From Conception to Early Childhood: Managing pain, fever, and neurodevelopmental risk. Time to apply some common sense? Time for NAC?

 

Donald Trump recently reignited debate about Tylenol (paracetamol/acetaminophen) in pregnancy. His comments drew attention to research linking prenatal use to higher rates of autism and ADHD.

A large review of 46 studies, including work from Harvard, found consistent associations between paracetamol in pregnancy and neurodevelopmental risks. The FDA now advises caution: use the lowest dose for the shortest time.

 

Tylenol in pregnancy linked to higher autism risk, Harvard scientists report

Researchers reviewing 46 studies found evidence linking prenatal acetaminophen (Tylenol) exposure with higher risks of autism and ADHD. The FDA has since urged caution, echoing scientists’ advice that the drug be used only at the lowest effective dose and shortest duration. While important for managing fever and pain in pregnancy, prolonged use may pose risks to fetal development. Experts stress careful medical oversight and further investigation.

 Why the concern?

• Paracetamol depletes glutathione (GSH), the body’s main antioxidant.
• This raises oxidative stress in both mother and fetus.
• The fetus has weak antioxidant defences, so damage may occur during critical brain development.

But here is the dilemma: the fever, pain, or inflammation that drives a mother to take paracetamol is itself risky. We have long known from maternal immune activation models that fever and cytokine surges in pregnancy can disturb fetal brain development and cause autism or schizophrenia. There is also evidence linking maternal immune activation to ADHD in the offspring.

So, what is the solution? Pair paracetamol with NAC.

Why NAC?

• NAC (N-acetylcysteine) is a precursor to glutathione.
• It’s used worldwide in emergency rooms to save lives after paracetamol/ acetaminophen overdose.
• In pregnancy, NAC has been shown to reduce miscarriage risk by 50%,

N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss

• Increased pregnancy continuation: Women receiving NAC and folic acid were 2.9 times more likely to continue their pregnancies beyond 20 weeks compared to those receiving folic acid alone
• Higher take-home baby rate: The NAC group had a 1.98 times higher rate of delivering a live baby.
• These findings suggest that NAC, an antioxidant, may help mitigate oxidative stress, a factor implicated in pregnancy loss.

  

A combined Paracetamol/acetaminophen + NAC pill would:

• Prevent liver toxicity,
• Buffer oxidative stress in the fetus,
• Eliminate the overdose suicide risk that haunts current paracetamol use.

So far, no company has produced it. Perhaps the “rotten egg” smell of NAC is a barrier—but solid sustained-release tablets avoid this.

 

Why Paracetamol/acetaminophen use is problematic in under 5s

Paracetamol depletes glutathione (GSH), the body’s primary antioxidant, increasing oxidative stress. A fetus with some genetic predispositions might already be in a state of oxidative stress, as might the mother

Paracetamol is mainly metabolized in the liver. A small fraction is metabolized into NAPQI — a reactive toxic metabolite. Glutathione (GSH) neutralizes NAPQI by forming a harmless conjugate.

If GSH stores are low (or paracetamol is taken in high doses), NAPQI accumulates, causing liver toxicity and GSH is exhausted raising oxidative stress.

Acute oxidative stress can be very damaging to developing brains. The risk after 5 years old fades away, other than in those who have already exhibited a profound metabolic/mitochondrial condition.

Why Oxidative Stress Rises in Pregnancy

Placental development: Early pregnancy is low-oxygen; as blood flow increases, oxygen surges and generates reactive oxygen species (ROS).

High metabolic demand: The mother and placenta require much more energy, leading to increased mitochondrial ROS.

Immune adaptations: Pregnancy involves a shift in maternal immunity, with inflammatory cytokines contributing to oxidative stress.

Fetal growth: Rapid cell division and organ development naturally produce oxidative byproducts, while the fetus’s antioxidant defenses are immature.

Limited antioxidant reserves: Maternal antioxidants (glutathione, vitamins C & E, enzymes) are partly depleted as pregnancy progresses.

 

Compounding Risk Factors

Polycystic Ovary Syndrome (PCOS): Associated with high androgens, insulin resistance, and chronic inflammation. These increase oxidative stress and are linked to higher autism risk in offspring.

Gestational Diabetes: Maternal hyperglycemia and insulin resistance increase ROS, damage the placenta, and expose the fetus to oxidative and metabolic stress.

Other amplifiers: Obesity, infection, fever, or poor nutrition further elevate oxidative stress.

 

How Oxidative Stress Affects the Fetus

Neurodevelopmental disruption: ROS can damage neural stem cells, impair migration, and disturb synapse formation.

Epigenetic reprogramming: Oxidative stress alters DNA methylation and gene expression, shaping long-term brain function.

Immune activation: Inflammatory cytokines cross the placenta and disturb fetal brain development.

Mitochondrial dysfunction: ROS damage fetal mitochondria, reducing energy for developing neurons.

Neurotransmitter imbalance: Antioxidant depletion disrupts glutamate/GABA balance and monoamine systems.

 

Consequences for the Unborn Child

Most pregnancies manage oxidative stress without harm, thanks to maternal–fetal antioxidant defences.

When oxidative stress overwhelms these defences—especially in mothers with PCOS, GDM, or infections—the risk of complications rises:

Preterm birth, growth restriction, or preeclampsia

Higher vulnerability to neurodevelopmental disorders, including autism spectrum disorder (ASD) and ADHD.

