Purpose: To characterize various RHO mutations, including rare and incompletely characterized ones, causing ADRP exhibiting a consistently altitudinal phenotype

Methods: Eight patients were examined (age range: 35-68 years; M/F: 5/3), presenting with the G106R mutation (n= 2), the incompletely described phenotypes associated with the N15S (n= 1) and the P180A (n= 3) mutation, and the previously uncharacterized E341K mutation (n= 2). Visual function was assessed via best corrected visual acuity (BCVA), semiautomated kinetic perimetry (SKP), dark adapted chromatic (DAC) perimetry, and full-field flash ERG (ffERG). Retinal imaging studies included ultra-wide field fundus autofluorescence (UWF-FAF) and photography, and spectral domain optical coherence tomography (SD-OCT)

Results: Most patients presented with late-onset symptoms, good visual acuity, excellent ffERG preservation, and regional/altitudinal retinal changes and visual field loss (Class B1 phenotype) also late in the disease. Some affected patients were subjectively asymptomatic but showed the same Class B1 phenotype. DAC perimetry showed excellent rod function preservation with regional losses corresponding to clinically more affected areas. An unusually large decrease in cone-driven ffERGs was found in N15S, E341K and P180A patients (cone≥ rod pattern). Hyper-autofluorescent (AF) bands on FAF images were closely correlated with the portions of the visual field with best vision (I4e SKP target) and best preserved rod-mediated function (DAC perimetry). The external limiting membrane (ELM) and ellipsoid zone (EZ) on SD-OCT corresponded closely with the outer and inner boundaries, respectively, of the hyper-AF bands. Reduced but persistent perimetric sensitivity was seen also outside the boundaries of the hyper-AF bands, where the EZ was no longer detectable.

Conclusions: Mutations in both the intradiscal and the cytoplasmic domains can be associated with an altitudinal/regional Class-B1 phenotype, including the C-terminal and previously uncharacterized E341K mutation. Despite consistently mild disease also into the 7th decade of life, an unexpected severity of cone disease was observed in some patients. Our investigation expands the spectrum of RHO-associated altitudinal ADRP, and increases our understanding on this unique subgroup of ADRP patients.