As readers
will be aware, many people with more severe autism are also affected by
epilepsy. Siblings of those with autism
also seem to be at greater risk of epilepsy.
There are frequent
comments that once starting on AEDs (Anti-Epileptic Drugs) aspects of autism
also seem to improve. This should not be
surprising given the suggested action of these drugs and the overlapping causes
of epilepsy and autism.
Today’s post
is prompted by the observation that in very low, apparently sub-therapeutic,
doses some AEDs seem to improve autism in some cases. This is relevant because the usual high doses
of these drugs are associated with some side effects and indeed a small number
can be habit forming.
What is epilepsy?
Genetics is believed to be
involved in the majority of cases, either directly or indirectly. Some
epilepsies are due to a single gene defect (1–2%); most are due to the
interaction of multiple genes and environmental factors. Each of the single gene defects is rare, with
more than 200 in all described. Most
genes involved affect ion channels, either
directly or indirectly. These include genes for ion channels
themselves, enzymes, GABA, and G
protein-coupled receptors.
Much of the
above applies equally to autism, including the genetic dysfunctions associated
with GABA. The ion channel dysfunctions
in epilepsy are thought to be mainly sodium channels, like Nav1.1. We previously came across this channel when
looking at Dravet Syndrome.
Dravet Syndrome
Dravet Syndrome is rare form of epilepsy, but is highly comorbid with autism. It is cause by dysfunctions of the SCN1A gene, which
encodes the sodium ion channel Nav1.1.
There is a mouse model of this condition, used in autism research. Dravet Syndrome is known to cause a
down-regulation of GABA (the neurotransmitter) signaling. We saw how tiny doses of Clonazepam corrected
this dysfunction in mice.
Known ASD-associated mutations occur in the genes CACNA1C,
CACNA1F, CACNA1G, and CACNA1H, which encode the L-type
calcium channels Cav1.2 and Cav1.4 and the T-type calcium channels Cav3.1 and
Cav3.2, respectively; the sodium channel genes SCN1A and SCN2A,
which encode the channels Nav1.1 and Nav1.2, respectively; and the potassium
channel genes KCNMA1 and KCNJ10, which encode the channels BKCa
and Kir4.1, respectively.
Dr Catterall, the researcher, then went on to test low dose clonazepam in a different mouse of autism model and found it equally effective. It also appears to work in some human forms of autism.
Sodium Valproate
Valproate is
a long established epilepsy drug that has also been used widely as a mood
stabilizer and particularly to treat Bipolar Disorder.
One side
effect can be hair loss. Hair
loss/growth and also hair greying are frequently connected with drugs and genes
linked to autism (BCL-2, biotin, TRH etc).
One regular
reader of this blog has pointed out that a tiny dose of Valproate, when
combined with Bumetanide, appeared to have a significant and positive
effect. We know that bumetanide works
via NKCC1 and the GABAA receptor to make GABA more inhibitory.
Many modes
of action are proposed for Valproate, but the most mentioned one is that it
increases GABA “turnover”; so it would make sense that having shifted the
balance from excitatory to inhibitory, a stimulation to increase GABA signaling
might be beneficial.
What is odd
is that this is happening at a dose 20
times less than used in epilepsy, bipolar or mood disorders.
The use of
Clonazepam, discovered by Dr Catterall, is also at a dose 20 to 50 times less than the typical dose.
Clonazepam
and Valproate are both AEDs. There are
not so many of these drugs and while using them at high doses, without dire
need, might be highly questionable, their potential effectiveness at tiny doses
is very interesting.
Clonazepam
is a Benzodiazepine in the table below.
The above table is
from the following paper:-
Low Dose
Clonazepam
Low dose Clonazepam was shown to be effective by its action of modulating
the GABAA receptor to make it more inhibitory. There are different types of GABAA receptor
and the low dose effect was sub-unit specific.
Other benzodiazepine drugs were found to have the opposite effect.
The mouse research showed that the effect only appeared with a narrow
range of low dosages.
Low Dose
Valproate
Valproate is known to affect sodium channels like Nav1.1, but also some
calcium channels.
For an insight into some known potential effects of Valproate, here is a
paper from the US National Institute of Mental Health:-
In the paper it highlights the less well known effects of
Valproate:-
inhibits HDACs
Modulates
Neurotrophic and Angiogenic Factors (BDNF, GDNF, VEGF)
PI3K/Akt Pathway
Wnt/β-Catenin
Pathway
MEK/ERK
Pathway
Oxidative
Stress Pathways
Enhanced
Neuroprotection
Enhancing
the Homing and Migratory Capacity of Stem Cells
Here is a list of the suggested new applications of Valproate, many
highly appropriate to many types of autism:-
Having read that paper I am now not surprised that a tiny dose of
valproate can have a positive behavioral effect in autism. What would be interesting to know is how the effects and dominant modes of action vary with dosage. I presume the dosage has been optimized to
control/prevent seizures.
Valproate is a cheap drug and is available as a liquid, so accurate low dosing is possible. It has been
shown to be neuro-protective, even shown promise as a treatment for traumatic
brain injury.
While not written about autism, some of you may find the following collection of research interesting:-
It does talk about the wider potential use of Valproate, but not at tiny
doses.
Interestingly, an orphan drug was developed in the European Union to
treat Dravet Syndrome. It is included on
the list of AEDs above.
Even though that drug, Stiripentol, is not approved by the FDA, most
sufferers in the US are able to acquire it under the FDA’s Personal Importation Policy(PIP).
So it is
indeed possible to acquire drugs prior to approval in your home country.
Hopefully,
once Bumetanide is approved for autism in Europe, similarly people will be able
to access it easily in the US.
I wonder if anybody with Dravet Syndrome has tried low dose Clonazepam. In theory it should be helpful.