Folate Metabolism, the Folate Trap, and finding the right therapy for your specific autism

  

Most of the folate and folic acid we eat must be converted into the active form, known as L-methylfolate or 5-MTHF. However, some dietary folate is already in the active form when we eat it and therefore does not rely on MTHFR.

In treating autism, folate metabolism is a key area of therapeutic focus. While folate supplementation seems simple on the surface, the biology behind it is complex — and, if misunderstood, you may even worsen symptoms.

This post explains how folate metabolism works, what the methyl folate trap is, and how different folate and B12 formulations affect outcomes in children and adults with autism, especially those with MTHFR, MTR, or MTRR mutations.

The Normal Folate Cycle 

Folate, a B-vitamin, plays a central role in:

• DNA synthesis 
• Methylation 
• Neurotransmitter production (via SAMe) 

Here is how it works, if you like details:  

• 5,10-methylene-THF helps make thymidine (for DNA).
• Some of this is converted to 5-MTHF by MTHFR.
• 5-MTHF donates a methyl group to homocysteine, converting it to methionine, in a process catalyzed by methionine synthase, which requires vitamin B12.
• This regenerates THF, which goes back into the cycle.

 

The Methyl Folate Trap

 

If there is a vitamin B12 deficiency, or methionine synthase (MTR) dysfunction, the conversion of 5-MTHF → THF is blocked. This causes:

·         5-MTHF to accumulate (it’s “trapped”)

·         THF and 5,10-methylene-THF to fall

·         DNA synthesis to halt

·         Elevated homocysteine, and low SAMe

The result:

·         Anemia

·         Neurological symptoms

·         Behavioral worsening in autism

This is known as the methyl folate trap — and it explains why giving high-dose folate without enough B12 can backfire.

In summary, the methyl folate trap occurs when B12 deficiency or methionine synthase dysfunction prevents 5-MTHF from recycling to THF, stalling DNA synthesis and methylation, even if folate levels are high.

  

Could the Folate Trap Cause Aggressive or Behavioral Regression?

Yes. In autism, worsening behaviors (irritability, aggression etc) after high-dose folinic acid may reflect a relative B12 deficiency or impaired methionine synthase, leading to:

·    Folate trapping

·   Disrupted neurotransmitter synthesis (especially dopamine/serotonin)

·    Low SAMe

In these cases, adding B12 (methylcobalamin or hydroxycobalamin) often improves tolerance to folate therapy and reduces side effects.

 

Other reasons for a possible negative reaction to calcium folinate

Folate metabolism is tightly connected to glutamate and GABA balance.

High folate dosing in some sensitive individuals may cause excess glutamate activity (excitatory), triggering aggression or anxiety-like behaviors.

Children with fragile neurochemical balance may not tolerate sudden shifts in methylation or neurotransmitter levels. A rapid increase in serotonin, dopamine, or norepinephrine can destabilize mood or cause agitation/aggression. This is why you start low and gradually increase your folate supplement.

In such children 5-MTHF may work better, but you still B12.

Apparently, some doctors prescribe antipsychotics to treat agitation caused by calcium folinate; I am not sure that is a good idea.

 

 Choosing the Right Folate: Folinic Acid vs 5-MTHF

	Calcium Folinate / Leucovorin	5-MTHF
Form	Precursor to 5-MTHF	Final active form
Requires MTHFR?	Yes	No
Can enter CSF?	Indirectly	Directly
Behavioral reactions?	More common in some	Usually better tolerated

For whom is 5-MTHF better?

1.      Those with MTHFR mutations (esp. C677T)

2.      Those who react negatively to folinic acid

3.      Those needing direct CNS access

Folinic acid /Leucovorin is converted to 5-MTHF (active folate) through a series of enzymatic steps. First, it is converted into 5,10-methylenetetrahydrofolate, and then the enzyme MTHFR  converts it to 5-MTHF.

In people with MTHFR mutations, this final step may be slower or impaired, meaning folinic acid may not fully convert to active folate. Direct supplementation with 5-MTHF is often preferred in those with these genetic variants.

