By: Sofia Arreguin
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FOLR1 Genetic Mutation
What is FOLR1?
The FOLR1 gene, also known as FBP, Adult Folate-Binding Protein, or FR-alpha, delivers instructions for the production of the folate receptor alpha protein, responsible for managing the transport of B-vitamin folate towards the body’s cells (National Library of Medicine, 2014). Folate, commonly referred to as vitamin B9, is essential for the maintenance of DNA, primarily by assisting in its development and repair, expression of genes, and production of proteins (National Library of Medicine, 2014). Folate is naturally found in many foods, and when consumed, is absorbed by the intestines and released as 5-methyl-tetrahydrofolate (5-MTHF) into the bloodstream. Once in the bloodstream, it is transported throughout the body’s cells and tissues to help with the maintenance and functioning of such tissues and organs. The 5-MTHF then binds to the folate receptor alpha (FRA), situated within the cell membrane, to facilitate the uptake of vitamin B9. These receptors are found in large quantities within the choroid plexus, a system of blood vessels and cells within a region of the brain responsible for producing cerebrospinal fluid (CSF), a fluid that functions to protect the brain and spinal cord from physical injury, assist in the removal of waste, and transport essential nutrients to the brain (National Library of Medicine, 2014). One such nutrient is folate, which is necessary for the production of neurotransmitters and myelination of neurons; myelin sheaths, a fatty substance, envelop nerve fibers, promoting rapid and stable communication between neurons, essentially acting as a protective cover over the neuron’s axon.
FOLR1-Related Epilepsy
Disruptions or mutations in the FOLR1 gene can result in Cerebral Folate Transport Deficiency (FOLR1-CFTD), specifically from the loss of performance from the folate receptor alpha protein. The mutation is usually present as a consequence of a variation of a single amino acid in the FRA, leading to defective or insufficient amounts of the protein and folate, thereby resulting in decreased levels of 5-MTHF (National Library of Medicine, 2014). This neurological condition often manifests within the age of one, but at two years of age, children begin to see a decline in their motor and cognitive skills (National Organization for Rare Disorders, 2019). Normally, this condition is composed of low levels of CSF and a gradual deterioration of intellectual and developmental skills, cognitive impairment, seizures, and difficulties with bodily movement. Patients experiencing muscle difficulties may endure tremors or involuntary muscle movements, known as ataxia, resulting in clumsy gestures, hypotonia or low muscle tone, spasticity, or constant stiffening and contraction of muscles, and microcephaly, which is slow head growth (National Organization for Rare Disorders, 2019). Seizures that are often encountered are identified as myoclonic, involving jerky muscle movements, or tonic, characterized by stiffening muscles. Such seizures are often considered severe because of their association with status epilepticus, wherein seizures persist for five or more minutes, or patients experience recurrent seizures without regaining consciousness between each episode (Goldman, 2025).
Causes
Disturbances in the folate receptor alpha are connected to three problems: antibodies, metabolic disorders, and variants within the FOLR1 gene.
Antibodies. One of two antibodies attaches to the folate receptor alpha, blocking 5-MTHF from binding to the receptor and facilitating the uptake of folate (National Organization for Rare Disorders, 2019). As mentioned, folate is an essential nutrient for the maintenance of DNA, protein synthesis, and the production of CSF, essentially supporting the health of an individual. Without its uptake, these procedures become defective.
Metabolic Disorders. Also referred to as mitochondrial disease, these disorders negatively affect the energy levels required for the transport of folate to the brain (National Organization for Rare Disorders, 2019). Mitochondria are a significant producer of energy, which the folate receptor alpha uses to carry folate into the brain. However, metabolic abnormalities primarily target the mitochondria, hindering their ability to produce energy and fundamentally advancing their dysfunction. As a result, energy levels are depleted, limiting the energy reservoir available for the receptor alpha’s use.
Variation in the FOLR1 Gene. Patients inherit a mutation in the FOLR1 gene through an autosomal recessive pattern, in which each parent possesses one mutated version of the gene and transmits both to their offspring; as a result, the child inherits two copies of the mutated gene (National Organization for Rare Disorders, 2019). The folate receptor alpha protein is either absent or contains abnormalities in its structure, contributing to the deficiency of folate and malfunctions of cellular processes.
