Cerebral folate transport deficiency is a disorder that develops from a shortage (deficiency) of the B-vitamin folate (also called vitamin B9) in the brain. Affected children have normal development during infancy, but around age 2 they begin to lose previously acquired mental and movement abilities (psychomotor regression). They develop intellectual disability, speech difficulties, and recurrent seizures (epilepsy). Movement problems such as tremors and difficulty coordinating movements (ataxia) can be severe, and some affected individuals need wheelchair assistance. Affected individuals have leukodystrophy, which is a loss of a type of brain tissue known as white matter. White matter consists of nerve fibers covered by a fatty substance called myelin that promotes the rapid transmission of nerve impulses. Leukodystrophy contributes to the neurological problems that occur in cerebral folate transport deficiency. Without treatment, these neurological problems worsen over time.

Mutations in the FOLR1 gene cause cerebral folate transport deficiency. The FOLR1 gene provides instructions for making a protein called folate receptor alpha. This protein is found within the cell membrane where it attaches (binds) to folate, allowing the vitamin to be brought into the cell. Folate receptor alpha is produced in largest amounts in the brain, specifically in an area of the brain called the choroid plexus. This region releases cerebrospinal fluid (CSF), which surrounds and protects the brain and spinal cord. Folate receptor alpha is thought to play a major role in bringing folate from the bloodstream into brain cells. It transports folate across the choroid plexus and into the CSF, ultimately reaching the brain. In the brain, folate is needed for making myelin and chemical messengers called neurotransmitters. Both of these substances play essential roles in transmitting signals in the nervous system. Additionally, folate is involved in the production and repair of DNA, regulation of gene activity (expression), and protein production.

FOLR1 gene mutations result in a lack of protein or malfunctioning protein. As a result, folate from the bloodstream cannot be transported into the CSF. Without folate, many processes in the brain are impaired, leading to the neurological problems typical of cerebral folate transport deficiency.

The signs and symptoms of cerebral folate transport deficiency do not begin until late infancy because other mechanisms can compensate for this loss. For example, another protein called folate receptor beta is responsible for folate transport before birth and in early infancy.

Normal Function

The FOLR1 gene provides instructions for making a protein called folate receptor alpha. This protein helps regulate transport of the B-vitamin folate into cells. Folate (also called vitamin B9) is needed for many processes, including the production and repair of DNA, regulation of gene activity (expression), and protein production. Folate from food is absorbed in the intestines and then released in a form called 5-methyl-tetrahydrofolate (5-MTHF) into the bloodstream, where it can be taken in by cells in various tissues.

Folate receptor alpha is found within the cell membrane, where it attaches (binds) to 5-MTHF, allowing the vitamin to be brought into the cell. Folate receptor alpha is produced in largest amounts in the brain, specifically in an area of the brain called the choroid plexus. This region releases cerebrospinal fluid (CSF), which surrounds and protects the brain and spinal cord. Folate receptor alpha is thought to play a major role in transporting folate from the bloodstream into brain cells. It transports folate across the choroid plexus and into the CSF, ultimately reaching the brain. In the brain, folate is needed for making chemical messengers called neurotransmitters and a fatty substance called myelin, which insulates nerve fibers and promotes the rapid transmission of nerve impulses. Both of these substances play essential roles in transmitting signals in the nervous system.

Health Conditions Related to Genetic Changes

Cerebral folate transport deficiency

At least 11 mutations in the FOLR1 gene have been found to cause cerebral folate transport deficiency, a disorder characterized by neurological problems that begin around age 2. Most of these mutations change single protein building blocks (amino acids) in folate receptor alpha. FOLR1 gene mutations result in a lack of protein or malfunctioning protein. Without folate receptor alpha in brain cells, 5-MTHF in the bloodstream cannot be transported into the CSF and passed to the brain. A shortage (deficiency) of folate in the brain impairs normal cell functions such as the production of DNA, proteins, and neurotransmitters. Folate deficiency affects the stability of myelin, leading to impaired production or increased breakdown of this tissue, a condition known as leukodystrophy. These brain abnormalities caused by a lack of folate lead to the intellectual disability, movement problems, and recurrent seizures (epilepsy) typical of cerebral folate transport deficiency.

Other Names for This Gene

• adult folate-binding protein
• FBP
• folate binding protein
• folate receptor 1 (adult)
• folate receptor alpha
• folate receptor, adult
• FOLR
• FR-alpha
• KB cells FBP

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The prevalence of cerebral folate transport deficiency is unknown. Fewer than 20 affected individuals have been described in the scientific literature.