 

  

The Problem with Synthetic Folic Acid

 Status of mandatory folic acid fortification in 2019

 

In countries like the US folic acid is added to many foods such as flour, bread, pasta and rice in addition to products like breakfast cereals. This is to reduce the incidence of neural tube defects like spina bifida that occur when a fetus lacks sufficient folate in the first 28 days of life.

In Europe there is much less mandatory supplementation of folic acid due to the negative effects. In older people folic acid supplementation can mask vitamin B12 deficiency. High intake of synthetic folic acid can correct the anemia caused by B12 deficiency without correcting the neurological damage. This can lead to delayed diagnosis of B12 deficiency, increasing the risk of irreversible nerve damage, cognitive decline, and dementia in the elderly.

Folic acid is synthetic and must be converted by DHFR (slow, limited in humans).

It competes with both folinic acid and 5-MTHF for cellular entry.

High levels of unmetabolized folic acid can block folate receptors and worsen autism symptoms in some.

Some people with autism should avoid folic acid supplements and fortified foods.

 

The Dilemma: One Size Does not Fit All

While folic acid fortification benefits the general population, especially women of childbearing age, it may pose risks for other groups:

·    Elderly: Risk of masking B12 deficiency

·    Children with autism or FRAA: Risk of blocked folate receptors and behavioral regression

·    Those with MTHFR variants. They have reduced ability to activate folic acid because their ability to convert folic acid into the active form, 5-MTHF, is reduced. This can lead to unmetabolized folic acid (UMFA) in the blood, which may interfere with normal folate metabolism. It can lead to blocking the transport of natural folates into the brain.

 

Here is a study showing that folic acid impairs the transport of active folate (5-MTHF) across the blood brain barrier.

 

Folic acid inhibits 5-methyltetrahydrofolate transport across the blood–cerebrospinal fluid barrier:Clinical biochemical data from two cases

Results: Both patients had low CSF 5MTHF before treatment and high-dose FA therapy did not normalize CSF 5MTHF. There was a dissociation between serum total folate and 5MTHF concentrations during FA therapy, which was considered to be due to the appearance of unmetabolized FA. The addition of folinic acid did not improve low CSF 5MTHF in the KSS patient and the cessation of FA resulted in the normalization of CSF 5MTHF. In the patient homozygous for MTHFR C677T, minimization of the FA dosage resulted in the normalization of CSF 5MTHF and an increased CSF-to-serum 5MTHF ratio.

Conclusions: Our data suggest that excess supplementation of FA impaired 5MTHF transport across the blood-CSF barrier. In the treatment of CFD, supplementation of folinic acid or 5MTHF (in cases of impaired 5MTHF synthesis) is preferred over the use of FA. The reference values of CSF 5MTHF concentration based on 600 pediatric cases were also provided.

  

B12 - Forms and why it matters

To prevent the folate trap, adequate B12 is critical.

                          

Methylcobalamin        Active, supports methylation directly

Hydroxycobalamin      Longer-lasting, converted to methyl- or adeno-B12

Adenosylcobalamin     Active in mitochondria

Cyanocobalamin         Synthetic, less ideal, may not work in autism

 

Methylcobalamin or hydroxycobalamin are best for autism and CFD.

 

Can it be oral?

Yes, but high doses needed (1–5 mg daily)

Subcutaneous injections may be better absorbed in some

 

What About Betaine / TMG?

Betaine (trimethylglycine) provides methyl groups to convert homocysteine to methionine via the BHMT pathway (mostly in the liver, not brain).

Useful if:

·         Homocysteine is high

·         B12 metabolism is impaired

·         Need extra methylation support

 But, it does not bypass the folate trap in the brain — you still need functional methionine synthase and B12.

 

When Do You Need More SAMe?

SAMe (S-adenosylmethionine) is the body’s master methyl donor, essential for: 

·         Neurotransmitter synthesis

·         Myelination

·         Detox pathways

 

You may need extra SAMe if:

·         You have low methionine/SAMe

·         There is fatigue, depression, or tics

·         Homocysteine is high despite folate + B12

Oral SAMe is poorly absorbed unless enteric-coated.

