Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies - PubMed (original) (raw)

Review

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

Vincent Th Ramaekers et al. Nutrients. 2022.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Structural formula of folic acid. This is composed of an unreduced 2-amino-4-hydroxypteridine molecule linked through methylene (C6-position) to p-aminobenzoylmono-glutamate, while R represents the one-carbon group at different oxidation states in the form of methyl-, methenyl-, methylene-, or formyl-, attached to the N5- and/or N-10 positions as shown in the drawing. The metabolically active form tetrahydrofolate is reduced at the 5,6,7,8 positions of the pteridine ring.

Figure 2

Figure 2

Pathways of folate metabolism after FRα mediated flux of 5-methyl-tetrahydrofolate (5-methyl THF) across the choroid plexus into the CSF and then to the brain. Inside neurons, most methyl-THF will be stored while a proportion actively participates in metabolism. Methyl-THF transfers its methyl group to the B12-dependent methionine synthase (MS) enzyme, converting homocysteine to methionine. In the methionine cycle methionine is the precursor of the universal methyl-donor SAM, used in more than 100 methylation reactions. In the remethylation cycle, tetrahydrofolate (THF) receives a mono-carbon group from serine and is converted to 5,10-methylene THF. Part of 5,10-methylene THF is reduced by methylene-THF reductase (MTHFR B2) to 5-methyl-THF, while another portion is used to produce thymidine or is converted to 10-formyl THF, needed for purine synthesis. On the left side of the picture, the purine metabolite GTP serves as substrate for the GTP-cyclohydrolase I enzyme (GTPCH) to produce tetrahydrobiopterin (BH4), which is the co-factor for enzymes producing dopamine, serotonin and NO. At the upper right of the figure the transsulfuration pathway is shown. It converts accumulated homocysteine to the antioxidant glutathione to ameliorate oxidative stress. Abbreviations: BH4: tetrahydrobiopterin; D2: dopamine-2 receptor; GTP: Guanosine Tri Phosphate; NO: Nitric oxide; NOS: Nitric oxide synthase; RFC1: Reduced Folate Carrier-1; ROS: reactive oxygen species; TH: Tyrosine hydroxylase; TPH2: neuronal Tryptophane hydroxylase; 5HT2a: serotonin 2A receptor; SAM: S-adenosyl methionine; SAH: S-adenosyl homocysteine.

Figure 3

Figure 3

Comparison of CSF methyl-folate levels and FRα autoantibodies in infantile CFD, autism with neurologic deficits (Autism + ND), infantile autism and healthy controls.

Figure 4

Figure 4

Age-dependent classification of CFDS.

Figure 5

Figure 5

Diagnostic alghorhytm for infantile CFD and autistic syndromes.

Figure 6

Figure 6

(A). Genetic counseling FRαAb testing for first child with autism and parents to prevent the reoccurrence of autism in further offspring. (B). Various situations with positive FRα autoanti- bodies in child and parents.

Similar articles

Cited by

References

    1. Ramaekers V.T., Blau N. Cerebral folate deficiency. Dev. Med. Child Neurol. 2004;46:843–851. doi: 10.1111/j.1469-8749.2004.tb00451.x. - DOI - PubMed
    1. Ramaekers V.T., Sequeira J.M., Quadros E.V. The basis for folinic acid treatment in neuro-psychiatric disorders. Biochimie. 2016;126:79–90. doi: 10.1016/j.biochi.2016.04.005. - DOI - PubMed
    1. Ramaekers V., Sequeira J.M., Quadros E.V. Clinical recognition and aspects of the cerebral folate deficiency syndromes. Clin. Chem. Lab. Med. 2013;51:497–511. doi: 10.1515/cclm-2012-0543. - DOI - PubMed
    1. Grapp M., Wrede A., Schweizer M., Hüwel S., Galla H.J., Snaidero N., Simons M., Bückers J., Low P.S., Urlaub H., et al. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat. Commun. 2013;4:2123. doi: 10.1038/ncomms3123. - DOI - PubMed
    1. Castaño E., Caviedes L., Hirsch S., Llanos M., Iñiguez G., Ronco A.M. Folate Transporters in Placentas from Preterm Newborns and Their Relation to Cord Blood Folate and Vitamin B12 Levels. PLoS ONE. 2017;12:e0170389. doi: 10.1371/journal.pone.0170389. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

This research received no external funding.

LinkOut - more resources