Cerebral Folate Deficiency: Everything you need to know

From an early age, our parents never fail to remind us to eat our vegetables. They recognize the importance of a healthy, vitamin-rich diet. What if simply consuming vitamins cannot protect from disease? Cerebral folate deficiency is a rare neurological disorder impairing the body’s use of folate—an essential nutrient. The unique mechanism of cerebral folate deficiency is associated with developmental delays, autism, epilepsy, and more.

Cerebral Folate Deficiency
Cerebral Folate Deficiency In Infancy

Types of Folate

Folate is an essential water-soluble B vitamin (B9). The human body utilizes folate to produce red and white blood cells in the bone marrow, for DNA and RNA synthesis, and preserve brain function and hearing. Since folate is an umbrella term, it includes two common types.

Methyltetrafolate (5-MTHF)

Dietary folate naturally occurring in fruits and vegetables is converted to the most active form of folate known as methyltetrafolate (5-MTHF). Once converted in the digestive tract, 5-MTHF enters the bloodstream.

Folic Acid

Folic acid is the synthetic form of folate often found in fortified foods and dietary supplements. The majority of folic acid is not converted to the body’s active form. Instead, folic acid enters the bloodstream not fully metabolized. It is not as efficient.

Regardless of how folate enters the bloodstream, the vitamin is designed to pass the blood-brain barrier to carry out its functions.

What is Cerebral Folate Deficiency?

Cerebral folate deficiency is a neurological disorder characterized by reduced levels of folate (5-MTHF) in the cerebral spinal fluid. The condition vastly differs from nutritional folate deficiency. Unlike a typical deficiency of folate, folate concentrations remain normal in blood plasma in cerebral folate deficiency.

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A lack of folate prevents adequate manufacturing of neurotransmitters and myelin—the protein sheath protecting the nerve cells in the brain. Cerebral folate deficiency disrupts the chemical messages transmitted throughout the nervous system.

Causes of Cerebral Folate Deficiency

According to the Genetics Home Reference, “the prevalence of cerebral folate deficiency is unknown” (2014). Multiple causes lead to the condition.
For classic cerebral folate deficiency related to genetic mutations, there are currently less than 20 documented cases. Cerebral folate deficiency can occur at any age, but it is commonly found in infants and young children.

FOLR 1 Mutation

Due to its location in the brain, folate receptor alpha is a protein thought to be responsible for transporting folate from the bloodstream and into the brain. The protein receives its instructions from the FOLR1. Mutations in the FOLR1 gene prevent folate transport because they lead to either a lack of folate receptor alpha or dysfunction of protein receptor alpha.

Gene mutations that cause cerebral folate deficiency are present from birth. However, symptoms do not begin until two years of age.

Cerebral Folate Deficiency with Autoantibodies

In many cases of infantile cerebral folate deficiency, as well as adult onset, antibodies bind to folate transport receptors in choroid plexus. Binding of the antibodies blocks the folate receptor transport into the cerebral spinal fluid. Reasons for developing autoantibodies are speculated.

One theory is an adverse immune response from dairy proteins. Antibody production is also increased in a number of autoimmune conditions—specifically rheumatoid arthritis. The variety of antibodies produced by autoimmune patients has prompted experts to believe there is an occasional autoimmune component to cerebral folate deficiency.

Metabolic Disorders

Cerebral folate deficiency is frequently noted in metabolic disorders.
Kearns-Sayre syndrome and mitochondrial diseases can alter the way the body transports folate. The underlying conditions result in a cellular energy crisis from faulty mitochondria facilitating the entire folate process.

Symptoms of Cerebral Folate Deficiency

  • Agitation: The first symptom to manifest is usually agitation and marked irritability. Infants cry excessively.  
  • Sleep problems: Insomnia and poor sleep quality contribute to the agitation.
  • Microcephaly: The brain does not develop properly with head deceleration.
  • Developmental delays: Development is normal until 4-6 months. Delays include decelerated psychomotor retardation, learning disabilities, speech problems, and autistic features.
  • Seizures: Myoclonic epilepsy improved with folinic acid rather than anticonvulsants.
  • Ataxia: Muscle involvement—tremors, difficulty coordinating movements
  • Spasticity: Muscles become rigid and contracted.  
  • Dyskensia: Arms, legs, head can develop involuntary movements (i.e. jerking, swaying, bobbing).
  • Hypotonia: Low muscle tone
  • Visual Disturbances: Hallucinations, seeing objects that are not there, develop later in childhood.
  • White Matter Disease: Structures of the brain atrophy prematurely.
  • Hearing Loss: Normal folate levels prevent age-related hearing loss. Patients with cerebral folate deficiency are prone to hearing loss at an early age.

Autism and Cerebral Folate Deficiency

The correlation was determined when those with low-functioning autism had lower measured amounts of folate in their cerebral spinal fluid than control groups. Studies found that 60% of children with autism spectrum disorder (ASD) were positive for blocking folate receptor antibodies (Frye, 2013). Deficits from folate induce symptoms of ASD by generating oxidative stress in the brain.

