Cerebral folate deficiency syndrome (CFDS) is a neurological condition where their is a deficiency of the active form of B9 known as 5-methylfolate (5MTHF) in the brain tissues, even though levels in the rest of the body are normal. This condition occurs because cerebral folate deficiency occurs due to disrupted folate transport into the brain, despite normal systemic levels. It is a very rare condition, affecting only about 1% of the US population.

5-Methyl Folate has crucial roles in DNA synthesis, gene regulation, neurotransmitter synthesis, cognitive processes, and overall brain health.

Diagnosis: Diagnosis is often delayed because many symptoms are associated with CFDS. Many practitioners are often unaware of the condition, which can cause a misdiagnosis and further delays.

CFDS is diagnosed with a combination of a clinical evaluation of symptoms, blood tests to measure folate levels in the body and cerebrospinal fluid, as well as genetic testing. Genetic testing identifies gene mutations affecting folate transport or metabolism that can cause folate deficiency. Additionally, testing for folate receptor autoantibodies (FRAAs) can indicate if there is a functional folate deficiency due to blocked folate transport into the brain.

Age: Symptoms can appear in infants during early childhood and even later, depending on the underlying cause, such as autoimmune dysfunction and genetic factors that affect folate transport into the brain.

Emerging research: Clinical research indicates that treatment with L-methylfolate or folinic acid has an essential role in restoring normal methylfolate levels in the brain. Early diagnosis and treatment are crucial for managing symptoms and supporting improvements in mental processing and physical development, which help enhance a child's quality of life.  Additionally, the role of methionine synthase in folate metabolism is being studied for its impact on neurological health.

There are a wide number of symptoms, including:

Developmental Delays: Young children with CFDS may show delayed developmental milestones, such as walking and talking later.

Loss of the original developed milestones, including in areas such as speech, movement, and social interactions.

Movement Disorders: Symptoms can include difficulties with coordination, muscle weakness, and involuntary movements.

Behavioral Changes: Individuals with CFDS might exhibit irritability, hyperactivity, or symptoms of autism spectrum disorders.

Seizures: Seizures of various types are common in individuals suffering from CFDS due to the brain's impaired function.

Sleep Disturbances: Problems with sleep, including difficulty falling asleep or staying asleep, are often noted.

Speech Difficulties: Delayed speech development or losing the ability to speak are significant indicators of CFDS.

Auto-immune dysfunction

Autoimmune dysfunction if often the main cause of CFDS The immune system mistakenly produces autoantibodies that target and attack the folate receptors made by the FOLR1 gene. When this happens, these receptors are damaged, making it hard for folate to be transported into the brain. This blockage can lead to a 5-methyl folate deficiency, which is crucial for its proper function and can contribute to neurological problems because the brain isn't getting the folate it needs to perform the critical function needed for a healthy brain

Genetic Factors and Gene Mutations

The FOLR1 gene

The folate receptor alpha hene (FOLR1 gene) produces special receptors called FORL1 receptors that help transport folate into the brain. If there are changes in this gene, it can affect how these receptors work, making it harder for folate absorption. This issue is significant in conditions like Cerebral Folate Deficiency Syndrome (CFDS), where the brain doesn't get enough folate due to these receptor problems, leading to 5-methyl folate deficiency and various neurological issues.

The MTHFR gene

The 5-methyltetrahydrofolate gene (MTHFR gene) is crucial for converting folate to its active form and is used throughout the body, including the brain. Mutations in this gene can lead to less efficient folate transport to the brain, which can create 5-methyl folate deficiency. The reduced folate carrier (RFC1) also plays a role in mediating the absorption of folates, particularly in the intestinal epithelial cells, and is essential for folate transport across various barriers like the blood-brain barrier.

Genetic testing

The genetic testing typically includes:

1. Sequencing of the FOLR1 gene: This test looks for mutations in the FOLR1 gene that can lead to dysfunction in the folate receptor, which is crucial for transporting folate across into the cerebrospinal fluid (CSF).
2. CSF 5-MTHF levels assessment: Although not a genetic test, measuring the levels of 5-MTHF in the CSF is important for confirming CFD. Low levels of this metabolite in the CSF, despite normal serum folate levels, indicate a possible folate transport problem Autoantibodies test for folate receptors: This test detects autoantibodies against folate receptors in the serum. These autoantibodies can block the transport of folate into the CSF, leading to cerebral folate deficiency

Medications

Certain medications, like antiepileptic drugs, can interfere with folate metabolism or transport, reducing the availability of folate to the brain.

