- Email: [email protected]
Rhegmatogenous Retinal Detachment in Nonsyndromic High Myopia Associated with Recessive Mutations in LRPAP1
Rhegmatogenous Retinal Detachment in Nonsyndromic High Myopia Associated with Recessive Mutations in LRPAP1 Moustafa S. Magliyah, MD,1 Sulaiman M. Alsulaiman, MD,2 Sawsan R. Nowilaty, MD,2 Fowzan S. Alkuraya, MD,3,4 Patrik Schatz, MD, PhD2,5 Purpose: To describe a new form of childhood-onset rhegmatogenous retinal detachment (RRD) in autosomal recessive high myopia associated with mutations in LRPAP1. Design: Retrospective cohort study. Participants: A total of 12 children (24 eyes) with recessive LRPAP1 mutations and associated high myopia. Methods: Serial ophthalmological examination and retinal imaging during 4.61.9 (mean standard deviation) years. Retinal interventions included prophylactic laser and surgical retinal repair. Main Outcome Measures: Incidence and recurrence rate of RRD and retinal break formation. Association between LRPAP1 genotypes and RRD characteristics. Results: Some 42% of children (5 children [6 eyes]) developed RRD at the age of 10.430.97 years. Four of the children who developed RRD were male (80%), and 1 was female (20%). Visual acuity was significantly reduced in eyes with RRD at presentation and at the most recent visit compared with eyes with no RRD (P < 0.001 for both). Two eyes had inoperable RRD. Four eyes for which primary retinal repair was done had redetachment (100% of operated eyes) due to variable degrees of proliferative vitreoretinopathy (PVR). Reattachment after surgical repair, which was maintained at least during 6 months of follow-up, was achieved in 3 eyes (75%), with final visual acuities of 20/300 in 2 eyes and 20/400 in 1 eye. Conclusions: This is the first description of a nonsyndromic, high myopia-related, recessive RRD without any signs of vitreoretinal degeneration. Recessive LRPAP1 gene mutations confer a high risk of childhood-onset RRD and PVR. Proliferative vitreoretinopathy in turn increases the risk of recurrent RRD and may lead to blindness. Recognizing the LRPAP1-related high myopia phenotype is important, and early childhood examination with additional close follow-up and prophylactic retinal laser should be considered. Ophthalmology Retina 2019;:1e7 ª 2019 by the American Academy of Ophthalmology
Rhegmatogenous retinal detachment (RRD) has long been regarded as a mainly age-related disease induced through mechanical changes in the vitreous, associated with myopia. However, during recent years, it has become increasingly clear that there may be strong genetic components influencing the development of syndromic and nonsyndromic forms of myopia and RRD. Approaches to decipher the genetic causes of RRD have included genome-wide association studies of large samples of unrelated patients, as well as clinical and genetic workup of families with hereditary forms of RRD. Such knowledge may lead to novel potential therapeutic targets and to a further understanding of the mechanisms of RRD development and associated pathological processes such as proliferative vitreoretinopathy (PVR), which is the most common reason of failure of surgical repair of RRD. The list of syndromic and nonsyndromic genetic associations with RRD is growing and has been reviewed by Johnston et al.1 Nonsyndromic high myopia may be inherited in autosomal dominant, autosomal recessive, or X-linked recessive 2019 by the American Academy of Ophthalmology Published by Elsevier Inc.
