Showing posts with label GABA. Show all posts
Showing posts with label GABA. Show all posts

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.

Tuesday 6 November 2018

When is an SSRI not an SSRI? Low dose SSRIs as Selective Brain Steroidogenic Stimulants (SBSSs) via Allopregnanolone modifying GABAa receptors and neonatal KCC2 expression

Today’s post might seem to have a very complicated tittle, but to regular readers it is really just another take on what we have seen time and time again.
Today we see how another steroid imbalance in autism – low levels of allopregnenolone in this case – affects the neurotransmitter GABA and indeed the chloride transporter KCC2.

Putting Prozac/Zoloft to a better use?

I did report previously on a trial in adults with autism where pregnenolone was used.

Recall that disturbed hormonal homeostasis is a key feature of autism. What matters is the level of each hormone inside the brain (i.e. centrally), not in your blood. The only way to get a reliable idea of what is going on would be to take a sample of spinal fluid.

Today we look at boosting allopregnenolone not with a steroid hormone, but with a 1/10th dose of Prozac (Fluoxetine) or indeed Zoloft (Sertraline). Prozac is a selective serotonin reuptake inhibitor (SSRI) when given at the usual dose of 20-80mg, but at 2.5mg it does not function as an SSRI.
At regular doses selective serotonin reuptake inhibitors (SSRI) drugs like Prozac are well known to cause problems, as do benzodiazepines like Clonazepam.
Thanks to Professor Catterall we saw in earlier posts how tiny doses of Clonazepam have an effect on one particular sub-unit of GABAA receptors. By fine tuning the response of this receptor we saw how a cognitive improvement can be achieved, in some people. The dose is so low there appear to be no long term side effects. At least one other professor of medicine, I am in contact with, has been treating his son with autism with low dose clonazepam for years.
Many adults and children with autism are prescribed Prozac for anxiety. Even Temple Grandin has said she takes Prozac.
At low, non-serotonergic doses, some drugs like Prozac show a different mode of action, they potently, positively, and allosterically modulate GABA action at GABAA receptors. These drugs achieve this by increasing the amount of the steroid hormone allopregnanolone.
Neurosteroid biosynthesis down‐regulation and changes in GABAA receptor subunit composition are a feature of several neurological conditions, including some autism.
Stimulating allopregnenalone biosynthesis will have multiple effects including on TSPO and endocannabinoid receptors.

Brain principal glutamatergic neurons synthesize 3α-hydroxy-5α-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABAA receptors. Cerebrospinal fluid (CSF) Allo levels are decreased in patients with posttraumatic stress disorder (PTSD) and major depression. This decrease is corrected by fluoxetine in doses that improve depressive symptoms. Emotional-like behavioral dysfunctions (aggression, fear, and anxiety) associated with a decrease of cortico-limbic Allo content can be induced in mice by social isolation. In socially isolated mice, fluoxetine and analogs stereospecifically normalize the decrease of Allo biosynthesis and improve behavioral dysfunctions by a mechanism independent from 5-HT reuptake inhibition. Thus, fluoxetine and related congeners facilitate GABAA receptor neurotransmission and effectively ameliorate emotional and anxiety disorders and depression by acting as selective brain steroidogenic stimulants (SBSSs).                               
When the results of these in vitro studies are compared to those of our in vivo studies, it becomes evident that in mice the doses of fluoxetine and norfluoxetine that cause a rapid increase in brain Allo levels do not exceed brain concentrations in the low nanomolar range, whereas the fluoxetine concentrations that directly activate 3a-HSD in vitro are in the micromolar range. Moreover, the high potency and stereospecificity of fluoxetine and norfluoxetine in decreasing aggressive behavior and normalizing brain Allo content during social isolation (see Table 1, and Figure 3) support the notion that these compounds facilitate the action of 5a-R type I or 3a-HSD by an unidentified indirect mechanism, which is most probably perturbed by protracted social isolation.

Thus, these drugs, which were originally termed ‘SSRI’ antidepressants, may be beneficial in psychiatric disorders because in doses that are inactive on 5-HT reuptake mechanisms, they increase the bioavailability of neuroactive GABAergic steroids. On the basis of these considerations, we now propose that the term ‘SSRIs’ should be changed to the more appropriate term ‘selective brain steroidogenic stimulants’ (SBSSs), which more accurately defines the pharmacological mechanisms expressed by fluoxetine and its congeners.


The pharmacology of the S stereoisomers of fluoxetine and norfluoxetine appears to be prototypic for molecules that possess specific neurosteroidogenic activity. The doses of S-fluoxetine and S-norfluoxetine required to normalize brain Allo content downregulation, pentobarbital action, aggressiveness, and anxiety in socially isolated mice are between 10-fold to 50-fold lower than those required to induce SSRI activity. However, the precise mechanisms of action by which S-fluoxetine and S-norfluoxetine increase neurosteroids remain to be investigated.