Much research has been conducted focused on the reduction of symptoms in autism spectrum disorders through treating cerebral folate deficiency. Those with ASD treated for cerebral folate deficiency sooner (before 2 years) had noticeable benefits in autistic behaviors.

How To Diagnose Cerebral Folate Deficiency

Testing for cerebral folate deficiency is generally ordered by a neurologist—a medical doctor specialized in conditions of the nervous system. A lumbar puncture, also called a spinal tap, is the only accurate means for diagnosis of cerebral folate deficiency. During a lumbar puncture, a doctor inserts a hollow needle into the spine to retrieve a sample of cerebral spinal fluid. The spinal fluid obtained is then measured for methyltetrafolate (5-MTHF). Levels below average range are indicative of cerebral folate deficiency.

Reduced neurotransmitter levels in cerebral spinal fluid add support to the diagnosis of cerebral folate deficiency. Folate is required for the nervous system to manufacture neurotransmitters like dopamine and serotonin. So, low levels, in combination with low 5-MTHF, give evidence of an issue with folate transport.

The next step is to test plasma-blood levels for folate and neurotransmitters. Normal levels alongside a positive spinal tap confirms the diagnosis. Titers check for receptor antibodies.

Treatment for Cerebral Folate Deficiency: Folinic Acid Supplementation 

Treatment for cerebral folate deficiency is mainly focused on increasing cerebral spinal fluid levels of 5-MTHF. Symptoms continue to progress without restoring folate levels. Aside from supplementation with folinic acid, there are few helpful therapies.

Folinic acid is used as a replacement of folic acid. It consists of the metabolically active, non-methylated form of folate that the body does not have to convert. Dosing is dependent on the patient’s weight. Supplementation takes at least a year to restore 5-MTHFR levels.

Two medications are prescribed for cerebral folate deficiency:  

  • Leucovorin Calcium
  • Deplin

Side effects for Leucovorin and Deplin are benign. Hives, trouble breathing, dizziness, and rash can occur indicate a serious allergy.

Treatment for Cerebral Folate Deficiency: Cobalamin (B12)

Cobalamin (B12) is another essential B vitamin that works with folate (B9). Together they fuel the folate cycle. B12 remethylates homocysteine to methionine, which is needed for the body to use folate. Because those with cerebral folate deficiency struggle with folate metabolism, it consequently impedes B12 metabolism. This is thought to be “methyl trapping” (Gutstein). When the body cannot make use of the folate available, it masks a potential B12 deficiency. Supplementing with methylcobalamin, a non-synthetic form of B12 that the body can easily process, decreases the chance of irreversible neurological damage.

Treatment for Cerebral Folate Deficiency: Avoiding Synthetic Folic Acid

Exposure to folate in the incorrect form, like folic acid, provokes adverse effects in patients with cerebral folate deficiency. Synthetic folic acid is hidden in refined, processed foods. Over the counter vitamins encouraged by many pediatricians is contain folic acid too. The consumption of folic acid increases symptoms of epileptic seizures, ataxia, and agitation. A crucial factor in cerebral folate deficiency is avoiding fortified foods and vitamins.

Cerebral Folate Deficiency: Everything you need to know
Folate VS. Folic Acid

Treatment for Cerebral Folate Deficiency: No Dairy

There is substantial evidence that cow/bovine milk has a negative effect on the immune system. A considerable amount of infants developed cerebral folate deficiency after switching from their mother’s milk to bovine milk. Experts suspect that human folate receptors are incompatible and soluble folate receptors in the bovine milk elicit an immune response (Ramaekers, 2009). The immune response involves the production of folate receptor antibodies. Patients positive for folate receptor antibodies benefit from a dairy free diet accompanying 5-MTHF supplementation. Studies of children with cerebral folate deficiency reflect that going dairy free decreased the number of antibodies and severity of symptoms, but the antibodies returned with worsened symptoms once dairy was incorporated back into the diet.

Early detection and treatment implementation is crucial to the outcome. Although relatively new, cerebral folate deficiency is a neurological condition on the forefront of groundbreaking research.


Frye, R. E., Sequeira, J. M., Quadros, E. V., James, S. J., & Rossignol, D. A. (2012). Cerebral folate receptor autoantibodies in autism spectrum disorder. Molecular psychiatry18(3), 369-81.

Gordon, N. (2009). Cerebral Folate Deficiency. Developmental Medicine & Child Neurology. https://doi.org/10.1111/j.1469-8749.2008.03185.x

Gutstein S, et al. Failure of response to N5-methyltetrahydrofolate in combined folate and B12 deficiency. Am J Dig Dis 1973;18:142–146.

Ramaekers, V. T., Sequeira, J. M., Blau, N., & Quadros, E. V. (2008). A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Developmental medicine and child neurology, 50(5), 346-52.

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