modes.2 To date, autosomal recessive mutations in 3 genesdCathepsin H (CTSH, Online Mendelian Inheritance in Man [OMIM]* 116820), low-density lipoprotein receptorerelated protein-associated protein 1 (LRPAP1, OMIM* 104225), and LEPREL1 (Prolyl 3 Hydroxylase 2, OMIM* 610341)dhave been associated with largely nonsyndromic high myopia.3-7 However, facial dysmorphism was described in CTSH-related myopia, and LEPREL1-related myopia was shown to be associated with vitreoretinal degeneration, early onset cataract, ectopia lentis, and RRD.4,5 By contrast, LRPAP1-related high myopia was not reported to include any of these associated features. Specifically, no RRD was reported in the original cohort of patients with high myopia and recessive LRPAP1 mutations.5 LRPAP1 is a widely expressed gene that encodes lowdensity lipoprotein receptorerelated protein-associated protein 1, a 357 amino acid protein that is thought to act as a chaperone that binds and protects the lipoprotein receptorerelated proteins LRP1 and LRP2. LRPAP1 https://doi.org/10.1016/j.oret.2019.08.005 ISSN 2468-6530/19
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Ophthalmology Retina Volume -, Number -, Month 2019 mutations were described to lead to a deficiency of LRP1, which, in turn, induced upregulation of transforming growth factor beta (TGF-b), leading to disruption of elastic tissues.6 This effect, which is also known to result in vascular elongation and aneurysms in Marfan syndrome, is thought to cause scleral expansion through remodeling of the extracellular matrix.7 Furthermore, high levels of TGF-b are considered to lead to a decrease of retinal elasticity and may increase retinal stiffness through the induction of epithelial mesenchymal transition in which, for example, retinal pigment epithelium (RPE) and Muller cells acquire mesenchymal phenotypes,8 which, in combination with scleral enlargement, could make the retina liable to develop breaks and RRD, even in the absence of any clinically noticeable vitreoretinal degeneration. Therefore, we hypothesized that children with LRPAP1-related high myopia may be at risk of RRD. To test this hypothesis, we retrospectively studied the cohort described by Khan et al5 and an additional 3 children who were identified to have LRPAP1-associated high myopia to determine the frequency, characteristics, and outcomes of any associated RRD in this cohort.
Methods This is a retrospective cohort study including all known children with high myopia associated with autosomal recessive mutations in LRPAP1 gene seen between 2014 and 2018 at King Khaled Eye Specialist Hospital. The patients were recruited from the original cohort of patients in whom the gene was identified,5,7 and a recognizable nonsyndromic high myopia phenotype, which included diffuse severe chorioretinal atrophy and optic nerve head peripapillary conus but no vitreoretinopathy and no RRD, was described.5,7 We also included 3 children who were ascertained by genetic analysis because they had high myopia and RRD. Approval was obtained from the Institutional Review Board at King Khaled Eye Specialist Hospital. The study adhered to the tenets of Declaration of Helsinki. Informed consent was obtained from all patients. Details of ophthalmological examinations, including best-corrected visual acuity, cyclorefraction, axial length measurement, and multimodal retinal imaging were performed (Spectralis OCT, Heidelberg Engineering, Inc., Heidelberg, Germany; and Optos PLC, Dunfermline, UK) for all applicable eyes with clear media. B-scan ultrasonography was performed in case of media opacities. Interventions included prophylactic laser treatment for peripheral retinal breaks with attached retina and retinal surgical repair for RRD with or without PVR. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS Inc., Chicago IL). Data were presented as the mean standard deviation. The chi-square test was used to compare nominal variables such as gender and development of RRDs. Children (eyes) who developed RRD were compared with children (eyes) who did not using the analysis of variance test. Differences were considered significant at P < 0.05.
