Treating KCC2 Down-Regulation in Autism, Rett/Down Syndromes, Epilepsy and Neuronal Trauma ?

In this composite image, a human nerve cell derived from a patient with Rett syndrome shows significantly decreased levels of KCC2 compared to a control cell.  This will be equally true of about 50% people with classic autism, people with Down syndrome, many with TBI and many with epilepsy

In a recent post I highlighted an idea from the epilepsy research to treat a common phenomenon also found in much classic autism.  Neurons are in an immature state with too much intracellular chloride, the transporter that brings it in, called NKCC1, is over-expressed and the one that takes it out, KCC2, is under-expressed.  The net result is high levels of intracellular chloride and this leaves the brain in an over-excited state (GABA working in reverse) reducing cognitive function and with a reduced threshold to seizures.

The epilepsy research noted that increased BDNF is one factor that down regulates KCC2, which would have taken chloride out of the cells.  So it was suggested to block BDNF, or something closely related called trkB.

Unfortunately there is no easy way to this.  But I did some more digging and found various other ways to upregulate KCC2.

There is indeed a clever safe way that may achieve this and it is a therapy that I have already suggested for other reasons, intranasal insulin.

BDNF is a neurotrophin and other neurothrophins also have the ability to regulate KCC2. IGF-1 is another such neurotrophin and we even have very recent experimental data showing its effect on KCC2.

Regular readers will know that several trials with IGF-1, or analogs thereof, are underway.

I actually am rather biased against IGF-1 as a therapy, since in my son’s case the level of IGF-1 in blood is already high.  So I do not want to inject him with IGF-1 or even give him an oral analog.

However by using intranasal insulin the effect would be just within the CNS and insulin binds at the same receptors as IGF-1. So if IGF-1 upregulates KCC2 so will insulin.

We know from extensive existing trial data and direct feedback from one researcher that intranasal insulin is well tolerated and has no effect outside the CNS.

So rather to my surprise there seems to be a safe, cheap way to treat KCC2 down-regulation and this would also be applicable in epilepsy, traumatic brain injury (TBI) and any other condition involving immature neurons or neuronal trauma. 

The Science

There is a very thorough recent review paper that looks at all the ways that KCC2 expression is regulated.

Current view on the functional regulation of the neuronal K⁺-Cl⁻ cotransporter KCC2

The epilepsy researchers consider trkB, top left in the figure below.  But just next to it is IGFR which can be activated by both insulin and IGF-1.

In Rett syndrome they are already using IGF-1 to modulate KCC2.  The research is done at Penn State.

As you can see in the figure the mechanism for IGF-1 and insulin is not the same as BNDF/trkb, but Penn State have already shown that IGF-1 works in vitro.

We saw in early posts regarding intranasal insulin that this was a safe way to deliver insulin to the brain without effects in the rest of the body.

So we know it is safe and in theory it should achieve the same thing that the Penn State researchers are trying to achieve.

Signaling pathways controlling KCC2 function. The regulation of KCC2 activity is mediated by many proteins including kinases and phosphatases. It affects either the steady state protein expression at the plasma membrane or the KCC2 protein recycling. All the different pathways are explained and discussed in the main text. The schematic drawings of KCC2 as well as other membrane molecules do not reflect their oligomeric structure. GRFα2, GDNF family receptor α2; BDNF, Brain-derived neurotrophic factor; TrKB, Tropomyosin receptor kinase B; Insulin, Insulin-like growth factor 1 (IGF-1); IGFR, Insulin-like growth factor 1 receptor; mGluR1, Group I metabotropic glutamate receptor; 5-HT-2A, 5-hydroxytryptamine (5-HT) type 2A receptor; mAChR, Muscarinic acetylcholine receptor; NMDAR, N-methyl-D-aspartate receptor; mZnR, Metabotropic zinc-sensing receptor (mZnR); GPR39, G-protein-coupled receptor (GPR39); ERK-1,2, Extracellular signal-regulated kinases 1, 2; PKC, Protein kinase C; Src-TK, cytosolic Scr tyrosine kinase; WNKs1–4, with-no-lysine [K] kinase 1–4; SPAK, Ste20p-related proline/alanine-rich kinase; OSR1, oxidative stress-responsive kinase -1; Tph, Tyrosine phosphatase; PP1, protein phosphatase 1; Egr4, Early growth response transcription factor 4; USF 1/2, Upstream stimulating factor 1, 2.