Do not assume “more folate = better” without addressing B12

 

Conclusion

Whether a person with autism stands to benefit from tuning up their folate metabolism will depend on their unique situation. Many people need no intervention at all.

For others it is highly beneficial to customise an intervention plan. It would include some, or all, of the following. 

·   Reduce expose to synthetic folic acid used to fortify flour, pasta, bread, rice, breakfast cereals etc.

·   Supplement with 5-MTHF or calcium folinate / Leucovorin

·   Supplement vitamin B12, in the form of methylcobalamin or hydroxycobalamin

·    Supplement Betaine/TMG

·    Supplement SAM

     ·  Consider supplementing PQQ if positive for FRAA 

 

The only substance that is prescription-only is calcium folinate / Leucovorin. It looks like 5-MTHF is actually the better choice for most people and it is much more accessible.

We have seen that the potency of generic calcium folinate / Leucovorin is highly variable, possibly due to different excipients that are added. How reliable the OTC 5-MTHF supplements are is an open question.

If you find this subject confusing, use ChatGPT to help you. You can even upload a screenshot of your MTHFR/MTR/MTRR mutations and then get tailored advice. It is free !!  (for now)

 

If you are someone who likes lab tests, the options include: 

• Folate receptor antibodies (FRAA) – to check for blocking autoantibodies www.fratnow.com
• Serum and CSF 5-MTHF – to detect cerebral folate deficiency
• Homocysteine – elevated if methylation is impaired
• MMA (methylmalonic acid) – elevated in B12 deficiency
• Vitamin B12 – ideally with active B12
• Genetic testing – particularly MTHFR, MTR, and MTRR variants to assess methylation capacity

High MMA = likely B12 deficiency, even if serum B12 is "normal".

This is especially important in people with neurological symptoms or MTHFR-related metabolism issues.

 

Measuring serum (blood) 5-MTHF provides insight into how much active folate is circulating in the body. This helps detect:

• Folate trap from B12 deficiency (high folate, low methylation)
• Impaired folate metabolism in MTHFR or MTR/MTRR variants
• Folate absorption or transport problems, especially if CSF 5-MTHF is also tested
  It’s particularly useful when deciding whether folinic acid, 5-MTHF, or B12 supplementation is effective or needed.

CSF 5-MTHF (cerebrospinal fluid via lumbar puncture) gives a direct measure of active folate availability inside the brain. This is important because:

• Some children with autism or FRAA (folate receptor autoantibodies) have low CSF 5-MTHF even with normal blood folate. Some have FRAA and normal CSF 5-MTHF
• High serum folic acid can block transport of 5-MTHF into the brain, lowering CSF levels.
• It can help diagnose Cerebral Folate Deficiency (CFD), especially if symptoms improve with folinic acid.

Low CSF 5-MTHF with normal serum levels suggests a transport problem, not a folate intake issue.

PQQ as a Folate Transport Enhancer

A supplement called Pyrroloquinoline quinone (PQQ) may help bypass folate receptor autoantibody (FRAA) blockage by upregulating alternative folate transporters (RFC and PCFT) in the brain. This could improve delivery of both calcium folinate (leucovorin) and 5-MTHF into the brain when folate receptor alpha (FRα) is blocked.

Human data is lacking; all evidence from animal/cell studies. Some people report adverse effects (e.g. fatigue, overactivation)

For individuals with FRAA, PQQ might enhance the effectiveness of folinic acid or 5-MTHF by improving alternative transport into the brain.

Consequences of folate deficiency – treated by immunomodulators (Infliximab, IVIG, Propes and Inflamafertin) and the relevance of mutations in MTHFR, MTR, and MTRR genes in identifying those at risk. Plus the effect of rTMS and tDCS on milder autism

 

Today’s post returns to folate deficiency, but before that a quick mention of magnetic/electrical brain stimulation therapies for autism without impaired cognition.

I encountered a new term IC-ASD. It stands for intellectually capable autism spectrum disorder. Most people with autism these days seem to have IC-ASD. Some struggle and some do not.