Derivatives of S-fluoxetine and S-norfluoxetine, acting with high potency and specificity on brain neurosteroid expression at doses devoid of significant action on brain 5-HT reuptake mechanisms, may represent a new class of pharmacological tools important for the management of anxiety, related mood disorders, dysphoria, fear, and impulsive aggression.

On the basis of these data, new drugs devoid of SSRI activity but that are potent neurosteroidogenic agents should be developed for the treatment of psychiatric disorders that result from the downregulation of neurosteroid expression, including major depression, and in the prevention of PTSD.

France often gets very negative comments about how it treats people with autism, but in the case studies below it looks like some innovative work is going on in some of their day hospitals, where boys and girls with severe autism are sent to pass their time. 

The system in England has recently been highlighted as being pretty appalling, where over 2,000 people with autism are currently detained in Assessment and Treatment Units (ATUs), privately run secure residential "hospitals", at great cost paid for by the State. Those inside might enter with the approval of their family to stay for 3 weeks for respite care, but end up being detained for 3 years, or even longer. The State assumes their guardianship and the individual and parents are powerless. The individuals are kept in prison-like conditions and not surprisingly get worse not better, the worse they get, the harder it is ever to be released. Hard to believe this is still happening.  If you live in England, best not to hand your child over to the State. Someone has even written a book about escaping from such a unit. This is no better than the old State Hospitals in the US, that finally were closed down in the 1970s, that warehoused mentally disabled people, until their premature death.

Autism Spectrum Disorder (ASD) is defined by the copresence of two core symptoms: alteration in social communication and repetitive behaviors and/or restricted interests. In ASD children and adults, irritability, self-injurious behavior (SIB), and Attention Deficit and Hyperactivity Disorders- (ADHD-) like symptoms are regularly observed. In these situations, pharmacological treatments are sometimes used. Selective Serotonin Reuptake Inhibitors- (SSRI-) based treatments have been the subject of several publications: case reports and controlled studies, both of which demonstrate efficacy on the symptoms mentioned above, even if no consensus has been reached concerning their usage. In this article four clinical cases of children diagnosed with ASD and who also present ADHD-like symptoms and/or SIB and/or other heteroaggressive behaviors or irritability and impulsivity treated with low doses of fluoxetine are presented.
Case 1 
An 8-year-old girl (19 kg) had an ASD diagnosis according to the DSM-5 and ADI-R criteria based on information provided by parents. She also had significant mental retardation, with severe SIB (banging her head against objects and biting her hands), forcing her entourage to maintain a daily and permanent physical restraint. She spends most of her time in a day hospital. She received the following pharmacological treatment: risperidone 2 mg/d and cyamemazine 80 mg/d without modifications to her SIB and at the price of a major slowing down and a manifestation of a tendency toward blunting. The CGI severity of illness score was at five (markedly ill). We decreased and stopped risperidone and started valproic acid. After four weeks of valproic acid 400 mg/d in combination with cyamemazine (60 mg/day), SIBs did not improve. Then, we added fluoxetine 2.5 mg/d and increased it after one week to 5 mg/d and to 10 mg/d in the third week. After one week, the CGI improvement scale (CGI-I) was at two; after three weeks, it lowered to 1 (very much improved). We also observed a significant decrease in anxiety as well as the disappearance of SIB (disappearance of the behavior consisting of the banging and rubbing her head against objects). However, it should be noted that the entourage kept the bandages on her hands because she continued to bite them, even if she did it with less intensity than before. There were no side effects. After three months of fluoxetine, her clinical state remains stable.

Case 2 
A 12-year-old boy (70 kg), with DSM-5 criteria for an ASD and ADI-R confirming this diagnosis, exhibited extreme irritability, violence, and impulsiveness as well as SIB (he had thrown seven television sets out of the window). The CGI severity illness scoring was at six (severely ill). In the day hospital where he spent most of his time, it was difficult for staff to manage his impulsivity and unpredictability. His treatment included risperidone 4 mg/d as well as loxapine 80 mg/d. Despite this pharmacological treatment, episodes of aggression and SIBs continued. This treatment induced a significant weight gain (8 kg in 5 months). Treatment with fluoxetine 2.5mg/d was introduced and increased to5mg/d after one week and to 10 mg/d at the beginning of the third week. After one week, there was a CGI-I score of three, which decreased to two after two weeks of treatment and to one after three weeks. Such a positive clinical response allowed for a reduction in risperidone to 2mg/d and in loxapine to 60 mg/d. The treatment was tolerated well by the patient, and he began to lose weight (4 kg). After two months off luoxetine, his clinical state remains stable.

