How do Folate Receptor Autoantibodies contribute to CFD?

Cerebral Folate Deficiency Syndrome

Cerebral folate deficiency syndrome is a unique neurological condition in which development is typically normal in the first year of life, however, thereafter affected children may start to lose mental and motor skills (psychomotor regression). Symptoms of cerebral folate deficiency syndrome may begin to appear as early as four to six months of age. These initial symptoms can manifest as irritability and sleep problems (insomnia). Additionally, other symptoms may include slow head growth, low muscle tone (hypotonia), ataxia, loss of voluntary movement (dyskinesia), constant contracted muscles (spasticity), visual disturbances, hearing loss, speech complications, and epilepsy. The severity of motor issues, such as tremors and ataxia, can be quite severe.


Cerebral folate deficiency syndrome is primarily caused by a disruption in the function of the folate receptor alpha (FRA). Folate receptor alpha is one of the main transporters of Vitamin B9 (folate) and is located inside the cell membrane. The receptor binds to folate, which allows it to be transported into the cell. The protein is created in greatest quantities in the choroid plexus in the brain. Folate receptor alpha moves folate through the choroid plexus and into the cerebrospinal fluid that will spread to the brain. The choroid plexus releases cerebrospinal fluid, which then protects the brain and spinal cord.
Folate (Vitamin B9) is vital for constructing myelin and chemical messengers (neurotransmitters) that transmit signals in the brain. The absence of folate in the brain triggers many neurological complications associated with this condition.

Dysfunction of the Folate Receptor Alpha can occur from three distinct causes:

  1. The most common cause results from the presence of folate receptor autoantibodies. Autoantibodies are proteins produced by the immune system that are directed against one or more of an individual’s own proteins. In this case, folate receptor autoantibodies attack the folate receptor alpha and render it dysfunctional. There are two different autoantibodies (blocking and binding) but both ultimately have the same effect on hindering folate transport. Further elucidation is needed to determine the origins of these autoantibodies, but one probable mechanism for autoantibody production is that soluble folate receptors from milk may trigger an immune response such as this.
  2. Metabolic disorders such as mitochondrial dysfunction are the second most common cause of disruption in FRA function. The FRA requires energy to function adequately since folate needs to be actively transported into the brain because the folate concentration in the brain is higher than it is in the blood. Mitochondria is important for producing this energy, so any metabolic disorder that disrupts mitochondrial function can interfere with folate transport into the brain.
  3. Mutations in the FOLR1 gene can result in production of abnormal or missing FRA protein. Although these cases are rare, they contribute to cerebral folate deficiency syndrome. Termed an autosomal recessive genetic condition, it is inherited.

Cerebral folate deficiency syndrome is challenging to diagnose as there may be normal folate levels in the serum and red blood. However, evaluation of the cerebrospinal fluid shows a decreased level of 5MTHF. The brain may appear normal on an MRI, but in some affected children, a loss of white matter in the brain (leukodystrophy) may be seen. Frontotemporal atrophy and impairment of the protective layer that surrounds nerve fibers in the brain and spinal cord (subcortical demyelination) can be seen as early as 18 months.

A neurological exam will identify symptoms of cerebral folate deficiency syndrome such as small head circumference, hypotonia, ataxia, and any unsteady walking. Hearing and ophthalmological examinations may also be conducted. An MRI of the brain can help determine if there is irregular subcortical white matter and an Electroencephalography (EEG), a test used to record electrical activity of the brain, may show unusual arrays that involve high amplitude and irregular waves (hypsarrhythmia).

Molecular genetic testing for mutations in the FOLR1 gene is available to confirm the diagnosis. and a lumbar puncture (spinal tap) can measure 5MTHF concentration in the cerebrospinal fluid.

Most recently, a test termed FRAT® will screen for the two FRA autoantibodies (blocking autoantibody and binding autoantibody). This simple blood test will confirm the presence of the folate receptor autoantibodies, indicating that these autoantibodies are responsible for cerebral folate deficiency syndrome.

Possible Therapies

Oral treatment with folinic acid (leucovorin calcium) has been shown to improve symptoms and stabilize the level of 5MTHF in the cerebrospinal fluid. The overall outcome seems to depend on the age at which treatment is initiated. The earlier the treatment the better the outcome. Supplementation with folic acid is not recommended because it is associated with adverse effects such as producing epileptic seizures. No serious adverse effects have been recorded during leucovorin calcium treatment. A milk-free diet in combination with folinic acid has also been reported to improve symptoms, especially when used in the early stages of the disease.

As with any diagnosis and treatment, a physician’s guidance and approval are required. Please speak with your medical doctor about cerebral folate deficiency syndrome if you suspect any symptoms.

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