 

The effects of rTMS and tDCS on repetitive/stereotypical behaviors,cognitive/executive functions in intellectually capable children and young adults with autism spectrum disorder: A systematic review and meta-analysis of randomized controlled trials

 

Objective

This study aims to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on repetitive/stereotypical behaviors and cognitive/executive functions in children and young adults with intellectually capable autism spectrum disorder (IC-ASD).

Methods

Literature searches across PubMed, Web of Science, Cochrane Library, Embase, and Scopus were performed to identify randomized controlled trials (RCTs) evaluating the efficacy of rTMS and tDCS in children and young adults with IC-ASD. The search encompassed articles published up to April 25, 2025. The standardized mean difference (SMD) with 95 % confidence intervals (CI) was calculated and pooled. Sensitivity and subgroup analyses were conducted to assess potential sources of heterogeneity and refine the robustness of the findings.

Results

This meta-analysis included 18 RCTs involving 813 participants. Compared with sham interventions, tDCS demonstrated significant improvements in social communication, repetitive and stereotypical behaviors, cognitive and executive functions among individuals with IC-ASD (e.g., Social Responsiveness Scale: SMD = –0.48; 95 % CI: –0.75 to –0.22; p < 0.01). Similarly, rTMS improved social communication, repetitive and abnormal behaviors (Social Responsiveness Scale: SMD = –0.21; 95 % CI: –0.42 to –0.00; p < 0.05; Repetitive Behavior Scale-Revised: SMD = –0.62; 95 % CI: –1.17 to –0.07; p = 0.04; Aberrant Behavior Checklist: SMD = –0.53; 95 % CI: –0.79 to –0.26; p < 0.01). No significant heterogeneity was observed across studies.

Conclusion

tDCS and rTMS may enhance cognitive and executive functions and reduce repetitive behaviors in children and young adults with IC-ASD. However, these findings require careful interpretation due to the limited high-quality studies and variability in treatment protocols. Future research should prioritize the development of standardized protocols to address inconsistencies in stimulation parameters (including frequency, intensity, and duration) and core outcome sets. Additionally, larger-scale, rigorously blinded multi-center RCTs are necessary to accurately evaluate the clinical efficacy and applicability of these neuromodulation techniques in these populations.

 

rTMS and tDCS look like interesting non-pharmaceutical options for those with milder types of autism. How well they work in those with lower cognitive function is not addressed.

 

Back to Folate Deficiency

Stephen recently highlighted a Chinese study that looked at the relevance of mutations in the genes MTHFR, MTR, and MTRR to try and identify those most at risk of folate deficiency.

I also highlight research into treating some of the downstream consequences that occur when folate metabolism is impaired. The lack of folate disrupts the immune system causing anomalies such as low NK cells, low NKT cells, high TNF-alpha.

Immunodeficiency (Low NK and NKT cells): The deficiency in these crucial innate immune cells means the body's ability to fight off infections (particularly opportunistic ones) and perform immune surveillance (e.g., against abnormal cells) is compromised. This immunosuppression is a direct consequence of the impaired cell proliferation due to the folate cycle defect.

Systemic Inflammation (High TNF-alpha): Despite the low numbers of certain immune cells, there can be an overproduction of pro-inflammatory cytokines like TNF-alpha. This leads to chronic systemic inflammation. This phenomenon is often referred to as hypercytokinemia.

Beyond TNF-alpha, you might expect a possible overproduction of:

• Interleukin-1 beta (IL-1β): This is a potent pro-inflammatory cytokine involved in various immune responses and neuroinflammation.
• Interleukin-6 (IL-6): Another major pro-inflammatory cytokine that plays a role in systemic inflammation and can affect brain development and function.
• Interferon-gamma (IFN-γ): This is a key cytokine in Th1 immune responses and is also pro-inflammatory.

 

The recent Chinese study concludes that high-dose folinic acid appears to be a promising intervention for children with autism. Its efficacy is notably associated with specific folate metabolism gene polymorphisms. The researchers suggest that high-dose folinic acid may help to improve neurodevelopmental outcomes by alleviating the folate metabolism abnormalities caused by single or combined mutations in these genes.