Genetic predispositions in antioxidant or mitochondrial pathways may make some fetuses especially sensitive to these oxidative challenges.

Pregnancy naturally involves a controlled increase in oxidative stress, but when combined with maternal conditions like PCOS, gestational diabetes, or acute infections, the oxidative burden can exceed protective capacity. This imbalance may impair placental function and fetal brain development, increasing the risk of adverse outcomes, including autism. 

 

Pregnancy: Choosing safer options for pain and fever

• Paracetamol → Remains the best option if pain relief is absolutely needed, but should be paired with NAC.
• NSAIDs (ibuprofen, mefenamic acid) → Unsafe in later pregnancy due to fetal kidney damage and premature closure of the ductus arteriosus. Premature closure of the ductus arteriosus is a serious condition that occurs when the fetal blood vessel connecting the pulmonary artery to the aorta closes before birth. Do not use NSAIDs!
• NAC supplementation → Low-cost, safe, and evidence-backed for reducing oxidative stress.

 

Infancy and Early Childhood

• Paracetamol
• Licensed from birth.
• Effective for pain and fever, but still depletes glutathione.
• In at-risk infants (metabolic or mitochondrial issues), consider pairing with NAC.
• NSAIDs (ibuprofen, Ponstan)
• Suitable from 3–6 months (depending on guidelines).
• Do not deplete glutathione, making them safer for oxidative stress.
• Hydration matters to protect kidneys.

 

Vaccinations, Fever, and Oxidative Stress

Vaccines work by briefly activating the immune system. This triggers a short burst of oxidative stress—far smaller than that caused by actual infections.

• Healthy children clear this easily.
• At-risk children (mitochondrial disease, metabolic errors, weak antioxidant systems) may struggle, leading to fatigue, regression-like symptoms, or metabolic instability.

Medication choices around vaccines

• NSAIDs → Good for post-vaccine fever. Avoid routine pre-dosing to prevent dampening immunity, unless the child is in the at-risk group.
• Paracetamol → Pre-vaccine dosing can reduce antibody production and reduce GSH. Post vaccine should be paired with NAC.
• Montelukast → Anti-inflammatory, theoretically helpful in at-risk children, but not tested in trials, but is used at metabolic/mitochondrial clinics treating children.
• NAC → Biologically plausible support for antioxidant status, though not studied formally in this setting.

Mainstream pediatrics avoids routine prophylactic anti-inflammatories, but some specialists (e.g., Dr. Kelley, Johns Hopkins) do use them selectively in fragile children. Using paracetamol without NAC is a bad idea.

 

Metabolic Decompensation: The Hidden Risk

Some children with mitochondrial or metabolic disorders cannot handle stress from fever or illness. This can trigger:

• Energy failure (low ATP)
• Accumulation of toxic metabolites (lactate, ammonia)
• Seizures or regression

In developing brains, these crises can leave permanent autism-like features and/or intellectual disability. These symptoms are secondary to brain injury. Prevention is key:

• Hydration, glucose support
• Early fever control
• Antioxidant support (NAC, vitamins C & E)

 

Key Takeaways

• Pregnancy: If pain relief is needed, paracetamol + NAC is safer than paracetamol alone. Avoid NSAIDs.
• Infancy: Paracetamol is widely used, but NSAIDs are safer from 3 months onward when oxidative stress is a concern.
• Vaccination: Vaccines prevent far greater oxidative stress from infections. At-risk children may benefit from antioxidant or anti-inflammatory support, but this should be individualized.
• Metabolic decompensation: Recognize and prevent crises in vulnerable children—this reduces risk of secondary neurodevelopmental injury.

 

Conclusion

Paracetamol has been trusted for decades, but its link with oxidative stress and neurodevelopmental risk is becoming harder to ignore. A Paracetamol + NAC pill makes both medical and common sense—safer for mothers, safer for children, and suicide-proof.

Until then, thoughtful use of NAC, NSAIDs, and tailored fever management could make a real difference in protecting brain development from conception through early childhood.

 

My original draft post was rather long, so here is the “optional” part 2, for any avid readers out there!

 

 

Part 2: Vaccines, Oxidative Stress, and Children at Risk

Why some kids may react differently — and what parents and clinicians can do

Vaccines are one of the greatest public health achievements, protecting children from infections that would otherwise cause significant illness, hospitalization, or death. But for children with mitochondrial disorders, metabolic diseases, or weak antioxidant systems, even routine vaccination can temporarily stress the body.

How Vaccines Trigger Oxidative Stress

• Vaccination works by activating the immune system, prompting cytokine release, mild inflammation, and reactive oxygen species (ROS) production.
• In healthy children, this burst is short-lived. Antioxidant defences like glutathione, superoxide dismutase, and dietary vitamins C & E neutralize ROS quickly.
• In children with mitochondrial or metabolic vulnerabilities, baseline ROS is already elevated, and antioxidant defences may be limited. A small extra load from vaccination can feel disproportionately stressful.

 

Why Some Children React Differently

Mitochondrial Disorders

• Mitochondria produce ATP and ROS. Dysfunction means higher baseline oxidative stress and lower energy reserves.
• A vaccine-induced oxidative spike can linger longer, leading to fatigue, metabolic stress, or regression-like symptoms.