Other Disorders

Conditions like mitochondrial disease are also associated with CFDS, though they're not fully understood. Cerebral folate deficiency is also associated with Rett syndrome due to mutations in X-linked MECP2 and the expression of non-functional FR pseudogenes, which are suspected to act as competitive non-functional inhibitors of FRα protein.

Both folinic acid and 5-methyl folate are both bioactive forms of vitamin B9 and better absorb folate and folic acid.

The main difference between folinic acid and L-methylfolate is in their forms and biological availability.

Folinic acid needs further conversion before it is available as active 5-methylfolate. where L-methylfolate is almost identical to 5-methylfolate and directly available to the body’s cells without any need for further conversion.

Because it is directly available and unaffected by gene mutations or immune dysfunction, L-methyl folate may be a better option for treating CFDS.

Dosage Guidelines

A medical doctor must diagnose and prescribe the correct dosage of L-methylfolate.

They will offer guidance based on symptoms, genetic test results, and the dose. CFDS is treated holistically

The general guidance suggests starting with lower doses of 0.5–1 mg/kg/day.

In some cases, higher doses ranging from 2–3 mg/kg/day may be necessary to normalize cerebrospinal fluid levels of 5-methylfolate.

Improvement is typically seen when early treatment is started before six years of age, with regular follow-up and monitoring to adjust dosage as needed to avoid over- or under-dosing.

Methyl-Life®: L-methlyfolate and activated B12 supplements for managing cerebral folate deficiency syndrome (CFD)

Methyl-Life® L-methylfolate 7.5 mg or 15 mg withh activated vitamin B12 

Methyl-Life® L-Methyl Folate 7.5 mg -15mg 

Potential side-effects and allergic reactions: Generally, there are very few side effects associated with therapeutic levels of l-methylfolate supplements. However, some people may experience a side effect or an allergic reaction. If this is the case, please contact your practitioner. You should seek help immediately.

 Key Insights

• Cerebral Folate Deficiency Syndrome (CFDS) developed because of a deficiency in the biologically active form of vitamin B9. It can cause a number of developmental delays and neurological issues.
• Auto-antibodies that block folate transport into the brain and genetic changes that affect folate metabolism are the main causes of CFDS.
• In cases where there are FOLR1 gene mutations or MTHFR mutations, new research shows that treatment with L-methylfolate (5-methyltetrahydrofolate) could be better than treatment with folinic acid.
• A medical diagnosis was to be made by my medical need doctor. Early diagnosis and an integrated health approach can make a significant difference in reducing symptoms and improving neurological impairments.
• Medication and treatment with L-methylfolate needs to be individualized and monitored to avoid over- or under-dosing.

FAQ's: 

What causes CFDS?

CFDS may be caused by immune or genetic changes that prevent folate from being transported or used. Certain medications or other health issues can also limit the absorption of folate, causing a deficiency in the brain.

How is CFDS diagnosed?

CFDS is diagnosed through a combination of clinical evaluation of symptoms, blood tests to measure folate levels in the body and cerebrospinal fluid, and possibly genetic testing to identify genetic changes (mutations) affecting folate metabolism or transport.

What are the common symptoms of CFDS?

Symptoms of CFDS include developmental delays, behavioral changes, communication difficulties, neurological symptoms like uncoordinated movements and seizures, and learning disabilities.

What treatments are available for CFDS?

Treatment typically involves supplementation with forms of folate that can bypass issues with absorption or metabolism. L-methylfolate has advantages over other forms of folate as it is directly absorbed into the protective fluid surrounding the brain as well as other tissues.

Can CFDS be cured?

While there is no cure for CFDS, appropriate management with folate supplementation and supportive therapies can significantly improve symptoms and quality of life. Early diagnosis and intervention are crucial to managing the condition effectively.