This research indicates that providing a metabolically active form of folate (folinic acid, calcium folinate, leucovorin etc) can be a direct approach to address the underlying metabolic challenges in a subset of people with autism who have specific genetic predispositions related to folate metabolism. Children with MTHFR A1298C or MTRR A66G mutations showed greater improvements in various developmental domains compared to those with the standard versions.

The intervention group demonstrated significantly greater improvements in social reciprocity compared to the control group.

No significant adverse effects were observed during the intervention period.

 

How does this fit in with US research into brain folate deficiency in autism

US researchers consider an autoimmune mechanism where the body produces antibodies that specifically target the Folate Receptor Alpha (FRα). FRα is a crucial protein responsible for transporting folate across the blood-brain barrier (and into other cells).

When these antibodies bind to FRα, they block or interfere with the normal transport of folate into the cells, particularly into the brain. This results in Cerebral Folate Deficiency (CFD), where folate levels in the cerebrospinal fluid are low, despite potentially normal folate levels in the blood.

US research indicates that FRAAs are prevalent in a significant percentage of children with ASD (up to 70% in some studies) and are associated with specific physiological and behavioral characteristics.

Treatment with folinic acid/ leucovorin has been shown to be effective in many children with autism who are positive for FRAAs, improving symptoms like communication, irritability, and stereotypical behaviors. It is believed that high doses of folinic acid can overcome the transport blockade caused by the antibodies

The US and Chinese research avenues complement each other by identifying different, but potentially converging, pathways that lead to folate dysfunction in autism, both of which demonstrate the therapeutic potential of folinic acid.

Here is the Chinese paper: 

Safety and Efficacy of High-Dose Folinic Acid in Children with Autism: The Impact of Folate Metabolism Gene Polymorphisms

Background/Objectives: Research on the safety and efficacy of high-dose folinic acid in Chinese children with autism spectrum disorder (ASD) is limited, and the impact of folate metabolism gene polymorphisms on its efficacy remains unclear. This trial aimed to evaluate the safety and efficacy of high-dose folinic acid intervention in Chinese children with ASD and explore the association between folate metabolism gene polymorphisms and efficacy. Methods: A 12-week randomized clinical trial was conducted, including 80 eligible children with ASD, randomly assigned to an intervention group (n = 50) or a control group (n = 30). The intervention group was administered folinic acid (2 mg/kg/day, max 50 mg/day) in two divided doses. Efficacy was measured using the Psycho-Educational Profile, Third Edition (PEP-3) at baseline and 12 weeks by two trained professionals blind to the group assignments. Methylenetetrahydrofolate reductase (MTHFR C677T, MTHFR A1298C), methionine synthase (MTR A2756G), and methionine synthase reductase (MTRR A66G) were genotyped by the gold standard methods in the intervention group. Results: 49 participants in the intervention group and 27 in the control group completed this trial. Both groups showed improvements from baseline to 12 weeks across most outcome measures. The intervention group demonstrated significantly greater improvements in social reciprocity compared to the control group. Children with MTHFR A1298C or MTRR A66G mutations demonstrated greater improvements in various developmental domains than wild type. Folinic acid may be more effective in certain genotype combinations, such as MTHFR C677T and A1298C. No significant adverse effects were observed during the intervention. Conclusions: High-dose folinic acid may be a promising intervention for children with ASD, and its efficacy is associated with folate metabolism gene polymorphisms. High-dose folinic acid intervention may promote better neurodevelopmental outcomes by alleviating folate metabolism abnormalities caused by single or combined mutations in folate metabolism genes.

 

Treating the downstream consequences of low brain folate

Today’s next papers highlight Infliximab, IVIG, Propes, and Inflamafertin as immunomodulatory therapies that target the downstream consequences of folate deficiency; they do not address or improve the underlying lack of folate.

Folate Deficiency in the Brain: This means there is an inherent problem in the body's ability to process or utilize folate, even if dietary intake is sufficient. It is often due to mutations in genes encoding enzymes of the folate cycle (like MTHFR) or transporters. This leads to issues with DNA synthesis, cell proliferation, and methylation, impacting various systems, including the immune system.

