One of the most interesting concepts I
have come across writing this blog is the idea of treating people with mental
retardation (MR) / intellectual disability (ID). I do keep using the term MR,
because 90% of the world has no idea what ID means. MR is a very precise
description, which is increasingly rare these days.
I still recall several years ago going
to a French-speaking neighbour’s barbecue. The French are generally very
family-oriented, but quite traditional when it comes to parenting, (hence their
low rates of ADHD diagnosis). At that time, Monty aged around 8, could act strangely
and was rather obsessed with fire, matches and cigarette lighters. Our neighbour
introduced us to his French friends and explained Monty with a brief use of the
word “retardé”, which did
not prompt any comments or requests for clarification. In the English language
this might have been regarded as a big faux-pas; it did not bother me. It seemed to work very well to forewarn
people not to over-react to any unexpected behaviours.
In the English language, autism has
become a nice word and seems the new ADHD, with people even wanting to be
diagnosed with it. MR/ID is still something
reserved for other people; it is not something most people want to be
associated with. I do use the term cognitive dysfunction, which is just as
explicit as MR but does not seem to upset people.
Cognitive dysfunction (MR/ID) is an
inevitable consequence of more severe autism and it is just a question of
degree. It is not a comorbidity, it is all part of the same package.
In Down Syndrome (DS) IQ is usually between 45 and 71 and worsens with age. MR/ID is defined as an IQ less than 70 and accounts for 2.3% of the general population. An IQ of 100 would put you in the middle of the IQ bell curve. People with DS tend to be very happy and contented, without the problematic behaviors that can occur in autism.
In Down Syndrome (DS) IQ is usually between 45 and 71 and worsens with age. MR/ID is defined as an IQ less than 70 and accounts for 2.3% of the general population. An IQ of 100 would put you in the middle of the IQ bell curve. People with DS tend to be very happy and contented, without the problematic behaviors that can occur in autism.
The good news is that cognitive
dysfunction (MR/ID) is likely to be treatable, as some readers of this blog
have discovered. You just need to figure out how, which in itself is more about your perseverance than your IQ. You do not need to be an Einstein (IQ > 160), rather a marathon runner.
I just had the uncanny experience at school
during the parent-teacher meetings, to be told that other class members could
learn from my younger son Monty, aged 14 with autism; that he has the neatest
handwriting in class, his essay had the best structure and that when his
geography teacher told his assistant to skip the final question in the test (using
longitude and latitude) because it was hard, the assistant said just let him
try it; he was the only one to get it right.
So from aged 8 to 14 he has gone from “retardé” to being something quite different. The teachers do love his assistants, who are
great; but he has had an assistant from the age of 4 and back then things moved
forward extremely slowly. He learnt to read and write the very hard way, with
a vast amount of 1:1 instruction and the school was amazed when his then
assistant taught him to read; I don’t think they expected it ever to happen. By
treating cognitive dysfunction pharmacologically for five years normal learning
became possible and remains a big surprise to everyone. His new English teacher knows him from
back in the darker old days and seemed more shocked than surprised, after a month of teaching him. "Is this the same boy?"
For the first time at school I am
being told to be proud of my younger son’s academic achievements, rather than how talented my older son is. Big brother certainly did not expect such a day
and his response was along the lines of “well the others in his class must be
really thick then” (like it or not, this is a typical teenage male comment). Little
brother still has autism, but it is much less disabling. Big brother is
currently teaching him to fence (sword fighting), which he would not have
bothered to try doing until recently, because it would not have ended well. Years
ago Monty did learn to ski, play basketball and soccer, but that all took a lot
of effort with very patient (mostly female) instruction; he initially had no
idea what to do if a ball was rolled towards him. Last week he happily sat through the new Blade Runner film, which is nearly three hours long with the trailers.
Perhaps there is no need for further
“breakthroughs” with my Polypill therapy.
It may be good enough already.
It just seems a pity that more people
with cognitive dysfunctions are not treated. There are some extremely
intelligent parents with children who have severe autism, indeed an ironic
twist of genetics. Some even write autism research, or indeed fund it. Even
these people are not treating it. Their
fear of quackery blinds them. There certainly are quacks and there are also
those who straddle the line, some of what they say is nonsense, but other ideas
may not be.
Imagine having a conversation with Bill Gates, who is using his billions to use vaccines to save millions of lives in poor countries, about the possibility that in some people vaccines might trigger mitochondrial disease and autism. Any organization talking about autism in relation to vaccines, chelation, aluminium, heavy metals etc and anyone who associates with them are in effect blacklisted.
Imagine having a conversation with Bill Gates, who is using his billions to use vaccines to save millions of lives in poor countries, about the possibility that in some people vaccines might trigger mitochondrial disease and autism. Any organization talking about autism in relation to vaccines, chelation, aluminium, heavy metals etc and anyone who associates with them are in effect blacklisted.
Why does the global head of
neuroscience at Novartis not attend the Autism One or TACA conferences? He does
have a son with severe autism. It would be very difficult for him to apply any therapy
promoted by anyone who attends these events.
Why does a Professor of Medicine from the US Ivy League apply ideas from this blog to his son, but never leave a comment? It is very clear to me why.