Results A total of 24 eyes of 12 patients with homozygous LRPAP1 mutations were observed during 4.6 (mean) 1.9 (standard deviation) years (Table 1). Some 42% of children (5 children [6 eyes]) developed RRD at the age of 10.430.97 years. Of these, 1 child developed bilateral total RRDs. Four of the eyes developed
2
total RRDs, and 2 eyes developed subtotal macular-involving RRD. All RRDs were associated with primary PVR. Male gender and the presence of the c.863_864delTC mutation were more common in patients with RRD; however, the effect was not statistically significant in this small cohort (P ¼ 0.171 and P ¼ 0.52, respectively). Slightly higher refractive errors (25.31.54 vs. 21.865.3) and axial length measurements (32.72.26 mm vs. 31.15 3.4 mm) were observed in eyes with RRD with insignificant risks (P ¼ 0.265 and P ¼ 0.314, respectively). Bestcorrected visual acuity at presentation and at most recent visit were significantly poorer in eyes with RRD compared with eyes that did not develop any RRD (P < 0.001 for both). Two total RRDs were deemed inoperable with extensive PVR and bare to no light perception at presentation. Two total RRDs and 1 subtotal RRD had grade C PVR and were repaired by pars plana vitrectomy with silicone oil implantation, whereas 1 subtotal RRD that had grade A PVR was initially repaired by cryopexy with scleral buckle. All 4 repaired eyes (100%) developed recurrent RRD with PVR, requiring further surgical intervention in 3 of the 4 eyes (Table 1, Fig 1). One of these eyes was deemed as inoperable with extensive PVR. The 3 reoperated eyes were reattached throughout 6 months of follow-up with 2 eyes maintaining 20/300 vision and 1 maintaining 20/400. One eye of one child who developed a total inoperable RRD in the other eye was managed successfully with repeated prophylactic laser only for emerging retinal breaks and did not develop any RRD during more than 4 years of follow-up (Table 1, Fig 2). One eye of 1 child presented with optic atrophy, without developing any RRD, and was presumed to have had congenital glaucoma (Table 1). Most of the patients in this study had the homozygous c.863_864delTC mutation in LRPAP1 (Table 1). A subgroup analysis of all patients with this specific mutation was subsequently carried out, comparing the children who developed RRD with those who did not develop any RRD in the search of factors that could contribute to a variable expressivity of RRD among patients with the homozygous recessive c.863_864delTC mutation. There was no significant difference regarding the age of the children with RRD compared with those who did not develop any RRD nor was the observation period longer for the children who developed RRD compared with those who did not. However, the axial length was significantly longer in eyes that developed RRD (mean 32.671.88 mm) compared with those without any RRD (mean 30.92.36 mm, P < 0.05).
Discussion We observed 24 eyes of 12 patients with homozygous LRPAP1 mutations during 4.6 years (Table 1). Six eyes developed RRD, amounting to an annual average incidence of 6 RRDs per 12 patients per 5 years, which is equal to 0.25. Although 3 of the children in this cohort were ascertained by genetic testing because of RRD, implying that the rate of RRD in a population of children with LRPAP1 mutations may be somewhat lower, this number (0.25) is considerably higher than that reported for RRD in the general population, which is approximately 10/100 000, which is equal to 0.0001.9 By adjusting for high myopia more than 3 diopters in the general
Table 1. Characteristics of Patients with Nonsyndromic High Myopia Associated with Recessive Mutations in LRPAP1
Patient 1
Age at Most Recent Visit 11
Eye
Refraction (D)
AL (mm)
Retinal Break
First Retinal Detachment and Degree of PVR (Age)
c.863_864delTC
4
R
N/A
31.57
Yes
L
20.75
36.14
Yes
Total RRD with grade C PVR (10) No
c.605delT
4
R L
N/A N/A
39.92 37.11
No Yes
3
9
c.863_864delTC
1
R
26.00
32.43
Yes
4
13
c.863_864delTC
6
L R
25.00 26.00
30.87 32.40
No Yes
No Total RRD with grade C PVR (11)
L
N/A
30.60
Yes
R L R L R L R L R L R L
9.00 10.00 21.75 16.00 25.00 25.00 20.00 20.00 25.00 26.00 23.50 24.00
26.37 26.85 30.15 29.72 35.22 34.89 28.40 29.12 29.52 29.88 31.78 32.09
No No No No No No No No No No No Yes
R L R L
27.50 27.00 23.50 23.00
31.55 30.95 29.64 29.80
No No No No
Total RRD with grade C PVR (11) No No No No No No No No No No No Subtotal RRD with Grade A PVR (10) No No No No
5
23
c.605delT
5
6
13
c.605delT
5
7
15
c.863_864delTC
5
8
22
c.863_864delTC
7
9
9
c.863_864delTC
6
10
11
c.863_864delTC
1
11
15
c.863_864delTC
6
12
11
c.863_864delTC
6
No Total RRD with grade C PVR (12) Subtotal RRD with grade C PVR (9)
None
LP (irreparable RRD)
Prophylactic laser (several sessions) None PPV þ MP þ SO
20/80
1. PPV þ MP þ SO, 2. PPV þ MP þ SO þ SB 3. PPV þ MP þ SO None 1. PPV þ MP þ SO þ SB 2. PPV þ MP þ SO 3. PPV þ MP þ SO None None None None None None None None None None None None 1. Cryopexy þ SB 2. PPV þ MP þ SO None None None None
NLP (optic atrophy) LP (irreparable RRD) 20/400 (flat under SO) 20/80 20/300 (flat under SO) LP 20/40 20/60 20/40 20/60 20/50 20/100 20/125 20/160 20/50 20/40 20/40 20/300 (flat under SO) 20/40 20/50 20/50 20/60
AL ¼ axial length; L ¼ left; LP ¼ light perception; MP ¼ membrane peeling; MSO ¼ silicone oil; N/A ¼ unable to get good red reflex for cyclorefraction; NLP ¼ no light perception; PPV ¼ pars plana vitrectomy; PVR ¼ proliferative vitreoretinopathy; R ¼ right; RRD ¼ rhegmatogenous retinal detachment; SB ¼ scleral buckling; SO ¼ silicone oil. All mutations are homozygous. Patients 4e12 were included in the article by Khan et al,5 whereas patients 1e3 have not been reported previously.
