The absence of folate in the brain triggers the neurological complications associated with this condition.įunction of the FRA can result from three main causes.
Folate is important for constructing myelin and chemical messengers (neurotransmitters) that transmit signals in the brain. Folate receptor alpha moves folate through the choroid plexus and into the cerebrospinal fluid that will spread to the brain. The choroid plexus releases cerebrospinal fluid that protects the brain and spinal cord. The protein is created in greatest quantities in the choroid plexus in the brain. Folate receptor alpha is located inside the cell membrane and binds to folate, which allows it to be transported into the cell. 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.Ĭerebral folate deficiency is caused by a disruption in the function of the folate receptor alpha (FRA). 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. Additional signs may involve visual disturbances, hearing loss and autistic features.Įven though there may be normal folate levels in the serum and red blood, evaluation of the cerebrospinal fluid shows a decreased level of 5MTHF. 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. The symptoms of cerebral folate deficiency may begin as early as four to six months of age with irritability and sleep problems (insomnia). This condition can be treated with leucovorin calcium (aka folinic acid). Lastly, rare mutation in the FOLR1 gene can result in an autosomal recessive genetic condition which disrupts FRA function.
The FRA is highly dependent on mitochondrial function leading to disrupting in FRA function in mitochondrial and other metabolic disorders. The most common etiology involves one of two autoantibodies blinding to the FRA resulting in a disruption in its function. The function of the FRA can be disrupted by several causes. 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). Motor issues such as tremors and lack of muscle control or coordination of voluntary movements (ataxia) can become severe. Some early symptoms are intellectual disability, speech difficulties, and development of recurrent seizures in a third of affected children.
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