing the impact of when pH control within the cell is dysfunctional.

 

GPR89A - the Golgi “Post Office” gene that keeps our cells running

When we think about genes involved in neurodevelopment, most people imagine genes that directly control brain signaling or neuron growth. But some genes quietly do their work behind the scenes, keeping our cellular “factories” running smoothly. One such gene is GPR89A, a gene that plays a critical role in regulating Golgi pH — and when it malfunctions, the consequences can ripple all the way to autism and intellectual disability (ID).

 

The Golgi Apparatus: The Cell’s Post Office

To understand GPR89A, it helps to picture the cell as a factory:

• The endoplasmic reticulum (ER) is the protein factory, producing raw products — proteins and lipids.
• The Golgi apparatus is the post office, modifying, sorting, and shipping these products to their proper destinations.

Just like a real post office, the Golgi must maintain precise conditions to function. One key condition is pH, the acidity inside the Golgi.

 

GPR89A: The Golgi’s pH Regulator

Inside the Golgi, acidity is carefully balanced by:

• V-ATPase pumps, which push protons (H⁺) in to acidify the lumen.
• Anion channels like GPR89A, which allow negative ions (Cl⁻, HCO₃⁻) to flow in, neutralizing the electrical charge and keeping the pH just right.

Think of GPR89A as the electrical wiring in the post office: without it, the machinery may be overloaded or misfiring, even if the raw materials (proteins) are fine.

 

When Golgi pH Goes Wrong

If GPR89A is mutated:

1.     The Golgi cannot maintain its normal acidic environment.

2.     Enzymes inside the Golgi — responsible for adding sugar chains to proteins (glycosylation) — cannot work properly.

3.     Proteins may become misfolded, unstable, or misrouted. Some may be sent to the wrong destination, while others are degraded.

This is akin to a post office with wrong sorting labels: packages (proteins) either go to the wrong address or get lost entirely.

 

Consequences for the Brain

Proteins are not just passive molecules; many are receptors, ion channels, adhesion molecules, or signaling factors essential for brain development. Mis-glycosylated proteins can lead to:

• Disrupted cell signaling
• Impaired synapse formation
• Altered neuronal communication

The end result can manifest as intellectual disability, autism spectrum disorders, or other neurodevelopmental conditions, because neurons are particularly sensitive to these trafficking and signaling errors.

 

Could Modulating Blood pH Help?

Since Golgi pH depends partly on cellular bicarbonate and proton balance, I have speculated whether small changes in blood pH could indirectly influence Golgi function:

• Sodium/potassium bicarbonate
• Increases extracellular bicarbonate and buffering capacity.
• Might slightly influence intracellular pH and indirectly affect Golgi pH.
• Acetazolamide (Diamox):
• Inhibits carbonic anhydrase, altering H⁺ and bicarbonate handling in cells.
• Could theoretically shift intracellular pH including Golgi pH

 

Systemic pH changes are heavily buffered by cells, so the impact on Golgi pH is likely to be modest at best.

Neither approach has been validated in human studies for improving glycosylation. Currently, there is no established therapy for GPR89A mutations.

Because there is no treatment, a reasonable option is a brief, carefully monitored trial.

• Try both interventions (bicarbonate then Diamox) for a short period.
• Observe for any measurable benefit in function or clinical outcomes.
• If there is no benefit, stop the trial — nothing is lost.

This approach allows cautious exploration without committing to a long-term therapy that may be ineffective.

 

The Bigger Picture

Even though GPR89A itself is not classified as a major autism or ID gene, its role in Golgi ion balance and glycosylation highlights how basic cellular “infrastructure” genes can profoundly affect brain development.

GPR89A reminds us that neurodevelopment is not only about neurons or synapses but also about the tiny cellular logistics systems that make them function. Maintaining Golgi pH is not glamorous, but without it, the entire cellular supply chain collapses, illustrating a pathway from a single gene mutation → cellular dysfunction → potential autism and ID outcomes.

Manipulating blood pH with bicarbonate or Diamox is an intriguing idea, will it provide a benefit?

 

Conclusion

pH regulation is a critical but underappreciated factor in autism, epilepsy, and mitochondrial disease. Subtle shifts in acidity or alkalinity affect calcium handling, ASIC activation, and neuronal excitability. Therapeutic strategies—from bicarbonates to carbonic anhydrase inhibitors—show that intentionally modulating pH can be both protective and symptomatic. Understanding the individual’s underlying metabolic and genetic context (eg mitochondrial function, ASIC mutations etc) will help determine whether a person might benefit more from raising or lowering pH.

For people with inflammatory conditions like some autism, or even MS, the simple idea of using baking soda to activate the vagus nerve is interesting.

·      Sodium bicarbonate → slight systemic alkalization.

·      Alkalization → reduced acidosis-related inflammatory signals.

·      Sensory neurons detect the pH change → activate vagus nerve.