Case 3
 A 6-year-old male child (30 kg) with DSM-5 criteria and ADI-R for an ASD exhibited problems of SIB and repetitive behaviors (washing his hands for more than 30 minutes at least two to three times per day), severe irritability, frequent crying, social withdrawal, and inappropriate speech. Treatment with risperidone 2mg/d had improved irritability and partially the SIB, but it had also produced significant weight gain (four kg in three months). A decrease in the risperidone dosage seemed necessary. Treatment with fluoxetine2.5mg/d was begun, which quickly led to a reduction in inappropriate behavior (for example, impulsive crawling on the ground in the classroom). After one week, the CGI-I scoring was at two. The dosage was gradually increased to 5 mg/d the second week and to 7.5mg/d the third week. The repetitive behaviors gradually subsided. After three weeks the CGI-I score was at one, and it remained stable for nine weeks. The risperidone dosage could be decreased to 0,5 mg/day and the patient’s weight remained the same.
Case 4 
A 12-year-old boy (62kg) withDSM-5 and ADI-R criteria for a severe case of ASD, including severe ADHD-like symptoms, often required physical restraint and did not improve despite a long-term treatment of risperidone 3 mg/d as well as melaton in 4mg at bedtime. The CGI severity illness scoring was at 6 (severely ill). The behavioral pattern included irritability, marked agitation, crying, severe hyperactivity, and other behaviors typical of this disorder. He was also anxious, rendering the situation at his day hospital where he spent most of his time all the more difficult. A prescription of fluoxetine 2.5mg/d was initiated with an immediate and complete improvement of ADHD-like symptoms:CGI-I at one week of treatment was at a one, making this case the most remarkable of the four presented here. Treatment with fluoxetine was continued with a dosage increase up to 5 mg/d to allow for a decrease in the risperidone dose to 1 mg/d. CGI-I score remained stable at one for the duration of the nine weeks.

Our reader Mira, whose son has FXS, recently referred to Dr Hagerman’s trial of low dose Sertaline/Zoloft in Fragile X. GABAA malfunction appears to be a feature of Fragile X, but it is not necessarily the identical malfunction to those with idiopathic autism who respond to bumetanide.


Observational studies and anecdotal reports suggest sertraline, a selective serotonin reuptake inhibitor (SSRI), may improve language development in young children with fragile X syndrome (FXS). We evaluated the efficacy of six months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 52 children with FXS ages 2–6 years.


Eighty-one subjects were screened for eligibility and 57 were randomized to sertraline (27) or placebo (30). Two subjects from the sertraline arm and three from the placebo arm discontinued. Intent-to-treat analysis showed no difference from placebo on the primary outcomes: the Mullen Scales of Early Learning (MSEL) expressive language age equivalent and Clinical Global Impression-Improvement (CGI-I). However, analyses of secondary measures showed significant improvements, particularly in motor and visual perceptual abilities and social participation. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events occurred.


This randomized controlled trial of six-months of sertraline treatment showed no primary benefit with respect to early expressive language development and global clinical improvement. However, in secondary, exploratory analyses there were significant improvements seen on motor and visual perceptual subtests, the Cognitive T score sum on the MSEL, and on one measure of Social Participation on the Sensory Processing Measure–Preschool. Further, post hoc analysis found significant improvement in early expressive language development as measured by the MSEL among children with ASD on sertraline. Treatment appears safe for this 6-month period in young children with FXS, but we do not know the long-term side effects of this treatment. These results warrant further studies of sertraline in young children with FXS using refined outcome measures, as well as longer term follow-up studies to address long-term side effects of low-dose sertraline in early childhood.

Neurosteroid biosynthesis down‐regulation and changes in GABAA receptor subunit composition: a biomarker axis in stress‐induced cognitive and emotional impairment

By rapidly modulating neuronal excitability, neurosteroids regulate physiological processes, such as responses to stress and development. Excessive stress affects their biosynthesis and causes an imbalance in cognition and emotions. The progesterone derivative, allopregnanolone (Allo) enhances extrasynaptic and postsynaptic inhibition by directly binding at GABAA receptors, and thus, positively and allosterically modulates the function of GABA. Allo levels are decreased in stress-induced psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), and elevating Allo levels may be a valid therapeutic approach to counteract behavioural dysfunction. While benzodiazepines are inefficient, selective serotonin reuptake inhibitors (SSRIs) represent the first choice treatment for depression and PTSD. Their mechanisms to improve behaviour in preclinical studies include neurosteroidogenic effects at low non-serotonergic doses. Unfortunately, half of PTSD and depressed patients are resistant to current prescribed 'high' dosage of these drugs that engage serotonergic mechanisms. Unveiling novel biomarkers to develop more efficient treatment strategies is in high demand. Stress-induced down-regulation of neurosteroid biosynthesis and changes in GABAA receptor subunit expression offer a putative biomarker axis to develop new PTSD treatments. The advantage of stimulating Allo biosynthesis relies on the variety of neurosteroidogenic receptors to be targeted, including TSPO and endocannabinoid receptors. Furthermore, stress favours a GABAA receptor subunit composition with higher sensitivity for Allo. The use of synthetic analogues of Allo is a valuable alternative. Pregnenolone or drugs that stimulate its levels increase Allo but also sulphated steroids, including pregnanolone sulphate which, by inhibiting NMDA tonic neurotransmission, provides neuroprotection and cognitive benefits. In this review, we describe current knowledge on the effects of stress on neurosteroid biosynthesis and GABAA receptor neurotransmission and summarize available pharmacological strategies that by enhancing neurosteroidogenesis are relevant for the treatment of SSRI-resistant patients. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit

Too little allopregnanalone can induce autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABAA receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1mg/kg, i.p.) and methylphenidate (MPH: 2.5mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABAA receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD.

Some steroids, whose levels are raised in autism (allopregnanolone, androsterone, pregnenolone, dehydroepiandrosterone and their sulfate conjugates) are neuroactive and modulate GABA, glutamate, and opioid neurotransmission, affecting brain development and functioning. These steroids may contribute to autism pathobiology and symptoms such as elevated anxiety, sleep disturbances, sensory deficits, and stereotypies among others.

Tuning the Brain
I did write a post a while back to show the effect of tuning GABAa receptors.

The effect of allopregnanolone of KCC2 expression and hence the level of chloride within neurons.

Neonatal allopregnanolone or finasteride administration modifies hippocampal K(+) Cl(-) co-transporter expression during early development in male rats.


The maintenance of levels of endogenous neurosteroids (NS) across early postnatal development of the brain, particularly to the hippocampus, is crucial for their maturation. Allopregnanolone (Allop) is a NS that exerts its effect mainly through the modulation of the GABAA receptor (GABAAR). During early development, GABA, acting through GABAAR, that predominantly produces depolarization shifts to hyperpolarization in mature neurons, around the second postnatal week in rats. Several factors contribute to this change including the progressive increase of the neuron-specific K(+)/Cl(-) co-transporter 2 (KCC2) (a chloride exporter) levels. Thus, we aimed to analyze whether a different profile of NS levels during development is critical and can alter this natural progression of KCC2 stages. We administrated sustained Allop (20mg/kg) or Finasteride (5α-reductase inhibitor, 50mg/kg) from the 5th postnatal day (PD5) to PD9 and assessed changes in the hippocampal expression of KCC2 at transcript and protein levels as well as its active phosphorylated state in male rats. Taken together data indicated that manipulation of NS levels during early development influence KCC2 levels and point out the importance of neonatal NS levels for the hippocampal development.                                                                                                                           

Add very low dose Prozac to the long list of possible SIB therapies, more practical than electroconvulsive therapy (ECT), that is for sure!

This post was long waiting in my “to-complete” pile. I thought it would be a short one, but it kept growing.  It does draw together several interesting issues and shows there is a pattern developing in all these blog posts.
The majority of psychiatric drugs have such severe drawbacks that the great majority of children are better off without them.  However, there are many existing drugs that have little known neurological effects that can be highly beneficial and are known to be safe to use long term.
Psychiatric drugs that can be repurposed at lower dosages for different purposes may indeed be free of the major drawbacks encountered at higher doses.
It looks like humans with Fragile X Syndrome (FXS) are leading the way with low dose SSRI therapy to modulate GABA.  It would seem highly plausible that other idiopathic autism might also benefit and the French case studies in this post are examples of those who did benefit.
I think this is another example of fine-tuning the brain to optimize its functioning. It probably will not produce miracles, but the science shows that allopregnenalone can be tuned to vary mood in humans.  Low levels of allopregnenalone can produce autistic-like behaviours in mouse models.
The effect of allopregnenalone on KCC2 expression may only be present in tiny babies, if it continues into childhood that would be another reason to consider it as a target for modulation.  If that were the case, then Finasteride the cheap generic drug for prostate enlargement, should be investigated.
As is always the case in autism, both extremes are likely to exist; some people will likely benefit from low dose SSRIs but it will make some others worse (anxiety, SIB etc). If you start with elevated allopregnenalone, you would want less, not more.
Repurposing existing drugs has huge unrealized potential.
The OTC antihistamine Clemastine, which I highlighted in an earlier post as being a Positive Allosteric Modulator (PAM) of P2X7, and so helps remyelination, is yet another example of repurposing a safe drug.  Reportedly, it has this effect even below the regular dosage for allergy; at the high dosage usage in MS trials it will send you to sleep and risk some other side effects. As MS is not a singular condition, it seems that some people respond much more so than others. It also seems to have a benefit is some psychiatric disorders; not bad for a cheap OTC antihistamine.