The Penn State research on using IGF-1 to increase KCC2 in Rett Syndrome

Discovery of a new drug target could lead to novel treatment for severe autism

The researchers also showed that treating diseased nerve cells with insulin-like growth factor 1 (IGF1) elevated the level of KCC2 and corrected the function of the GABA neurotransmitter. IGF1 is a molecule that has been shown to alleviate symptoms in a mouse model of Rett Syndrome and is the subject of an ongoing phase-2 clinical trial for the treatment of the disease in humans.

"The finding that IGF1 can rescue the impaired KCC2 level in Rett neurons is important not only because it provides an explanation for the action of IGF1," said Xin Tang, a graduate student in Chen's Lab and the first-listed author of the paper, "but also because it opens the possibility of finding more small molecules that can act on KCC2 to treat Rett syndrome and other autism spectrum disorders."

More Melatonin?

As Agnieszka pointed out in the previous post it appears that extremely high doses of melatonin can increase KCC2 in traumatic brain injury (TBI). In this example BDNF was increased by the therapy, so I think TBI may be a specific case.  In most autism BDNF starts out elevated and in epilepsy, seizures are known to increase BDNF and that process is seen as down regulating KCC2 expression.  So in much autism and epilepsy you want less BDNF.

Melatonin attenuates neuronal apoptosis through up-regulation of K+ -Cl- cotransporter KCC2 expression following traumatic brain injury in rats

Compared with the vehicle group, melatonin treatment altered the down-regulation of KCC2 expression in both mRNA and protein levels after TBI. Also, melatonin treatment increased the protein levels of brain-derived neurotrophic factor (BDNF) and phosphorylated extracellular signal-regulated kinase (p-ERK). Simultaneously, melatonin administration ameliorated cortical neuronal apoptosis, reduced brain edema, and attenuated neurological deficits after TBI. In conclusion, our findings suggested that melatonin restores KCC2 expression, inhibits neuronal apoptosis and attenuates secondary brain injury after TBI, partially through activation of BDNF/ERK pathway.

More Science

There is plenty more science on this subject.

It is suggested that in addition to IGF-1/insulin it may be necessary to involve Protein tyrosine kinase (PTK).

Insulin-Like Growth Factor 1 and a Cytosolic Tyrosine Kinase Activate Chloride Outward Transport during Maturation of Hippocampal Neurons

Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes, including proliferation, growth, and differentiation, and has also been implicated in synaptogenesis. Protein tyrosine kinases are subdivided into the cytosolic nonreceptor family and the transmembrane growth factor receptor family, which includes receptors for insulin and insulin-like growth factor (IGF-1). The maturation of postsynaptic inhibition may require both a cytoplasmic PTK, which increases GABA_A receptor-mediated currents, and insulin, which was shown to induce a rapid translocation of GABA_A receptors from intracellular compartments to the plasma membrane. KCC2 is also known to have a C-terminal PTK consensus site. Therefore, the maturation of postsynaptic inhibition may, in addition to other mechanisms, also involve the effects of PTK and insulin acting on KCC2.

Development and regulation of chloride homeostasis in the central nervous system

Conclusion

I would infer from all this science that intranasal insulin is likely to increase KCC2 expression in the brain, certainly worthy of investigation.

Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes.  This might be a limiting factor on the effectiveness of insulin in raising KCC2.  This would then add yet more complexity.

