Cerebral Folate Deficiency

What Is Cerebral Folate Deficiency?

Folate, also refers to as folic acid, is a natural water-soluble vitamin B9 that is widely found in a variety of foods, such as meat, fresh fruits, and vegetables. It serves as a cofactor or coenzyme playing significant roles in protein metabolism, nucleic acid synthesis and repair, red blood cell formation, cell division, and many other cellular processes. Since folate cannot be synthesized by the human body, it is an essential nutrient taken from the dietary supplement. Folate deficiencies will be caused once it is lacking, such as neural tube defects, folate deficiency anemia, even tumors.

Cerebral folate deficiency (CFD) occurs when 5-methyltetrahydrofolate, the biologically active form of folate, is deficient in the cerebrospinal fluid even though is normal in the circulating blood. CFD is a neurological syndrome whose symptoms mainly appear in infancy over 4 months, manifesting intellectual disability, poor muscle tone, seizures, sleep disorders, developmental delay, getting worse until visual impairment, and hearing loss.

Causes of Cerebral Folate Deficiency

In CFD patients, the 5-methyltetrahydrofolate deficiency has been reported to result from several factors, which include but are not limited to:

1. Genetic factor: mutations in the FOLR1 gene can result in abnormal or absent expression of human folate receptor alpha, a protein mediating the delivery of 5-methyltetrahydrofolate into the cell interior. Therefore, the autosomal recessive disease FOLR1 gene mutation can lead to insufficient active folate in neurons, thereby, causing CFD.
2. Autoantibodies factor: folate receptor autoantibodies caused by autoimmune disorders also disturb or block the folate receptor alpha functions, leading to the deficiency of 5-methyltetrahydrofolate in the neural system and CFD.
3. Disease factors: metabolic disorders, such as Kearns-Sayre syndrome and mitochondrial disease, also are common causes of dysfunctions of folate receptor alpha, which interferes with the transportation of folate into the brain, thereby causing CFD.

Role of Folate Receptor Alpha in Cerebral Folate Deficiency

Folate receptor alpha (FRA), also known as folate receptor 1, is an important membrane protein that is responsible for binding folic acid and related derivatives and transporting 5-methyltetrahydrofolate into cells. FRA is widely expressed in the choroid plexus in the brain where it transports folate and derivatives into the cerebrospinal fluid through the choroid plexus, allowing them to spread to the brain. In the neural system, folate has been recognized as an important factor for neuro-signal transmission, myelin construction, DNA methylation, and neural tube formation. Thus, FRA dysfunctions, such as FOLR1 gene mutations and folate receptor autoantibodies, can result in insufficient active folate delivered into the brain even though the folate concentration in the blood is normal.

Fig.1 Folic acid metabolism and 5-methyltetrahydrofolate transport across the choroid plexus epithelium in the brain. (Mafi, 2020)

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Reference

1. Mafi, S.; et al. Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease. Brain Sciences. 2020, 10(11): 762.