Sunday 16 June 2024

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 GABAA receptors, in the short term

·        Down regulating GABAA 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 GABAA, glycine and NMDA receptors Therefore, taurine can partially substitute for GABA by causing inhibition of neuronal excitability. However, the regulation of the GABAA receptor by taurine is complex. While acute taurine administration activates the GABAA receptor, chronic taurine feeding promotes the downregulation of the GABAA 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 GABAA receptors in taurine-fed mice


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.


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. 


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. 


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.



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.



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 KAT6ASIRT1SIRT3NAMPT1Mt-ND6NDUFA9PANK2mtACPPDH (E1 subunit α2), KGDH (E2 subunit), SOD1SOD2, 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.

A useful site is genecards:


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.

Friday 24 May 2024

Cilantro (Coriander leaves) for sound sensitivity? cGPMax for some Pitt Hopkins and Rett syndrome. Plus, microdeletion of 2P16.3 NRXN1 and mutations in GPC5


Today’s post combines a very simple therapy for sound sensitivity that landed in my inbox from New Zealand with two more genes that I was recently asked about.

Before I get started I would like to thank our reader Daniel who is trying to spread that word that the IGF-1 targeting therapy cGPMax works in some Rett syndrome (half a capsule daily). I did go into the science of IGF-1 related therapies at the recent conference in Abu Dhabi. In that presentation I pointed out that the cGPMax therapy might well be helpful in Pitt Hopkins syndrome. I saw today that Soko, an 8 year old girl with Pitt Hopkins, had already made a trial and her parents are impressed:-

“Equally significant has been the positive shift in Soko's emotional well-being. Her struggles with irritability and mood fluctuations feel like are not as frequent and we feel like there is more often a sense of calm and emotional regulation. This has had a profound ripple effect on our little family and our stress levels.

Perhaps most striking has been the accelerated rate at which Soko acquires new skills. CGP Max has seemingly unlocked hidden potentials within her. This rapid skill acquisition has been very exciting for us. In the last year she has gone from being unable to walk to walking unassisted and even tackling steps no handed!”

I did some checking and some other parents have tried cGPMax for Pitt Hopkins. For Rett syndrome Daniel found that a lower dose was more beneficial than a higher dose. It is always best to start with low doses and gradually increase them.

This does link to today’s post because a  microdeletion of NRXN1 can cause Pitt Hopkins Like Syndrome 2 (PHLS2). In theory all these syndromes are untreatable, but try telling that to Soko’s parents.


Back to sound sensitivity

Today’s sound sensitivity is the type that is moderated by Ponstan (mefenamic acid) and indeed Diclofenac. It might well include those whose sound sensitivity responds to a simple potassium supplement.

If you want to look into the details, you can see from previous posts how potassium and potassium ion channels play a fundamental role in both hearing and its sensory processing. They also play a key role in excitability of neurons and so can play a key role in some epilepsy and some intellectual disability.

It turns out that Cilantro/Coriander leaves contains a chemical that activates the ion channels  KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3). This effect is shared by Ponstan and Diclofenac.

In the case of Andy from New Zealand the effect of a 425mg Cilantro supplement lasts very much longer than taking a low dose of Ponstan or Diclofenac.

So, if your child responds well to Ponstan and can then happily take off his/her ear defenders, but you do not want to medicate every day, then a trial of Cilantro could be interesting.

I was curious as to why the effect would last so much longer than Ponstan/Diclofenac.  All of these drugs lower potassium levels within neurons.  Is the beneficial effect coming from lowering potassium levels and so reducing neuronal excitability?  Or, is the effect coming directly from a specific ion channel?

Nobody can tell you the half-life of the active component of cilantro,  (E)-2-dodecenal, in humans.  Andy thinks it must have a long half-life.


Cilantro (Coriander leaves)

If you live in North America you will know what cilantro is, for everyone else it means coriander leaves. Coriander seeds are the dried fruit of the coriander plant and, confusingly, in American English coriander means coriander seeds.

The medicinal properties of the leaves and seeds are not the same.

