Original Investigation | Clinical Sciences

Phenotypic Conservation in Patients With X-Linked Retinitis Pigmentosa Caused by RPGR Mutations

Sarwar Zahid, MD, MS1; Naheed Khan, PhD1; Kari Branham, MS1; Mohammad Othman, PhD1; Athanasios J. Karoukis, BS1; Nisha Sharma1; Ashley Moncrief, BS1; Mahdi N. Mahmood1; Paul A. Sieving, MD, PhD2; Anand Swaroop, PhD2; John R. Heckenlively, MD1; Thiran Jayasundera, MD1
[+] Author Affiliations
1Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor
2National Eye Institute, National Institutes of Health, Bethesda, Maryland
JAMA Ophthalmol. 2013;131(8):1016-1025. doi:10.1001/jamaophthalmol.2013.120.
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Importance  For patients with X-linked retinitis pigmentosa and clinicians alike, phenotypic variability can be challenging because it complicates counseling regarding patients’ likely visual prognosis.

Objective  To evaluate the clinical findings from patients with X-linked retinitis pigmentosa with 13 distinct RPGR mutations and assess for phenotypic concordance or variability.

Design  Retrospective medical record review of data collected from 1985 to 2011.

Setting  Kellogg Eye Center, University of Michigan.

Patients  A total of 42 patients with X-linked retinitis pigmentosa with mutations in RPGR. Age at first visit ranged from 4 to 53 years, with follow-up ranging from 1 to 11 visits (median follow-up time, 5.5 years; range, 1.4-32.7 years, for 23 patients with >1 visit).

Main Outcomes and Measures  Clinical data assessed for concordance included visual acuity (VA), Goldmann visual fields (GVFs), and full-field electroretinography (ERG). Electroretinography phenotype (cone-rod vs rod-cone dysfunction) was defined by the extent of photopic vs scotopic abnormality. Qualitative GVF phenotype was determined by the GVF pattern, where central or peripheral loss suggested cone or rod dysfunction, respectively. Goldmann visual fields were also quantified and compared among patients.

Results  Each mutation was detected in 2 or more related or unrelated patients. Five mutations in 11 patients displayed strong concordance of VA, while 4 mutations in 16 patients revealed moderate concordance of VA. A definitive cone-rod or rod-cone ERG pattern consistent among patients was found in 6 of 13 mutations (46.2%); the remaining mutations were characterized by patients demonstrating both phenotypes or who had limited data or nonrecordable ERG values. Concordant GVF phenotypes (7 rod-cone pattern vs 4 cone-rod pattern) were seen in 11 of 13 mutations (84.6%). All 6 mutations displaying a constant ERG pattern within the mutation group revealed a GVF phenotype consistent with the ERG findings.

Conclusions and Relevance  While VA and ERG phenotypes are concordant in only some patients carrying identical mutations, assessment of GVF phenotypes revealed stronger phenotypic conservation. Phenotypic concordance is important for establishing proper counseling of patients diagnosed as having X-linked retinitis pigmentosa, as well as for establishing accurate patient selection and efficacy monitoring in therapeutic trials.

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Figure 1.
Examples of Goldmann Visual Field (GVF) Phenotypes and Phenotypic Concordance and Discordance

Illustrations show an example of discordant GVF phenotypes in 2 cousins with the same mutation (p.Glu746fs) (A, cone-rod phenotype and B, rod-cone phenotype). The rod-cone phenotypes show an example of GVF phenotypic concordance in 2 brothers with the same mutation (exon 2-3 deletion) (C and D). Isopters shown in this figure include IV4e (red), III4e (green), and I4e (black).

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Figure 2.
Graphical Representation of Mutations in RPGR Identified in Our Cohort

Ten of the identified mutations were located in ORF15. RCC1 indicates regulator of chromosome condensation 1.

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Figure 3.
Overall Longitudinal LogMAR Visual Acuity (VA) Deterioration

Average logMAR VA from all visits from 40 patients was plotted against age, which showed that VA tended to worsen with age. A, Least-squares regression analysis with a slope reflecting VA deterioration with time (in logMAR units/y) and corresponding R2 coefficient. B, Polynomial regression analysis with corresponding R2 coefficient. Visual acuity measurements from patients younger than age 5 years or those taken from patients after initiation of experimental therapies were excluded. The R2 values for these calculations did not improve with setting a floor of analysis at higher ages (eg, excluding data points at younger than age 20 years).

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Figure 4.
Summary of Phenotypic Concordance in Visual Acuity (VA), Electroretinography (ERG), and Goldmann Visual Field (GVF) Data

Numbers of mutations exhibiting strong, moderate, or weak concordance for each modality are shown. Phenotypic concordance was highest when assessed by comparing GVF phenotypes between patients.

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Figure 5.
Comparison of Quantified Goldmann Visual Fields for Select RPGR Mutations

Visual fields from patients with the same mutations who were within 6 years of age at time of testing were quantified using Adobe Photoshop CS3. Normal total I4e area was determined by calculating the average total I4e from 10 normal eyes to determine the percentage of normal in patients. A and B represent 2 siblings (exon 2-3 deletion) both exhibiting a rod-cone phenotype. The percentage difference between the 2 I4e areas was 0.13%. C and D also represent 2 siblings with a rod-cone phenotype (p.Gly753fs), whose percentage difference was 0.09%. E and F represent 2 siblings with a mutation near the 3′-end of RPGR (p.Glu1014fs) who both exhibit a cone-rod Goldmann visual field phenotype. Their quantified percentage difference was larger at 22.1%, but both patients displayed relatively large visual fields with the I4e isopter.

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