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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

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 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.

 

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.






28 comments:

  1. Thank you. I found this fascinating on Taurine. Do you think this ultimately could be in the Agmatine/NAC power supplement category for autism? It seems to correct things vs. manage a symptom. However, if one is already getting 400 or so from a diet, do you think the direct effect of getting 500 is what can change things. Sometimes I read things -- and I get over ebullient (sp?) about it.

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    1. I think it is likely to be something that is helpful to some, but has no effect on others.
      It is not a new idea. I think you would need to try it for a month. Taking it 3 times a day is a bit of bother. Taking it just once a day may miss the benefit.
      If you buy it as a bulk powder it is very cheap.
      I do not think the effect of taurine produced from diet and by the body itself will be exactly the same as from a supplement. The effect on the gut cannot be the same.
      The more I read about it the more interested I became. I do not see any downside. It also looks beneficial for all older adults, just like for pets.

      Delete
  2. Hello Peter,
    What do you think about ivermectin. I have read many parents saying that it has helped pull their kid from pans flare completely. PANS could be any infection (parasite, viral or Bacterial). One of the mom said as long as she gives it helps overall but when she stops the symptoms returns quickly within a week. Do you think there is any other way that this medication is working.

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    1. Mandy, anti-parasite drugs often have interesting secondary effects, ivermectin is a good example. There are many more (suramin, mebendazole etc).

      Ivermectin has been shown in the research to have anti-inflammatory and immunomodulatory effects. I wrote long ago about its effect as a PAK1 inhibitor - this might account for its anti-cancer effects.

      Post Covid, some activists/extremists get very upset by the mention of Ivermectin with autism. They even infiltrate the parent groups on Facebook.

      The issue with repurposing anti-parasite drugs is toxicity. This is why ivermectin was not pursued to treat neurofibromatosis, where it should in theory be beneficial.

      Delete
    2. Hello Peter, Thanks for your response. I thought it may have been helping with inflammation and maybe viral load. Do you have any link to read more on toxicity? That sounds scary for parents using it and not knowing about toxicity.

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    3. Mandy, here is one study on the subject.

      Characteristics of ivermectin toxicity in patients taking veterinary and human formulations for the prevention and treatment of COVID-19

      https://pubmed.ncbi.nlm.nih.gov/36374218/

      Ivermectin toxicity developed in predominantly male patients >60 years old who ingested higher than recommended doses and developed neurologic symptoms. Patients who took a veterinary formulation of ivermectin ingested large single doses or large daily doses for several days and developed rapid onset of neurotoxicity. Patients with chronic toxicity developed milder symptoms and tended to take typical therapeutic doses, but continued therapy for weeks rather than days.

      Delete
  3. Hi Peter,

    In the third image you put in this post regarding microglial activation diagram and extra synapses, from post mortem analysis of asd brains they found that most autistic people do seem to have extra synapses and the researchers at that university suggested that it is due to overactive mTOR that causes this. I have always wondered though if overactive mTOR was just a downstream issue and not the root cause.

    LPS coming from the gut ,through leaky gut caused by SIBO or some other issue with the gut, and then activating microglia makes a lot of sense and from what i have read it seems that once a microglia cell is 'primed' it cannot be reverted back to its original 'free-roaming' state but rather pushed into a non inflammatory primed state instead as the best case scenario. It seems that high dose omega 3 or sulforaphane may be able to do this.

    I think ultimately pruning synapses is what most autistic people need, but I wonder if most even have leaky gut? Especially as the leaky gut needs to happen before the age of 5-6 for synaptic pruning to effected

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    1. I like the model of autism that splits it into hyper/hypo active pro-growth signaling pathways. mTOR is just one of these pathways.

      There are very many possible causes of autism, but the downstream consequences are often overlapping. Activated microglia is definitely an important feature of autism. The OTC antihistamine clemastine has been shown to significantly suppress microglial M1 activation.

      Some people with autism have major gut dysbiosis. My son never had any of these issues.

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  4. Peter, please read this study on hydrocephalus and folate.

    Neonatal hydrocephalus is a result of a block in folate handling and metabolism involving 10‐formyltetrahydrofolate dehydrogenase

    https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.13686

    I wouldn't be surprised if folate receptor autoantibodies create a form of hydrocephalus.

    Co-occurring hydrocephalus in autism spectrum disorder: a Danish population-based cohort study - PMC

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082886/

    Stephen

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  5. This is not related to this post, but I have a question. My almost adult child uses "covert speech". He is mouthing his thoughts (it's not scripting but more talk, could be positive self-talk, or saying to get it together, etc). There is no auditory, and I don't think it is hallucinations or scripting. Does anyone else have this situation and is there something that could help this? I find he does it a lot, even in public.It is not wrong, but I am wondering if CBT or something might help to make it more internal dialogue. I am curious if people have experienced this. Thanks! Anne

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    1. Anne, is your son verbal and what level of autism and IQ does he have?

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  6. He is verbal, Asperger’s and in junior college. Anne

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    1. CBT (cognitive behavioral therapy) would seem a good option to try and redirect the behavior. It is widely used in autism.

      I suppose the question is whether he sees this as a behavior he wants to change; the trend these days is to let people do what they want to do, regardless of it seeming an odd behavior. Maybe you can involve a friend or a similarly aged relative to talk to him about it.

