A novel ocular phenotype associated with pathogenic variants in MFSD8 leading to macular dystrophy

Background: The major facilitator superfamily domain-containing protein 8 (MFSD8) pathogenic variants are classically associated with autosomal recessive neuronal ceroid lipofuscinosis-7. Case reports have recently demonstrated an association of MFSD8 variants causing autosomal recessive macular dystrophy with central cone involvement without neurologic sequelae. We report a patient with a novel ocular phenotype associated with MFSD8 pathogenic variants causing macular dystrophy without systemic findings. Case presentation: A 37-year-old female presented with a 20-year history of progressive bilateral vision loss. Fundus examination was notable for a slight pigmentary ring around the fovea in both eyes. Optical coherence tomography (OCT) of the macula showed bilateral subfoveal ellipsoid zone loss without outer retinal changes. Fundus autofluorescence (FAF) demonstrated foveal hypo-autofluorescence (AF) in both eyes as well as hyper-AF nasally to the optic nerve in the perifoveal area. Full-field and multifocal electroretinography demonstrated cone dysfunction with diffuse macular changes in both eyes. Subsequent genetic testing identified two pathogenic MFSD8 variants. The patient had no neurologic symptoms consistent with variant-late infantile neuronal ceroid lipofuscinosis. Conclusion: MFSD8 pathogenic variants are known to cause macular dystrophies. We report a novel MFSD8-associated macular dystrophy phenotype demonstrating foveal-limited disease with cavitary changes on OCT without inner retinal atrophy and foveal-specific changes on FAF. A threshold model can explain how a hypomorphic missense variant heterozygous with a loss-of-function nonsense variant can lead to a predominantly ocular phenotype with preserved neurologic function. We recommend careful monitoring of these patients for future signs of both retinal and systemic disease progression.