What Is Cerebral Folate Deficiency? Understanding This Neurological Disorder

Cerebral Folate Deficiency (CFD) is a neurological disorder characterised by low levels of 5-methyltetrahydrofolate (5-MTHF), the active form of folate, in the cerebrospinal fluid despite normal folate levels outside the nervous system. This deficiency results in impaired folate transport to the brain, leading to various neuropsychiatric and developmental symptoms.

Causes of Cerebral Folate Deficiency

The condition is caused by mutations in the FOLR1 gene, which encodes the folate receptor alpha (FRα), or by the presence of autoantibodies against this receptor, which block folate transport across the blood-brain barrier.

Symptoms of Cerebral Folate Deficiency

Symptoms can include seizures, developmental delays, movement disorders, and cognitive impairment. Early diagnosis and treatment with folinic acid or other forms of folate can improve outcomes, as it helps restore folate levels in the brain and mitigate neurological deficits.

Connection to Autism and PANS/PANDAS

More recently, we have found that Folate Receptor Antibodies are commonly present in cases of Autism and PANS/PANDAS. For further insights, please refer to the OT&P blogs that expand on this topic.

Dr Tim Trodd

Family Medicine, Functional Medicine, General Practice

MBBS (London)
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FHKAM (Family Medicine)

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References

Ramaekers, V.T. and Quadros, E.V. (2022) 'Cerebral folate deficiency syndrome: early diagnosis, intervention and treatment strategies', Nutrients, 14(15), 3096. doi:10.3390/nu14153096.
Rossignol, D.A. and Frye, R.E. (2021) 'Cerebral folate deficiency, folate receptor alpha autoantibodies and leucovorin (folinic acid) treatment in autism spectrum disorders: a systematic review and meta-analysis', Journal of Personalized Medicine, 11(11), 1141. doi:10.3390/jpm11111141.
Steinfeld, R., Grapp, M., Kraetzner, R., Dreha-Kulaczewski, S., Helms, G., Dechent, P. et al. (2009) 'Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism', American Journal of Human Genetics, 85(3), pp. 354–363. doi:10.1016/j.ajhg.2009.07.003.
Wells, L., O'Hara, N., Frye, R.E., Hullavard, N. and Smith, E. (2024) 'Folate receptor alpha autoantibodies in the pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) population', Journal of Personalized Medicine, 14(2), 166. doi:10.3390/jpm14020166.