Metabolic Disorders

• Children with amino acid, fatty acid, or urea cycle defects have limited antioxidant capacity.
• ROS accumulation may overwhelm defences, causing secondary mitochondrial stress or toxic metabolite build-up.

Genetic Variants

• Some children carry variants that reduce glutathione production or antioxidant enzyme activity (e.g., GSTM1/GSTT1 deletions, MTHFR variants, impaired SOD/catalase).
• Even minor oxidative challenges can temporarily disturb synapse formation, neurotransmitter balance, and myelination in the developing brain.

 

Medications Around Vaccination

NSAIDs

• Symptom-driven use for fever or pain post-vaccine is generally safe.
• Routine prophylactic use is usually avoided because it can reduce antibody responses, but specialists consider this is likely minimal

Paracetamol

• Pre-vaccine dosing can modestly blunt antibody formation in some vaccines and is unwise because it reduces GSH just before it will be needed most.
• Post-vaccine, symptom-driven use is often considered safe, but is unwise due to the ruction in GSH when needed most
• High-risk children should always avoid paracetamol unless paired with NAC to protect glutathione and limit oxidative stress.

NAC (N-acetylcysteine)

• Biologically plausible support for antioxidant status in at-risk children.
• Safely used during pregnancy and by babies
• Not yet studied in formal vaccine trials, but safe and used in clinical settings for other oxidative stress conditions.

Montelukast

• Anti-inflammatory, may reduce oxidative stress, but not proven for vaccine prophylaxis.
• Used by children at vaccination time when already prescribed it for asthma/allergic disease.

 

Managing Vaccination in At-Risk Children

1.     Ensure good hydration, feeding, and metabolic stability before vaccination.

2.     Monitor closely for post-vaccine fever, fatigue, or regression-like symptoms.

3.     Have supportive measures ready:

o    NAC or other antioxidant support

o    Symptom-driven NSAIDs

o    Avoid paracetamol unless paired with NAC

o    Quick access to a specialist if metabolic stress occurs

 

Takeaways for Parents and Clinicians

• Vaccines do cause a small, transient oxidative stress, but it is far less than the oxidative burden from infections.
• Children with mitochondrial or metabolic vulnerabilities may need extra care before and after vaccination.
• NAC, hydration, symptom-driven NSAIDs, and careful monitoring can reduce risk without compromising immunity.
• Always coordinate with a metabolic or mitochondrial specialist when planning vaccination for high-risk children.

By understanding oxidative stress, supporting antioxidant defences, and tailoring care, parents and clinicians can protect both immunity and neurodevelopment.

Since most parents, in reality, do not have access a mitochondrial specialist it pays to do your homework in advance. All the needed resources are in plain view.

You do wonder why nobody makes a combined Paracetamol/acetaminophen + NAC pill.

Such a pill is perfect for pregnant women.

Nobody would be able to commit suicide with this pill. This pill blocks the harmful effect on the liver that ultimately can lead to death.

NAC does smell of rotten eggs. One argument against such a pill is that it would stink and pregnant women are often feeling nausea. If the pill is solid (like NAC Sustain) there is no smell of rotten eggs. So you certainly can have a combined pill.

Personally, I would ban all liquid formulations of Paracetamol, other than for babies under 3 months. Many countries have long used exclusively Ibuprofen or Ponstan for children. Once a child is 5 years old the potential for paracetamol to do neurodevelopmental harm should have faded.

You can give babies NAC, it is sold in a liquid form for this purpose. NAC acts as a mucolytic, meaning it thins mucus in the airways.

How common is Metabolic Decompensation as a cause of severe autism? We know it exists, but I think we will never know how common it is. Hannah Poling is the best-known example. Evidence of an inconvenient truth.

 

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!

 

Taurine for subgroups of Autism? Plus, vitamin B5 and L Carnitine for KAT6A syndrome?

 

   A Red Bull Formula 1 racing car

 

Today’s post should be of wide interest because it concerns the potential benefit from the OTC supplement taurine. There is a section at the end answering a query about mutations in the KAT6A gene.

Taurine is an amino acid and it is found in abundance in both mother’s milk and formula milk.  It has long been used as a supplement by some people with autism. It is finally going to be the subject of a clinical trial in autism and not surprisingly that will be in China - nowadays home to much autism research.

Taurine is also a key ingredient in energy drinks like Red Bull.

 

In a study of children with autism a third had low levels of taurine. Since taurine has anti-oxidant activity, children with ASD with low taurine concentrations were then examined for abnormal mitochondrial function. That study suggests that taurine may be a valid biomarker in a subgroup of ASD.

Taurine has several potential benefits to those with autism and it is already used to treat a wide variety of other conditions, some of which are relevant to autism. One example is its use in Japan to improve mitochondrial function in a conditional called MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes).

The effects that are suggested to relate to some types of autism include:-

 

·        Activating GABA_A receptors, in the short term

·        Down regulating GABA_A receptors, after long term use

·        Enhancing the PTEN/mTOR/AKT pathway

·        Reverse autophagy impairment caused by microglial activation

·        Reduce NMDA mediated activation of calcium channels

·        Protective effect on mitochondria and upregulating Complex 1

·        Improving the quality of the gut microbiota

 

If you have a pet you may know that taurine is widely given to cats and dogs. All cat food has taurine added and some breeds of dog need supplementation.

