Genetic Characteristics and Long-Term Follow-Up of Slovenian Patients with RPGR Retinal Dystrophy

Abstract

Genetic characteristics and a long-term clinical follow-up of 18 Slovenian retinitis pigmentosa GTPase regulator (RPGR) patients from 10 families with retinitis pigmentosa (RP) or cone/cone-rod dystrophy (COD/CORD) are reported. RP (eight families) was associated with two already known (p.(Ser407Ilefs*46) and p.(Glu746Argfs*23)) and five novel variants (c.1245+704_1415-2286del, p.(Glu660*), p.(Ala153Thr), c.1506+1G>T, and p.(Arg780Serfs*54)). COD (two families) was associated with p.(Ter1153Lysext*38). The median age of onset in males with RP (N = 9) was 6 years. At the first examination (median age of 32 years), the median best corrected visual acuity (BCVA) was 0.30 logMAR, and all patients had a hyperautofluorescent ring on fundus autofluorescence (FAF) encircling preserved photoreceptors. At the last follow-up (median age of 39 years), the median BCVA was 0.48 logMAR, and FAF showed ring constriction transitioning to patch in 2/9. Among females (N = 6; median age of 40 years), two had normal/near-normal FAF, one had unilateral RP (male pattern), and three had a radial and/or focal pattern of retinal degeneration. After a median of 4 years (4–21) of follow-up, 2/6 exhibited disease progression. The median age of onset in males with COD was 25 years. At first examination (median age of 35 years), the median BCVA was 1.00 logMAR, and all patients had a hyperautofluorescent FAF ring encircling foveal photoreceptor loss. At the last follow-up (median age of 42 years), the median BCVA was 1.30 logMAR, and FAF showed ring enlargement. The majority of the identified variants (75%; 6/8) had not been previously reported in other RPGR cohorts, which suggested the presence of distinct RPGR alleles in the Slovenian population.

Molecular Mechanisms Governing Sight Loss in Inherited Cone Disorders

“…RPGR appears to play a role in outer-segment maintenance [ 82 ]. Nonsense or truncating mutations predominantly cause X-linked retinitis pigmentosa (XLRP) [ 78 , 81 ], but rod–cone or cone–rod dystrophies can develop [ 83 , 84 ]. The location of the variants seemingly affects the phenotype of RPGR mutations, with disease-causing mutations within exons 1–14 predominantly causing retinitis pigmentosa, truncating mutations within ORF15 leading to CORD, and mutations in the C-terminal basic domain causing a COD phenotype [ 85 ].…”

“…Furthermore, the 30 Hz flicker gives no/very little measurable response [ 16 ]. The average age of onset is 25 years, reaching legal blindness by 42 years [ 83 , 84 ].…”