Belgium is famous for many things from chocolate and beer to comic books like Tintin.
Even the Smurfs are from Belgium.
If you want
to investigate autism you might need the skills of the most famous fictional
Belgian, Hercule Poirot.
Today’s post
is about the detective work of Dr Ramaekers from Liège.
Liège is a city in the French-speaking part of
Belgium. The northern half of Belgium speak Dutch and southern half speak
French. The capital Brussels is
officially a bilingual city, but if you do not want to upset an unknown local,
the safest language to use is actually English.
Liège
used to be a major European centre for steel making. My elder son tells me that Liège is still
famous for making guns.
In 2020 Liège is the European home of Folate receptor antibodies
research and more importantly, its treatment.
Outside
of Brussels the touristy parts of Belgium include Bruges, Gent and Antwerp,
where your French from school is less useful. If you like medieval towns,
excellent food and mayonnaise on fries/chips these places are well worth a
visit, on a sunny day. I used to
go there on business.
The
point of today’s post goes beyond the fact that Dr Ramaekers and Dr Frye have
demonstrated that a large sub-group of autism benefit from supplementation with
calcium Folinate (Leucovorin).
Ramaekers
is looking at Folate Receptor
Autoimmunity in the parents, to understand why/how the child developed autism
in the first place and then taking the very logical step to prevent future
autism.
My elder son is
very keen that I master the art/science of preventing future autism, so as to
ensure his own children will be neurotypical.
Attempting to prevent future autism will very likely also give some protection against all those "autism-lite conditions", like selective eating, AD(H)D, dyslexia, dyspraxia etc.
At the 2020 Synchrony
autism conference, Dr Ramaekers spoke about how several healthy babies have now
been born to parents treated with Leucovorin for their Folate Receptor
Autoimmunity. I assume the parents
already have at least one child with autism and do not want more. I thought that was a bold move by Dr Ramaekers. Dr
Ramaekers has been publishing research on Folate Receptor Autoimmunity for many years and so
I suppose he has the freedom to do this.
In some countries I think you would not be able to do this, or at least
talk about it. Anyway, “dix points Dr
Ramaekers” (ten out of ten).
As with
the potential use by mothers of the antioxidant NAC during pregnancy, the mode
of action is epigenetic and preventing differentially expressed genes (DEGs),
or just call them miss-expressed genes.
In Dr Ramaeker's case he does have a biomarker to identify parents likely to benefit from his autism prevention strategy. He uses the FRα autoantibody test and so could you.
I have been having an interesting public discussion with Dr Ramaeker's on the online app used for the Synchrony 2020 autism conference. The key point arising is that you can avoid the side effects of using Leucovorin (Calcium Folinate) by slowing increasing the dosage over several weeks. Here is the relevant part:-
You had one naughty remark concerning the Use of folinic acid causing agression. My response is that folinic acid will increase the production of BH4 which will suddenly increase the synaptic levels of dopamine AND serotonin AND cause temporarily overstimulation of downregulated dopamine AND serotonin receptors. After about 6 weeks will settle down as a new equilibrium will be installeer. So I begin with low dosage folinic acid AND slowly increase at interval of 4 weeks.It was a wonderfull overview about your sons history.
For anyone interested to watch my Bumetanide presentation, that Dr Ramaekers, AJ and Lisa seem to have enjoyed, here is a link.
https://drive.google.com/file/d/15s_1x01VR2v-iMNpgbsFtt12Ug4xbGTh/view
The paper by Dr Ramaekers below is open access and many people will find it interesting to read the entire paper. Just skip over any parts that get too complicated.
Background. In contrast to multiple rare monogenetic abnormalities, a common biomarker among children with infantile autism and their parents is the discovery of serum autoantibodies directed to the folate receptor alpha (FRα) localized at blood-brain and placental barriers, impairing physiologic folate transfer to the brain and fetus. Since outcome after behavioral intervention remains poor, a trial was designed to treat folate receptor alpha (FRα) autoimmunity combined with correction of deficient nutrients due to abnormal feeding habits.