Taurine is crucial for several bodily functions in pets, including: 

Heart Health: Taurine helps regulate heart rhythm and improves heart muscle function. It can help prevent a type of heart disease called dilated cardiomyopathy (DCM) in both cats and dogs.

Vision: Taurine plays a role in maintaining healthy vision and can prevent retinal degeneration, a serious eye disease.

Immune System Function: Taurine may help boost the immune system and fight off infections.

 

From China we have the following recent study showing a benefit in the BTBR model of autism:

Taurine Improved Autism-Like Behaviours and Defective Neurogenesis of the Hippocampus in BTBR Mice through the PTEN/mTOR/AKT Signalling Pathway

Effective treatment of patients with autism spectrum disorder (ASD) is still absent so far. Taurine exhibits therapeutic effects towards the autism-like behaviour in ASD model animals. Here, we determined the mechanism of taurine effect on hippocampal neurogenesis in genetically inbred BTBR T⁺ tf/J (BTBR) mice, a proposed model of ASD. In this ASD mouse model, we explored the effect of oral taurine supplementation on ASD-like behaviours in an open field test, elevated plus maze, marble burying test, self-grooming test, and three-chamber test. The mice were divided into four groups of normal controls (WT) and models (BTBR), who did or did not receive 6-week taurine supplementation in water (WT, WT+ Taurine, BTBR, and BTBR+Taurine). Neurogenesis-related effects were determined by Ki67 immunofluorescence staining. Western blot analysis was performed to detect the expression of phosphatase and tensin homologue deleted from chromosome 10 (PTEN)/mTOR/AKT pathway-associated proteins. Our results showed that taurine improved the autism-like behaviour, increased the proliferation of hippocampal cells, promoted PTEN expression, and reduced phosphorylation of mTOR and AKT in hippocampal tissue of the BTBR mice. In conclusion, taurine reduced the autism-like behaviour in partially inherited autism model mice, which may be associa­ted with improving the defective neural precursor cell proliferation and enhancing the PTEN-associated pathway in hippocampal tissue.

 

A trial in humans with autism is scheduled in Guizhou, China. In this trial they seem to believe the benefit may come from modification to the gut microbiota.

 

Study on the Treatment of Taurine in Children With Autism

In the treatment of autism spectrum disorders (ASD), medication is only an adjunct, and the main treatment modalities are education and behavioral therapy. People with autism incur huge medical and educational costs, which puts a great financial burden on families. Taurine is one of the abundant amino acids in tissues and organs, and plays a variety of physiological and pharmacological functions in nervous, cardiovascular, renal, endocrine and immune systems. A large number of studies have shown that taurine can improve cognitive function impairment under various physiological or pathological conditions through a variety of mechanisms, taurine can increase the abundance of beneficial bacteria in the intestine, inhibit the growth of harmful bacteria, and have a positive effect on intestinal homeostasis. This study intends to analyze the effect of taurine supplementation on ASD, and explore the possible mechanism by detecting intestinal symptoms, intestinal flora, markers of oxidative stress and clinical symptoms of ASD.

Taurine granules mixed with corn starch and white sugar, 0.4g in 1 bag, taken orally. One time dosage: 1 bag each time for 1-2 years old, 3 times a day, 1.5 bags each time for 3-5 years old, 3 times a day, 2 bags each time for 6-8 years old, 3 times a day, 2.5-3 bags each time for 9-13 years old, 3 to 4 bags each time for children and adults over 14 years old, 3 times a day. The use of taurine is strictly in accordance with the specifications of Chinese Pharmacopoeia. 

 

Roles of taurine in cognitive function of physiology, pathologies and toxication

Taurine is a key functional amino acid with many functions in the nervous system. The effects of taurine on cognitive function have aroused increasing attention. First, the fluctuations of taurine and its transporters are associated with cognitive impairments in physiology and pathology. This may help diagnose and treat cognitive impairment though mechanisms are not fully uncovered in existing studies. Then, taurine supplements in cognitive impairment of different physiologies, pathologies and toxicologies have been demonstrated to significantly improve and restore cognition in most cases. However, elevated taurine level in cerebrospinal fluid (CSF) by exogenous administration causes cognition retardations only in physiologically sensitive period between the perinatal to early postnatal period. In this review, taurine levels are summarized in different types of cognitive impairments. Subsequently, the effects of taurine supplements on cognitions in physiology, different pathologies and toxication of cognitive impairments (e.g. aging, Alzheimer' disease, streptozotocin (STZ)-induced brain damage, ischemia model, mental disorder, genetic diseases and cognitive injuries of pharmaceuticals and toxins) are analyzed. These data suggest that taurine can improve cognition function through multiple potential mechanisms (e.g. restoring functions of taurine transporters and γ-aminobutyric acid (GABA) A receptors subunit; mitigating neuroinflammation; up-regulating Nrf2 expression and antioxidant capacities; activating Akt/CREB/PGC1α pathway, and further enhancing mitochondria biogenesis, synaptic function and reducing oxidative stress; increasing neurogenesis and synaptic function by pERK; activating PKA pathway). However, more mechanisms still need explorations.