Cilantro leaves contain a compound called (E)-2-dodecenal, which has been shown to activate a specific family of potassium ion channel called KCNQ, otherwise known as Kv7 . These channels are found in neurons, and they play an important role in regulating the electrical activity of the brain.

When (E)-2-dodecenal binds to KCNQ/Kv7 channels, it causes them to open, which allows potassium ions to flow out of the neuron. This outflow of potassium ions helps to stabilize the neuron's membrane potential and makes it less likely to fire an action potential.

The level of potassium inside neurons is much higher than the level outside. Having it too high, or indeed too low, would affect the excitability of the neuron.

I am wondering if the problem with potassium is mirroring the problem we have with chloride; perhaps both are elevated inside neurons. That would be nice and simple.

The discovery that cilantro can activate KCNQ channels helps to explain its potential anticonvulsant properties.  KCNQ channel dysfunction has been linked to certain types of epilepsy, and drugs that activate these channels are being investigated as potential treatments for these conditions.

Research suggests cilantro's active compound, (E)-2-dodecenal, targets multiple KCNQ channels, particularly:

  • KCNQ2/KCNQ3: This is the most common type of KCNQ channel found in neurons.
  • KCNQ1 in complex with KCNE1: This form is mainly present in the heart. KCNE1 acts as a regulatory subunit that influences KCNQ1 channel function.


Cilantro leaf harbors a potent potassium channel-activating anticonvulsant

Herbs have a long history of use as folk medicine anticonvulsants, yet the underlying mechanisms often remain unknown. Neuronal voltage-gated potassium channel subfamily Q (KCNQ) dysfunction can cause severe epileptic encephalopathies that are resistant to modern anticonvulsants. Here we report that cilantro (Coriandrum sativum), a widely used culinary herb that also exhibits antiepileptic and other therapeutic activities, is a highly potent KCNQ channel activator. Screening of cilantro leaf metabolites revealed that one, the long-chain fatty aldehyde (E)-2-dodecenal, activates multiple KCNQs, including the predominant neuronal isoform, KCNQ2/KCNQ3 [half maximal effective concentration (EC50), 60 ± 20 nM], and the predominant cardiac isoform, KCNQ1 in complexes with the type I transmembrane ancillary subunit (KCNE1) (EC50, 260 ± 100 nM). (E)-2-dodecenal also recapitulated the anticonvulsant action of cilantro, delaying pentylene tetrazole-induced seizures. In silico docking and mutagenesis studies identified the (E)-2-dodecenal binding site, juxtaposed between residues on the KCNQ S5 transmembrane segment and S4-5 linker. The results provide a molecular basis for the therapeutic actions of cilantro and indicate that this ubiquitous culinary herb is surprisingly influential upon clinically important KCNQ channels

Activation of KCNQ5 by cilantro could also contribute to its gut stimulatory properties, as KCNQ5 is also expressed in gastrointestinal smooth muscle, and its activation might therefore relax muscle, potentially being therapeutic in gastric motility disorders such as diabetic gastroparesis.

The KCNQ activation profile of (E)-2-dodecenal bears both similarities and differences to that of other KCNQ openers. We recently found that mallotoxin, from the shrub Mallotus oppositifolius that is used in African folk medicine, also activates KCNQ1-5 homomers, prefers KCNQ2 over KCNQ3, and in docking simulations binds in a pose reminiscent to that predicted for (E)-2-dodecenal, between (KCNQ2 numbering) R213 and W236 In addition to the widespread use of cilantro in cooking and as an herbal medicine, (E)-2-dodecenal itself is in broad use as a food flavoring and to provide citrus notes to cosmetics, perfumes, soaps, detergents, shampoos, and candles (59).

Our mouse seizure studies suggest it readily accesses the brain, and it is likely that its consumption as a food or herbal medicine (in cilantro) or as an added food flavoring would result in KCNQ-active levels in the human body; we found the 1% cilantro extract an efficacious KCNQ activator, and (E)-2-dodecenal itself showed greater than half-maximal opening effects on KCNQ2/3 at 100 nM (.10 mV shift at this concentration) (EC50, 60 6 20 nM). We anticipate that its activity on KCNQ channels contributes significantly to the broad therapeutic spectrum attributed to cilantro, which has persisted as a folk medicine for thousands of years throughout and perhaps predating human recorded history.