When deprived of folate receptor alpha in neurons, 5-MTHF cannot be transferred from the bloodstream into the CSF and, therefore, cannot be supplied to the brain. As a result, the synthesis of neurotransmitters, DNA, and proteins is disrupted, hindering normal functioning, and, most prominently, the process of myelination ceases to occur (National Organization for Rare Disorders, 2019). Seizures normally result from a deterioration or weakening of myelin, as the axons of the neurons are more likely to become excitable. With the loss of myelin, the means for accelerating transmission of electrical signals between neurons decays; communication may stop completely as the action potential, necessary for producing such electrical signals, experiences a deficiency of power required to fire a signal to a corresponding neuron. Without the protective covering around neurons that promotes stable communication pathways, the electrical signals of a neuron may experience a leakage of excitable energy onto other neurons, producing a highly excitable environment and, therefore, seizures; as multiple neurons become excitable, they begin to fire simultaneously and excessively, overwhelming the brain’s neural network.
The diagnosis for this condition often involves evaluating the amount of 5-MTHF in the CSF, primarily accomplished through a lumbar puncture, or a spinal tap. This procedure requires the insertion of a needle into the spinal canal, managing to collect CSF into a tube; the fluid is then sent to a laboratory for further analysis of abnormalities (National Organization for Rare Disorders, 2019). An electroencephalogram (EEG) may also be administered to observe the effects of FOLR1-CFTD, specifically by detecting abnormally slow brain wave patterns or high-amplitude spikes of electrical activity often associated with cerebral dysfunctions or seizures.
Management and Treatment Options
Although there is no assured cure for the complications associated with the mutations of the FOLR1 gene, medical professionals have some suggestions to help manage symptoms. Administered either orally at high doses or intramuscularly, through injection, at lower doses, leucovorin calcium, the pharmaceutical label for a state of folate known as 5-formyltetrahydrofolate (5-formylTHF), is a treatment option that helps bring folate levels back to normal (Goldman, 2025). By stabilizing folate levels, brain and neuronal health can be promoted, reducing the risk of cerebral complications. A diet free from milk, but with the addition of leucovorin, is also recommended to manage symptoms. Milk contains proteins that normally benefit consumers, but for many with FOLR1-CFTD, the proteins found in bovine milk, produced by cows, are similar in structure to the folate-binding proteins found in the body (Ramaeker et al., 2008). Because the body perceives the milk’s proteins as foreign, it triggers the release of antibodies to attack them; however, as a result of the likeness of both the milk and folate-binding proteins, the antibodies may attack the body’s own folate receptor alpha (Ramaeker et al., 2008). Such antibodies may even bind to the receptors to block the folate from attaching to the receptor and triggering the uptake of folate into the brain.
Nevertheless, there is one treatment route that is not recommended: the administration of folic acid. Rather than supporting the transport of folate, this synthetic folic acid counters its effects. Since the receptor has a high magnetic attraction for the synthetic folic acid, the folic acid binds tightly to the receptor (Goldman, 2025). However, it is unable to be readily converted into the active form of folate needed by the brain, effectively preventing other available, usable forms of folate from reaching the brain. In these cases, this synthetic acid folate contributes to the occurrence of seizures by depriving the brain of folate. Despite this inadequate form of treatment, there are still other available therapies for managing folate deficiency.
As with many diseases and treatments, early intervention is better to obtain a more favorable course of symptom management. Consulting one’s doctor can help affected individuals live a more comfortable lifestyle by effectively addressing their symptoms.
References
Goldman, D. (2025). FOLR1-Related Cerebral Folate Transport Deficiency. In M.P. Adam et al. (Eds), GeneReviews® [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK599286/
National Library of Medicine. (2014, September 1). FOLR1 gene. MedlinePlus. https://medlineplus.gov/genetics/gene/folr1/
National Organization for Rare Disorders. (2019, August 22). Cerebral Folate Deficiency. https://rarediseases.org/rare-diseases/cerebral-folate-deficiency/
Ramaekers, V. T., et al. (2008). A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Developmental Medicine and Child Neurology, 50(5), 346–352. https://doi.org/10.1111/j.1469-8749.2008.02053.x
