This post is
not about your IPad, it’s still about autism.
There are a
few important substances that I have not fully addressed yet in this blog; as
is often the case in biology, the names do all rather look alike. A complete understanding of these 4 Gs will
definitely help to understand the literature and hopefully separate science
from pseudoscience and the voodoo.
We know for
a fact that in autism some strange things are going on here, but it remains to
be proved exactly what is going on, and whether all types of autism are
similarly affected. So it may be
premature to visit the supplement shop.
The 4 Gs
Glutamine,
like Creatine, is one of those chemicals that is widely used by body builders
and sometimes given to children with autism.
It is an amino acid.
Glutamine is
a precursor chemical to Glutamate. Glutamate
is a major excitatory neurotransmitter in the brain.
Glutamate is a precursor chemical to GABA, another very important
neurotransmitter.
Glutamate is converted to GABA by the
neuronal enzyme glutamate decarboxylase (GAD).
Glutamate is synthesized from glutamine via
glutaminase, but after release in the synapse, glutamate is converted back into
glutamine in glial cells, by glutamine synthetase.
Some Facts
Glutamine
Glutamine is
known to help heal injuries and recover from abdominal surgery. It was thought that this would extend to
helping maintain the gut barrier, which is sometimes implicated in autism. DAN type doctors use glutamine to “heal the
gut”; however, when trials were made in Crohn’s disease, an inflammatory bowel
disease similar to the type sometimes implicated in autism, supplementing with
glutamine had no effect.
Glutamate
|
Glutamine + H2O
|
NH3
is ammonia, which is also important and plays a role in some people’s autism
theories.
Excessive
glumate release is implicated in autism.
Glutamic acid is implicated in epilepsy, which is highly comorbid with
autism.
Glutamate decarboxylase (GAD) is an enzyme that catalyzes the conversion of glutamate
to GABA and CO2.
HOOC-CH2-CH2-CH(NH2)-COOH
→ CO2 + HOOC-CH2-CH2-CH2NH2
Where HOOC-CH2-CH2-CH2NH2
is GABA (Gamma-Aminobutyric acid)
GABA
GABA is
another amino acid and important neurotransmitter. It is also known to regulate muscle tone,
which is often affected in autism.
GABA works by binding at receptors, this binding causes
the opening of ion channels to allow the flow of either negatively charged
chloride ions into the cell or positively charged potassium ions out of the cell.
The drug Baclofen is an agonist for the GABAB
receptors. A version of this drug called Arbaclofen is being developed as a
treatment for autism and Fragile X.
Baclofen is a drug to treat spasticity, which is a
condition where there can be strange effects on the muscles like spasms,
stiffness and tightness. Some people
with ASD have a tendency to clasp their hands and fingers in a strange tight
claw-like fashion and indeed some walk with an odd gait. That would appear to me to be a form of
spasticity. Baclofen was stumbled upon
by accident as a possible autism drug, where it would treat a form of mental
spasticity.
Baclofen also has a long forgotten secondary effect that
interested me; it stimulates the production of GH (Growth Hormone). GH does appear to be implicated in autism
along with IGF-1 and its analogues.
An antagonist of the GABAA receptor,
bumetanide, works by blocking the NKCC1 cation-chloride co-transporter,
and thus decreases internal chloride concentration in neurons. In turn, this
concentration change makes the action of GABA in some people with autism,
returning it from excitory to inhibitory, where is should be.
I think it is clear that GABA plays a major role in some
types of autism.
Recent Studies
As noted in previous
posts, some very practical research comes out of Iran these days."2.1. Glutamate
Glutamate is a major excitatory
neurotransmitter in the brain. The high level of plasma glutamate level
especially in children with normal IQ is supposed to be a diagnostic screening
test. The increased plasma level in adults with autism is also reported. Higher
glutamate level is not limited to plasma, and some studies confirmed its higher
level in some brain regions (amygdala-hippocampal regions but not in parietal
region) of patients with autism compared to the controls. The increased plasma
glutamic acid is not limited to patients with autism, but its level is
increased in their siblings and parents. "
"2.2. Glutamine
The low level of plasma glutamine level is
suggested as a screening test for detecting autism in children especially those
with normal IQ. The decreased level has been reported before in all children
with autism."
A very
recent study by King's College London looked at the level of glutamate and
glutamine in adults with ASD using clever proton magnetic resonance spectroscopy in two brain regions.
They found reduced
levels of the combined signal of glutamate and glutamine in autism versus the
control group. It all sounds very clever
until you get to the discussion part, where they say:-
"Hence, it could be
that serotonergic abnormalities underlie the differences in Glx we
observed—either indirectly via influences on neurodevelopment or through direct
action on glutamate metabolism."
This may be
the case of over-analyzing certain variables, because the technology exists,
even though you can only understand 20% of the problem. The end result is lots of complicated looking
data and analysis that may actually lead nowhere.
A reality
check is required. We have to come back
to definitive facts otherwise the research is just generating confusion.
We already
know serotonergic abnormalities are present in autism. We know that drugs that increase brain serotonin,
such as LSD and Prozac, improve autistic behaviours. So the researchers at Kings College have very
likely just measured a consequence of these abnormalities. As a result, the glutamate/glutamine issue
may indeed join the long list of consequences, rather than causes of autism.
The fever effect (again)
Another
reason for this post is that both Glutamine and Glutamate have been put forward
as possible explanations for the fever effect in autism; that is a reduction in
autistic behaviour when person is sick, with a high temperature.
The fever
effect is so dramatic in some people, that it would be ever so easy to validate
a hypothesis. In doing so, you would open
the door to a very useful therapy for many people.
This paper
was published in the Journal Medical Hypotheses, but the full version is not
always available free, the first link is to the author’s own site. It is a very thorough analysis and worth a
read, but in the end the author seems to disprove his own hypothesis.
A preliminary version of
this paper was sent to several hundred ASD practitioners (DAN Doctors) formerly
listed on the ARI site, for feedback. Fourteen replies suggest ASD
practitioners commonly give oral glutamine to heal the intestines, from 250 mg
to 8 g/day, with few side effects (some hyperactivity) but few notable improvements in behavior.
So now on to
the next candidate, glutamate.
The second
hypothesis is by Ghanizadeh, the Iranian author of the paper I referred to
earlier.Could fever and neuroinflammation play a role in the neurobiology of autism? A subject worthy of more research.
Abstract
Autism
is neuropsychiatric disorder in which a hyperglutamate state may play a role.
It is suggested here that fever or hyperthermia may be able to alter glutamate
levels in the brain and may therefore be able to impact on the symptoms of
autism. More study on this possibility is clearly warranted.
Conclusion
Of the 4 Gs,
I am sticking with GABA as the key one, but I will not be buying any GABA
supplements, even though they do exist. Some
DAN-type doctors favour Glutamine supplements, even though some well-known “holistic” type
doctors like Dr Mercola say specifically not to give it to kids with ASD and
ADHD.
I have no
doubt that glutamate plays an important role in autism, but as with GABA it is
not just a matter of swallowing some.
There is a
line to be drawn between science, pseudoscience and pure voodoo. For the time
being, you have to find this line yourself.