CLINICAL CHARACTERIZATION OF DISEASE SEVERITY AND PROGRESSION IN X–LINKED RETINITIS PIGMENTOSA (XLRP) ASSOCIATED WITH RPGR MUTATIONS:

Abstract

Abstract: : Purpose: Comprehensive gene mutation analysis¹ was conducted in a 4–yr clinical trial cohort of patients with XLRP. Clinically–defined disease severity and rate of progression was compared among the spectrum of identified mutations. Methods: Young males diagnosed with XLRP (n=44; mean age=16.2yrs) were screened for mutations by linkage analysis and/or direct sequencing of the RP2 and RPGR genes including exons 1–19 and ORF15. Visual function measurements included standard full–field ERGs obtained using the ISCEV protocol, peripheral field assessment, dark adaptation, and visual acuity. Mutation analysis and visual function testing was also conducted on the heterozygous mother when available (n=24; age=40yrs) for comparison to reference normal females (n=72; age=46yrs). Results: Mutations were identified in 5/44 patients (age=14.6yrs) for RPGR exons 1–14 (RPGR/1–14), 13/44 patients for ORF15 (age=16.9yrs), and none for RP2. Linkage analysis found 2/44 patients linked to the RP24 locus. Phenotypic comparison in male patients found 62 to 75% lower cone and rod ERG amplitudes, respectively, for mutations in RPGR /1–14 compared to ORF15 (p=0.046 and 0.12; age–corrected ANOVA). Although visual acuity, dark–adapted thresholds and progression (measured by loss in yearly cone ERG amplitude) were not significantly different between the groups, visual fields were marginally smaller in males with RPGR/1–14 mutations (7 vs 11 degrees). Mean rod and cone ERG amplitudes in XLRP carriers were reduced 70% (p<0.0001) compared to normal females. Visual function parameters did not differ significantly between RPGR/1–14 (n=5) and ORF15 (n=9) mutations in this limited sample of carriers. Conclusions: ORF15 mutations have been reported² to be associated with a slightly less severe RPGR phenotype. Here early stage XLRP patients with ORF15 mutations had, on average, better rod and cone ERG amplitudes as well as marginally larger visual field areas compared to RPGR/1–14 mutations. ¹ Breuer et al. (2002) Am. J. Hum. Genet.; ² Sharon et al. (2003) Am. J. Hum. Genet.

Keywords: genetics • mutations • retinal degenerations: hereditary