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

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.

New Therapeutic Approaches to Inherited Metabolic Pediatric Epilepsies

“…The clinical phenotype commonly includes neurodevelopmental deficits, megaloblastic anemia, leukoencephalopathy, and myoclonic seizures. 11 Primary etiologies of CFDs include function alterations of the FOLR1 gene coding for folate receptor-alpha (FRα) and IMDs in which there is a deficiency of methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase, and 5,10 methyltetrahydrofolate synthetase (MTHFS). Folate deficiency can also be secondary to other IMDs, such as mitochondrial disorders (especially Kearns-Sayre syndrome) and serine deficiency, and due to FRα autoantibodies that hinder the transport of folate into the cerebrum.…”

“…Treatment approaches for the primary causes of CFDs include folinic acid, betaine in the case of MTHFR deficiency, and 5-methyltetrahydrofolate and intramuscular methylcobalamin in the case of MTHFS deficiency. 11 Complementary to classic vitamin-sensitive disorders, new vitamin-responsive neurometabolic disorders continue to be identified. While classic biotinidase deficiency, with a phenotype of developmental impairment, hypotonia, focal or generalized tonic-clonic seizures, ataxia, and cutaneous lesions, including alopecia, responds to biotin dosing of 10 mg daily, holocarboxylase synthetase deficiency and biotin responsive basal ganglia disease are also biotin responsive.…”

“…Treatment approaches for the primary causes of CFDs include folinic acid, betaine in the case of MTHFR deficiency, and 5-methyltetrahydrofolate and intramuscular methylcobalamin in the case of MTHFS deficiency. 11…”

Methylenetetrahydrofolate Reductase C677T Gene Variant in Relation to Body Mass Index and Folate Concentration in a Polish Population

“…There are about 40 natural folate compounds. They differ from each other in the degree of oxidation of mono-carbon groups, such as methyl (-CH 3 ), methylene (-CH 2 -), methenyl (-CH=), formyl (-CH=O) and formimino (-CH=NH), as well as in the number of glutamic acid residues attached [ 11 ]. Folates supplied by the diet are metabolized to 5-MTHF in several steps.…”

A case of folate deficiency showing behavioural variant of frontotemporal dementia‐like symptoms

“…Regarding folate deficiency and brain imaging, myelination defects in cerebral white matter and cerebral and cerebellar atrophy have been reported in paediatric patients with congenital folate malabsorption. 5 By contrast, reports on adult patients are still lacking. In our patient's case, chronic folate deficiency resulted in disturbed metabolism of neural tissue, causing atrophy and reduced blood flow in the temporal and medial frontal lobes, which likely contributed to the bvFTD-like symptoms.…”