 

Effects and Mechanisms of Taurine as a Therapeutic Agent

Taurine as an inhibitory neuromodulator

Although ER stress assumes an important role in the cytoprotective actions of taurine in the central nervous system (CNS), another important mechanism affecting the CNS is the neuromodulatory activity of taurine. Toxicity in the CNS commonly occurs when an imbalance develops between excitatory and inhibitory neurotransmitters. GABA is one of the dominant inhibitory neurotransmitters, therefore, reductions in either the CNS levels of GABA or the activity of the GABA receptors can favor neuronal hyperexcitability. Taurine serves as a weak agonist of the GABA_A, glycine and NMDA receptors Therefore, taurine can partially substitute for GABA by causing inhibition of neuronal excitability. However, the regulation of the GABA_A receptor by taurine is complex. While acute taurine administration activates the GABA_A receptor, chronic taurine feeding promotes the downregulation of the GABA_A receptor  and the upregulation of glutamate decarboxylase, the rate-limiting step in GABA biosynthesis. Therefore, complex interactions within the GABAeric system, as well as in the glycine and NMDA receptors, largely define the actions of taurine in the CNS.

Pharmacological characterization of GABA_A receptors in taurine-fed mice

Background

Taurine is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. Chronic supplementation of taurine in drinking water to mice increases brain excitability mainly through alterations in the inhibitory GABAergic system. These changes include elevated expression level of glutamic acid decarboxylase (GAD) and increased levels of GABA. Additionally we reported that GABAA receptors were down regulated with chronic administration of taurine. Here, we investigated pharmacologically the functional significance of decreased / or change in subunit composition of the GABAA receptors by determining the threshold for picrotoxin-induced seizures. Picrotoxin, an antagonist of GABAA receptors that blocks the channels while in the open state, binds within the pore of the channel between the β2 and β3 subunits. These are the same subunits to which GABA and presumably taurine binds.

Methods

Two-month-old male FVB/NJ mice were subcutaneously injected with picrotoxin (5 mg kg-1) and observed for a) latency until seizures began, b) duration of seizures, and c) frequency of seizures. For taurine treatment, mice were either fed taurine in drinking water (0.05%) or injected (43 mg/kg) 15 min prior to picrotoxin injection. 

Results

We found that taurine-fed mice are resistant to picrotoxin-induced seizures when compared to age-matched controls, as measured by increased latency to seizure, decreased occurrence of seizures and reduced mortality rate. In the picrotoxin-treated animals, latency and duration were significantly shorter than in taurine-treated animas. Injection of taurine 15 min before picrotoxin significantly delayed seizure onset, as did chronic administration of taurine in the diet. Further, taurine treatment significantly increased survival rates compared to the picrotoxin-treated mice. 

Conclusions

We suggest that the elevated threshold for picrotoxin-induced seizures in taurine-fed mice is due to the reduced binding sites available for picrotoxin binding due to the reduced expression of the beta subunits of the GABAA receptor. The delayed effects of picrotoxin after acute taurine injection may indicate that the two molecules are competing for the same binding site on the GABAA receptor. Thus, taurine-fed mice have a functional alteration in the GABAergic system. These include: increased GAD expression, increased GABA levels, and changes in subunit composition of the GABAA receptors. Such a finding is relevant in conditions where agonists of GABAA receptors, such as anesthetics, are administered.

 

Taurine as used in Japan to treat MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes)

Taurine powder 98% "Taisho" [Prevention of stroke-like episodes of MELAS]

Effects of this medicine

This medicine improves mitochondrial dysfunction related to cell energy production etc., and suppresses stroke-like episodes.
It is usually used for prevention of stroke-like episodes of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes).

·         Your dosing schedule prescribed by your doctor is ((        to be written by a healthcare professional))

·         In general, take as following dose according to your weight, 3 times a day after meals. If you weigh less than 15 kg, take 1.02 g (1 g of the active ingredient) at a time. If your weight ranges 15 kg to less than 25 kg, take 2.04 g (2 g) at a time. If your weight ranges 25 kg to less than 40 kg, take 3.06 g (3 g) at a time. If you weigh 40 kg and more, take 4.08 g (4 g) at a time. Strictly follow the instructions.

·         If you miss a dose, take the missed a dose as soon as possible. However, if it is almost time for the next dose, skip the missed a dose and continue your regular dosing schedule. You should never take two doses at one time.

·         If you accidentally take more than your prescribed dose, consult with your doctor or pharmacist.

·         Do not stop taking this medicine unless your doctor instructs you to do so.