Protein kinases are enzymes that add a phosphate(PO₄) group to a protein, and can modulate its function.  A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases.

Abnormal protein tyrosine kinases (PTKs) cause many human leukaemias, so there is research into PTK inhibitors (PTK-Is).

As we know from Abha Chauhan’s mammoth book, oxidative stress controls the activities of PTK.

A Possible Therapy for Rett-like Autism Variants, as well as MCI and even Schizophrenia?

Today’s post was triggered by an intriguing comment left on this blog.

As we have seen in previous posts, the single gene causes of “autism” like fragile X and Rett syndrome are themselves on a spectrum, with some people worse affected than others.  Boys almost always being more severely affected than girls.

It also appears possible that a partial dysfunction of this same gene/protein may lead to a much milder version of these same syndromes.

Rett syndrome is well studied and as we saw in the earlier post about growth factors in autism, one key feature is an almost complete lack of Nerve Growth Factor (NGF).  Reduced levels of NGF are associated with several diseases and also the aging process.  In many cases of Mild Cognitive Impairment (MCI), as seen in dementia in older people, reduced NGF can be the root problem.

Rett Syndrome

Rett syndrome usually gets grouped as part of autism.

Almost all people with Rett syndrome are female; here is why.  

Rett syndrome is caused by mutations in the gene MECP2 located on the X chromosome. Because the disease-causing gene is located on the X chromosome, a female born with an MECP2 mutation on her X chromosome has another X chromosome with an ostensibly normal copy of the same gene, while a male with the mutation on his X chromosome has no other X chromosome, only a Y chromosome; thus, he has no normal gene. Without a normal gene to provide normal proteins, the male fetus is unable to slow the development of the disease, hence the failure of male fetuses with a MECP2 mutation to survive.

MECP2 is known to play a wider role in some autism, epilepsy and MR/ID

https://gene.sfari.org/GeneDetail/MECP2

We saw that the Italian Nobel Laureate, Rita Levi-Montalcini, who discovered Nerve Growth factor (NGF), maintained her mental sharpness into her 90s by taking her homemade NGF eye drops in her old age.

Human Growth Factors, Autism and the Centenarian Nobel Laureate

The problem with NGF is that it does not cross the blood brain barrier (BBB), so there are no NGF tablets.  Rita’s solution was eye drops; I expect the nasal route might also be possible.

Dompe Farmaceutici are developing NGF eye drops as an orphan drug to treat Retinitis pigmentosa

Bypassing the BBB is of great interest to medical science as we have seen in earlier posts.

Stimulating NGF with Hericium Erinaceus (Lion’s Mane Mushroom)

There is a surprising amount of literature about the use of a mushroom called Hericium Erinaceus, or Lion’s Mane, to treat various neurological conditions.  The made mode of action is stimulating production of NGF.

It was Lion’s Mane that the reader of this blog is giving to his daughter.  This is not typical autism, but in this era of diagnosing almost any childhood developmental dysfunction as autism, I expect autism is label many would apply to it.  

“Our 14 year old daughters previous diagnoses of PDD has recently been dropped, re-evaluated, and named Mild Cognitive Disability with Anxiety and Dementia. This turned out to be a great turn of phrase for us because we began to see and approach her condition differently. To begin with we started look at the similarities between her poor working memory and irritability as more similar to the dementia you would see in early stages of Alzheimer’s than something that could be treated with ABA as we had previously tried”

Is this a mild version of Rett Syndrome, like the Zappella variant is?

Anyway, it responds to a therapy that increases NGF, a key deficit in Rett Syndrome.

Studies supporting the use of Hericium Erinaceus / Lion’s Mane/ Yamabushitake and also Amyloban 3399

Lion’s mane is also called Yamabushitake and a rather expensive concentrated product derived from it is called Amyloban 3399.

As always, the problem with supplements is quality control, lack of standardization and even contamination.

There would seem to be the potential to make an effective drug based on Lion’s Mane.