From the University of California: 

How cilantro works as a secret weapon against seizures

In a new study, researchers uncovered the molecular action that enables cilantro to effectively delay certain seizures common in epilepsy and other diseases.

The study, published in FASEB Journal, explains the molecular action of cilantro (Coriandrum sativum) as a highly potent KCNQ channel activator. This new understanding may lead to improvements in therapeutics and the development of more efficacious drugs.

“We discovered that cilantro, which has been used as a traditional anticonvulsant medicine, activates a class of potassium channels in the brain to reduce seizure activity,” said Geoff Abbott, Ph.D., professor of physiology and biophysics at the UC Irvine School of Medicine and principal investigator on the study.

“Specifically, we found one component of cilantro, called dodecenal, binds to a specific part of the potassium channels to open them, reducing cellular excitability.”


KCNQ channels and autism

There is a growing body of research suggesting a connection between KCNQ channels and autism.

·        KCNQ channel mutations: Genetic studies have identified mutations in several KCNQ channel genes (including KCNQ2, KCNQ3) in individuals with ASD. These mutations might disrupt the normal function of KCNQ channels, leading to abnormal brain activity.

  • Neuronal excitability: KCNQ channels help regulate the electrical activity of neurons by controlling the flow of potassium ions. Mutations or dysfunction in KCNQ channels could lead to increased neuronal excitability, which has been implicated in ASD. 
  • Shared features: Epilepsy is a common comorbidity with autism. Interestingly, KCNQ channel dysfunction is also linked to certain types of epilepsy. This suggests some shared mechanisms between these conditions.


KCNQ Dysfunction and Intellectual Disability

Mutations in certain KCNQ genes can lead to malfunctions in the corresponding potassium channels. These malfunctions can disrupt normal neuronal activity and contribute to intellectual disability.

  • KCNQ2/3 Mutations: Research suggests increased activity in KCNQ2 and KCNQ3 channels, due to mutations in their genes, might be associated with a subset of patients with intellectual disability alongside autism spectrum disorder. 
  • KCNQ5 Mutations: Studies have identified mutations in the KCNQ5 gene, leading to both loss-of-function and gain-of-function effects on the channel. These changes in KCNQ5 channel activity can contribute to intellectual disability, sometimes accompanied by epilepsy.


The other naming system

KCNQ channels belong to a larger potassium channel family called Kv7. So, you might see them referred to as Kv7.1 (KCNQ1), Kv7.2 (KCNQ2), and so on, based on their specific gene and protein sequence.


Mefenamic acid and Kir channels (inwards rectifying potassium ion channels)

Ponstan (mefenamic acid) affects Kir channels and KCNQ channels.

Different Kir channel subtypes contribute to various brain functions, including:

  • Neuronal excitability: Kir channels help regulate the resting membrane potential of neurons, influencing their firing activity.
  • Potassium homeostasis: They play a role in maintaining the proper balance of potassium ions within and outside neurons, crucial for normal electrical signaling.
  • Synaptic inhibition: Some Kir channels contribute to inhibitory neurotransmission, which helps balance excitatory signals in the brain.

Kir Channels are primarily inward rectifiers, meaning they allow potassium ions to flow more easily into the cell than out. They play a role in setting the resting membrane potential of cells, influencing their excitability.

KCNQ Channels can be voltage-gated or regulated by other factors. They contribute to various functions like regulating neuronal firing in the brain,


Other effects of Cilantro

It is certainly could be just a coincidence that Cilantro and Ponstan affect KCNQ channels. Cilantro has many other effects.

Coriandrum sativum and Its Utility in Psychiatric Disorders

Recent research has shown that Coriandrum sativum offers a rich source of metabolites, mainly terpenes and flavonoids, as useful agents against central nervous system disorders, with remarkable in vitro and in vivo activities on models related to these pathologies. Furthermore, studies have revealed that some compounds exhibit a chemical interaction with γ-aminobutyric acid, 5-hydroxytryptamine, and N-methyl-D-aspartate receptors, which are key components in the pathophysiology associated with psychiatric and neurological diseases. 


