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:
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.
Vitamin
B5 and L carnitine for KATA6A Syndrome
I was asked about KATA6A syndrome recently. This syndrome is researched by Dr Kelley, the same doctor who coined the term Autism secondary to mitochondrial dysfunction (AMD).
KAT6A
Research and Treatment An Update by Richard I Kelley , MD, PHD
Some kids
with KATA6A, like Peter below, respond very well to Dr Kelley’s mito cocktail.
Peter’s Experience with a Mitochondrial Cocktail
Here’s my experience with the mitochondrial cocktail:
– At 4 weeks after the start of the cocktail, Peter became
potty-trained during the day without any training. He pulled his pull up off,
refused to put it back on.
-At 2 months, Peter started riding his bike with no training
wheels and playing soccer. He became able to kick the ball and run after it
till he scores.
-At 2.5 months, he started skiing independently. I used to
try to teach how to ski since he was 3yo. I used to spend hours and hours
picking him up off the snow with no result. I tried different kind of
reinforcers (food,..) with no result. After the cocktail, he just went down the
hill by himself, He can ski independently now and knows how to make turns.
-At 2-3 months, I started noticing an increased strength in
playing ice hockey and street hockey with a better understanding of the game.
His typing ability improved too, he used to have severe apraxia while typing
(type the letter next to the letter he wants to type…).
-At 3-4 months, Peter’s fingers on the piano became stronger,
he became able to play harder songs with less training and less frustration. I
also noticed an increase in “common sense” like for example putting his
backpack in the car instead of throwing it on the floor next to the car and
riding the car without his backpack. Another example, when we go to the public
library, he knows by himself that he has to go to the children section, and
walks independently without showing him directions to the play area inside the
children section. In the past, he used to grab books the time he enters the
library, throw a tantrum on the floor. The most important milestone is that
Peter started to say few words that I can understand.
-At 11 months, Peter became potty-trained at night. His
speech is slowly getting clearer. His fine and gross motor skills are still
getting better.
Some readers
of this blog have been in touch with Dr Kelley and he does give very thorough replies.
Generally
speaking, the therapies for mitochondrial diseases/dysfunctions seem to be
about avoiding it getting worse, rather than making dramatic improvements. In
the case of Peter (above) the effects do look dramatic. There are many other ideas
in the research that do not seem to have been translated into therapy.
A study from
two years ago does suggest that vitamin B5 and L carnitine should be trialed.
Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome
Mutations in several genes involved in the
epigenetic regulation of gene expression have been considered risk alterations
to different intellectual disability (ID) syndromes associated with features of
autism spectrum disorder (ASD). Among them are the pathogenic variants of the
lysine-acetyltransferase 6A (KAT6A) gene, which causes KAT6A syndrome. The KAT6A enzyme participates in
a wide range of critical cellular functions, such as chromatin remodeling, gene
expression, protein synthesis, cell metabolism, and replication. In this
manuscript, we examined the pathophysiological alterations in fibroblasts
derived from three patients harboring KAT6A mutations. We addressed survival in
a stress medium, histone acetylation, protein expression patterns, and
transcriptome analysis, as well as cell bioenergetics. In addition, we evaluated the therapeutic
effectiveness of epigenetic modulators and mitochondrial boosting agents, such
as pantothenate and L-carnitine, in correcting the mutant phenotype.
Pantothenate and L-carnitine treatment increased histone acetylation and
partially corrected protein and transcriptomic expression patterns in mutant
KAT6A cells. Furthermore, the cell bioenergetics of mutant cells was
significantly improved. Our
results suggest that pantothenate and L-carnitine can significantly improve the
mutant phenotype in cellular models of KAT6A syndrome.
Next, we analyzed the expression changes of
specific genes in treated and untreated conditions. We found that the
expression levels of downregulated genes in the mutant KAT6A fibroblasts, such
as KAT6A, SIRT1, SIRT3, NAMPT1, Mt-ND6, NDUFA9, PANK2, mtACP, PDH (E1 subunit α2), KGDH (E2 subunit), SOD1, SOD2,
and GPX4 were
significantly restored after pantothenate and L-carnitine treatment. The
proteins encoded by these genes are involved in acetylation-deacetylation
pathways, CoA metabolism, mitochondria, and antioxidant enzymes, all of which
are critical for intracellular processes in embryonic and childhood
development.
KAT6A acts
as a master regulator by fine-tuning gene expression through chromatin
modifications, so we should expect it to have wide ranging effects. All the
closest interactions are will other genes that modify gene expression.
https://string-db.org/cgi/network?taskId=b9YRZJrlHtMF&sessionId=b1EyJebcKvBK
A useful site is genecards:
https://www.genecards.org/cgi-bin/carddisp.pl?gene=KAT6A
KAT6A mutations are indeed linked to
microcephaly, a condition characterized by a smaller than average head circumference.
Most autism is associated with
hyperactive pro-growth signalling pathways; only a minority is associated with the opposite and this would fit with
microcephaly, which is typical in KAT6A.
Microcephaly is a very common feature
of Rett syndrome.
Among the features of KAT6A syndrome
there will be overlaps with other syndromes.
Dr Kelley analyses amino acids looking
for mitochondrial dysfunction. He has found this present in KAT6A, but this is
only one treatable feature of the syndrome.
Targeting growth signaling pathways
might well be worth pursuing. You would be looking a what works in other people
with smaller heads.
I wrote quite a lot about IGF-1
previously in this blog.
It would be highly plausible that
these related therapies might be of benefit. The easy one to try is cGPMax,
because it is sold OTC. IGF-1 itself might be beneficial, you would have to
find a helpful endocrinologist to trial it.
All the therapies of idiopathic autism
could be trialed.
If the child has a paradoxical
reaction to any benzodiazepine drug, then you know that bumetanide is likely to
be beneficial.
Since mitochondrial function is
impaired in KAT6A, taurine is another thing to trial.
