Downloaded from http://bjo.bmj.com/ on May 6, 2015 - Published by group.bmj.com
BJO Online First, published on April 16, 2015 as 10.1136/bjophthalmol-2014-306224 Clinical science
Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia Thomas Chassine,1 Béatrice Bocquet,2,3,4 Vincent Daien,3,5,6 Almudena Avila-Fernandez,7,8 Carmen Ayuso,7,8 Rob WJ Collin,9,10 Marta Corton,7,8 J Fielding Hejtmancik,11 L Ingeborgh van den Born,12 B Jeroen Klevering,13 S Amer Riazuddin,14,15 Nathacha Sendon,1 Annie Lacroux,2,3,4 Isabelle Meunier,1,2,3,4 Christian P Hamel1,2,3,4 For numbered affiliations see end of article. Correspondence to Professor Christian P Hamel, INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital Saint-Eloi, BP 74103, 80, rue Augustin Fliche, 34091 Montpellier Cedex 5, France; [email protected] and BB contributed equally Received 4 October 2014 Revised 13 March 2015 Accepted 26 March 2015
ABSTRACT Objective To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. Methods Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1 mutation, 8 and 33 had X-linked RP (xlRP) with RP2 and RPGR mutations, respectively, 198 and 93 had Usher syndrome and arRP without RP1 mutations, respectively. The median of the spherical equivalent (SE) and the IQR (Q25–Q75) was determined and multiple comparisons were performed. Results arRP patients with RP1 mutations had SE median at −4.0 dioptres (D) OD (Ocula Dextra); −3.88 D OS (Ocula Sinistra), whereas arRP patients without RP1 mutations (−0.50 D OD; −0.75 D OS) and Usher syndrome patients (−0.50 D OD; −0.38 D OS) were significantly less myopic ( pT c.1625C>G/c.4804C>T c.1625C>G/c.4804C>T c.5173C>T c.1625C>G c.1625C>G c.1625C>G c.1625C>G c.1625C>G c.1625C>G c.1625C>G/c.366insGC c.1625C>G c.4703delA c.5400delA c.5400delA c.686delC c.368_369dup/c.4141_4142del
p.K1518* p.N1143Ifs*25 p.N1143Ifs*25 p.E1227Mfs*29 p.H31Qfs*47 p.H31Qfs*47 p.H31Qfs*47 p.V157Wfs*15 p.G1140Kfs*4 p.R326* p.S542*/p.Q1602* p.S542*/p.Q1602* p.Q1725* p.S542* p.S542* p.S542* p.S542* p.S542* p.S542* p.S542*/p.V51Dfs*27 p.S542* p.R1519fs*1 p.N1751fs*3 p.N1751fs*3 p.P229Qfs*35 p.P124Afs*20/p.H1414Qfs*5
Hoz Hoz Hoz Hoz Hoz Hoz Hoz Hoz Hoz Hoz C Hez C Hez Hoz Hoz Hoz Hoz Hoz Hoz Hoz C Hez Hoz Hoz Hoz Hoz Hoz C Hez
−6.0/−5.5 −4.5/−5.125 −0.75/−0.75 −8.0/−5.125 −2.875/−2.0 −1.75/−1.875 −8.75/−8.625 −12.75/−12.875 −9.50/−10.25 −7.75/−7.875 −2.50/−3.125 −12.375/−13.50 −1.0/−1.50 −11.0/−11.0 −9.0/−9.0 −3.50/−3.375 −0.625/−0.625 −2.75/−1.375 −0.75/−0.25 −3.25/−3.25 −12.75/−14.50 −3.125/−3.125 −2.125/−1.50 −8.375/−4.375 −1.875/−1.875 −12.0/−7.0
C Hez, compound heterozygote; Hoz, homozygote; LE, left eye; RE, right eye; SE, spherical equivalent.
2
Chassine T, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306224
Downloaded from http://bjo.bmj.com/ on May 6, 2015 - Published by group.bmj.com
Clinical science Table 2 Cohorts of patients in this study Patient group
Number of males
Autosomal recessive RP with RP1 mutations Autosomal dominant RP with RP1 mutations X-linked RP with RP2 mutations X-linked RP with RPGR mutations Autosomal recessive RP without RP1 mutations Usher syndrome
Number of females
Median of age in years (IQR)
16
10
21.0 (14.0–28.0)
13
12
54.0 (37.0–63.0)
8 33 48
0 0 45
19.0 (9.5–49.0) 28.0 (20.0–46.0) 34.0 (24.0–44.0)
105
93
33.0 (22.0–47.0)
RP, retinitis pigmentosa.
