NORD gratefully acknowledges Amanda Wong, NORD Editorial Intern from the Keck Graduate Institute, Richard E. Frye, MD, PhD, Department of Neurology, Phoenix Children’s Hospital, Barbara Ohnemus-Kawamura, DO, MPA and Myles Kawamura, DO, FACEP, Mercy Medical Center, Des Moines, Iowa, for assistance in the preparation of this report.
Cerebral folate deficiency is a neurological syndrome in which development is usually normal in the first year of life, but at approximately 2 years of age, affected children start to lose mental and motor skills (psychomotor regression). Some early symptoms are intellectual disability, speech difficulties, and development of recurrent seizures in a third of affected children. Motor issues such as tremors and lack of muscle control or coordination of voluntary movements (ataxia) can become severe. Cerebral folate deficiency occurs because of a deficiency of vitamin B folate (vitamin B9) in the brain caused by a low level of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid due to a disruption in the function of the folate receptor alpha (FRA). The function of the FRA can be disrupted by several causes. The most common etiology involves one of two autoantibodies blinding to the FRA resulting in a disruption in its function. The FRA is highly dependent on mitochondrial function leading to disrupting in FRA function in mitochondrial and other metabolic disorders. Lastly, rare mutation in the FOLR1 gene can result in an autosomal recessive genetic condition which disrupts FRA function. This condition can be treated with leucovorin calcium (aka folinic acid).
The symptoms of cerebral folate deficiency may begin as early as four to six months of age with irritability and sleep problems (insomnia). Delays in development may be noted including slow head growth, low muscle tone (hypotonia), ataxia, loss of voluntary movement (dyskinesia), constant contracted muscles (spasticity), speech complications, and epilepsy. Additional signs may involve visual disturbances, hearing loss and autistic features.
Even though there may be normal folate levels in the serum and red blood, 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.
Cerebral folate deficiency is caused by a disruption in the function of the folate receptor alpha (FRA). Folate receptor alpha is located inside the cell membrane and 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. The choroid plexus releases cerebrospinal fluid that protects the brain and spinal cord. Folate receptor alpha moves folate through the choroid plexus and into the cerebrospinal fluid that will spread to the brain. Folate is important for constructing myelin and chemical messengers (neurotransmitters) that transmit signals in the brain. The absence of folate in the brain triggers the neurological complications associated with this condition.
Function of the FRA can result from three main causes. The most common cause results from one of two autoantibodies attaching to the FRA and disrupting its function. Autoantibodies are proteins produced by the immune system that are directed against one or more of an individual’s own proteins. One probable mechanism for autoantibody production is that soluble folate receptors from milk may trigger an immune response.
Metabolic disorders such as mitochondrial disease are the second most common cause of a 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. The mitochondria is important for producing this energy, so any metabolic disorder that disrupts mitochondrial function can interfere with folate transport into the brain.
Lastly, mutations in the FOLR1 gene that result in production of abnormal or missing FRA protein are rare causes of the disorder. This form of cerebral folate deficiency is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Fewer than 20 individuals with cerebral folate deficiency have been reported in scientific literature. The exact prevalence of this condition is unknown.
A neurological exam will identify symptoms of cerebral folate deficiency such as hypotonia, ataxia, unsteady walking, and small head circumference. MRI of the brain can help determine if there is irregular subcortical white matter.
Cerebral folate deficiency is diagnosed by measuring 5MTHF concentration in the cerebrospinal fluid. This is done with a lumbar puncture (spinal tap), a procedure where a needle is carefully inserted into the spinal canal low in the back.
Electroencephalography (EEG), a test used to record electrical activity of the brain, may show unusual arrays that involve high amplitude and irregular waves (hypsarrhythmia). Hearing and ophthalmological examinations may also be conducted.
Molecular genetic testing for mutations in the FOLR1 gene is available to confirm the diagnosis.
Testing for the two FRA autoantibodies (blocking antibody and binding autoantibody) can be performed to determine if autoantibodies are responsible for cerebral folate deficiency.
Oral treatment with 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 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 leucovorin Calcium acid has been reported to improve symptoms, especially when used in the early stages of the disease.
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Cerebral folate transport deficiency – Genetics Home Reference. U.S. National Library of Medicine. Reviewed Sept. 2014. https://ghr.nlm.nih.gov/condition/cerebral-folate-transport-deficiency#synonyms Accessed May 13, 2019
Cerebral folate deficiency. Genetic and Rare Diseases Information Center. Last updated: 5/1/2019 https://rarediseases.info.nih.gov/diseases/10594/cerebral-folate-deficiency Accessed May 13, 2019.
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