Bioactivities of isolated compounds from Coriandrum sativum by interaction with some neurotransmission systems involved in psychiatric and neurological disorders.



Understanding 2p16.3 (NRXN1) deletions

One parent contacted me to ask about the genetic test results they had received for their child.

To understand what happens when parts of the NRXN1 gene are missing you need to read up on neurexins and neuroligins.


Neurexins and Neuroligins

Neurexins ensure the formation of proper synaptic connections, fine-tune their strength, and contribute to the brain's adaptability. Understanding their role is crucial for understanding brain development, function, and various neurological disorders.

Neurexins and neuroligins are cell adhesion molecules that work together to ensure proper synapse formation, function, and ultimately, a healthy and functioning brain.

Neuroligins are located on the postsynaptic membrane (receiving neuron) of a synapse.

Neurexins are located on the presynaptic membrane (sending neuron) of a synapse.

Mutations in either neurexin or neuroligin genes have been linked to various neurodevelopmental disorders, including autism.

A comprehensive presentation for families is below:


Understanding 2p16.3 (NRXN1) deletions


A microdeletion in the NRXN1 gene on chromosome 2p16.3 can cause a condition similar to Pitt-Hopkins syndrome, but referred to as Pitt-Hopkins like syndrome 2 (PHLS2).


NRXN1 Gene:

  • NRXN1 codes for a protein called neurexin 1 alpha, which plays a critical role in the development and function of synapses, the junctions between neurons in the brain.
  • Neurexin 1 alpha helps neurons connect with each other and transmit signals.


  • A microdeletion is a small deletion of genetic material from a chromosome.
  • In PHLS2, a microdeletion occurs in the NRXN1 gene, removing some of the genetic instructions needed to produce functional neurexin 1 alpha protein.

Pitt-Hopkins Like Syndrome 2 (PHLS2):

  • PHLS2 is a genetic disorder characterized by intellectual disability, developmental delays, and various neurodevelopmental features.
  • Symptoms can vary depending on the size and specific location of the NRXN1 microdeletion.
  • Common features include:
    • Intellectual disability (ranging from mild to severe)
    • Speech and language impairments
    • Developmental delays in motor skills
    • Stereotypies (repetitive movements)
    • Seizures
    • Behavioral problems (e.g., hyperactivity, anxiety)
    • Distinctive facial features (not always present)


What has this got to do with Pitt Hopkins syndrome (loss of TCF4)?

“TCF4 may be transcribed into at least 18 different isoforms with varying N-termini, which impact subcellular localization and function. Functional analyses and mapping of missense variants reveal that different functional domains exist within the TCF4 gene and can alter transcriptional activation of downstream genes, including NRXN1 and CNTNAP2, which cause Pitt-Hopkins-like syndromes 1 and 2.”


NRXN1 interactions with other genes/proteins

Given the function of neurexins and neuroligins, you would expect that the common interactions of NRXN1 are with neuroligins. We see below the NLGNs (neuroligin genes/proteins)

Our more avid readers may recall that neuroligins are one mechanism for regulating the GABA switch. This is the developmental switch that should occur in all humans about two weeks after birth.  If it does not occur, the brain cannot develop and function normally. Autism and intellectual disability are the visible symptoms.


An unexpected role of neuroligin-2 in regulating KCC2 and GABA functional switch,expression%20level%20was%20significantly%20decreased.


We report here that KCC2 is unexpectedly regulated by neuroligin-2 (NL2), a cell adhesion molecule specifically localized at GABAergic synapses. The expression of NL2 precedes that of KCC2 in early postnatal development. Upon knockdown of NL2, the expression level of KCC2 is significantly decreased, and GABA functional switch is significantly delayed during early development. Overexpression of shRNA-proof NL2 rescues both KCC2 reduction and delayed GABA functional switch induced by NL2 shRNAs. Moreover, NL2 appears to be required to maintain GABA inhibitory function even in mature neurons, because knockdown NL2 reverses GABA action to excitatory. 