RP1 alleles, therefore occurring in case of presumably absent RP1 protein. Since it is known that the patients with xlRP associated to either RPGR or RP2 mutations have often high myopic refractive errors, we also determined the refraction in xlRP patients from the Montpellier’s clinical files and compared them with those of RP1-associated arRP patients. We found that xlRP patients with an RPGR mutation had an SE at −4.50 (range −8.50; −1.13) D for the RE and at −5.25 (range −7.88; −1.13) D for the LE (table 3). Similarly, RP patients with an RP2 mutation had an SE at −6.25 (range −8.56; −2.95) for the RE and at −6.88 (range −9.06; −2.44) D for the LE (table 3). When we compared the three groups, RP1-associated arRP, xlRP with RPGR or RP2 mutations, there were no significant differences between them; arRP RP1 vs xlRP RP2 p value for RE and LE=10.95 and 7.35, respectively, and arRP RP1 vs xlRP RPGR p value for RE and LE=9.30 and 14.6, respectively. This indicates that the patients in those three groups had similar levels of refractive error (table 4). As expected, myopic refractive error in xlRP with RPGR or RP2 mutations were, like for RP1, significantly higher than arRP patients without RP1 mutations and Usher syndrome patients (table 4). Astigmatism values for each group of patients are shown in table 5. In contrast to the SE, there were no differences between most groups except for adRP patients with RP1 mutations when compared with patients of other groups, and only in the RE ( p=0.007), but not in the LE ( p=0.386). This indicates that the astigmatism values were not related to differences seen in myopic refractive errors.
that the level of the refractive error was independent of the amino acid position of the mutation (figure 1A). In contrast to RP1-associated arRP patients, the 93 patients with arRP without RP1 mutations and the 198 patients with Usher syndrome who have typical signs of RP had a smaller myopic refractive error. Indeed, the median SE for arRP without RP1 mutations was −0.50 (range −1.88; +0.50) D for the RE and −0.75 (−2.00; +0.50) D for the LE, and for the Usher syndrome −0.50 (−2.25; +0.50) D for the RE and −0.38 (−2.00; +0.63) D for the LE. Table 4 shows p values for post-hoc pairwise comparisons corrected using the Bonferroni method. A significant difference in the refraction values was observed between RP1-associated arRP compared with arRP caused by mutations in other genes ( p
BJO Online First, published on April 16, 2015 as 10.1136/bjophthalmol-2014-306224 Clinical science
Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia Thomas Chassine,1 Béatrice Bocquet,2,3,4 Vincent Daien,3,5,6 Almudena Avila-Fernandez,7,8 Carmen Ayuso,7,8 Rob WJ Collin,9,10 Marta Corton,7,8 J Fielding Hejtmancik,11 L Ingeborgh van den Born,12 B Jeroen Klevering,13 S Amer Riazuddin,14,15 Nathacha Sendon,1 Annie Lacroux,2,3,4 Isabelle Meunier,1,2,3,4 Christian P Hamel1,2,3,4 For numbered affiliations see end of article. Correspondence to Professor Christian P Hamel, INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital Saint-Eloi, BP 74103, 80, rue Augustin Fliche, 34091 Montpellier Cedex 5, France; [email protected] and BB contributed equally Received 4 October 2014 Revised 13 March 2015 Accepted 26 March 2015
ABSTRACT Objective To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. Methods Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1 mutation, 8 and 33 had X-linked RP (xlRP) with RP2 and RPGR mutations, respectively, 198 and 93 had Usher syndrome and arRP without RP1 mutations, respectively. The median of the spherical equivalent (SE) and the IQR (Q25–Q75) was determined and multiple comparisons were performed. Results arRP patients with RP1 mutations had SE median at −4.0 dioptres (D) OD (Ocula Dextra); −3.88 D OS (Ocula Sinistra), whereas arRP patients without RP1 mutations (−0.50 D OD; −0.75 D OS) and Usher syndrome patients (−0.50 D OD; −0.38 D OS) were significantly less myopic ( pT c.1625C>G/c.4804C>T c.1625C>G/c.4804C>T c.5173C>T c.1625C>G c.1625C>G c.1625C>G c.1625C>G c.1625C>G c.1625C>G c.1625C>G/c.366insGC c.1625C>G c.4703delA c.5400delA c.5400delA c.686delC c.368_369dup/c.4141_4142del
