People keep telling me that my blog is too complicated; compared to the
literature it really is not. If your child has a disabling condition you really should be willing to invest all the time needed to learn about it, rather than be a passive bystander.
I think you can investigate even complex sounding genetic disorders without
being an expert, which is what happens in today’s post.
Are there 20,000 types of jeans?
As readers may recall, humans only have about 20,000 genes, far less than
originally was thought. Each gene provides the instructions to make one thing,
usually a protein.
For the great majority of genes we have two copies, one from Mum and one
from Dad. Mitochondrial genes all come from Mum.
These genes are stored on chromosomes (like recipe books).
For 22 of these recipe books you have two copies, so if one page got damaged
at least you have an undamaged version from the other book.
The 23rd pair of books is special because while females have two copies,
males do not. This is the X chromosome and if a male has a problem on any page
in this little book, he has a big problem, while his sister has less of a
problem, because she has a spare copy. The male has a Y chromosome in place of
a second copy of X.
Examples of problems on the X chromosome:-
·
The MECP2 gene is on the X
chromosome and when there is one working copy and one mutated version you have
Rett syndrome and you must be female. If you were male with one mutated version
you cannot survive.
·
In Fragile X syndrome a
problem with the FMR1 gene
means not enough not enough fragile X mental retardation protein (FMRP), which
is required for normal development of the connection between neurons. Females
would normally have a clean spare copy of the FMR1 gene and so show much less severe
symptoms that a male with Fragile X.
Problems on chromosomes 1
to 22:-
If you have a problem in the first 22 chromosomes (recipe books), boys and
girls are equal. If one page got damaged you can always look up the recipe in
the other book.
In case one gene got mutated but the other copy is fine, things can work
out just fine, in which case it is called haplosufficiency.
You get to make enough of that protein.
In some cases you really need to use that recipe a
lot; that particular protein is in big demand. One copy of that gene just is
not enough. This is called haploinsufficiency.
In most cases when the gene has a problem, it just fails to produce the
intended protein. In some cases it actually produces a mutated protein, which
can be worse than no protein.
Pitt Hopkins
In Pitt Hopkins Syndrome there is a problem on chromosome 18, where you
find the TCF4 gene. Not enough
expression of TCF4 means not enough Transcription
Factor 4; this is an example of haploinsufficiency.
Now the reason why these rare conditions are important to many other people
is that they not only affect people who happened to have a random mutation and
hence a severe deficit of the protein; moderately reduced transcription of this
gene, for any reason, can also result in troubling symptoms.
So in the case of the Pitt Hopkins and the gene TCF4, as was pointed out to
me recently, reduced expression is a feature of some MR/ID and indeed schizophrenia.
Instead of just a tiny number of people with Pitt Hopkins, you can see that
upregulating TCF4 expression could help a lot of people.
It appears that people with Pitt Hopkins have a “clean copy” of TCF4, so it
is just a case of making it work a little harder. There are ways being
researched to achieve just that.
I suspect people with schizophrenia have two “clean copies” of TCF4, but
for some reason have a deficiency of the protein encoded by it.
In the above paper it was shown that Protein Kinase A (PKA) plays a key role in regulating what your TCF4
gene is producing.
We have come across PKA before in this blog and we know that in regressive
autism there can be a deficit of PKA. There is also PKB and PKC. All three are
very important, but complicated.
It all gets very
complicated, but PKA is controlled by something called cAMP. In turn cAMP is
controlled by PDE. PDE4 is known to be disturbed in the brains of some people
with autism.
It appears that
you can activate PKA with a PDE4 inhibitor. The long established Japanese asthma
drug Ibudilast is such a PDE4 inhibitor. At least one reader of this blog uses Ibudilast long term.
PDE4 inhibitors
have been explored to treat various neurological conditions like schizophrenia.
So logically if you feed a PDE4 inhibitor to a Pitt Hopkins mouse, you might expect something good to happen. There now is such a mouse model.
I think I could keep that mouse quite busy.
The point being you do not have to figure things out
100%, before starting to see what you have in your drug library might be
truly beneficial.
Some of the things in the drug library are actually in
the kitchen cupboard, as we have already seen.
Protein Kinase A
Protein kinase A (PKA) is something
that is both complicated and important.
The effects of PKA activation vary with cell type.
PKA has always been considered important in formation of a memory. Formation of a normal memory is highly
sensitive to PKA levels; too much is bad and too little is bad.
ARID1B in
Autism and Corpus Callosum Abnormalities
I don’t think anyone has set up a research foundation for agenesis of the Corpus Callosum (ACC), perhaps they should.
