Showing posts with label Sotos. Show all posts
Showing posts with label Sotos. Show all posts

Monday, 21 November 2016

Agenesis of the Corpus Callosum

Today’s post is about another supposedly rare cause of autism called Agenesis of the Corpus Callosum (ACC).

As regular readers of this blog will have noted, extremely rare causes of autism, taken as a group are not so rare after all.  In fact it seems that autism is just a very large collection of somewhat rare biological conditions. 
Of the very few "Autism Dads" I have had a face to face conversation with, one has a child with ACC and another has a son with the even rarer Sotos syndrome. Sotos syndrome is characterized by gigantism, mild ID/MR and often autism. Mutations in the NSD1 gene cause Sotos syndrome

ACC is physical malformation of the brain that shows up clearly on MRI scans and potentially shows up on the mother’s regular ultrasound scans. 

The corpus callosum is a wide, flat bundle of fibers about 10 cm long that connects the left and right sides of the brain.  It facilitates communication between the two sides of the brain.
Agenesis of the corpus callosum (ACC) is a birth defect in which there is a complete or partial absence of the corpus callosum.

ACC leads to behaviors compatible with a diagnosis of autism or Asperger’s in about half of cases.

Symptoms of ACC  vary greatly among individuals, as they do in all types of autism.  Seizures are common, some people have poor motor coordination, and some people are non-verbal.

It is suggested by many that a diagnosis of ACC is not compatible with a diagnosis of autism; this just shows a lack of understanding.
Autism is just a description of behaviors, ACC is a biological diagnosis, like Fragile X syndrome or Down Syndrome.  So if a person has autistic behaviors caused by ACC, it is still autism, it is just autism with an explanation of its origin.

The most famous person with ACC was Kim Peek who was the inspiration for the character played by Dustin Hoffman in the well-known film Rain Man.

In addition to having the physical ACC malformation it has been suggested that the cause of ACC in his case was likely FG Syndrome.

Most mutations that cause FG syndrome can be found in the MED12 gene. However, mutations have also been found in FMR1, FLNA, UPF3B, CASK, MECP2, and ATRX genes. Mutations on these different genes lead to the different types of FG syndrome, all with similar characteristics.  Congenital heart defects are common and Peek died of a heart attack aged 58, outlived by his father.  

Agenesis of the Corpus Callosum and broader Autism

Undoubtedly there are people diagnosed with autism, who have undiagnosed ACC, since they never had an MRI scan.  Just like there are many people with autism who have an undiagnosed, but treatable, Chiari “brain hernia”.

It also appears that having a smaller corpus callosum, but falling short of what would be diagnosed as ACC by the MRI scan, is a feature of some people’s autism. You could consider it as partial ACC, like we had partial biotin/biotinidase deficiency.

A very recent paper from the 2016 Society for Neuroscience annual meeting suggested one reason why autism is more prevalent in males.  The study looked at infecting pregnant rats with group B streptococcus to activate the mothers immune system.  Inflammation was then triggered in the fetal side of the placenta, but only in male fetuses.
The males go on to develop brain and behavioral features reminiscent of autism.
Female fetuses were somehow protected and developed normally.  Hopefully Barons Cohen will read this and stop looking for undiagnosed females with autism. There are many good reasons why autism is less prevalent in females, and they are not just “better at hiding it”, as the so-called expert claims. 

What is interesting is that in the male pups with “autism” they had an unusually thin corpus callosum. It turns out that such minor malformations occur in broader human autism. 

The largest of the white matter tracts is known as the corpus callosum, which allows communication between the two hemispheres (halves) of the brain.
"The size of the corpus callosum was smaller in the group with autism, suggesting that inter-regional brain cabling is disrupted in autism," Dr. Just said.

In essence, the extent to which the two key brain areas (prefrontal and parietal) of the autistic participants worked in synchrony was correlated with the size of the corpus callosum. The smaller the corpus callosum, the less likely the two areas were to function in synchrony. In the normal participants, however, the size of the corpus callosum did not appear to be correlated with the ability of the two areas to work in synchrony.

"This finding provides strong evidence that autism is a disorder involving the biological connections and the coordination of processing between brain areas," Dr. Just said.


These longitudinal results suggest atypical early childhood development of the corpus callosum microstructure in autism that transitions into sustained group differences in adolescence and adulthood. This pattern of results provides longitudinal evidence consistent with a growing number of published studies and hypotheses regarding abnormal brain connectivity across the life span in autism.

The study suggests that white matter abnormalities manifest early in autism, says Thomas Frazier, director of Center for Autism at the Cleveland Clinic in Ohio. “It also serves as a nice demonstration that brain abnormalities in autism will become clearest and most helpful for pointing to etiology when we look at them developmentally, longitudinally, rather than at a single age," he says.

The findings do not imply that corpus callosum abnormalities cause autism, cautions Ralph-Axel Müller, professor of psychology at San Diego State University, who was not involved with the work. Rather, any irregularities in the corpus callosum may stem from other abnormalities in the brain that have been associated with autism, Müller says.

Still, changes in the corpus callosum may help to explain why autism symptoms worsen in some individuals and improve in others, Travers says. "Is there some aspect of white matter micro-structure occurring early in the developmental pathology that locks in persistent autism across the lifespan? What are the mechanisms? Can they be unlocked?” she says. “These will be important questions for future research.”



It is estimated that at one in 4,000 individuals has a disorder of the corpus callosum. I suspect it is more, but you would need to routinely give MRI scans to people diagnosed with autism to find out.

It is clear that milder disorders of the corpus callosum may be a feature of many people’s autism and those changes over time in the corpus callosum may help to explain why autism symptoms worsen in some individuals and improve in others.

Friday, 16 October 2015

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

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 18th 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. 

·        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.

GABAA 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.

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.

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.

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 GABAA 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.


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.