It would also seem logical to trial  Dompe Farmaceutici’s NGF eye drops in children with Rett Syndrome and in older people with early dementia, not to mention adults with schizophrenia (see study on  Amyloban 3399 below).

Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial.

 

Abstract

 

A double-blind, parallel-group, placebo-controlled trial was performed on 50- to 80-year-old Japanese men and women diagnosed with mild cognitive impairment in order to examine the efficacy of oral administration of Yamabushitake (Hericium erinaceus), an edible mushroom, for improving cognitive impairment, using a cognitive function scale based on the Revised Hasegawa Dementia Scale (HDS-R). After 2 weeks of preliminary examination, 30 subjects were randomized into two 15-person groups, one of which was given Yamabushitake and the other given a placebo. The subjects of the Yamabushitake group took four 250 mg tablets containing 96% of Yamabushitake dry powder three times a day for 16 weeks. After termination of the intake, the subjects were observed for the next 4 weeks. At weeks 8, 12 and 16 of the trial, the Yamabushitake group showed significantly increased scores on the cognitive function scale compared with the placebo group. The Yamabushitake group's scores increased with the duration of intake, but at week 4 after the termination of the 16 weeks intake, the scores decreased significantly. Laboratory tests showed no adverse effect of Yamabushitake. The results obtained in this study suggest that Yamabushitake is effective in improving mild cognitive impairment.

  

Compounds for dementia from Hericium erinaceum

Our group has been conducting a search for compounds for dementia derived from medicinal mushrooms since 1991. A series of benzyl alcohol derivatives (named hericenones C to H), as well as a series of diterpenoid derivatives (named erinacines A to I) were isolated from the mushroom Hericium erinaceum. These compounds significantly induced the synthesis of nerve growth factor (NGF) in vitro and in vivo. In a recent study, dilinoleoyl-phosphatidylethanolamine (DLPE) was isolated from the mushroom and was found to protect against neuronal cell death caused by b-amyloid peptide (Ab) toxicity, endoplasmic reticulum (ER) stress and oxidative stress. Furthermore, the results of preliminary clinical trials showed that the mushroom was effective in patients with dementia in improving the Functional Independence Measure (FIM) score or retarding disease progression.

Reduction of depression andanxiety by 4 weeks Hericium erinaceus intake.

 

Abstract

Hericium erinaceus, a well known edible mushroom, has numerous biological activities. Especially hericenones and erinacines isolated from its fruiting body stimulate nerve growth factor (NGF) synthesis, which expects H. erinaceus to have some effects on brain functions and autonomic nervous system. Herein, we investigated the clinical effects of H. erinaceus on menopause, depression, sleep quality and indefinite complaints, using the Kupperman Menopausal Index (KMI), the Center for Epidemiologic Studies Depression Scale (CES-D), the Pittsburgh Sleep Quality Index (PSQI), and the Indefinite Complaints Index (ICI). Thirty females were randomly assigned to either the H. erinaceus (HE) group or the placebo group and took HE cookies or placebo cookies for 4 weeks. Each of the CES-D and the ICI score after the HE intake was significantly lower than that before. In two terms of the ICI, "insentive" and "palpitatio", each of the mean score of the HE group was significantly lower than the placebo group. "Concentration", "irritating" and "anxious" tended to be lower than the placebo group. Our results show that HE intake has the possibility to reduce depression and anxiety and these results suggest a different mechanism from NGF-enhancing action of H. erinaceus.

Peripheral Nerve Regeneration Following Crush Injury to RatPeroneal Nerve by Aqueous Extract of Medicinal Mushroom Hericium erinaceus (Bull.:Fr) Pers. (Aphyllophoromycetidea

Improvement of refractory schizophrenia on using Amyloban_3399 extracted from Hericium erinaceum

We treated 10 patients with schizophrenia in this study, randomly selected by each doctor, working at six different institutions. Patients ranged across age, duration of illness, sex, or psychotropic drugs used.