 

Infliximab

Infliximab is a TNF-alpha inhibitor. It blocks the activity of TNF-alpha, a key pro-inflammatory cytokine.

It does not put more folate into the system or fix how folate is metabolized. It is like putting out a fire (inflammation) that was started because of a broken electrical wire (folate deficiency's impact on immunity).

 

IVIG (Intravenous Immunoglobulin)

IVIG is a broad-acting immunomodulatory therapy composed of pooled antibodies from thousands of healthy donors. Its mechanisms are complex and include neutralizing autoantibodies, blocking Fc receptors, modulating cytokine production, affecting T and B cell function, and influencing complement activation.

IVIG aims to rebalance a dysregulated immune system, reduce inflammation, and sometimes provide passive immunity. It is like resetting an overactive or misdirected immune alarm system. The effect may not last.

 

Propes

Propes contains alpha- and beta-defensins and has a "pronounced immunoactivating and lymphoproliferative effect." It directly stimulates the growth and activity of immune cells like NK and NKT cells. It directly addresses the numbers and activity of NK and NKT cells that are deficient due to the folate cycle problem. It makes the existing cells (or promotes the creation of new ones) work better, despite the underlying folate issue.

 

Inflamafertin

This drug, containing alarmines and adrenomedulin of placental origin, has "pronounced anti-inflammatory and immunomodulatory effects mediated by the induction of interleukin 10 synthesis." Its role is to temper the immune activation  and ensure a more balanced, anti-inflammatory environment.

 

In summary

These therapies are all symptomatic or compensatory treatments for the consequences of genetic folate deficiency on the immune system and the body. They address the resulting immunodeficiency, inflammation, and associated clinical symptoms (like behavioral issues or opportunistic infections).

 

They do not:

• Add more folate to the body (like folic acid or L-methylfolate supplementation would).
• Correct the genetic defect that causes the folate cycle deficiency.
• Improve the body's intrinsic ability to metabolize folate.

Genetic deficiency in the folate cycle disrupts fundamental cellular processes required for the normal development, proliferation, and function of NK and NKT cells, leading to their deficiency in affected children. This deficiency, in turn, contributes to the complex immune dysregulation often seen in autism.

 

Key Findings on NK Cells:

• Initial Deficiency: A significant number of children in the study group (53 patients) had an initial deficiency of NK cells.
• Response to Immunotherapy:
• During the 3-month course of Propes and Inflamafertin, the average number of NK cells in the blood almost doubled.
• NK cell counts reached the lower limit of normal in 74% (39 out of 53) of the patients with a deficiency.
• There was a strong statistical link between the immunotherapy and NK cell normalization.
• Sustainability: A notable finding was that the NK cell numbers returned to almost their initial level within 2 months after the immunotherapy was stopped. This suggests that the effect on NK cells might be temporary and dependent on continuous treatment.

 

Key Findings on NKT Cells:

• Initial Deficiency: A larger proportion of children in the study group (87 patients) had an initial deficiency of NKT cells.
• Response to Immunotherapy:
• The average number of NKT cells in the blood increased by half during the 3-month immunotherapy course.
• NKT cell counts were normalized in 89% (78 out of 87) of the patients with a deficiency.
• There was an even stronger statistical link between the immunotherapy and NKT cell normalization compared to NK cells.
• Sustainability: Importantly, the NKT cell numbers continued to grow for an additional 2 months after the discontinuation of the immunotropic drugs. This suggests a more sustained and potentially longer-lasting effect on NKT cells.

Overall Conclusions from the Study:

• Combination immunotherapy with Propes and Inflamafertin is presented as an effective treatment strategy for the immunodeficiency (specifically NK and NKT cell deficiency) found in children with ASD linked to genetic folate deficiency.
• Both biological drugs were able to normalize the reduced numbers of NK and NKT cells during the 3-month treatment period.
• The study highlights that the effect on NKT cells was more frequent, stronger, and more lasting compared to the effect on NK lymphocytes.

