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Is a Folate Deficiency Worsening Your Child’s Autism?

Autism is a complex medical diagnosis with only two FDA-approved medications. The approved medications do not treat the core symptoms of autism but rather disruptive behavior. In fact, there is no approved medication to address the root causes of autism. However, a recent meta-analysis showed that many patients with ASD have cerebral folate deficiency. This finding could have significant implications on the future of autism treatment

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 In rare cases, scientists link autism to folate deficiency

“I suspect that children with the folate problem is a special subgroup of children with autism, but we donʼt know how big this subgroup is in the whole population,” says Ramaekers, head of the Center for Autism at the University of Liege in Belgium. Experts say children with autism should routinely be screened for folate deficiency. “Most doctors, especially if theyʼre psychiatry people, donʼt think about spinal taps in these cases,” says Chez. “But in a young child with severe motor delay, itʼs imperative to check that.” Though children with CFD have low levels of folate in their spinal fluid, folate levels in their blood are normal. “So the major hypothesis is that there has to be an abnormality in the transport of folate from the blood to the central nervous system,” Moretti explains. “The question for us is, what is the nature of that insult?”

 What is leucovorin, the drug the Trump administration says can treat autism?

So can giving children folate, in the form of leucovorin, help them to function better with autism? The evidence says maybe yes, and here’s what we know so far. A review of the evidence in 2021 analysed the results of 21 studies that used leucovorin for autism or cerebral folate deficiency. Children who took the drug generally had improved autism symptoms. But the authors also said more studies were needed to confirm the findings.

 What to Know About Leucovorin, an Old Drug Rebranded as an Autism Treatment

The drug is only approved to treat the effects of chemotherapy. But with the FDA’s latest action, doctors can prescribe it for CFD. “Autism may also be due to an autoimmune reaction to a folate receptor on the brain not allowing that important vitamin to get into the brain cells,” Makary said during the press conference. “We have a duty to let doctors and the public know we are going to change the label to make it available. Hundreds of thousands of kids, in my opinion, will benefit.” The branded version of the drug, made by GSK, was originally released in the early 1980s, but the company stopped marketing it in 1999, and the FDA withdrew approval. Generic versions have since emerged, and some doctors began prescribing it off label for autism patients. The FDA is now working with GSK to re-introduce the drug with its new indication for CFD.

Articles of Interest

Leucovorin (folinic acid) may help with improving verbal communication in certain individuals who have a cerebral vitamin deficiency

Research shows that some individuals who experience speech challenges have a folate (folic acid, a form of vitamin B9) deficiency in the brain. This vitamin deficiency is caused by an autoimmune response where antibodies block folate from entering the brain through the Folate Receptor Alpha (FR⍺). These antibodies can be detected through a blood test that can be ordered by a physician. Of note, studies indicate that individuals with speech delays and autism spectrum disorder (ASD) can have an increased likelihood of having these antibodies present; more research is needed to determine the proportion of individuals with these antibodies.

When Folate Can’t Get In: The Hidden Block That’s Sabotaging Your Child’s Brain

If you’ve been told your child might have low folate in the brain, you may have come across terms like folinic acid, leucovorin, MTHFR, or folate receptor antibodies. For many families, the next step seems obvious: add folate. But in practice, the story is far more complex.

A Closer Look at the Drug Trump Is Touting for Autism

Some doctors say leucovorin holds promise as a potential therapy, but others caution that more, bigger studies are needed.

Efficacy of oral folinic acid supplementation in children with autism spectrum disorder...

Folate receptor autoantibodies are more prevalent in children with autism spectrum disorder (ASD) compared to typically developing children. • Folate receptor autoantibodies play a significant role in the neuropathogenesis of autism spectrum disorder.

FDA Recognizes Leucovorin As A Treatment For Some Autistic Children

“I have seen it be helpful for expressive language,” says Donna Kirchoff MD, an integrative developmental and behavioral pediatrician in Portland Oregon. As a doctor, she loves that leucovorin is safe for use in her patients, and that she can use a lab test for folate receptor autoantibodies to determine which kids are more likely to benefit from trying it.

FDA, in unusual step, aims to repurpose old GSK drug as autism treatment

After reviewing existing published literature, the agency initiated the approval of Wellcovorin — which GSK stopped selling more than two decades ago — for a condition associated with autism.

Folinic acid improves verbal communication in children with autism and language impairment...

