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Cerebral Folate Deficiency in Autism

Folate (Vitamin B9) is very important for brain development. Current research reveals that many kids with autism have low folate in their brains. Positive news is that this condition, called Cerebral Folate Deficiency (CFD), is treatable.

Why is Folate Important?

Folate supports the metabolism of purines and pyrimidines, which are the building blocks of RNA and DNA, and they are a requisite for proper energy generation.

What is Cerebral Folate Deficiency?

CFD is a disorder, which has been fairly new. In the condition, there is low 5-MTHF (5-methyltetrahydrofolate) in the cerebrospinal fluid (CSF) but normal (or even elevated) 5-MTHF in the blood.

What Are The Symptoms of CFD?

  • Irritability and anxiety  
  • Poor sleep
  • Gross motor problems or problems with co-ordination
  • Tics
  • Seizures (including absence seizures)    
  • If the child has untreated CFD, seizures may start at puberty  
  • Problems with vision    
  • Developmental delay and/or slowing of typical development    
  • Smaller head circumference (but certainly not always)    
  • Rett Syndrome may be an indicator of CFD    
  • Depression    

What Causes CFD?

Folate Receptor Antibodies (FRAs)

Autoimmune problems can cause the body to produce folate receptor antibodies (FRAs). These FRAs block the transport of folate into the cerebral spinal fluid.

FRAs are found at an alarming rate in children with autism. A study from 2013 by Dr. Frye and Dr. Rossignol has revealed that lower cerebrospinal fluid 5-MTHF concentrations are associated with higher blocking FRA titers. This was a small study of only 93 ASD children, but out of these children, 75% of the ASD kids had FRAs. However, to arrive at further conclusions, larger and more comprehensive studies are needed.  

A blood test can determine if your child has FRAs. It is important to note that this test cannot tell you whether or not your child has CFD. Only a lumbar puncture can do that. However, testing for FRAs in the blood can give you an idea if this autoimmune problem is an issue for your child. If it is, there could be a functional folate deficiency.    
Your child can have a negative FRA test, and still have CFD, because there are other possible causes of CFD.

Mitochondrial Dysfunction or Disease

The body needs energy to push folate into the cells. If the mitochondria are not working at optimum levels, many functions of the body are impacted. Research shows that mitochondrial dysfunction is very common in autism.


Varying gene mutations and polymorphisms can impact folate transport into the cells and the brain.

How is CFD Diagnosed?

By definition, CFD is a lack of folate in the cerebral spinal fluid, so the only definitive way to diagnose it is with a lumbar puncture (spinal tap). Since many parents are hesitant to order a lumbar puncture (LP) because it is so invasive, many functional medicine doctors are starting treatment without a LP to see if kids improve.

My Child’s Blood Level of Folate is Normal or High. Does This Rule Out CFD?

No.  Folate levels in the blood do not reflect blood levels in the brain. In fact, high levels in the blood may reflect that the folate is not being properly utilized by the body.

What Kind of Doctor Do I Need to See to Discuss CFD?

  • A pediatric neurologist that understands the connection between CFD and ASD and how to treat it. Please bring studies when you see a neurologist
  • A functional medicine doctor    

What is The Treatment For CFD?

In addition to dietary changes, treatment options for CFD include prescription medication, supplementation with high-dose methyfolate, or sometimes a combination of both.

Prescription Medications and Supplementation  

Currently, the treatment for CFD is Leucovorin (prescription high dose calcium folinic acid). Per studies, the recommended dose is anywhere from 0.5mg/kg to 2.0mg/kg.

Some doctors choose to use Deplin, which is prescription strength L-methylfolate, which is dosed differently. Some doctors prescribe a combination of Leucovorin and Deplin to treat CFD.

The idea is to get the level of 5MTHF in the CSF up to mid-range (78-82). Normal range is shown as anywhere from 40-120, but some kids will have symptoms and seizures when their levels are below mid-range.

Functional medicine doctors want to see the level between 78-82 for optimal function. Increasing levels of 5MTHF in the cerebral spinal fluid can take months if not years, so improvement is usually very slow and steady once you start treatment.

Should I Supplement Folic Acid?

No. Using folic acid is not advised. Folic acid is the oxidized form of folate. It can block folate receptors in some kids, making the problem worse.

Will Smaller Amounts of Folinic Acid or L-5MTHF Help, if My Child Has CFD?

Small amounts of folinic acid or L-5MTHF are used to support methylation, but are not necessarily enough to boost levels of folate in the cerebral spinal fluid. If your child has CFD, your doctor can help find the correct dose of leucovorin for your child.

Do Dolate Levels Change as The Child’s Age Increases?

Yes. A recent study suggests that as a child with autism gets older, their level of folate decreases. This study released in June of 2016, shows levels of 5MTHF decreasing in ASD kids as they age.

Dietary Changes

A dairy free diet is also part of the treatment for CFD because mammal’s milk blocks folate receptors.


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