Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies

Nutrients. 2022 Jul 28;14(15):3096. doi: 10.3390/nu14153096.


Cerebral folate deficiency syndrome (CFDS) is defined as any neuropsychiatric or developmental disorder characterized by decreased CSF folate levels in the presence of normal folate status outside the nervous system. The specific clinical profile appears to be largely determined by the presence or absence of intrauterine folate deficiency as well as postnatal age at which cerebral folate deficiency occurs. The primary cause of CFDS is identified as the presence of serum folate receptor-alpha (FRα) autoantibodies impairing folate transport across the choroid plexus to the brain whereas, in a minority of cases, mitochondrial disorders, inborn errors of metabolism and loss of function mutations of the FRα (FOLR1) gene are identified. Early recognition and diagnosis of CFDS and prompt intervention is important to improve prognosis with successful outcomes. In this article we focus on FRα autoimmunity and its different age-dependent clinical syndromes, the diagnostic criteria, and treatments to be considered, including prevention strategies in this at-risk population.

Keywords: cerebral folate deficiency; folate receptor autoantibodies; folate transport; inborn errors of folate metabolism; prenatal folate deficiency.

Publication types

  • Review

MeSH terms

  • Early Diagnosis
  • Folate Receptor 1 / deficiency
  • Folate Receptor 1 / genetics
  • Folate Receptor 1 / therapeutic use
  • Folic Acid Deficiency* / metabolism
  • Folic Acid* / therapeutic use
  • Humans
  • Neuroaxonal Dystrophies
  • Syndrome


  • FOLR1 protein, human
  • Folate Receptor 1
  • Folic Acid

Supplementary concepts

  • Neurodegeneration Due To Cerebral Folate Transport Deficiency

Grants and funding

This research received no external funding.