LRPAP1-Associated Retinal Detachment
20
Outcome
2
Interventions
Magliyah et al
Mutation
Follow-up Duration (yrs)
3
Ophthalmology Retina Volume -, Number -, Month 2019
Figure 1. Fundus of the right eye of a 9-year-old female child (patient 3 in Table 1) with the homozygous mutation c.863_864delTC in the LRPAP1 gene who presented 1 year earlier after undergoing pars plana vitrectomy with silicone oil tamponade, with a macula-involving rhegmatogenous retinal detachment (RRD) in the right eye, with a large inferior break (A) and retinal folds compatible with grade C proliferative vitreoretinopathy (PVR). She underwent scleral buckle, pars plana vitrectomy, membrane peeling, and silicone oil injection and the inferior retina subsequently redetached under silicone oil (B). A third pars plana vitrectomy with silicone oil injection followed and shows attached retina (C) after the procedure. The axial length was >32 mm.
population, which was reported to yield a 10-fold increased risk for RRD,10 the number would be 0.001, which is still less by a factor of 250 compared with the incidence of RRD in our cohort of patients with LRPAP1 mutations. Thus, according to available literature on the risk of RRD in relation to high myopia in the general population, the risk seems to be considerably higher in patients with homozygous LRPAP1 mutations, which would suggest that the RRD risk in these children is caused by other factors in addition to high myopia. On the other hand, there are no data from the general population regarding the RRD risk in patients with a comparable degree of extremely high myopia as seen in LRPAP1 mutations, so the pathogenesis of RRD in these patients requires further study. A different approach could be to compare with another well-defined population with a genetically induced childhood-onset high myopia, such as that seen in congenital stationary night blindness due to recessive TRPM1 mutations. To date, no RRD has been reported in these patients, including a recent study by Miraldi Utz et al11 in which 7 patients were followed for 11 years, and our own patients (n ¼ 4) who have been observed for 4 to 10 years (Al-Hujaili et al. submitted manuscript, 2019). A PubMed search for “TRPM1 rhegmatogenous retinal detachment” (https://www.ncbi.nlm.nih.gov/pubmed/?term ¼trpm1þrhegmatogenousþretinalþdetachment, conducted on August 11, 2019), yielded no results. Khan et al5 reported the clinical appearance of children with LRPAP1-related myopia. The retina was typical for very high myopia with diffuse severe chorioretinal atrophy and optic nerve head peripapillary conus, but neither lacquer cracks nor neovascularization was seen. Vitreopathy was not observed. None of the patients were described to have any RRD-predisposing peripheral degeneration, such as lattice degeneration.5 None of the patients in the original description of the high myopia phenotype associated with LRPAP1 mutations by Khan et al5 were noted to have had any RRD at the time of that publication. However, 2 of the patients included in the
4
original cohort subsequently developed RRD during further follow-up (patients 4 and 10, Table 1). Furthermore, none of the patients in this study developed any lattice degeneration throughout follow-up. This is in keeping with a different mechanism for the development of lattice degeneration compared with LRPAP1-high myopia and RRD. The pathogenesis of lattice degeneration has been associated with variants in COL4A4 gene, which codes for the alpha-4 chain of type IV collagen, involved in the development of basement membranes.12 The mechanism of RRD in children with LRPAP1 mutations may be partially related to the high myopia, which is known to be an independent risk factor for RRD.1 Additionally, a postulated TGF-beinduced scleral wall remodeling, similar to Marfan syndrome, combined with loss of retinal elasticity, could contribute considerably