·      Vagus nerve triggers cholinergic anti-inflammatory pathway → lowers pro-inflammatory cytokines.

We saw this in an old post and the researchers even went as far as severing the vagus nerve to prove it.

Potassium bicarbonate is a better long-term choice than sodium bicarbonate (baking soda) since most people lack potassium and have too much sodium already. It is cheap and OTC.

Diamox, Meldonium and Zonisamide are all used long term.

If you mention any of this to your doctor, expect a blank look coming back! Unless he/she is a mountaineer or perhaps a Latvian sports doctor!

 

Time for T? Targeting language-associated gene Cntnap2 with a T-type calcium channel blocker corrects hyperexcitability driving sensory abnormalities, repetitive behaviors, and other ASD symptoms, but will it improve language? Will it also benefit Pitt Hopkins syndrome (PTHS) and broader autism?

 

  

 

There are at least 2 Natasas I can think of who will like this post.

Today’s post revisits the subject of calcium channels in autism.  Ion channel dysfunctions are a favourite area of mine because many should be treatable by repurposing safe, existing drugs. I do take note that many readers of this blog have reported success by targeting L-type calcium channels.

Many years ago, at the start of this blog, I recall reading about Timothy syndrome and a researcher at Stanford, Ricardo Dolmetsch, who was exploring treatment using a T-type calcium channel blocker.  It turned out that he had a son with severe autism, which was driving his interest at that time. He won all kinds of awards, but I always wondered why he did not treat his own son.

It is quite strange because Timothy syndrome is caused by a gain of function of an L-type channel. This mutation causes the Cav1.2 channel to fail to inactivate properly after opening. As a result, there is prolonged calcium influx into cells.

Instead of blocking Cav1.2, the researchers blocked the T-channels Cav3.2 and 3.3.

I did my homework on idiopathic autism a dozen years ago and concluded I needed to block Cav1.2. I went ahead and did it – it works like a charm.

It was a real drama back in those days, with self-injury and aggression, so Timothy syndrome and T channels remains stuck in my mind a decade later.

 

Language Genes

Even before parents worry about self-injurious behavior (SIB), they go through the phase of worrying about if their child will ever speak. Some do and some do not.  What really matters is communication, rather than speech.

 

FOXP2 - The language Gene

FOXP2 is a transcription factor involved in the development of neural circuits related to speech and language production, particularly in areas such as the basal ganglia and cerebellum. Mutations in FOXP2 can lead to speech and language deficits.

FOXP2 influences motor control and vocalization processes that are critical for speech, and it is thought to have evolved specifically in humans to support complex language abilities.

 

CNTNAP2 - The language-associated gene

CNTNAP2 (Contactin-associated protein-like 2) is a gene that encodes a cell adhesion protein. It plays a critical role in the development of neural connectivity and the formation of synapses in areas of the brain involved in language, such as the broca’s area and temporal lobes. CNTNAP2 is also involved in the regulation of neuronal excitability and is crucial for the development of white matter tracts that connect language-related brain regions.

Mutations in CNTNAP2 have been implicated in neurodevelopmental disorders such as specific language impairment (SLI), autism, and developmental language disorders.

 

FOXP2 and CNTNAP2 Interaction

FOXP2 and CNTNAP2 work together in the development of the neural circuits that are crucial for language and speech. They are both involved in the formation and maintenance of synaptic connections in key brain regions like the cortex, basal ganglia, and cerebellum, which are critical for motor control, vocalization, and language processing.

There is evidence to suggest that FOXP2 may regulate the expression of CNTNAP2 as part of a broader gene network that governs language development. FOXP2 may influence CNTNAP2 gene expression, which in turn impacts neural connectivity and synaptic function in brain regions responsible for speech and language.

 

CNTNAP2 sounds familiar?

We have come across this gene before.

At least one reader has a child with a mutation in this gene.

We also discovered that the Pitt Hopkins gene TCF4 regulates CNTNAP2 and that

“PTHS (Pitt Hopkins syndrome) is characterised by severe intellectual disability, absent or severely impaired speech, characteristic facial features and epilepsy. Many of these features are shared with patients carrying CNTNAP2 mutations, leading researchers to test patients with PTHS-like features for CNTNAP2 mutations”

Several readers have children with PTHS (Pitt Hopkins syndrome).

It is not inconceivable that what works for CNTNAP2 will also work for at least some PTHS (Pitt Hopkins syndrome).

The question is whether what works for CNTNAP2 will work much more broadly and could it even improve language development?