There was a post on this a while back, prompted by meeting someone whose
son has this condition.
The Corpus Callosum is just a fancy name for what joins the two sides of the brain together. Agenesis of the Corpus Callosum (ACC) is what they call it when there is a complete or partial absence of the corpus callosum.
ACC is we are told a very rare condition, but clearly smaller corpus callosum
variations are a key part of some autism.
For example, in Pitt Hopkins a small corpus callosum is typical.
An estimated 7 percent of children
with autism and macrocephaly (big heads) carry a PTEN mutation. This is
associated with an enlarged corpus callosum.
PTEN is an autism gene, but it is more
usually thought of as a tumor suppressor, making it a cancer gene. In older
people, losing PTEN appears to be often a first step to developing cancer; up to 70% of men with
prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis (https://www.ncbi.nlm.nih.gov/pubmed/16079851).
PTEN is interesting because too little can allow cancer to develop, but too
much may eventually result in type 2 diabetes. So, as always, it is a balance.
Evidently from the comments in this blog, regarding tumors/cancers, people with autism are likely shifted towards
the direction of lacking tumor suppressing proteins. The exception would be
those born very small, or with small heads.
ARID1B gene
ARID1B is another tumor suppressing gene, like PTEN, and like PTEN it is
also an autism gene.
What I found interesting was the link between ARID1B and corpus callosum anomalies.
ARID1B mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability
Corpus callosum abnormalities are common brain
malformations with a wide clinical spectrum ranging from severe intellectual
disability to normal cognitive function. The etiology is expected to be genetic
in as much as 30–50% of the cases, but the underlying genetic cause remains
unknown in the majority of cases.
Additional functional studies including a systematic
search for ARID1B
target genes may show how haploinsufficiency of ARID1B predispose to
CC defects and to an array of cognitive defects, including severe speech
defects
Several readers of this blog have highlighted a recent study:-
We showed that cognitive
and social deficits induced by an Arid1b mutation in mice are reversed by
pharmacological treatment with a GABA receptor modulating drug. And, now we
have a designer mouse that can be used for future studies."
The full study:-
Clonazepam also reversed the reduced time spent in the center
and reduced moving distance displayed by Arid1b-mutant mice in the open field
test (Fig. 7c,d and Supplementary Fig. 14c). However, depression
measures, using the forced swim test and the tail suspension test, showed no
reversible effect of clonazepam in Arid1b+/− mice compared with controls
(Fig. 7e,f). Our results show that clonazepam rescues impaired
recognition, social memory, and elevated anxiety in Arid1b+/− mice.
Our mouse model effectively mirrors the behavioral
characteristics of intellectual disability and ASD. Arid1b+/− and
Arid1bconditional-knockout mice displayed impaired spatial learning,
recognition memory, and reference memory. Open field and social behavior tests
also revealed decreased social interaction in the mice. Mice with mutations in
genes encoding Smarca2 and Actl6b, other subunits of the BAF complex, have
severe defects in social interaction and long-term memory35. Thus, this
chromatin remodeling complex may provide a cellular and molecular platform for
normal intellectual and social behavior. In addition, Arid1b+/− mice showed
heightened levels of anxiety- and depression-related behaviors, which are
common symptoms of ASD36.
For people with
intellectual disability, the prevalence of anxiety disorders has likewise been
shown to be much higher. This may be due to reduced cognitive function and
increased vulnerability to environmental demands. Communication difficulties
may also make it more difficult for people with cognitive disabilities to deal
with anxiety or fear. ARID1B haploinsufficiency may be
responsible for multiple facets of characteristic ASD behaviors. Other
isoforms of Arid1b that are not affected by the Arid1b mutation could exist in
the mouse line. Additionally, it is possible that the genetic background for
the mouse line may impact the effect of Arid1b haploinsufficiency. Thus it is
important to consider allele specificity, genetic backgrounds, and knockout
strategies for comparing phenotypes of other Arid1bhaploinsufficiency models.
GABA allosteric
modulators, including clonazepam, a benzodiazepine, have been used to treat
seizures and anxiety. We found that clonazepam injection rescued deficits in
object and social recognition and anxiety in Arid1b+/− mice. These results suggest that treatment with a benzodiazepine
could be a potential pharmacological intervention for symptoms of ASD.
Furthermore, our results suggest that pharmacological manipulation of GABA
signaling is a potential treatment strategy for cognitive and social
dysfunctions in ASD- or intellectual disability-associated disorders due to
mutations in chromatin remodeling genes.
