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

Abstract

Objectives: The objective of this case report was to describe the first report of FOLR1 variants associated with adult-onset paucisymptomatic leukoencephalopathy associated with cerebral folate deficiency (CFD).

Methods: Considering the patient's symptoms, a nonprogressive leukoencephalopathy was suspected. CSF 5-methyltetrahydrofolate levels were low (10 nmol/L, normal range 41-117). With no other identifiable causes, a genetic analysis was conducted, revealing a compound heterozygous FOLR1 variation (c.45G>T and c. 493+2T>C).

Results: A 47-year-old man with a history of drug and alcohol abuse was admitted to the hospital for double vision and postural instability. MRI of the brain was performed, which showed bilateral leukoencephalopathy. Diffusion tensor imaging revealed a diffuse reduction in fractional anisotropy, suggesting microstructural changes. MRI of the brain and overall clinical picture were stable on subsequent serial examinations.

Discussion: Scientific evidence supports the deleterious effect of c.45G>T and c.493+2T>C variations on the folate receptor-α (FRα) protein structure and function. The weakness of the expression and function of FRα without elimination of its function caused by specific compound heterozygous variations may explain the atypical features observed in our patient. Although rare, CFD should be considered in paucisymptomatic adult patients with stable diffuse MRI white matter changes.

Figure. MRI FLAIR Axial Images Performed at Symptoms Onset and 2 Years Later and Correspondent Baseline Diffusion Tensor Imaging (DTI) Analysis Comparing the Patient With a Sex-Matched and Age-Matched Healthy Control (HC) Subject

MRI of the brain showed diffuse, bilateral, and symmetric supratentorial hyperintensities on FLAIR images, without enhancement after gadolinium injection (A) stable 2 years later (B). DTI revealed a diffuse decrease in fractional anisotropy in the CFD patient (C) when compared with a HC (D), suggesting a widespread microstructural damage beyond the lesional tissue.