 

On the Potential Therapeutic Roles of Taurine in Autism Spectrum Disorder

 

Contemporary research has found that people with autism spectrum disorder (ASD) exhibit aberrant immunological function, with a shift toward increased cytokine production and unusual cell function. Microglia and astroglia were found to be significantly activated in immuno-cytochemical studies, and cytokine analysis revealed that the macrophage chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and transforming growth factor β-1 (TGFB-1), all generated in the neuroglia, constituted the most predominant cytokines in the brain. Taurine (2-aminoethanesulfonic acid) is a promising therapeutic molecule able to increase the activity of antioxidant enzymes and ATPase, which may be protective against aluminum-induced neurotoxicity. It can also stimulate neurogenesis, synaptogenesis, and reprogramming of proinflammatory M1 macrophage polarization by decreasing mitophagy (mitochondrial autophagy) and raising the expression of the markers of the anti-inflammatory and pro-healing M2 macrophages, such as macrophage mannose receptor (MMR, CD206) and interleukin 10 (IL-10), while lowering the expression of the M1 inflammatory factor genes. Taurine also induces autophagy, which is a mechanism that is impaired in microglia cells and is critically associated with the pathophysiology of ASD. We hypothesize here that taurine could reprogram the metabolism of M1 macrophages that are overstimulated in the nervous system of people suffering from ASD, thereby decreasing the neuroinflammatory process characterized by autophagy impairment (due to excessive microglia activation), neuronal death, and improving cognitive functions. Therefore, we suggest that taurine can serve as an important lead for the development of novel drugs for ASD treatment.

  

Taurine as a potential therapeutic agent interacting with multiple signaling pathways implicated in autism spectrum disorder (ASD): An in-silico analysis

  

Autism spectrum disorders (ASD) are a complex sequelae of neurodevelopmental disorders which manifest in the form of communication and social deficits. Currently, only two agents, namely risperidone and aripiprazole have been approved for the treatment of ASD, and there is a dearth of more drugs for the disorder. The exact pathophysiology of autism is not understood clearly, but research has implicated multiple pathways at different points in the neuronal circuitry, suggesting their role in ASD. Among these, the role played by neuroinflammatory cascades like the NF-KB and Nrf2 pathways, and the excitotoxic glutamatergic system, are said to have a bearing on the development of ASD. Similarly, the GPR40 receptor, present in both the gut and the blood brain barrier, has also been said to be involved in the disorder. Consequently, molecules which can act by interacting with one or multiple of these targets might have a potential in the therapy of the disorder, and for this reason, this study was designed to assess the binding affinity of taurine, a naturally-occurring amino acid, with these target molecules. The same was scored against these targets using in-silico docking studies, with Risperidone and Aripiprazole being used as standard comparators. Encouraging docking scores were obtained for taurine across all the selected targets, indicating promising target interaction. But the affinity for targets actually varied in the order NRF-KEAP > NF-κB > NMDA > Calcium channel > GPR 40. Given the potential implication of these targets in the pathogenesis of ASD, the drug might show promising results in the therapy of the disorder if subjected to further evaluations.

 

Is Taurine a Biomarker in Autistic Spectrum Disorder?

Taurine is a sulfur-containing amino acid which is not incorporated into protein. However, taurine has various critical physiological functions including development of the eye and brain, reproduction, osmoregulation, and immune functions including anti-inflammatory as well as anti-oxidant activity. The causes of autistic spectrum disorder (ASD) are not clear but a high heritability implicates an important role for genetic factors. Reports also implicate oxidative stress and inflammation in the etiology of ASD. Thus, taurine, a well-known antioxidant and regulator of inflammation, was investigated here using the sera from both girls and boys with ASD as well as their siblings and parents. Previous reports regarding taurine serum concentrations in ASD from various laboratories have been controversial. To address the potential role of taurine in ASD, we collected sera from 66 children with ASD (males: 45; females: 21, age 1.5-11.5 years, average age 5.2 ± 1.6) as well as their unaffected siblings (brothers: 24; sisters: 32, age 1.5-17 years, average age 7.0 ± 2.0) as controls of the children with ASD along with parents (fathers: 49; mothers: 54, age 28-45 years). The sera from normal adult controls (males: 47; females: 51, age 28-48 years) were used as controls for the parents. Taurine concentrations in all sera samples were measured using high performance liquid chromatography (HPLC) using a phenylisothiocyanate labeling technique. Taurine concentrations from female and male children with ASD were 123.8 ± 15.2 and 145.8 ± 8.1 μM, respectively, and those from their unaffected brothers and sisters were 142.6 ± 10.4 and 150.8 ± 8.4 μM, respectively. There was no significant difference in taurine concentration between autistic children and their unaffected siblings. Taurine concentrations in children with ASD were also not significantly different from their parents (mothers: 139.6 ± 7.7 μM, fathers: 147.4 ± 7.5 μM). No significant difference was observed between adult controls and parents of ASD children (control females: 164.8 ± 4.8 μM, control males: 163.0 ± 7.0 μM). However, 21 out of 66 children with ASD had low taurine concentrations (<106 μM). Since taurine has anti-oxidant activity, children with ASD with low taurine concentrations will be examined for abnormal mitochondrial function. Our data imply that taurine may be a valid biomarker in a subgroup of ASD.

  

The Role of Taurine in Mitochondria Health: More Than Just an Antioxidant

Taurine is a naturally occurring sulfur-containing amino acid that is found abundantly in excitatory tissues, such as the heart, brain, retina and skeletal muscles. Taurine was first isolated in the 1800s, but not much was known about this molecule until the 1990s. In 1985, taurine was first approved as the treatment among heart failure patients in Japan. Accumulating studies have shown that taurine supplementation also protects against pathologies associated with mitochondrial defects, such as aging, mitochondrial diseases, metabolic syndrome, cancer, cardiovascular diseases and neurological disorders. In this review, we will provide a general overview on the mitochondria biology and the consequence of mitochondrial defects in pathologies. Then, we will discuss the antioxidant action of taurine, particularly in relation to the maintenance of mitochondria function. We will also describe several reported studies on the current use of taurine supplementation in several mitochondria-associated pathologies in humans.