All patients were refractory to currently available antipsychotic agents, but improved without exception and with no adverse reactions.

Average scores on the positive and negative syndrome scale (PANSS) improved significantly for all items, including positive, negative, and general psychopathology.

Case Report: Recovery from Schizophrenia Using AmylobanⓇ3399, Compounds Extracted from Hericium erinaceum

  

AmylobanⓇ3399---contains Amycenon, a standardized extract of HE containing hericenones and amyloban – and is currently being tested for safety as a health food supplement (Mori, Inatomi, Ouchi et al., 2009). A clinical trial with 8 volunteers was conducted to demonstrate the cognition-enhancing properties of AmylobanⓇ3399 (Lotter, 2012). Results of the study showed that AmylobanⓇ3399 improved mood, memory and sense of wellbeing. Overall AmylobanⓇ3399 was generally well tolerated.

Schizophrenia is the most devastating disease of the major psychoses. It has been repeatedly observed in clinical practice that although positive symptoms may be reduced within a few week treatment period, while it takes months or years to see improvements in cognitive symptoms. Atypical neuroleptic clozapine is associated with reduced liability for extrapyramidal symptoms and is effective in treatment-resistant schizophrenia. However, adverse effects limit the widespread use of clozapine.

Amyloban3399 was originally thought to be a drug for dementia.

However, based on my clinical observation, I asked a schizophrenia patient presented in this report to take AmylobanⓇ3399. He had been treatment-resistant and suffered from severe side effects for more than 30 years. He agreed to take Amyloban3399 and he has experienced dramatic life improvements and has been doing quite well for these three years.

Conclusion

Most autism variants appear to have high NGF, so the therapies discussed here relate to Rett Syndrome and other low NGF variants of autism, not to mention dementia.

Signs of Rett syndrome that are not similar to autism:

• affects almost exclusively girls

Signs of Rett syndrome that are similar to autism:

·         incontinence

·         screaming fits

·         inconsolable crying

·         breath holding, hyperventilation & air swallowing

·         avoidance of eye contact

·         lack of social/emotional reciprocity

·         markedly impaired use of nonverbal behaviors to regulate social interaction

·         loss of speech

·         sensory problems

Signs of Rett syndrome that are also present in cerebral palsy (regression of the type seen in Rett syndrome would be unusual in cerebral palsy; this confusion could rarely be made):

·         possible short stature, sometimes with unusual body proportions because of difficulty walking or malnutrition caused by difficulty swallowing

·         hypotonia

·         delayed or absent ability to walk

·         gait/movement difficulties

·         ataxia

·         microcephaly in some - abnormally small head, poor head growth

·         gastrointestinal problems

·         some forms of spasticity

·         chorea - spasmodic movements of hand or facial muscles

·         dystonia

·         bruxism – grinding of teeth

In people with low NGF, therapies known to increase it, look well worth investigating.

It’s not Autism, it’s Sotos Syndrome – and more about GABA therapies

 Peter the wild boy, with Pitt Hopkins Syndrome

I recently returned from a 25 year class reunion; of the 200 or so class members about 120 turned up. Of the 200 we know that at least 5 have a son with autism and at least one has a nephew with autism.  So I had my first ever “autism lunch” discussing all those tricky issues we are left to deal with.

What was immediately apparent was how different each child’s “autism” was and that none of them were the autism-lite variants that are now being so widely diagnosed in older children. or even adults .  Of the six, two are non-verbal, one is institutionalized, yet one talks a lot.  Three sets of parents are big ABA fans and one child did not respond to ABA.

You may be wondering about that high incidence of autism.  This was not a gathering of science boffins or mathematicians; this was at a business school.  One thing is obvious, you can correlate some autism incidence with educational level.  You can connect all sorts of measures of IQ to autism, from having a math prodigy in the family, to having professors at Ivy league type Universities, particularly in Mathematics.  It does appear to be true that the so-called clever genes are also associated with some types of autism.