      Boys this age tend not to want to listen to their parents and he might get upset by the idea of a therapist. Some parents end up paying their child to attend therapy sessions, which cannot be a good idea.

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  7. Peter,
    After years trying many things for my asd son including bumetadine other prescription, suppliments.

    Only Methylene Blue is doing something on him.
    Here more aware, responsive, good mood, finally can ride cycle for few meters without support wheel.can understand emotions better, sleeps better.

    If you could publish a article about it more ppl would benifit I guess

    Thank you.

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    1. I am glad that you found an effective therapy.

      Methylene blue was covered in an earlier post.

      Here is a link to it.

      Methylene Blue - used for over a century in Psychiatry, also handy for your fish tank

      https://www.epiphanyasd.com/2023/01/methylene-blue-used-for-over-century-in.html

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    2. Could you please share what dosage do you use for MB?

      Peter, I have read your post about MB and a few coments from Dragos re MB but again I am not sure about the dosage. I've read that 0.5 mg/kg is the lowest dose and that 1 drop of 1% MB is usually 0.5mg. This means for 50kg person it is 50 drops. This seems impractical and costly. Do you know the dosage of MB?

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    3. Dosage used in humans is quoted as being 0.5 to 2 mg/kg. It is currently quite popular and lots of people are selling it online as well as in the pet store.

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  8. Hello Peter..not related to this post. Since last month my son was constantly crying and i was trying everything i can. For acidity i was using trisalts which has bicarbonates and charcoal binders. It was giving temporary relief. Later i noticed he cries more at night before sleep and so i thought of trying some H2 blocker. I used Ranitidine. It worked like magic and he stopped crying. I have found this problem is major and is there since birth and many times i was giving antifungals and what not and thinking it was pans/pandas symptoms and whenever i tries to do some detox he develops this acidity/reflux/gERd ? i am still not sure what exactly it is high acid or low acid? but this H2 blocker has done magic. Is it safe to use it long time or is there a safe alternate to it.

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    1. Reflux/GERD is common in autism. There are many contributing factors including gut dysbiosis, diet, stress, genetics and the side effects of drugs/supplements.

      H2 blockers are beneficial in some autism even when there is no reflux.

      If there is reflux it is not really a question of high/low acidity it is a question of the acid being in the wrong place. If you raise the head-end of your son's bed by 15-20 cm then gravity will help stop the acid rising up into his esophagus and causing the symptoms of reflux.

      Most people with reflux remove items from their diet that trigger the reflux and make sure not to eat within 3-4 hours of lying down.

      People do use H2 blockers long term, but that then lowers stomach acidity all day long which then effects absorbtion of things like calcium and vitamin B12. It also affects which bacteria grow where in the gut.

      The key is to remove the underlying cause of the reflux, if possible. For those people without reflux who benefit from an H2 blocker, they can use betaine HCL with meals to improve absorption of nutrients.

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    2. He might have EOE, maybe schedule an appointment with a gastro doc.

      -Stephen

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    3. Thanks Peter for your useful inputs. I will keep these points in mind. I noticed that the H2 blocker was also not doing its job since yesterday and he again have crying episodes and self injurious behaviour which he always have when he is in distress. I will try to look for underlying reason and remove foods that can be a problem.

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    4. Thanks you Stephen for this point i will look into it.

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    5. Guanfacine stopped Self injurious behavior in my son. It is dose dependendant. Clonidine also worked.

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    6. Great news Janu, it is amazing how many different therapies can be effective in SIB, but you have to find the one(s) that work in your specific case.

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    7. Thanks Peter! I was quite shocked when I realized alpha 2 adrenergic activity is calming, which I’ve never knew before.

      Do you still use C8 and BHB? I found some interesting parallels between C8 MCT and Valproic acid. Valproic acid is also a medium chain fatty acid of the Octanoic acid type and so is Alpha Lipoic Acid. I guess they all should have some overlapping effects. Valproate showed great effects. like my son started jumping for the first time, but I did not see anything more. After a while of continuous use, It also got him maniacal behaviors and SIB. Thankfully Guanfacine came to rescue. Also the gain that we got from Valproate is still not lost even after stopping. So I think, it still has a place, as that gain we saw was unmistakably from Valproate. I’m planning to try Valproate again with breaks. Also did you notice that C8 MCT is also available as salt form just like how Valproic acid is available as Sodium Valproate?

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    8. Janu, valproic acid is an HDAC inhibitor so it can make epigenetic changes in gene expression. It can therefore make some clever changes in those with altered gene expression. It might explain why some changes continue after cessation. Even low doses can be beneficial, but side effects can occur at higher doses.

      The news with ketones is that the next generation products sold in the US are much more potent and long lasting. An example is Ketonaid KE4.

      Where I live the ketone products are not so easy to get. For some people they are a core therapy, in our case the benefit was smaller, so I stopped. I do get people writing to me with rave reviews and a Spanish psychiatrist told me at a conference how beneficial the therapy is in his son.

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  9. Also, Peter, here is another theory for the autism basket.

    A Novel Thioredoxin-Mediated Mechanism in Autism Spectrum Disorder

    https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4844704

    -stephen

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    1. Stephen, nice to see that nitrosative stress is getting some coverage. Usually it is just oxidative stress.

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