 

Taurine is known not as a radical scavenger. Several potential mechanisms by which taurine exerts its antioxidant activity in maintaining mitochondria health include: taurine conjugates with uridine on mitochondrial tRNA to form a 5-taurinomethyluridine for proper synthesis of mitochondrial proteins (mechanism 1), which regulates the stability and functionality of respiratory chain complexes; taurine reduces superoxide generation by enhancing the activity of intracellular antioxidants (mechanism 2); taurine prevents calcium overload and prevents reduction in energy production and the collapse of mitochondrial membrane potential (mechanism 3); taurine directly scavenges HOCl to form N-chlorotaurine in inhibiting a pro-inflammatory response (mechanism 4); and taurine inhibits mitochondria-mediated apoptosis by preventing caspase activation or by restoring the Bax/Bcl-2 ratio and preventing Bax translocation to the mitochondria to promote apoptosis (mechanism 5).

Taurine Forms a Complex with Mitochondrial tRNA

Taurine Reduces Superoxide Generation in the Mitochondria

Taurine Regulates Intracellular Calcium Homeostasis

Taurine Inhibits Mitochondria-Mediated Apoptosis

 

Taurine therapy, therefore, could potentially improve mitochondrial health, particularly in mitochondria-targeted pathologies, such as cardiovascular diseases, metabolic diseases, mitochondrial diseases and neurological disorders. Whether the protective mechanism on mitochondria primarily relies on the taurine modification of mitochondrial tRNA requires further investigation.

 

Taurine and the gut microbiota 

We now regularly in the research see that you can make changes in the gut microbiota to treat medical conditions. I think the most interesting was the discovery that the ketogenic diet, used for a century to treat epilepsy, actually works via the high fat diet changing the bacteria that live in your gut; it has nothing at all to do with ketones. UCLA are developing a bacteria product that will mimic the effect of this diet.

We should not be surprised to see that one mode of action put forward for Taurine is changes it makes in the gut microbiota.  It is this very mechanism that the Chinese researchers think is relevant to its benefit in autism.

The paper below is not about autism, but it is about Taurine’s effect on the gut microbiota.

Effects of Taurine on Gut Microbiota Homeostasis: An Evaluation Based on Two Models of Gut Dysbiosis

Taurine, an abundant free amino acid, plays multiple roles in the body, including bile acid conjugation, osmoregulation, oxidative stress, and inflammation prevention. Although the relationship between taurine and the gut has been briefly described, the effects of taurine on the reconstitution of intestinal flora homeostasis under conditions of gut dysbiosis and underlying mechanisms remain unclear. This study examined the effects of taurine on the intestinal flora and homeostasis of healthy mice and mice with dysbiosis caused by antibiotic treatment and pathogenic bacterial infections. The results showed that taurine supplementation could significantly regulate intestinal microflora, alter fecal bile acid composition, reverse the decrease in Lactobacillus abundance, boost intestinal immunity in response to antibiotic exposure, resist colonization by Citrobacter rodentium, and enhance the diversity of flora during infection. Our results indicate that taurine has the potential to shape the gut microbiota of mice and positively affect the restoration of intestinal homeostasis. Thus, taurine can be utilized as a targeted regulator to re-establish a normal microenvironment and to treat or prevent gut dysbiosis.

  

Conclusion

Your body can synthesize taurine from other amino acids, particularly cysteine, with the help of vitamin B6. In most cases, this internal production is enough to meet your daily needs for basic bodily functions.

Infants and some adults may need taurine added to their diet.

Based on the small study in humans, about a third of children with autism have low levels of taurine in their blood.

Is extra taurine going to provide a benefit to the other two thirds?

Taurine looks easy to trial. It is normally taken three times a day after a meal. Each dose would be 0.4g to 4g depending on weight and what the purpose was. The 2 year olds in the Chinese autism trial will be taking 0.4g three times a day. Japanese adults with mitochondrial disease (MELAS) are taking 4g three times a day.

One can oF Red Bull contains 1g of taurine. Most supplements contain 0.5 to 1g. This is a similar dose to what is given to pet cats and dogs. Just like Red Bull contains B vitamins, so do the taurine products for cats and dogs. 

Some of the effects will be immediate, while others will take time to show effect. For example there can potentially be an increase in mitochondrial biogenesis. I expect any changes in gut bacteria would also take a long time to get established.

The effect via GABA on increasing brain excitability is an interesting one for people taking bumetanide for autism, where the GABA developmental switch did not take place. Based on the research you could argue that it will be beneficial or indeed harmful.

What I can say is that in Monty, aged 20 with ASD and taking bumetanide for 12 years, he responded very well on the rare occasions he drank Red Bull.

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Vitamin B5 and L carnitine for KATA6A Syndrome

I was asked about KATA6A syndrome recently.  This syndrome is researched by Dr Kelley, the same doctor who coined the term Autism secondary to mitochondrial dysfunction (AMD).

KAT6A Research and Treatment An Update by Richard I Kelley , MD, PHD

Some kids with KATA6A, like Peter below, respond very well to Dr Kelley’s mito cocktail.