I presume that if my science-only university organized such events the incidence of autism would be even higher.

On the way back home we met an acquaintance at the airport, who was telling us all about his son with Sotos Syndrome.  "It is not autism", we were informed, but then I am not quite sure what is.  When you look it up, many of the symptoms look just like autism.  In fact, it is a single gene dysfunction that leads to gigantism and various elements of autism.

This brings me to the painting above of Peter the Wild Boy; it is not me I should point out.  The above Peter was a German boy who came to live in England in the 18^th Century; he was non-verbal and is now thought to have had Pitt Hopkins Syndrome.  Like Sotos, this is another very rare single gene disorder.

We have already come across Rett Syndrome, which for some reason is treated as autism.

Fragile X is thought of as a syndrome where autism can be comorbid.

Timothy Syndrome is fortunately extremely rare, but I have already drawn on it in my own research into autism.

There are also autism related disorders involving multiple genes.

Prader–Willi syndrome  is a rare genetic disorder in which seven genes (or some subset thereof) on chromosome 15 (q 11–13) are deleted or unexpressed (chromosome 15q partial deletion) on the paternal chromosome.  If the maternally derived genetic material from the same region is affected instead, the sister Angelman Syndrome is the result.

The most frequent disorder caused by known multiple gene overexpression is Down Syndrome.  We saw in earlier post that DS is caused by the presence of all or part of a third copy of chromosome 21.  This results in over-expression of some 300 genes.

Why So Many Syndromes

Even before the days of genetic testing, these syndromes had been identified.  How could that be?  Each syndrome is marked by clear physical differences.

These physical differences where used to identify those affected.

Within autism too, sometimes there are physical differences.  Big heads, small heads, slim stature or heavy stature, advanced bone age or retarded bone age.

So many syndromes , but no therapies

Many of the rare syndromes have their own foundations funding research, mainly on the basis that if there is a known genetic dysfunction there should be matching therapy somewhere.

As of today, there are no approved therapies for any of these syndromes.

The Futility of Genetic Research?

A great deal of autism research funding goes into looking for target genes.  The idea goes that once you know which gene is the problem you can work out how to correct it.  There are numerous scientific journal dedicated to this approach.

Since no progress has been made in treating known genetic conditions leading to “autism”, is all this research effort well directed?  Some clever researchers think it is not.

All I can do is make my observations from the side lines.

What do Down Syndrome, Autism and Pitt Hopkins Syndrome all have in common?

In at least some of those affected, they have the identical excitatory-inhibitory imbalance of GABA, that can be corrected by Bumetanide.

If you did whole exome genetic testing on the responders with these three conditions you would not find a common genetic dysfunction; and yet they respond to the same therapy.

I am actually all for continued genetic research, but those involved have got to understand its limitations, as well as its potential.

More on GABA

This post returns to the theme of the dysfunctional GABA neurotransmitter because the research indicates it is present in numerous of the above-mentioned conditions. 

Table 1.  Summary of GABAA signaling alterations in neurodevelopmental disorders (click for the full Table)

·        Autism

·        Fragile X

·        Rett Syndrome

·        Down Syndrome

·        Neurofibromatosis type 1

·        Tourette syndrome

·        Schizophrenia

·        Tuberous sclerosis complex (TSC)

·        Prader-Willi syndrome

·        Angelman Syndrome

Based on feedback to me, we should add Pitt Hopkins Syndrome to the above list.

The GABA dysfunction is not the same in all the above conditions, but at least in some people, Bumetanide is effective in cases of autism, Down Syndrome and Pitt Hopkins Syndrome.  I suspect that since it works in mice with Fragile-X , it will work in at least some humans.

GABA_A has already been covered in some depth in this blog, but I am always on the lookout for more on this subject, since interventions are highly effective.  It is complicated, but for those of you using Bumetanide, Low Dose Clonazepam, Oxytocin and some even Diamox, the paper below will be of interest.

