Czech and Slovak Ophthalmology 503 Original article Clinical Findings in Members of a Czech Family with Retinitis Pigmentosa Caused by c.2426_2427delAG Mutation in RPGR Kousal Bohdan Skalická Eva Diblík Pavel Kuthan Pavel Langrová Hana https://orcid.org/0000-0001-8488-7208 Lišková Petra https://orcid.org/0000-0001-7834-8486 25 2 2013 1 2

Purpose: To describe the phenotype of members of the first Czech retinitis pigmentosa family with an identified molecular genetic cause (c.2426_2427delAG in RPGR), followed for more than 13 years. Methods: Medical records were reviewed and a detailed ophthalmic examination including spectral-domain optical coherence tomography and full-field and multifocal electroretinography (ERG) was performed in two affected males, three female carriers and one unaffected female. Results: A 22-year-old male who denied suffering from nyctalopia had a best corrected visual acuity (BCVA) of 0.63 in both eyes. Moderate myopia and myopic astigmatism were present bilaterally. Color vision and contrast sensitivity were normal. There was an eccentric constriction of the visual fields that spared the central 20 degrees in both eyes. Fundus examination revealed bilateral pigmentary changes in the mid-periphery. Full-field ERG documented a 10% rod and 20% cone response. The phenotype of his cousin, also aged 22 years, was more severe. He complained of nyctalopia since 12 years of age. His BCVA was 0.3 in the right eye and 0.5 in the left eye. Myopia and astigmatism were present bilaterally. Contrast sensitivity and color vision were severely impaired. Full field ERG was extinct, but some activity on multifocal ERG was still detectable. The constriction of the visual fields reached 5 degrees in both eyes. Fundus examination showed the typical retinitis pigmentosa appearance. All carriers denied that they suffered from nyctalopia, but two of them had decreased BCVA in at least one eye. None exhibited typical bone spicules or a tapetal-like reflex. Significant refractive errors were present in all eyes of the carriers. Conclusion: The finding of moderate or high myopia and astigmatism in males with retinitis pigmentosa as well as refractive errors in female relatives indicates possible X-linked inheritance, which may be especially important in pedigrees where the transmission pattern can not be clearly established. Our study highlights the inter-individual variability in phenotype observed in similar aged patients with identical ORF15 RPGR mutations.

 retinitis pigmentosa phenotype multifocal ERG mutation RPGR References Adamian, M., Pawlyk, BS., Hong, DH., et al.: Rod and cone opsin mislocalization in an autopsy eye from a carrier of X-linked retinitis pigmentosa with a Gly436Asp mutation in the RPGR gene. Am J Ophthalmol. 2006; 142: 515–8. Ayyagari, R., Demirci, FY., Liu, J., et al.: Xlinked recessive atrophic macular degeneration from RPGR mutation. Genomics. 2002; 80: 166–71. Bader, I., Brandau, O., Achatz, H., et al.: Xlinked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15. Invest Ophthalmol Vis Sci. 2003; 44: 1458–63. Beltran, WA., Cideciyan, AV., Lewin, AS., et al.: Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X- -linked retinitis pigmentosa. Proc Natl Acad Sci U S A. 2012; 109: 2132–7. Berendschot, TT., DeLint, PJ., van Norren, D.: Origin of tapetal-like reflexes in carriers of X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci. 1996; 37: 2716–23. Berger, W., Kloeckener-Gruissem, B., Neidhardt, J.: The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010; 29: 335–75. Breuer, DK., Yashar, BM., Filippova, E., et al.: A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. Am J Hum Genet. 2002; 70: 1545–54. Daiger, SP., Bowne, SJ., Sullivan, LS.: Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol. 2007; 125: 151–8. Demirci, FY., Rigatti, BW., Wen, G., et al.: X-linked cone-rod dystrophy (locus COD1): identification of mutations in RPGR exon ORF15. Am J Hum Genet. 2002; 70: 1049–53. Ebenezer, ND., Michaelides, M., Jenkins, SA., et al.: Identification of novel RPGR ORF15 mutations in X-linked progressive conerod dystrophy (XL- CORD) families. Invest Ophthalmol Vis Sci. 2005; 46: 1891–8. Fahim, AT., Bowne, SJ., Sullivan, LS., et al.: Allelic heterogeneity and genetic modifier loci contribute to clinical variation in males with X-linked retinitis pigmentosa due to RPGR mutations. PLoS One. 2011; 6: e23021. Fiorentino, F., Magli, MC., Podini, D., et al.: The minisequencing method: an alternative strategy for preimplantation genetic diagnosis of single gene disorders. Mol Hum Reprod. 2003; 9: 399–410. Fishman, GA., Farber, MD., Derlacki, DJ.: X-linked retinitis pigmentosa. Profile of clinical findings. Arch Ophthalmol. 1988; 106:369–75. Fishman, GA., Weinberg, AB., McMahon, TT.: X-linked recessive retinitis pigmentosa. Clinical characteristics of carriers. Arch Ophthalmol. 