 

Peter’s Experience with a Mitochondrial Cocktail

 

Here’s my experience with the mitochondrial cocktail:

– At 4 weeks after the start of the cocktail, Peter became potty-trained during the day without any training. He pulled his pull up off, refused to put it back on.

-At 2 months, Peter started riding his bike with no training wheels and playing soccer. He became able to kick the ball and run after it till he scores.

-At 2.5 months, he started skiing independently. I used to try to teach how to ski since he was 3yo. I used to spend hours and hours picking him up off the snow with no result. I tried different kind of reinforcers (food,..) with no result. After the cocktail, he just went down the hill by himself, He can ski independently now and knows how to make turns.

-At 2-3 months, I started noticing an increased strength in playing ice hockey and street hockey with a better understanding of the game. His typing ability improved too, he used to have severe apraxia while typing (type the letter next to the letter he wants to type…).

-At 3-4 months, Peter’s fingers on the piano became stronger, he became able to play harder songs with less training and less frustration. I also noticed an increase in “common sense” like for example putting his backpack in the car instead of throwing it on the floor next to the car and riding the car without his backpack. Another example, when we go to the public library, he knows by himself that he has to go to the children section, and walks independently without showing him directions to the play area inside the children section. In the past, he used to grab books the time he enters the library, throw a tantrum on the floor. The most important milestone is that Peter started to say few words that I can understand.

-At 11 months, Peter became potty-trained at night. His speech is slowly getting clearer. His fine and gross motor skills are still getting better.

 

Some readers of this blog have been in touch with Dr Kelley and he does give very thorough replies.

Generally speaking, the therapies for mitochondrial diseases/dysfunctions seem to be about avoiding it getting worse, rather than making dramatic improvements. In the case of Peter (above) the effects do look dramatic. There are many other ideas in the research that do not seem to have been translated into therapy.

A study from two years ago does suggest that vitamin B5 and L carnitine should be trialed. 

Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome

Mutations in several genes involved in the epigenetic regulation of gene expression have been considered risk alterations to different intellectual disability (ID) syndromes associated with features of autism spectrum disorder (ASD). Among them are the pathogenic variants of the lysine-acetyltransferase 6A (KAT6A) gene, which causes KAT6A syndrome. The KAT6A enzyme participates in a wide range of critical cellular functions, such as chromatin remodeling, gene expression, protein synthesis, cell metabolism, and replication. In this manuscript, we examined the pathophysiological alterations in fibroblasts derived from three patients harboring KAT6A mutations. We addressed survival in a stress medium, histone acetylation, protein expression patterns, and transcriptome analysis, as well as cell bioenergetics. In addition, we evaluated the therapeutic effectiveness of epigenetic modulators and mitochondrial boosting agents, such as pantothenate and L-carnitine, in correcting the mutant phenotype. Pantothenate and L-carnitine treatment increased histone acetylation and partially corrected protein and transcriptomic expression patterns in mutant KAT6A cells. Furthermore, the cell bioenergetics of mutant cells was significantly improved. Our results suggest that pantothenate and L-carnitine can significantly improve the mutant phenotype in cellular models of KAT6A syndrome.

Next, we analyzed the expression changes of specific genes in treated and untreated conditions. We found that the expression levels of downregulated genes in the mutant KAT6A fibroblasts, such as KAT6A, SIRT1, SIRT3, NAMPT1, Mt-ND6, NDUFA9, PANK2, mtACP, PDH (E1 subunit α2), KGDH (E2 subunit), SOD1, SOD2, and GPX4 were significantly restored after pantothenate and L-carnitine treatment. The proteins encoded by these genes are involved in acetylation-deacetylation pathways, CoA metabolism, mitochondria, and antioxidant enzymes, all of which are critical for intracellular processes in embryonic and childhood development.

 

KAT6A acts as a master regulator by fine-tuning gene expression through chromatin modifications, so we should expect it to have wide ranging effects. All the closest interactions are will other genes that modify gene expression.

 

https://string-db.org/cgi/network?taskId=b9YRZJrlHtMF&sessionId=b1EyJebcKvBK

A useful site is genecards:

https://www.genecards.org/cgi-bin/carddisp.pl?gene=KAT6A

 

KAT6A mutations are indeed linked to microcephaly, a condition characterized by a smaller than average head circumference.

Most autism is associated with hyperactive pro-growth signalling pathways; only a minority is associated with the opposite and this would fit with microcephaly, which is typical in KAT6A.

Microcephaly is a very common feature of Rett syndrome.

Among the features of KAT6A syndrome there will be overlaps with other syndromes.

Dr Kelley analyses amino acids looking for mitochondrial dysfunction. He has found this present in KAT6A, but this is only one treatable feature of the syndrome.

Targeting growth signaling pathways might well be worth pursuing. You would be looking a what works in other people with smaller heads.

I wrote quite a lot about IGF-1 previously in this blog.

It would be highly plausible that these related therapies might be of benefit. The easy one to try is cGPMax, because it is sold OTC. IGF-1 itself might be beneficial, you would have to find a helpful endocrinologist to trial it.

All the therapies of idiopathic autism could be trialed.

If the child has a paradoxical reaction to any benzodiazepine drug, then you know that bumetanide is likely to be beneficial.

Since mitochondrial function is impaired in KAT6A, taurine is another thing to trial.