Calcium Folinate (Leucovorin) to Prevent as well as Treat Autism?

 

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.

 

Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial

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.

Abnormal biomarker Daily oral supplement dosage Zinc deficiency 0.15-0.25 mg/kg zinc-sulfate Selenium deficiency 3-5 µg/kg sodium-selenite Manganese deficiency 5-10 mg/kg Vitamin C, 20 IU/kg Vitamine E, with 1 coffespoon Soya oil at night. Manganese excess idem Heavy metal excess (Cu, Al, Hg, Pb) idem Raised copper/zinc ratio idem Bèta-carotene excess idem; limit foods rich in bèta-carotene Vitamin A deficiency 600-1500 µg Vitamin D (25-hydroxy-D) 10 µg or 400 IU Vitamin C deficiency 5-10 mg/kg Vitamine C (maximal 500mg) Ubiquinon-10 deficiency 2 mg/kg co-enzyme Q10 Vitamin E deficiency 20 IU/kg Gamma-Tocopherole deficiency 1 coffeespoon soya, corn or sesame oil Bèta-carotene deficiency Consume tomato or carot juices Serum folate deficiency 0.5 mg/kg folinic acid RBC folate deficiency 0.5 mg/kg folinic acid Apolipoproteine B deficiency Supplement vitamins A D E, and vitamine K in case of secondary coagulation disorder FR-alpha antibodies Start with 0.5-1 mg/kg folinic acid daily;   Increase to 2 mg/kg daily without a clinical response after six months. Maximum daily dose 50 mg.

 

 

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

http://iliadneuro.com/

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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