Cerebral Folate Deficiency banner

Cerebral Folate Deficiency

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - Bachelor of Science in Nursing

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing
Jamie Hope - Founder of Methyl-Life

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

January 26, 2025

Table of Contents

    What is cerebral folate deficiency?

    Cerebral folate deficiency is a rare neurological condition in which a child is born with normal blood folate levels and low 5-methyltetrahydrofolate (5-MTHF) levels in the cerebrospinal fluid.

    Children with CFD usually appear normal until around the age of two, when their speech and motor skills begin to decline. This may lead to difficulty speaking and walking, microcephaly, generalized weakness, and spasticity. They may develop an intellectual disability or recurrent seizures.

    These symptoms occur due to a lack of folate in the nervous system. Folate plays a critical role in embryonic/fetal development and postnatal neurodevelopment, as well as producing the neurotransmitters required for proper brain function and supporting the myelin sheath surrounding nerves.

    What causes cerebral folate deficiency?

    Cerebral folate deficiency has been linked to a problem with the folate receptor alpha (FRA), a protein that transports folate into brain cells. The FRA is mainly found in the choroid plexus, a part of the brain that produces cerebrospinal fluid, which protects the brain and spine. Folate delivered to the brain is crucial for building myelin (a substance that insulates nerve cells) and producing neurotransmitters, which are chemicals that send signals in the brain. When folate is not available, the brain cannot function properly.

    FRA dysfunction has three main causes:

    1. Autoantibodies: The most common cause of CFD involves autoantibodies, which are immune proteins that mistakenly attack the folate receptor and block it from functioning properly. Some research suggests that this immune reaction can be triggered by folate receptors from sources such as milk.1
    2. Metabolic Disorders: Metabolic issues such as mitochondrial disease may also be a cause. The folate receptor requires energy to transport folate into the brain (where folate levels must be higher than in the blood), and a disorder that affects the mitochondria (the cell’s energy producers) can impair this process.
    3. Genetic Mutations: Although rare, mutations in the FOLR1 gene can lead to a missing or malfunctioning folate receptor. A child must inherit one mutated gene from each parent to develop the condition.

    Symptoms of Cerebral Folate Deficiency

    Symptoms of cerebral folate deficiency usually begin within the first two years of age, but may start as early as four months. 

    • Difficulty sleeping
    • Irritability 
    • Developmental delays 
    • Speech difficulties 
    • Slow head growth
    • Poor muscle tone
    • Ataxia (gait abnormality, speech changes, and abnormal eye movements)
    • Loss of voluntary movement 
    • Contracting muscles (spasticity)
    • Epilepsy (seizures)
    • Autism 

    Testing and diagnosis of Cerebral Folate Deficiency

    Cerebral folate deficiency is difficult to diagnose as folate levels in the serum and blood are usually normal, while 5MTHF levels in the cerebrospinal fluid are low. This is measured with a lumbar puncture (spinal tap), which involves inserting a needle into the spinal canal low in the back.

    FRA autoantibody testing and/or genetic testing will also help to confirm a diagnosis.

    An MRI of the brain will be used to detect whether white matter levels are abnormal, and a neurologist will examine muscle tone, gait, and head circumference. An electroencephalography (EEG) may be used to check for irregular brain waves. 

    Treatment of Cerebral Folate Deficiency

    Treatment that begins before age two may lead to full recovery. Recommendations based on scientific research may include:

    • Supplementation with L-5-methyl-tetrahydrofolate (L-Methylfolate calcium) or folinic acid (leucovorin calcium) is essential to restore folate levels to the normal range.2 CSF folate levels should be monitored to ensure dosage is correct.
      Screening for deficiencies in other B vitamins involved in folate methylation is also recommended.

    • Avoiding animal-derived milk may reduce exposure to folate receptor (FR) autoantibodies. This may help reduce antibody levels.

    • Medication for symptoms such as seizures may require corticosteroids to lower folate receptor autoimmunity.

