FOLR1 – Cerebral Folate Deficiency

Cerebral folate deficiency is an autosomal recessive neurodevelopmental disorder caused by bi‐allelic pathogenic variants in FOLR1, which encodes the brain‐specific folate receptor α. Affected infants present in late infancy with psychomotor regression, refractory epilepsy, hypomyelination, cortical involvement, ataxia, and polyneuropathy. Cerebrospinal fluid 5‐methyltetrahydrofolate (5-MTHF) is profoundly reduced despite normal peripheral folate levels. Early diagnosis is critical, as high‐dose folinic acid supplementation can ameliorate neurologic decline and improve seizure control.

Genetic evidence for FOLR1’s role in cerebral folate deficiency comprises at least 7 probands from 5 unrelated families with homozygous missense variants (c.466T>G (p.Trp156Gly), c.524G>T (p.Cys175Phe), c.197G>A (p.Cys66Tyr), c.245A>G (p.Tyr82Cys), c.148G>A (p.Glu50Lys)) ([PMID:27743887]; [PMID:33243190]; [PMID:33105619]; [PMID:37101857]; [PMID:39328591]). Segregation of disease with FOLR1 variants was confirmed in two sibships ([PMID:37101857]; [PMID:27066576]). All identified variants are absent or extremely rare in population databases and affect conserved residues critical for receptor structure.

Inheritance is autosomal recessive, with compound‐heterozygous or homozygous missense changes disrupting folate binding. Variant spectrum includes at least five missense alleles, each reported in at least one affected individual. The recurrent c.466T>G (p.Trp156Gly) allele has been observed in multiple consanguineous pedigrees, suggesting a potential founder effect in certain populations.

Functional studies demonstrate that glycosylation of FRα is essential for proper folding and surface expression. Site‐directed mutagenesis of FOLR1 glycosylation sites in CHO cells reduced folic acid binding affinity 2.7‐ to 3.5‐fold and abolished membrane localization when all three sites were disrupted ([PMID:9515058]). Folinic acid rescue experiments in patients and animal models confirm that supplementation restores CSF 5-MTHF levels and reverses neurologic symptoms, supporting a loss‐of‐function mechanism.

No conflicting genetic evidence has been reported; multi‐patient analyses of non‐FOLR1 CFD cases underscore the genetic heterogeneity of low CSF 5-MTHF but do not implicate FOLR1 variants in such cohorts ([PMID:21737328]).

Together, robust genotype–phenotype correlations and concordant functional data fulfill ClinGen criteria for a Strong gene–disease relationship. FOLR1 genetic testing should be integrated into the diagnostic workup of unexplained infantile leukodystrophy and epilepsy with low CSF folate. Early identification enables prompt folinic acid therapy, which can significantly improve neurologic outcomes.

References

• Brain & development • 2017 • Severe leukoencephalopathy with cortical involvement and peripheral neuropathy due to FOLR1 deficiency. PMID:27743887
• BMC medical genetics • 2020 • First case report of cerebral folate deficiency caused by a novel mutation of FOLR1 gene in a Chinese patient. PMID:33243190
• Brain sciences • 2020 • Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease. PMID:33105619
• Molecular genetics and metabolism reports • 2023 • Cerebral folate deficiency: A report of two affected siblings. PMID:37101857
• Neurology. Genetics • 2016 • Late diagnosis of cerebral folate deficiency: Fewer seizures with folinic acid in adult siblings. PMID:27066576
• 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

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