Modulation of GABAergic transmission indevelopment and neurodevelopmental disorders: investigating physiology andpathology to gain therapeutic perspectives

Regular readers will know that in autism high levels of chloride Cl⁻ inside the neuron have been shown to make GABA excitatory rather than inhibitory.  This leads to neurons firing too frequently;  this results in effects ranging from anxiety to seizures and with reduced cognitive functioning.  Therapies revolve around reducing chloride levels, this can be done by restricting the flow in ,or by increasing the flow out.  The Na⁺/K⁺/Cl⁻ cotransporter NKCC1  imports Cl⁻ into the neuron.  By blocking this transporter using Bumetanide you can achieve lower Cl⁻ within the neuron, but with this drug you also affect NKCC2, an isoform present in the kidney, which is why Bumetanide is a diuretic.  Some experimental drugs are being tested that block NKCC1 without affecting NKCC2 and better cross the blood brain barrier. 

The interesting new approach is to restore Cl⁻ balance by increasing KCC2 expression at the plasma membrane.  This means increasing the number of transporters that carry  Cl⁻  out of the neurons.

Chloride extrusion enhancers as novel therapeutics for neurological diseases

In the Modulation of GABAergic transmission paper there is no mention of acetazolamide (Diamox) which I suggested in my posts could also reduce Cl⁻, but via the AE3 exchanger.  This would explain why Diamox can reduce seizures in some people.

The paper does mention oxytocin and it does occur to me that babies born via Cesarean/Caesarean section will completely miss this surge of the oxytocin hormone.  This oxytocin surge is suggested to be key to the GABA switch, which should occur soon after birth when GABA switches from excitatory to inhibitory.  In much autism this switch never takes place.

That would suggest that perhaps all babies born via Caesarean section should perhaps receive an artificial dose of oxytocin at birth.  This might then reduce the incidence of GABA dysfunctions in later life, which would include autism and some epilepsy.

Indeed, children born by Caesarean section (CS) are 20% more likely to develop autism.

Association Between Obstetric Mode of Delivery and Autism Spectrum Disorder - :  A Population-Based Sibling Design Study

Conclusions and Relevance  This study confirms previous findings that children born by CS are approximately 20% more likely to be diagnosed as having ASD. However, the association did not persist when using sibling controls, implying that this association is due to familial confounding by genetic and/or environmental factors.

So as not to repeat the vaccine/autism scare, the researchers do not say that Caesarean section leads to more autism, rather that the kinds of people who are born by Caesarean section already had an elevated risk of autism.  This is based on analysing sibling pairs, but I do not entirely buy into that argument.  They do not want to scare people from having a procedure that can be life-saving for mother and baby.

If you look at it rationally, you can see that the oxytocin surge at birth is there for an evolutionary reason.  It is very easy to recreate it with synthetic oxytocin.

Another interesting point is in the conflict of interest statement:-

Laura Cancedda is on the Provisional Application: US 61/919,195, 2013. Modulators of Intracellular Chloride Concentration For Treating An Intellectual Disability

Regular readers will note that in this blog we have known for some time that modifying GABA_A leads to improved cognitive function.  I even suggested to Ben-Ari that IQ should be measured in their autism trials for Bumetanide.  IQ is much less subjective than measures of autism.

Conclusion

My conclusion is that while genetic testing has its place, it is more productive to look at identifying and treating the downstream dysfunctions that are shared by many individual genetic dysfunctions.

By focusing on individual genes there is a big risk of just giving up, so if you have Pitt Hopkins Syndrome, like Peter the Wild Boy, it is a single gene cause of “autism” and there is no known therapy.  Well it seems that it shares downstream consequences with many other types of autism, so it is treatable after all.

I also think more people need to consider that cognitive dysfunction (Intellectual Disability/MR) may indeed be treatable, and not just via GABA; so good luck to Laura Cancedda.