FOLR1 Gene Variation With Adult-Onset Cerebral Folate Deficiency and Stable Clinical and MRI Features up to 2 Years

Discussion

FOLR1 gene variations are associated with CFD, an autosomal recessive disorder characterized by low CSF 5-MTHF concentrations, normal plasma folate values, and late infantile onset with severe developmental regression, epilepsy, and leukodystrophy.^3,4 Folic acid and folates are essential for neurodevelopment and myelin formation^5,6 after intestinal absorption and are reduced, methylated, and enters the circulation as 5-MTHF. The FOLR1 gene encodes for the folate receptor-α (FRα), which is essential in allowing 5-MTHF to cross the blood-brain barrier.⁷

Our patient is the first reported case in the literature of a compound heterozygous variation of FOLR1 associated with adult-onset leukoencephalopathy and clinical paucisymptomatic picture. Based on the available data, patient's conditions have remained stable over time in the absence of treatment. Despite the mild clinical involvement, MRI changes were diffuse and DTI analysis showed the presence of diffuse microstructural changes beyond lesional white matter.

From a genetic standpoint, in our patient, we identified 2 genetic variations. The first variation is the c.45G>T variation, which is categorized as a missense variation. The second variation is the c.493+2T>C variation, affecting the donor site of the splice. In the ClinVar database, the c.45G>T variation has been reported with supporting evidence indicating its deleterious effects on protein structure and function, as suggested by silicon analysis. In addition, Grapp et al. conducted a study using FRα expression model cell systems and fibroblasts from a cohort of patients with missense variations in the FOLR1 gene. Their findings revealed that although FRα was expressed, it was not properly localized to the cell membrane. Instead, it was misdirected to various intracellular compartments, leading to a reduction in folic acid binding, thus compromising its primary target.⁷

The c.493+2T>C variation, despite having a total frequency of 0.3123% in the general population according to the genome aggregation database, could potentially lead to the loss of protein function and contribute to the development of the disease. However, conflicting data regarding the true pathogenicity of this variation have been reported in the literature.^8,9 Prediction software for splice alterations, such as BDGP and ESEfinder, suggests that the c.493+2T>C variation may disrupt or weaken the native splice donor site.

Therefore, one possible explanation for the atypical features observed in our patient could be that the presence of these specific compound heterozygous variations weakens the expression and function of FRα without completely eliminating its function. This partial impairment could result in a milder phenotype with late-onset symptoms and a relatively limited number of symptoms (pauci-symptomatic phenotype). The variations may cause a blurred picture of the disease presentation, deviating from the typical pattern seen in cases with a complete loss of function. This phenomenon highlights the complexity of genotype-phenotype correlations and suggests that variations in the degree of protein impairment can lead to diverse clinical manifestations.

In conclusion, this clinical case is an example of how variations in the FOLR1 gene can be present in adults with limited clinical findings and a stable disease course. Thus, it highlights the importance of considering the diagnosis of CFD in adult patients presenting with neurologic symptoms and exhibiting a leukodystrophy pattern on MRI. This case underscores the need for increased awareness and recognition of CFD in the adult population to ensure appropriate diagnosis and management of this condition.