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.

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

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.

Genetic Testing Information

• Genetic Testing Registry: Cerebral folate transport deficiency

Genetic and Rare Diseases Information Center

• Neurodegenerative syndrome due to cerebral folate transport deficiency

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• NEURODEGENERATION DUE TO CEREBRAL FOLATE TRANSPORT DEFICIENCY; NCFTD

Scientific Articles on PubMed

• PubMed

• Cario H, Bode H, Debatin KM, Opladen T, Schwarz K. Congenital null mutations of the FOLR1 gene: a progressive neurologic disease and its treatment. Neurology. 2009 Dec 15;73(24):2127-9. doi: 10.1212/WNL.0b013e3181c679df. No abstract available. Citation on PubMed
• Grapp M, Just IA, Linnankivi T, Wolf P, Lucke T, Hausler M, Gartner J, Steinfeld R. Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain. 2012 Jul;135(Pt 7):2022-31. doi: 10.1093/brain/aws122. Epub 2012 May 13. Citation on PubMed
• Grapp M, Wrede A, Schweizer M, Huwel S, Galla HJ, Snaidero N, Simons M, Buckers J, Low PS, Urlaub H, Gartner J, Steinfeld R. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun. 2013;4:2123. doi: 10.1038/ncomms3123. Citation on PubMed
• Hyland K, Shoffner J, Heales SJ. Cerebral folate deficiency. J Inherit Metab Dis. 2010 Oct;33(5):563-70. doi: 10.1007/s10545-010-9159-6. Epub 2010 Jul 29. Citation on PubMed
• Perez-Duenas B, Ormazabal A, Toma C, Torrico B, Cormand B, Serrano M, Sierra C, De Grandis E, Marfa MP, Garcia-Cazorla A, Campistol J, Pascual JM, Artuch R. Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects. Arch Neurol. 2011 May;68(5):615-21. doi: 10.1001/archneurol.2011.80. Citation on PubMed
• Perez-Duenas B, Toma C, Ormazabal A, Muchart J, Sanmarti F, Bombau G, Serrano M, Garcia-Cazorla A, Cormand B, Artuch R. Progressive ataxia and myoclonic epilepsy in a patient with a homozygous mutation in the FOLR1 gene. J Inherit Metab Dis. 2010 Dec;33(6):795-802. doi: 10.1007/s10545-010-9196-1. Epub 2010 Sep 21. Citation on PubMed
• Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S, Helms G, Dechent P, Wevers R, Grosso S, Gartner J. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet. 2009 Sep;85(3):354-63. doi: 10.1016/j.ajhg.2009.08.005. Citation on PubMed or Free article on PubMed Central
• Toelle SP, Wille D, Schmitt B, Scheer I, Thony B, Plecko B. Sensory stimulus-sensitive drop attacks and basal ganglia calcification: new findings in a patient with FOLR1 deficiency. Epileptic Disord. 2014 Mar;16(1):88-92. doi: 10.1684/epd.2014.0629. Citation on PubMed