    Prevalence of Cerebral Folate Deficiency

    Cerebral folate deficiency is rare. While the exact prevalence of CFD is unknown, fewer than 20 cases have been reported in scientific literature.
    However, CFD is often associated with anti-folate receptor antibodies (FRAb), which block the transport of folate into the brain. FRAb is a common cause of low cerebrospinal folate, which is now known to be common in children with autism spectrum disorder.3

    Life expectancy and prognosis

    The earlier treatment begins, the better the chance of recovery. Diagnosis and treatment with folinic acid/methylfolate before the age of two usually resolves signs and symptoms of CFD and leads to complete recovery.4

    Young children with autism and a folate receptor autoimmune disorder should also avoid animal-derived milk.

    Related health conditions

    Folate deficiency during pregnancy has been associated with neural tube defects and a higher risk of children being born with developmental disorders, such as autism. 

    Severe systemic folate deficiency has also been associated with macrocytic anemia and additional pancytopenia (low red and white blood cells and platelets), immune dysfunction, and neurologic disorder.

    Relation of Cerebral Folate Deficiency to MTHFR

    One possible cause of cerebral folate deficiency includes the MTHFR mutation, which can reduce enzyme activity and affect folate metabolism. When MTHFR enzyme activity is extremely low, symptoms such as high homocysteine levels, developmental delays, eye issues, and blood clots can occur. More common mutations (like C677T or C677T + A1298C) reduce enzyme activity by about 50-60%, sometimes without symptoms, but can still decrease folate availability for the brain, especially if riboflavin levels are low. A lack of folate in the brain can then affect cognitive function.5

    Cerebral Folate Deficiency

    Key Takeaways

    • Icon Cerebral folate deficiency is a rare condition in which 5-MTHF levels in the cerebrospinal fluid are very low.
    • Icon CFD can lead to cognitive impairment and developmental regression if not treated.
    • Icon Early treatment can lead to a full recovery.

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    Frequently Asked Questions about Cerebral Folate Deficiency

    What are the symptoms of cerebral folate deficiency?

    Symptoms of cerebral folate deficiency are usually noticed in children aged 1-2 years, and may include developmental delays, speech difficulties, small head growth, poor muscle tone, difficulty walking, and possibly seizures. Behavioral disorders such as autism have also been linked to cerebral folate deficiency.

    How to fix cerebral folate deficiency?

    If cerebral folate deficiency is diagnosed (with a spinal tap), a healthcare professional will recommend supplementation with L-5-methyl-tetrahydrofolate (L-methylfolate calcium) and/or folinic acid (leucovorin calcium) to restore folate levels to the normal range.

    What does lack of folic acid do to the brain?

    Folate deficiency in the brain can lead to impaired production of neurotransmitters and poor cognitive function, which in turn can lead to depression and other mental health issues. If the folate deficiency isn’t restored, there is a high risk of neurodegenerative disorders such as Cerebral Folate Deficiency, dementia, Alzheimer’s, and Parkinson’s disease.6

    Is there a cure for CFD?

    Early intervention has the best outcomes for CFD. Children who are treated with folinic acid or L-methylfolate therapy before the age of two can usually make a full recovery.

    References

    1. Natasha Bobrowski-Khoury, Vincent T Ramaekers, Jeffrey M Sequeira, Edward V Quadros; "Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention"; Journal Of Personalized Medicine; 2021 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC8398778/

    2. Vincent Th Ramaekers, Edward V Quadros; "Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies"; Nutrients; 2022 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC9370123

    3. Natasha Bobrowski-Khoury, Vincent T Ramaekers, Jeffrey M Sequeira, Edward V Quadros; "Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention"; Journal Of Personalized Medicine; 2021 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC8398778/

    4. V T Ramaekers, N Blau, J M Sequeira, M-C Nassogne, E V Quadros; "Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits"; Neuropediatrics; 2007 Dec

      https://pubmed.ncbi.nlm.nih.gov/18461502/

    5. P Frosst, H J Blom, R Milos, P Goyette, C A Sheppard, R G Matthews, G J Boers, M den Heijer, L A Kluijtmans, L P van den Heuvel, et al.; "A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase"; Nature Genetics; 1995 May

      https://pubmed.ncbi.nlm.nih.gov/7647779/

    6. E H Reynolds; "The neurology of folic acid deficiency"; Handbook Of Clinical Neurology; 2014

      https://pubmed.ncbi.nlm.nih.gov/24365361

    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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