 

The research papers:

EFFICACY OF INFLIXIMAB IN AUTISM SPECTRUM DISORDERS IN CHILDREN ASSOCIATED WITH GENETIC DEFICIENCY OF THE FOLATE CYCLE

 The notion of systemic inflammation in autism spectrum disorders in children has been established. A recent meta-analysis of randomized controlled trials published in 2019, which included a systematic review of 25 case-control studies, suggests an association between genetic deficiency of the folate cycle and autism spectrum disorders in children [18]. This evidence is consistent with an earlier meta-analysis of randomized controlled trials from 2013, which included data from 8 studies [17]. The encephalopathy that develops in children with genetic deficiency of the folate cycle and manifests as autism spectrum disorders is associated with oxidative stress. The reason for the latter can be seen in the suppression of the immune system with the development of a special form of immunodeficiency, which is based on the deficiency of natural killers, natural killer T lymphocytes and CD8 +  cytotoxic T cells [11]. Immunodeficiency mediates all three known mechanisms of brain damage in children with genetic deficiency of the folate cycle, namely the development of opportunistic infections [2, 15], autoimmune reactions against neuronal antigens [3, 6] and manifestations of systemic inflammation, which is based on the phenomenon of hypercytokinemia [13, 20]. Children with autism spectrum disorders have been shown to have overproduction of several proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta, and interleukin-6

In SG, there was a pronounced positive dynamics in the direction of hyperactivity, hyperexcitability and stereotyped behavior, but no significant effect was noted on the stability of eye contact and the development of expressive-receptive language, while in CG some positive changes were achieved specifically in terms of expressive language and the level of eye contact, which indicates different points of action of infliximab and specialized educational programs (Table 11.1). The psychotropic effect obtained with infliximab differs from that of intravenous immunoglobulin, which has also demonstrated clinical efficacy in ASD associated with GDFC [10, 12]. The changes induced by infliximab are more pronounced and develop in a shorter time frame, but they are significantly narrower in terms of the spectrum of positive psychotropic effects compared to high-dose immunoglobulin therapy, which has a total modifying effect on the psyche of such children.

Materials and methods. This prospective controlled single-center non-randomized clinical study included 225 children diagnosed with autism spectrum disorders associated with genetic deficiency of the folate cycle. The diagnosis of autism spectrum disorders was made by psychiatrists from regional hospitals or specialized departments according to DSM–IV–TR (Diagnostic and Statistical Manual of mental disorders) and ICD–10 criteria. Children were recruited into the study group (SG) in 2019–2020. These were patients from different regions of Ukraine aged 2 to 9 years, in whom elevated serum TNF-alpha concentrations were observed. As is known, the phenotype of genetic deficiency of the folate cycle includes 5 main syndromes: autism spectrum disorders, intestinal syndrome (persistent enteritis/colitis) [7], PANDAS [4, 9], epileptic syndrome [5] and signs of pyramidal tract damage.

 

Conclusions. Infliximab leads to significant improvements in hyperactivity and hyperexcitability, as well as stereotypic behavior in children with autism spectrum disorders associated with genetic deficiency of the folate cycle. Responders to immunotherapy are 76 % of patients with this pathology, which is twice as high as with standard therapy. However, there is no effect of infliximab on such manifestations of autism as the level of eye contact and language development. Psychotropic effects of infliximab immunotherapy are closely related to the normalization of previously elevated serum TNF-alpha concentrations and are probably due to the elimination of the pathological activating effect of this pro-inflammatory cytokine on CNS neurons. In parallel, there is an improvement in other clinical syndromes of genetic deficiency of the folate cycle in children with autism spectrum disorders – intestinal pathology, epileptic syndrome, and PANDAS, in the pathogenesis of which, as is known, TNF-alpha and the systemic and intracerebral inflammation induced by this cytokine are involved. However, under the influence of immunotherapy, there is no change in the dynamics of motor deficit in children with symptoms of pyramidal tract damage. Further clinical studies in this direction with a larger number of participants and randomization are necessary to obtain more convincing data.

