Genotype–Phenotype Correlation in Malattia Leventinese Patients With Homo–Heterozygote R345W Mutation in Fibulin 3

Abstract

Abstract: : Purpose: To correlate the clinical and pathologic phenotypes caused by homozygous and heterozygote R345W mutations in two patients (patient A and B respectively) with Malattia Leventinese (ML). Methods: The clinical charts of two deceased female ML patients who donated their eyes were retrospectively reviewed. Light microscopy (LM) was performed on eye globes from both patients. Transmission electron microscopy (TEM) was documented in patient B only. Mutation analysis was performed by bidirectional sequencing of exon 10 of Fibulin 3 (FBLN3). Results: The natural history of both patients was very similar in terms of central vision loss, slightly in favour of patient A. Their fundus examination at the 8^th decade of life showed widespread macular atrophy extending nasally to the optic disc with radial drusen–like deposits at its border. The rod and cone–driven b–waves amplitudes were decreased in both patients. On LM, patient A presented a diffuse, focally nodular, multilayered fibrillary thickening of entire Bruch’s membrane, above which the RPE and the outer retina showed various degrees of atrophy. The underlying choroid was slightly attenuated. TEM showed minimal basal linear deposits, no basal laminar deposits, but an important amount of granular deposits between RPE and Bruch’s membrane. In patients B similar deposits were visible at the posterior pole sparing the region anterior to the equator. Moreover, unlike in patient A, complete choroid, or RPE and retina atrophy was sometimes present unrelated to any deposits. Conclusions: The clinical outcome of both patients was roughly similar. LM revealed a different distribution of the deposits extending to the ora serrata in patient A and confined behind the equator in patient B. TEM showed the deposits to differ from age–related macular deposits. Altogether these data support complete dominance for this FBLN3 mutation.

Keywords: retina • genetics • pathology: human