ACC Research Foundation
If there actually was an ACC Research Foundation, they could explore
whether clonazepam was therapeutic in children who have Arid1b haploinsufficiency.
While they are at it,
they might want to look into Hereditary Motor and Sensory Neuropathy with
agenesis of the corpus callosum (HMSN/ACC), this is caused by mutations in the
potassium-chloride co-transporter 3 (SLC12A6/KCC3) gene. This I
stumbled upon a long time ago, when trying to upregulate KCC2, which causes elevated
intracellular chloride in many people with autism and likely many with Down
Syndrome.
KCC2 is usually associated with neuropathic pain and now we see that so is KCC3. Odd reaction to pain is a well known feature of autism. The rather ill-defined condition of fibromyalgia seems common in female relatives of those with autism and I do not think this is just a coincidence.
KCC2 is usually associated with neuropathic pain and now we see that so is KCC3. Odd reaction to pain is a well known feature of autism. The rather ill-defined condition of fibromyalgia seems common in female relatives of those with autism and I do not think this is just a coincidence.
The interesting thing is that the research shows you can potentially
upregulate KCC3 with curcumin.
HMSN/ACC is a severe and progressive
neurodegenerative disease that exhibits an early onset of symptoms. Signs of
HMSN/ACC, such as hypotonia and delays in motor development skills, are noticed
before 1 year of age. However, the motor abilities of patients progress slowly
to 4–6 years of age, and these children are able to stand and walk with some
help. This is followed by a motor deterioration that generally renders affected
subjects wheelchair-dependent by adolescence.
Accordingly, we found that curcumin relieved the ER retention of
dimerized R207C in mammalian cultured cells. A diet enriched in curcumin may
therefore be beneficial for the relief or delay of some of the HMSN/ACC
symptoms in patients bearing the R207C mutation, including the Turkish
patient described in this study (as patient has not yet reached puberty).
KCC3 defects also cause the very similar Andermann syndrome also known as agenesis of corpus callosum with neuronopathy (ACCPN).
KCC3 defects are associated with epilepsy.
My
question was can you have KCC3 under-expression with partial ACC, epilepsy but
no peripheral neuropathy? If this was
likely, then upregulating KCC3 with curcumin might help.
The gene for KCC3 is located at chromosome
15q14. Based on my “logic of associations”, if you have ACC and epilepsy you
should consider KCC3
under-expression.
I did suggest to my former classmate
whose son has partial ACC and epilepsy, but no neuropathy, that it might be worth trying some
curcumin. Since his son is already on anti-epileptic drugs (AEDs) my suggested
effect to look for was improved cognitive function.
6 months later it does indeed, apparently,
improve cognitive function. Of course
this does not establish that upregulating KCC3 had anything to do with it. It
is nonetheless a nice story and another parent has realized that you can change things for the better, in spite of what neurology currently says.
The question now is can you have
both ARID1B
under-expression and KCC3 under-expression, in which case you would add some
clonazepam, based on the latest research. At this point you should of course go
and talk to your neurologist, rather than read my blog and that was my recommendation.
We describe a patient who presented at our
epilepsy-monitoring unit with myoclonic jerks, and was diagnosed with juvenile myoclonic epilepsy
(JME). Imaging of his brain revealed partial agenesis of the corpus callosum (ACC). We
discuss the known genetic basis of both JME and ACC, as well as the role of the
corpus callosum (CC) in primary generalized epilepsy. Both JME and ACC are associated with gene loci on
chromosome 15q14. Structural brain abnormalities other than ACC, such as
atrophy of the corpus callosum have been reported in patients with JME. ACC has
been associated with seizures, suggesting an anti-epileptogenic role of the
corpus callosum
If you have a biological diagnosis you are one big step closer to finding a
therapy. Even if you have a diagnosis like partial Agenesis of the Corpus
Callosum (ACC), you can go one step further and ask why. You have a 50% chance
of being able to find out a specific gene that is the cause. If you know with
certainty which gene is the originator of the problem, you know a lot. I think you are then two big steps closer to a
therapy.
In the case of Rett Syndrome, a really good website is run by their
research foundation (Rett Syndrome Research Trust). They look like they mean
business.
If you look at the above site you might be left wondering why the much
larger and better financed autism organizations look so amateur by comparison. The big difference is that Rett Syndrome is a
biological diagnosis and autism is not. In many ways calling autism a spectrum
is not helpful, as the originators of the ASD concept are beginning to realize.
The precise biological dysfunctions are
what matter and lumping together hundreds of miscellaneous brain dysfunctions
into a pile labelled ASD may not be so clever, in fact I would call it
primitive.