Methods. All
participants with nonsyndromic infantile autism underwent a routine protocol
measuring CBC, iron, vitamins, coenzyme Q10, metals, and trace elements. Serum
FRα autoantibodies were assessed in patients, their parents, and
healthy controls. A self-controlled therapeutic trial treated nutritional
derangements with addition of high-dose folinic acid if FRα autoantibodies
tested positive. The Childhood Autism Rating Scale (CARS) monitored at baseline
and following 2 years of treatment was compared to the CARS of untreated
autistic children serving as a reference.
Results. In
this self-controlled trial (82 children; mean age ± SD: 4.4 ± 2.3 years;
male:female ratio: 4.8:1), FRα autoantibodies were found in 75.6 %
of the children, 34.1 % of mothers, and 29.4 % of fathers versus 3.3 % in
healthy controls. Compared to untreated patients with autism (n=84) whose CARS
score remained unchanged, a 2-year treatment decreased the initial CARS score
from severe (mean ± SD: 41.34 ± 6.47) to moderate or mild autism (mean ± SD:
34.35 ± 6.25; paired t-test p<0.0001), achieving complete recovery in 17/82
children (20.7 %). Prognosis became less favorable with the finding of higher
FRα autoantibody titers, positive maternal FRα autoantibodies,
or FRα antibodies in both parents.
Conclusions.
Correction of nutritional deficiencies combined with high-dose folinic acid
improved outcome for autism, although the trend of a poor prognosis due to
maternal FRα antibodies or FRα antibodies in both
parents may warrant folinic acid intervention before conception and during
pregnancy.
The treatment protocol for the self-controlled
treatment trial based upon abnormal biochemical findings and FRα autoantibodies.
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In the study
they used the CARS rating scale to measure the severity of autism.
A score
30 and above 30 means autism. 37 and above
means severe autism.
The
results do look good. This was not a
study with a placebo group for comparison.
Blue is before therapy and orange is after therapy.
The upper
figure (a) shows the plotted CARS with age for 84 untreated patients. The
middle figure (b) shows the effect of treatment among 82 treated patients (blue
bars represent CARS at baseline and orange bars the CARS after two years
treatment). Figure (c) represents the treatment results among different groups
with FR autoantibodies in the child (K), mother (M), or father (P).
Our self-controlled treatment trial showed that the presence
of maternal FRα autoantibodies or FRα antibodies in
both parents tended to be associated with a higher initial baseline CARS score
among affected children with autism. Thus, this may
explain that the final result and change in CARS score following 2-year
treatment was less pronounced as compared to all other groups, although the
small number of patients within each group did not allow a profound statistical
analysis. These issues will be clarified when more patients will be included
into similar treatment trials. Our findings in a minority of 7 out of 68
families (10%) identified no FRα autoantibodies in the children
whereas FRα antibodies could only be detected in the mother (N=5),
father (N=1), or both parents (N=1). Although feeding and nutrient problems for
each child have to be taken into account, this finding suggests that parental FRα antibodies
may impair folate transport into oocytes and spermatozoides and also block
sufficient folate transport across the placental barrier to the embryo and
fetus. Because an adequate folate pool is essential for purine and pyrimidine
synthesis, and for mediating epigenetic mechanisms involving DNA methylation
and histone modification, the initial embryonic development and subsequent
stages of neurodevelopment will rely heavily on availability of adequate
folate. Therefore, the risk of autism with its poor prognosis in the offspring
associated with parental FRα antibodies warrants FRα testing
among future parents followed by folinic acid intervention before conception
and during pregnancy.
The common feeding disturbances associated with autism
may provoke oxidative stress due to altered nutritional states where elevated
metals (copper, manganese) or beta-carotene act as prooxidants through
induction of Fenton chemistry. Nutritional
deficiencies of radical scavenging vitamins (vitamins A, C, E, and
gamma-tocopherol) as well as metals and trace elements (copper, zinc,
manganese, and selenium), being cofactors of antioxidative enzymes, predispose
to failing antioxidant defences. Moderate apolipoprotein B deficiency has been
encountered in a significant number of autistic subjects and leads to deficient
liposoluble vitamins A, D, E, and K. Deficiency of a number of vitamins and
coenzyme Q10 necessary for mitochondrial metabolism, will result in
mitochondrial dysfunction. Thus,
oxidative stress in the brain due to mitochondrial dysfunction, elevated
prooxidants, or deficient antioxidants on the one hand and FRα autoimmunity
on the other hand, represent two independent variables at the basis of autism
where correction of each variable showed a clinical response with a decline in
the CARS score.