Our data suggest that in addition to its conventional role as a cell adhesion molecule to regulate GABAergic synaptogenesis, NL2 also regulates KCC2 to modulate GABA functional switch and even glutamatergic synapses. Therefore, NL2 may serve as a master regulator in balancing excitation and inhibition in the brain.


It would seem plausible that in the case of microdeletions of the NRXN1 gene there will be a direct impact on the expression of NLGN2 gene that encodes neuroligin 2.

So plausible therapies to trial for microdeletions of the NRXN1 gene would include bumetanide, as well as cGPMax, due to the link with Pitt Hopkins.


GPC5 gene 

Finally, we move on to our last gene which is GPC5.

The protein Glpycan 5/GPC5 plays a role in the control of cell division and growth regulation.

Not surprising, GPC5 acts a tumor suppressor, making it a cancer gene. Because of this it is also an autism gene. It also plays a role in Alzheimer’s disease.

I was not sure I would be able to say anything about how you might treat autism caused by a mutation in GPC5.


Glycan susceptibility factors in autism spectrum disorders


I am assuming the mutation causes a loss of function, meaning there is a reduced level of the protein Glpycan 5.

Since one role of this gene is to suppress Wnt/beta-catenin signaling, you might want to replace this action.

This is actually covered in my blog in various places. One way is via a GSK-3β inhibitor.

GSK-3β inhibitor include drugs designed to block GSK-3β activity, examples include lithium (used for bipolar disorder), kenpaullone, and tideglusib. Certain natural compounds like curcumin and quercetin have been shown to possess GSK-3β inhibitory effects.

Atorvastatin, which my son has taken for 10 years, is indirectly a GSK-3β inhibitor

Some natural compounds like fisetin (found in fruits and vegetables) have been shown to promote beta-catenin phosphorylation, leading to its degradation.

In previous posts I pointed out that the cheap kids’ anthelmintic medication Mebendazole is indirectly another Wnt inhibitor. This is because it reduces TNIK. TNIK promotes Wnt signaling by stabilizing beta-catenin, a key player in the pathway. By reducing TNIK levels, mebendazole indirectly disrupts Wnt signaling. Mebendazole is therefore a novel cancer therapy and is being investigated to treat brain cancers, colon cancer, breast cancers etc.

Unlike what is says in the literature about GPC5, there actually are many options that can be safely trialed.

Note that you may not know for sure that any mutation is actually causal/pathogenic. Some people have several “likely pathogenic” mutations, some likely are not.



We have covered the potassium ion channel Kv7.1 previously. In Pitt Hopkins syndrome this ion channel is over expressed and so you would want to inhibit it. Do not take Cilantro, it would have the opposite effect to what you want.

It looks like cGPMAX is one thing you need to trial for Pitt Hopkins syndrome and Rett syndrome. For idiopathic autism it may, or may not help. Try a low dose first, observe the effect, then try a higher dose.

In Rett syndrome we know that people with have as much NKCC1 RNA — a molecule that carries the instructions to make the protein — as healthy individuals. However, their levels of KCC2 RNA are much lower, potentially disrupting the excitation/inhibition balance of nerve cell signaling. This will result in elevated chloride in neurons. This is correctable today using bumetanide.

People with NRXN1 microdeletions do seem to have treatment options, as do people with GPC5 mutations.

Note that out reader Janu, treating a mutation in GABRB2, reports success with a combination of the SSRI drug Lexapro and sodium valproate.

I am a fan of low dose Ponstan for sound sensitivity, it has numerous potentially beneficial mechanisms. It has been even shown to protect against Alzheimer’s disease.  There is no reason not to give cilantro a try as an alternative or complement to improve sound sensitivity.

Dried coriander is normally made from the seeds and is not what you need. In your supermarket you can buy fresh coriander leaves (Cilantro). The fresh herb is about 90% water, but when you dry the herb you will lose at lot of the active substance because it is volatile and will evaporate. My guess is that you will need 2-3 g of the fresh herb to equal Andy’s 425mg supplement.  You can eat the stalks as well as the leaves, it all has the same pungent taste.