Neurodegenerative syndrome due to cerebral folate transport deficiency

Neurodegenerative syndrome due to cerebral folate transport deficiency (also known as cerebral folate transport deficiency or hereditary folate malabsorption of the brain) is a rare autosomal recessive neurological disorder caused by mutations in the FOLR1 gene, which encodes the folate receptor alpha (FRα). This receptor is essential for transporting 5-methyltetrahydrofolate (5-MTHF) across the choroid plexus into the cerebrospinal fluid (CSF), making it available to the brain. When this transport mechanism is impaired, cerebral folate levels become critically low despite normal blood folate levels, leading to progressive neurodegeneration. The disease typically presents in late infancy or early childhood, usually between 2 and 3 years of age, after a period of initially normal development. Affected children develop progressive psychomotor regression, movement abnormalities (including ataxia, dyskinesia, and tremor), epileptic seizures, and visual and hearing impairment. Brain MRI often reveals progressive cerebral and cerebellar atrophy, as well as white matter abnormalities including delayed myelination or demyelination. CSF analysis characteristically shows very low or undetectable levels of 5-MTHF. Early diagnosis and treatment are critical, as the condition is potentially treatable. The mainstay of therapy is folinic acid (leucovorin) supplementation, which can bypass the defective receptor and partially restore cerebral folate levels. When treatment is initiated early, before significant neurological damage has occurred, clinical improvement or stabilization of symptoms can be achieved. However, delayed treatment may result in irreversible neurological deficits. The prognosis depends heavily on the timing of diagnosis and initiation of folinic acid therapy.

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