Efficacy of combined immunotherapy with Propes and Inflamafertin in selective deficiency of NK and NKT cells in children with autism spectrum disorders associated with genetic deficiency of the folate cycle

 Objectives. The results of previous small clinical trials indicate the potential benefit of combination immunotherapy with Propes and Inflamafertin to compensate for NK and NKT cell deficiency due to genetic deficiency of the folate cycle in children with autism spectrum disorders. The purpose of the research was to study the effectiveness of combined immunotherapy with Propes and Inflamafertin in NK and NKT cell deficiency in children with autism spectrum disorders associated with genetic deficiency of the folate cycle. Material and methods. This single-center, prospective, controlled, nonrandomized clinical trial included 96 children aged 2 to 10 years with autism spectrum disorders associated with a genetic folate deficiency (study group, SG). Children of SG received Propes at a dose of 2 ml IM every other day for 3 consecutive months (45 injections), and Inflamafertin at a dose of 2 ml IM every other day for 3 months in a row, alternating with Propes (45 injections). The control group (CG) consisted of 32 children of similar age and gender distribution who suffered from autism spectrum disorders associated with genetic deficiency of the folate cycle, but who did not receive immunotherapy. Outcomes. The number of NK cells reached the lower limit of normal in 39 out of 53 patients (74% of cases), with the resulting deficiency of these lymphocytes, and the average number of NK cells in the blood in SG almost doubling during the 3-month course of immunotherapy (р ˂ 0.05; Z ˂ Z0.05). However, it returned to almost initial level in the 2 months following the discontinuation of immunotherapeutic agents (р˃0.05; Z˃Z0.05). The number of NKT cells was normalized in 78 out of 87 patients (89% of cases) with an initial deficiency of these cells, and the average number of NKT cells in the blood in the DG increased during the course of immunotherapy by half (р ˂ 0.05; Z ˂ Z0.05) and continued to grow for the next 2 months after the discontinuation of immunotropic drugs (р ˂ 0.05; Z ˂ Z0.05). There was a link between immunotherapy and normalization of NK - (χ2 = 18.016; OR = 13.929; 95%CI = 3.498-55.468) and NKT-cells (χ2 = 60.65; OR = 46.800; 95%CI = 14.415-151.937) in the blood with a strong association between these processes (criterion φ = 0.504 and 0.715 respectively; С = 0.450 and 0.581 respectively). Conclusions. Combination immunotherapy with Propes and Inflamafertin is an effective strategy for the treatment of immunodeficiency caused by genetic deficiency of the folate cycle in children with autism spectrum disorders.

 

The results obtained in this controlled non-randomized clinical trial indicate that combination immunotherapy with Propes and Inflamafertin is an effective treatment strategy for immunodeficiency caused by genetic folate deficiency in children with autism spectrum disorders. These biological immunotropic drugs are able to normalize the previously reduced number of NK and NKT cells in the blood in this category of patients during a 3-month course of immunotherapy, with a more frequent, stronger and more lasting effect on NKT cells compared to NK lymphocytes.

  

Conclusion

Folinic acid supplementation is an effective therapy for many people with autism. There are many anomalies that appear, for example those people who test positive for the folate transporter antibodies but a lumbar punction then finds normal levels of folate in the brain.  Many people report agitation or aggression when children take calcium folinate at high doses, but this does not seem to get noted in clinical trials. Nonetheless it looks like everyone with autism should at least make a trial.

Note that you should always add a vitamin B12 supplement when giving high dose calcium folinate. This is because more B12 will be required by the biological processes ongoing in the brain and deficiency will cause side effects.

Many people who respond well to calcium folinate end up needing some kind of immunotherapy on top. IVIG is extremely expensive and quite a bother if you need to take it forever. Some of the therapies from the two papers today also involve a very large number of injections, so are not really practical.  The less intrusive immunotherapies look more practical but are not cheap.

I think that rTMS and tDCS will be attractive to those seeking non-pharmaceutical options that have a scientific basis. The same applies to low level laser therapy, also known as photobiomodulation therapy.