Here is the recent research from Stanford:

 

Reticular Thalamic Hyperexcitability Drives Autism Spectrum Disorder Behaviors in the Cntnap2 Model of Autism

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by social communication deficits, repetitive behaviors, and comorbidities such as sensory abnormalities, sleep disturbances, and seizures. Dysregulation of thalamocortical circuits has been implicated in these comorbid features, yet their precise roles in ASD pathophysiology remain elusive. This study focuses on the reticular thalamic nucleus (RT), a key regulator of thalamocortical interactions, to elucidate its contribution to ASD-related behavioral deficits using a Cntnap2 knockout (KO) mouse model. Our behavioral and EEG analyses comparing Cntnap2^+/+ and Cntnap2^-/- mice demonstrated that Cntnap2 knockout heightened seizure susceptibility, elevated locomotor activity, and produced hallmark ASD phenotypes, including social deficits, and repetitive behaviors. Electrophysiological recordings from thalamic brain slices revealed increased spontaneous and evoked network oscillations with increased RT excitability due to enhanced T-type calcium currents and burst firing. We observed behavior related heightened RT population activity in vivo with fiber photometry. Notably, suppressing RT activity via Z944, a T-type calcium channel blocker, and via C21 and the inhibitory DREADD hM4Di, improved ASD-related behavioral deficits. These findings identify RT hyperexcitability as a mechanistic driver of ASD behaviors and underscore RT as a potential therapeutic target for modulating thalamocortical circuit dysfunction in ASD.

Teaser RT hyperexcitability drives ASD behaviors in Cntnap2-/- mice, highlighting RT as a therapeutic target for circuit dysfunction.

 

Overall, this study identifies elevated RT burst firing and aberrant thalamic oscillatory dynamics in Cntnap2^−/− mice as a key driver of ASD-related behavioral deficits. If this is a common mechanism of ASD-circuit pathology arising from a variety of genetic causes, then compounds such as Z944, or subtype specific T-type calcium channel antagonists that would target the Cav3.2 and Cav3.3 expressed in RT neurons, might be an effective therapeutic strategy. Furthermore, future research should focus on elucidating RT’s roles in sensory, emotional, and sleep regulation to optimize therapeutic strategies in the context of ASD.

 

Existing T-type calcium channel blockers for humans

Mibefradil is one of the most well-known T-type calcium channel blockers. It was initially developed for hypertension and angina because of its ability to block T-type channels. However, mibefradil was withdrawn from the market in 1998 due to serious drug interactions with other medications, particularly those that inhibit liver enzymes involved in drug metabolism, like statins.

Despite its withdrawal, mibefradil has been studied for other potential uses, including in epilepsy and chronic pain, due to its effects on neuronal excitability.

Zonisamide is an anticonvulsant medication that has some T-type calcium channel blocking properties. It is approved for epilepsy and partial seizures, but it is not typically used specifically for Timothy syndrome or conditions involving T-type channel dysfunction.

Zonisamide is also used to treat seizures in pet dogs and cats.  

Zonisamide: chemistry, mechanism of action, and pharmacokinetics

Zonisamide is a novel antiepileptic drug (AED) that was developed in search of a less toxic, more effective anticonvulsant. The drug has been used in Japan since 1989, and is effective for simple and complex partial seizures, generalized tonic-clonic seizures, myoclonic epilepsies, Lennox–Gastaut syndrome, and infantile spasms. In Japan, zonisamide is currently indicated for monotherapy and adjunctive therapy for partial onset and generalized onset seizures in adults and children. In the United States, zonisamide was approved by the Food and Drug Administration (FDA) in 2000 as an adjunctive treatment for partial seizures.

The drug’s broad spectrum of activity and favorable pharmacokinetic profile offer certain advantages in the epilepsy treatment armamentarium. Chemically distinct from other AEDs, zonisamide has been shown to be effective in patients whose seizures are resistant to other AEDs. Zonisamide’s long plasma elimination half-life has allowed it to be used in a once-daily or twice-daily treatment regimen in Japan.

It is believed that zonisamide’s effect on the propagation of seizure discharges involves blocking the repetitive firing of voltage-sensitive sodium channels, and reducing voltage-sensitive T-type calcium currents without affecting L-type calcium currents. These mechanisms stabilize neuronal membranes and suppress neuronal hypersynchronization, leading to the suppression of partial seizures and generalized tonic–clonic seizures in humans.

Zonisamide possesses mechanisms of action that are similar to those of sodium valproate, e.g., suppression of epileptogenic activity and depression of neuronal responses. These mechanisms are thought to contribute to the suppression of absence and myoclonic seizures.

  

Conclusion

It would seem that zonisamide should be trialed in:

·        CNTNAP2-related neurodevelopmental disorder

·        Pitt Hopkins syndrome (PTHS)

·        Timothy syndrome

·        Idiopathic/polygenic autism

(But, don’t hold your breath!)

Due to the nature of CNTNAP2 disorder and PTHS, I think the greatest impact will be if given from a very young age. However, we do see improvements with many autism interventions regardless of age.

It is certainly conceivable that even mild autism can benefit from damping down reticular thalamic (RT) hyperexcitability.

If shown effective, zonisamide would join the long list of anti-epileptic drugs (AEDs) “repurposable” to treat certain subtypes of autism.