p.K1518* p.N1143Ifs*25 p.N1143Ifs*25 p.E1227Mfs*29 p.H31Qfs*47 p.H31Qfs*47 p.H31Qfs*47 p.V157Wfs*15 p.G1140Kfs*4 p.R326* p.S542*/p.Q1602* p.S542*/p.Q1602* p.Q1725* p.S542* p.S542* p.S542* p.S542* p.S542* p.S542* p.S542*/p.V51Dfs*27 p.S542* p.R1519fs*1 p.N1751fs*3 p.N1751fs*3 p.P229Qfs*35 p.P124Afs*20/p.H1414Qfs*5
Hoz Hoz Hoz Hoz Hoz Hoz Hoz Hoz Hoz Hoz C Hez C Hez Hoz Hoz Hoz Hoz Hoz Hoz Hoz C Hez Hoz Hoz Hoz Hoz Hoz C Hez
−6.0/−5.5 −4.5/−5.125 −0.75/−0.75 −8.0/−5.125 −2.875/−2.0 −1.75/−1.875 −8.75/−8.625 −12.75/−12.875 −9.50/−10.25 −7.75/−7.875 −2.50/−3.125 −12.375/−13.50 −1.0/−1.50 −11.0/−11.0 −9.0/−9.0 −3.50/−3.375 −0.625/−0.625 −2.75/−1.375 −0.75/−0.25 −3.25/−3.25 −12.75/−14.50 −3.125/−3.125 −2.125/−1.50 −8.375/−4.375 −1.875/−1.875 −12.0/−7.0
C Hez, compound heterozygote; Hoz, homozygote; LE, left eye; RE, right eye; SE, spherical equivalent.
2
Chassine T, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306224
Downloaded from http://bjo.bmj.com/ on May 6, 2015 - Published by group.bmj.com
Clinical science Table 2 Cohorts of patients in this study Patient group
Number of males
Autosomal recessive RP with RP1 mutations Autosomal dominant RP with RP1 mutations X-linked RP with RP2 mutations X-linked RP with RPGR mutations Autosomal recessive RP without RP1 mutations Usher syndrome
Number of females
Median of age in years (IQR)
16
10
21.0 (14.0–28.0)
13
12
54.0 (37.0–63.0)
8 33 48
0 0 45
19.0 (9.5–49.0) 28.0 (20.0–46.0) 34.0 (24.0–44.0)
105
93
33.0 (22.0–47.0)
RP, retinitis pigmentosa.
RP1 alleles, therefore occurring in case of presumably absent RP1 protein. Since it is known that the patients with xlRP associated to either RPGR or RP2 mutations have often high myopic refractive errors, we also determined the refraction in xlRP patients from the Montpellier’s clinical files and compared them with those of RP1-associated arRP patients. We found that xlRP patients with an RPGR mutation had an SE at −4.50 (range −8.50; −1.13) D for the RE and at −5.25 (range −7.88; −1.13) D for the LE (table 3). Similarly, RP patients with an RP2 mutation had an SE at −6.25 (range −8.56; −2.95) for the RE and at −6.88 (range −9.06; −2.44) D for the LE (table 3). When we compared the three groups, RP1-associated arRP, xlRP with RPGR or RP2 mutations, there were no significant differences between them; arRP RP1 vs xlRP RP2 p value for RE and LE=10.95 and 7.35, respectively, and arRP RP1 vs xlRP RPGR p value for RE and LE=9.30 and 14.6, respectively. This indicates that the patients in those three groups had similar levels of refractive error (table 4). As expected, myopic refractive error in xlRP with RPGR or RP2 mutations were, like for RP1, significantly higher than arRP patients without RP1 mutations and Usher syndrome patients (table 4). Astigmatism values for each group of patients are shown in table 5. In contrast to the SE, there were no differences between most groups except for adRP patients with RP1 mutations when compared with patients of other groups, and only in the RE ( p=0.007), but not in the LE ( p=0.386). This indicates that the astigmatism values were not related to differences seen in myopic refractive errors.
that the level of the refractive error was independent of the amino acid position of the mutation (figure 1A). In contrast to RP1-associated arRP patients, the 93 patients with arRP without RP1 mutations and the 198 patients with Usher syndrome who have typical signs of RP had a smaller myopic refractive error. Indeed, the median SE for arRP without RP1 mutations was −0.50 (range −1.88; +0.50) D for the RE and −0.75 (−2.00; +0.50) D for the LE, and for the Usher syndrome −0.50 (−2.25; +0.50) D for the RE and −0.38 (−2.00; +0.63) D for the LE. Table 4 shows p values for post-hoc pairwise comparisons corrected using the Bonferroni method. A significant difference in the refraction values was observed between RP1-associated arRP compared with arRP caused by mutations in other genes ( p