Therefore, in addition to treatment for FRα autoimmunity
[9, 10, 29], specific supplements are required to correct nutritional
deficiencies in order to ameliorate intermediary metabolism and to neutralize
abundant reactive oxygen species (ROS) deranging brain metabolism and function.
As stated above, it
appears from our findings in this study that the group of patients, where FRα antibodies
tested negative in the child and its parents, benefitted only through
correction of nutritional derangements as their CARS score dropped
significantly.
In our study we also detected deficiencies of serum and
red blood cell folate in 18.3 % of all patients. In vitro studies have
supported the concept of an existing link between oxidative stress and deranged
folate homeostasis. In a previous study we found that the generation of
superoxide anions in vitro catabolizes 5-methyl-tetrahydrofolate
by 75% within one hour, which can be prevented through preincubation with the
radical scavenger ascorbic acid [26]. This study also found that KB-cells in
culture exposed to superoxide anions and hydrogen peroxide reduces cellular
folate incorporation mediated by FRα or RFC1 transport mechanisms.
Thus transmembrane folate passage mediated by these transporters at the
placenta and choroid plexus is expected to be impaired in the presence of ROS
and predisposes to intrauterine folate deficiency and cerebral folate
deficiency.
The consequences of folate
deficiency affecting brain development may be more prominent in autistic
children from mothers with folate deficiency or the presence of maternal FRα autoantibodies
during pregnancy. Our
finding of a higher initial baseline CARS score and less favorable outcome in
these children confirms this hypothesis. In summary, the treatment response
will be influenced in a negative fashion by the presence of maternal FRα autoantibodies,
by late-onset treatment associated with a higher initial CARS score and in the
event of elevated antibody titers. Paternal FRα antibodies may also influence the outcome and
need to be further investigated, because we only identified one family.
5.
Conclusion
In
the pathogenesis of low-functioning autism, feeding disturbances predisposing
to oxidative stress and acquisition of folate receptor autoantibodies during
the pre- or postnatal period appear to play an important role by affecting
intermediary metabolism and
potentially deranging epigenetic control mechanisms. Early detection and
appropriate therapeutic intervention is postulated to reverse core features and
improve outcome.
Conclusion
Today’s paper showed several interesting things:-
·
Correcting the
effects of very poor diet can have a dramatic benefit on autism, regardless of
folate status.
·
Folate
receptor problems are very common in autism.
FRα autoantibodies were found in three quarters of children
with autism and a third of their mothers and fathers, versus just 3 % in healthy
controls.
· A trial of Calcium Folinate (Leucovorin) for anyone with autism looks like a “no-brainer” but, as Dr Ramaekers cautions, mega dose folate might be unwise in the 25% of autism who do not have FRα autoantibodies.
Note that in the study, prognosis became less favorable with the finding of higher FRα autoantibody levels, maternal FRα autoantibodies, or FRα antibodies in both parents.
·
Couples/parents
who want (more) children, but want to avoid autism, should consider first taking
the FRα autoantibody test
if you get a positive result, you might contact our man in Liège.
· Generic Calcium Folinate (Leucovorin) is cheap in most of the world. As usual, the exception is the United States.
I will have to write a post on prenatal bumetanide to prevent autism. Dr Ben Ari did mention again at the Synchrony event the potential for this therapy. It seems that the oxytocin released by the mother during delivery not only helps to trigger the developmental GABA switch that forces neurons to transition from immature to mature over the first couple of weeks after birth, but it also causes a one time shock reduction in chloride during delivery (this shock may indeeed be the GABA switch trigger). It seems that the fragile brain is given protection during delivery, with GABA switching from the fetal excitatory state to one of extreme inhibition, just for birthing. This protective sudden drop in chloride levels does not occur in autism models and likely not in human autism either. The logic would be to give the mother bumetanide for 2 weeks before her delivery date. This would protect the baby's brain during birth and hopefully help ensure the GABA switch occurs and the child develops normally.
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