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.

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.

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 

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 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.

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.

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.