As our reader Roger has commented, why do some leading autism researchers still go on about vaccines? It does their interests much more harm than good.
I think Roger could teach Dr Naviaux a thing or two about getting his Suramin research funded.
Enhancing Cognition
The first area I came across where
serious research is underway to treat MR/ID concerns RASopathies, a group of
disorders that share disturbed levels of a protein called RAS. It was actually French
research.
In Down Syndrome (DS) I highlighted
research that aims to increase cognitive function by targeting the alpha 5
subunit of the GABAA receptor. We also saw that the same abnormal
level of chloride within in cells that exists in much autism also occurs in
Down Syndrome (DS); this is why the Frenchman Ben Ari has patented Bumetanide
as a therapy for DS.
In schizophrenia and bipolar there is
also reduced cognitive function, but only in schizophrenia has there been much
research and clinical trials to improve it. Histamine receptors were one target
of this research.
Too much or too little CBS (Cystathionine-β-synthase )
One known cause of cognitive dysfunction
that has not been mentioned in my posts is CBS and since it was raised in a
comment I thought it should be included.
All you need to know if you want to
rule out a CBS problem is your level of homocysteine. If it is normal you do
not have a problem with CBS. If homocysteine is high you have a case of Hyper-homocystinuria, which may be caused by too little CBS, or
for a different reason. If you have very low levels of homocysteine (Hypo-homocystinuria) that may be caused by too much
CBS and if you have Down Syndrome elevated CBS is inevitable.
Normalizing CBS is very likely to help
cognition.
Cystathionine-β-synthase, also known as CBS, is an enzyme that in humans is
encoded by the CBS gene. It catalyzes the first
step of the transsulfuration pathway, from homocysteine to cystathionine:
Down syndrome is a medical condition characterized by an overexpression of cystathionine
beta synthase (CBS) and so a low level of homocysteine in the blood. It has
been speculated that cystathionine beta synthase overexpression could be the
major culprit in this disease (along with dysfunctioning of GABAA
and Dyrk1a). The phenotype of down syndrome is the opposite of
Hyperhomocysteinemia (described below). Pharmacological inhibitors of CBS have
been patented by the Jerome Lejeune Foundation and trials are planned.
Down's syndrome (DS) or trisomy 21 is
the most common genetic cause of mental retardation, and adults with DS develop
Alzheimer type of disease (AD). Cystathionine beta-synthase (CBS) is encoded on
chromosome 21 and deficiency in its activity causes homocystinuria, the most
common inborn error of sulfur amino acid metabolism and characterized by mental
retardation and vascular disease.
Here, we show that the levels
of CBS in DS brains are approximately three times greater than those in the
normal individuals. CBS is localized to astrocytes and those surrounding
senile plaques in the brains of DS patients with AD. The over-expression of CBS may cause the
developmental abnormality in cognition in DS children and that may lead
to AD in DS
It is a French foundation that is
funding research is develop CBS inhibitors to improve cognition in Down
Syndrome.
NovAliX will use its
expertise and capabilities in medicinal chemistry and structural biology to develop
small molecule lead candidates targeting the cystathionine-beta-synthase (CBS).
Indeed inhibition of CBS over-expression has been associated with restoration
of cognitive impairment in animal models afflicted with trisomy.
People with DS have a low incidence
of coronary atherosclerotic disease (CAD), which would seem to be linked to
their low level of homocysteine (high CBS), but their high level of DYRK1A (see
later) may be the cause of their early onset Alzheimer’s.
Some background on homocystinuria, courtesy of Wikipedia:-
Classical homocystinuria, also known as cystathionine beta synthase deficiency
or CBS deficiency, is an
inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase.
Homocystinuria represents a group of hereditary metabolic disorders
characterized by an accumulation of the amino acid homocysteine in the serum
and an increased excretion of homocysteine in the urine.
Signs and symptoms of homocystinuria that may be seen
include the following:
- A family history of homocystinuria
- Flush across the cheeks
- Musculoskeletal
- Tall, thin build resembling Marfanoid habitus
- Long limbs (dolichostenomelia)
- High-arched feet (pes cavus)
- Knock knees (genu valgum)
- Pectus excavatum and Pectus carinatum
- Intellectual disability
- Seizures
- Psychiatric disease
The term homocystinuria describes an increased excretion of homocysteine in urine (and
incidentally, also an increased concentration in plasma). The source of this increase may be one of many
metabolic factors, only one of which is CBS deficiency. Others include the
re-methylation defects (cobalamin defects, methionine sythase
deficiency, MTHFR) and vitamin
deficiencies (cobalamin (vitamin B12) deficiency, folate (vitamin B9)
deficiency, riboflavin deficiency (vitamin B2), pyridoxal phosphate deficiency (vitamin B6)). In light of this
information, a combined approach to laboratory diagnosis is required to reach a
differential diagnosis.
DYRK1A
You may have noticed that DYRK1A
was mentioned as another cause of cognitive loss in Down Syndrome. DYRK1A is yet another autism gene; it encodes
an enzyme that is important in how the brain develops. Too much DYRK1A also
leads to reduced levels of homocysteine.