This study found an improvement in an important core ASD symptom, verbal communication, in non-syndromic ASD children receiving high-dose folinic acid vs placebo, particularly in those participants who were positive for FRAAs. Improvement in a number of secondary outcomes was observed as well, with no significant adverse events. The effect of folinic acid is consistent with the therapeutic effect of early behavioral interventions.

Leucovorin and Autism Spectrum Disorder

Despite the challenges for treating ASD, emerging data suggests that folate pathway abnormalities may play a role in the pathogenesis of ASD. Specifically, abnormalities in methylation, including methylation metabolites such as methionine, S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH) are present in this population. Deficits in these metabolites, especially SAM are potentially important for DNA and histone methylation in the brain. Folate transport to the brain in patients with ASD may be compromised resulting in subsequent deficiencies in these important metabolites.

Leucovorin and Autism – a repurposed drug with a lot of promise

In this interview, Dr. Richard Frye discusses his research on leucovorin and its potential benefits for individuals with autism. His findings suggest that this repurposed drug can help improve language, cognition, and other symptoms in certain individuals.

Leucovorin for Autism

What does this have to do with MTHFR? Not much. There is no direct link between CFD in autism and MTHFR. MTHFR is a single nucleotide polymorphism (SNP) that is found in 40-60% of the population. It can make it harder for the body to use folate. However, the treatment for MTHFR is typically a low dose of 5MTHF (methylfolate), methyl B12, and B6. (These are typically the first things prescribed by a functional medicine doctor for autism.) By contrast, Cerebral Folate Deficiency (CFD) can result in a severe folate deficiency in the brain, and it is caused by autoimmunity, mitochondrial dysfunction, or specific genetic abnormalities. It requires a much higher dose of folinic acid to flood the brain with folate.

Q&A: What is leucovorin, now being hailed as an autism treatment?

It was discovered that about half of children with autism have more folate receptor auto antibodies than you see in children not on the autism spectrum, and we don’t yet know why. As a result, scientists thought to try leucovorin, because that drug gets folinic acid and folate into the cells of the brain because it bypasses those antibodies.

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

In conclusion, high-dose folinic acid can improve social reciprocity in 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.

The Soluble Folate Receptor in Autism Spectrum Disorder: Relation to Autism Severity and Leucovorin Treatment

Abnormalities in folate and folate related metabolism have been consistently related to ASD in multiple studies. For example, variation in several folate genes have been linked to increased risk of ASD.

Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder

Given the promising and compelling data, we believe that d,l-leucovorin and/or l-leucovorin have tremendous promise in improving the health, cognition and development of children with ASD.

Trump’s autism initiative embraces little-tested vitamin as a treatment

Leucovorin is commonly given to cancer patients to help counteract side effects of certain chemotherapies that interfere with folate metabolism. It has also been tested in a rare genetic condition called cerebral folate deficiency (CFD), estimated to occur in one in 1 million children. CFD occurs when the brain does not get enough folate even though overall levels in the blood are adequate. Children with the condition initially develop normally, but starting between 5 months and 2 years they begin to regress and develop symptoms that can resemble autism, including language delays and lack of motor control.

What Is Leucovorin, the Medicine Being Approved for Autism Treatment?

In studies, some children with autism who received folinic acid have seen big improvements in their receptive language, said Dr. Richard E. Frye, who researches autism. He has found that switch in the ability to understand spoken or written words, as well as in their expressive language, and the ability to communicate thoughts and feelings, particularly among the children who had antibodies that block folate transport to the brain.

What the evidence tells us about Tylenol, leucovorin, and autism

Could Tylenol, one of the most ubiquitous medicines in the U.S., be linked to some cases of autism spectrum disorder when taken during pregnancy? And could leucovorin, a form of folic acid, improve the verbal ability of some people with autism spectrum disorder?

Resources

Autism Science Foundation

Leucovorin is also known as folinic acid. Unlike regular folic acid, folinic acid can cross into the brain even when folate transport is impaired. Some studies suggest that folate transport is blocked in some children with autism, resulting in low brain levels of folate, but these findings have been inconsistent. Data suggesting that leucovorin may ameliorate some symptoms of autism come from four small randomized controlled trials indicating varying levels of effectiveness, all using different doses, different outcomes and different ways of measuring those outcomes. In one case, efficacy was reliant on a specific genetic variant. This science is still in very early stages, and more studies are necessary before a definitive conclusion can be reached. While this drug poses no apparent health risks, there is not sufficient data to show that it improves autism symptoms.