FOLR1 – neurodegenerative syndrome due to cerebral folate transport deficiency

FOLR1 encodes the folate receptor α (FRα), which mediates active transport of 5-methyltetrahydrofolate across the blood–CSF barrier. Biallelic pathogenic variants in FOLR1 cause an autosomal recessive neurodegenerative syndrome characterized by late-infantile onset of psychomotor regression, ataxia, movement disorders, epilepsy, cerebellar atrophy and hypomyelination in the CNS (PMID:20857335). Early CSF analysis reveals profound 5-MTHF deficiency with low CSF/plasma folate ratio, prompting FOLR1 mutation screening.

Genetic evidence supports a definitive gene–disease relationship. Over 30 probands have been reported worldwide (PMID:37443037), including a cohort of 10 unrelated children with AR inheritance and segregation in multiple families (PMID:22586289). Single-family segregation has been documented in at least three sibships, confirming co-segregation of homozygous variants and disease. The variant spectrum comprises missense (e.g., c.148G>A (p.Glu50Lys) (PMID:39328591)), nonsense (c.327_328delinsAC (p.Cys109Ter), c.382C>T (p.Arg128Trp)), frameshift (c.465_466delinsTG (p.Trp156Gly), c.466T>G (p.Trp156Gly)), splice-site and deep-intronic alleles.

Functional studies demonstrate loss-of-function due to impaired receptor glycosylation, mislocalization, and abolished folic acid binding. Site-directed mutagenesis at N-linked glycosylation sites showed that triple glycosylation mutants lacked cell surface expression and binding capacity (PMID:9515058). In patient-derived cells and transfected models, pathogenic variants abrogate FRα trafficking, confirming haploinsufficiency as the pathogenic mechanism.

Clinical rescue with folinic acid underscores therapeutic relevance. Early initiation of intramuscular or oral folinic acid resulted in stabilization or reversal of neurological signs, neuroradiological improvement, and partial recovery even in older children (PMID:37443037; PMID:27743887). Delayed treatment leads to incomplete seizure control and progression of ataxia.

No studies have refuted the association, and no alternative phenotypes have been convincingly linked to FOLR1 loss-of-function. The consistency of AR inheritance, robust segregation, and concordant functional data across multiple cohorts establish a definitive clinical validity.

In summary, FOLR1 variants cause a treatable AR cerebral folate transport deficiency. Early genetic diagnosis enables prompt folinic acid therapy, which can dramatically alter disease course and improve neurological outcomes.

References

• Journal of inherited metabolic disease • 2010 • Progressive ataxia and myoclonic epilepsy in a patient with a homozygous mutation in the FOLR1 gene. PMID:20857335
• Brain : a journal of neurology • 2012 • Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. PMID:22586289
• Archives of biochemistry and biophysics • 1998 • Role of individual N-linked glycosylation sites in the function and intracellular transport of the human alpha folate receptor. PMID:9515058
• Orphanet journal of rare diseases • 2023 • Hypomyelination caused by a novel homozygous pathogenic variant in FOLR1: complete clinical and radiological recovery with oral folinic acid therapy and review of the literature. PMID:37443037
• Brain & development • 2017 • Severe leukoencephalopathy with cortical involvement and peripheral neuropathy due to FOLR1 deficiency. PMID:27743887
• Journal of epilepsy research • 2024 • Cerebral Folate Transport Deficiency in 2 Cases with Intractable Myoclonic Epilepsy. PMID:38978529
• Frontiers in pediatrics • 2024 • Case Report: Cerebral folate deficiency caused by FOLR1 variant. PMID:39328591

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