An OTC DYRK1A inhibitor exists today, epigallocatechin gallate (EGCG).
DYRK1A
is important in neuronal development and function, and its excessive activity
is considered a significant pathogenic factor in Down syndrome and Alzheimer's
disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to
modify the disease. Very few compounds, however, have been reported to act as
inhibitors, and their potential clinical uses require further evaluation. Here,
we newly identify CX-4945,
the safety of which has been already proven in the clinical setting, as a
potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The
inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than
that of harmine, INDY or proINDY, which are well-known potent inhibitors of
DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau,
amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with
CX-4945 significantly restored the neurological and phenotypic defects induced
by the overexpression of minibrain, an ortholog of human DYRK1A, in the
Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed
Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate
that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has
therapeutic potential for DYRK1A-associated diseases
Neurodevelopmental alterations and cognitive disability are constant features of Down syndrome (DS), a genetic condition due to triplication of chromosome 21. DYRK1A is one of the triplicated genes that is thought to be strongly involved in brain alterations. Treatment of Dyrk1A transgenic mice with epigallocatechin gallate (EGCG), an inhibitor of DYRK1A, improves cognitive performance, suggesting that EGCG may represent a suitable treatment of DS. Evidence in the Ts65Dn mouse model of DS shows that EGCG restores hippocampal development, although this effect is ephemeral. Other studies, however, show no effects of treatment on hippocampus-dependent memory. On the other hand, a pilot study in young adults with DS shows that EGCG transiently improves some aspects of memory. Interestingly, EGCG plus cognitive training engenders effects that are more prolonged. Studies in various rodent models show a positive impact of EGCG on brain and behavior, but other studies show no effect. In spite of these discrepancies, possibly due to heterogeneity of protocols/timing/species, EGCG seems to exert some beneficial effects on the brain. It is possible that protocols of periodic EGCG administration to individuals with DS (alone or in conjunction with other treatments) may prevent the disappearance of its effects.
Conclusion
Understanding
emerging therapies that treat various types of MR/ID, and also the various
types of dementia, should unlock interesting avenues to raise cognitive
function in many types of autism.
Homocysteine
levels are very easy to measure.
Because
the gene miss-expression in Down Syndrome (DS) is fully understood, it makes
sense that treatment is more advanced than in autism, which is so heterogenous.
There are a lot of people in the world with DS and so there is a big market for
drug makers.
The
potential drug therapies to improve cognition in Down Syndrome (DS) appear to be:-
·
Basmisanil, a negative allosteric modulator of α5
subunit-containing GABAA receptors. It appears that sodium benzoate
may have a similar effect.
·
Bumetanide, an NKCC1 inhibitor
·
Potassium bromide, Br- displaces Cl- to
lower intracellular Cl-
·
CBS inhibitor
·
DYRK1A inhibitor, like Epigallocatechin gallate (EGCG), but a more potent inhibitor like CX-4945 (Silmitasertib) might be better.
There is mouse model research to show that a single dose just after birth of a drug that stimulates the sonic hedgehog signaling pathway results in a "normal" adult brain.
The risk of Down Syndrome (DS), caused by a third copy of chromosome 21 (trisomy 21), rises rapidly with increasing maternal age, nonetheless the number of births is stable to falling in most developed countries, due to increased prenatal testing and termination of pregnancy for fetal anomaly (TOPFA). TOPFA is not practiced in countries like Poland and Ireland. In Denmark screening has long been free and TOPFA has risen to 98%. In the UK two thirds of mothers opt for their free DS screening and 90% of those who test positive, opt for their free TOPFA. The one third letting nature take its course are probably mainly younger mothers.
The risk of Down Syndrome (DS), caused by a third copy of chromosome 21 (trisomy 21), rises rapidly with increasing maternal age, nonetheless the number of births is stable to falling in most developed countries, due to increased prenatal testing and termination of pregnancy for fetal anomaly (TOPFA). TOPFA is not practiced in countries like Poland and Ireland. In Denmark screening has long been free and TOPFA has risen to 98%. In the UK two thirds of mothers opt for their free DS screening and 90% of those who test positive, opt for their free TOPFA. The one third letting nature take its course are probably mainly younger mothers.
In Catholic countries you have both extremes - in Cork, Ireland DS is present 30
times per 10,000 births, but in Zagreb Croatia it is just 6 per 10,000. In the US
the CDC say it 14, while in the UK it is 10.
In South Africa 20 cases of DS occur per 10,000 births; mothers are
younger than in Ireland.
In developed countries, the natural
prevalence of DS looks to be 0.3%, which is the same as the incidence of strictly
defined autism (SDA), which I estimated in an earlier post to be 0.3%. It is
just that in developed countries most people with DS are never born.
I would have thought CX-4945 should be trialed by some clever Alzheimer's researcher and indeed for any Tauopathy. In the meantime perhaps Grandad should drink a lot of green tea to get his dose of EGCG.
I would have thought CX-4945 should be trialed by some clever Alzheimer's researcher and indeed for any Tauopathy. In the meantime perhaps Grandad should drink a lot of green tea to get his dose of EGCG.