1986; 104: 1329–35. Flaxel, CJ., Jay, M., Thiselton, DL., et al.: Difference between RP2 and RP3 phenotypes in X linked retinitis pigmentosa. Br J Ophthalmol. 1999; 83: 1144–8. Garcia-Hoyos, M., Garcia-Sandoval, B., Cantalapiedra, D., et al.: Mutational screening of the RP2 and RPGR genes in Spanish families with X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2006; 47: 3777–82. Gerth, C., Wright, T., Heon, E., et al.: Assessment of central retinal function in patients with advanced retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2007; 48: 1312–8. Girardet, A., Hamamah, S., Anahory, T., et al.: First preimplantation genetic diagnosis of hereditary retinoblastoma using informative microsatellite markers. Mol Hum Reprod. 2003; 9: 111–6. Goodwin, P.: Hereditary retinal disease. Curr Opin Ophthalmol. 2008; 19: 255–62. Hamel, C.: Retinitis pigmentosa. Orphanet J Rare Dis. 2006; 1: 40. Hamel, CP.: Cone rod dystrophies. Orphanet J Rare Dis. 2007; 2: 7. Hartong, DT., Berson, EL., Dryja, TP.: Retinitis pigmentosa. Lancet. 2006; 368: 1795–809. Haymes, SA., Roberts, KF., Cruess, AF., et al.: The letter contrast sensitivity test: clinical evaluation of a new design. Invest Ophthalmol Vis Sci. 2006; 47: 2739–45. Hood, DC., Holopigian, K., Greenstein, V., et al.: Assessment of local retinal function in patients with retinitis pigmentosa using the multi-focal ERG technique. Vision Res. 1998; 38: 163-79. Hosch, J., Lorenz, B., Stieger, K.: RPGR: role in the photoreceptor cilium, human retinal disease, and gene therapy. Ophthalmic Genet. 2011; 32: 1–11. Jacobson, SG., Cideciyan, AV., Ratnakaram, R., et al.: Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012; 130: 9–24. Jin, ZB., Gu, F., Ma, X., et al.: Identification of a novel RPGR exon ORF15 mutation in a family with X-linked retinitis pigmentosa. Arch Ophthalmol. 2007; 125: 1407–12. Jin, ZB., Liu, XQ., Hayakawa, M., et al.: Mutational analysis of RPGR and RP2 genes in Japanese patients with retinitis pigmentosa: identification of four mutations. Mol Vis. 2006; 12: 1167–74. Klouãek, F., Kubíãková, Z., Otradovec, J., et al.: Vy‰etfiení rozsáhlého rodokmenu s retinopathia pigmentosa, vázanou na pohlaví a studium vazby s Xg skupinou. âs. Oftal. 1979; 35: 120–5. Liskova, P., Colclough, T., Hart-Holden, N., et al.: Molecular genetic cause of X-linked retinitis pigmentosa in a Czech family. Acta Ophthalmol. 2011; 89: e213–5. Marmor, MF., Fulton, AB., Holder, GE., et al.: ISCEV Standard for full-field clinical electroretinography (2008 update). Doc Ophthalmol. 2009; 118: 69–77. Neidhardt, J., Glaus, E., Lorenz, B., et al.: Identification of novel mutations in X-linked retinitis pigmentosa families and implications for diagnostic testing. Mol Vis. 2008; 14: 1081–93. Otradovec, J., Klouãek, F., Kubíãková, Z., et al.: Variabilita klinického obrazu u heterozygotek pigmentové retinopatie, vázané na pohlaví. âs. Oftal. 1979; 35: 126–31. Pelletier, V., Jambou, M., Delphin, N., et al.: Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling. Hum Mutat. 2007; 28:81–91. Prokisch, H., Hartig, M., Hellinger, R., et al.: A population-based epidemiological and genetic study of X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2007; 48: 4012–8. Sandberg, MA., Rosner, B., Weigel- -DiFranco, C., et al.: Disease course of patients with X-linked retinitis pigmentosa due to RPGR gene mutations. Invest Ophthalmol Vis Sci. 2007; 48: 1298–304. Seeliger, M., Kretschmann, U., Apfelstedt-Sylla, E., et al.: Multifocal electroretinography in retinitis pigmentosa. Am J Ophthalmol. 1998; 125: 214–26. Sharon, D., Bruns, GA., McGee, TL., et al.: X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function. Invest Ophthalmol Vis Sci. 2000; 41: 2712–21. Sheng, X., Li, Z., Zhang, X., et al.: A novel mutation in retinitis pigmentosa GTPase regulator gene with a distinctive retinitis pigmentosa phenotype in a Chinese family. Mol Vis. 2010; 16: 1620–8. Shu, X., Black, GC., Rice, JM., et al.: RPGR mutation analysis and disease: an update. Hum Mutat. 2007; 28: 322–8. Sohrab, MA., Allikmets, R., Guarnaccia, MM., et al.: Preimplantation genetic diagnosis for Stargardt disease. Am J Ophthalmol. 2010; 149: 651–655 e2. Sundaram, V., Moore, AT., Ali, RR., et al.: Retinal dystrophies and gene therapy. Eur J Pediatr. 2012; 171: 757–65. Vajaranant, TS., Seiple, W., Szlyk, JP., et al.: Detection using the multifocal electroretinogram of mosaic retinal dysfunction in carriers of X-linked retinitis pigmentosa. Ophthalmology. 2002; 109: 560–8. Wang, DY., Chan, WM., Tam, PO., et al.: Gene mutations in retinitis pigmentosa and their clinical implications. Clin Chim Acta. 2005; 351: 5–16. Westall, CA., Dhaliwal, HS., Panton, CM., et al.: Values of electroretinogram responses according to axial length. Doc Ophthalmol. 2001; 102(2): 115–30. 46. Yang, Z., Peachey, NS., Moshfeghi, DM., et al.: Mutations in the RPGR gene cause X-linked cone dystrophy. Hum Mol Genet. 2002; 11: 605–11.