to the risk of RRD.6-8 This similarity with Marfan syndrome regarding these aspects may be due to a convergence of some of the pathomechanisms in Marfan syndrome and LRPAP1-related disease: Marfan syndrome is caused by loss of function mutations in Fibrillin-1, a protein that binds and immobilizes TGF-b, thus controlling its activation.13 Likewise, LRP1 was reported to be required for mediating a normal, growth inhibitory response of TGF-b by binding to it.14,15 Mordechai et al4 reported RRD in 30.7% of a cohort with recessive LEPREL1 mutations associated with nonsyndromic high axial myopia and vitreoretinal degeneration. However, the pathogenesis of ocular enlargement and LEPREL1-associated RRD occurs through defective collagen hydroxylation in the sclera, similar to Stickler syndrome. Thus, the pathogenesis of RRD in these 2 nonsyndromic forms of RRD (LEPREL1 vs. LRPAP1) differs, even if the risk of RRD seems to be comparable (Table 2). The observed risk of RRD in LRPAP1-related high myopia was comparable to Stickler syndrome (10%e73%) but higher than in Marfan syndrome (5%e11%).14,16 Rhegmatogenous retinal detachment in LRPAP1-related high myopia tended to develop at early childhood (9e12 years), earlier than Stickler syndrome17,18 and Marfan syndrome.19 One eye of
Magliyah et al
LRPAP1-Associated Retinal Detachment
Figure 2. Fundus of the left eye of an 11-year-old male child (patient 1 in Table 1) with the homozygous c.863>864delTC mutation in the LRPAP1 gene who presented 4 years earlier with an inoperable RRD in the right eye (not shown) and received prophylactic retinal laser in the left eye at the same time. A, At the age of 9 years, the patient presented with a new superior break. The break was treated with indirect laser photocoagulation under general anesthesia. B, Subsequently, another 2 superonasal breaks, further nasally compared with the original break, developed during the following 2 years, which were treated with laser at the slit-lamp. The retina remained attached until the most recent follow-up. The axial length of the left eye was >36 mm.
1 of the children who developed a total inoperable RRD in the other eye was managed successfully with repeated prophylactic laser only, for emerging retinal breaks. Taken together, this suggests that dilated fundus examination including the retinal periphery with periodic monitoring is necessary from early childhood for these children. Primary retinal repairs for RRD in children with LRPAP1 mutations had limited success rates, mainly due to PVR, which is similar to Stickler and Marfan syndromes.20,21 The high incidence and aggressive nature of PVR in this cohort of patients with LRPAP1 mutations could be induced by an uncontrolled RPE proliferation because of a deficiency of LRP1, which has been shown to regulate RPE proliferation.22 Furthermore, TGF-beinduced contraction of vitreous gel collagen and epithelial mesenchymal transition of RPE and Muller cells could contribute to PVR.23,24 Our study suggests that LRP1 may be a therapeutic target for PVR, and therefore, an approach toward controlling the potential role of LRP1 in the PVR process may be more powerful than attempting to control TGF-b, which has been attempted previously.25,26 However, to date, there is no clinically available, approved pharmacologic approach to prevent or manage PVR.
Although the numbers are small, the risk of RRD with the 2 observed homozygous mutations (which both lead to frame shifts and subsequent termination of the transcript; c.605delA, p.Asn202Thrfs*8; c.863_864del, p.Ile288Argfs*118) may differ depending on genotype. Four of the patients who presented with RRD or retinal breaks had the homozygous mutation c.863_864delTC in LRPAP1, whereas only 1 patient had the homozygous c.605delT mutation. It also remains to be determined if any of these mutations may play a role in high myopia or RRD in other populations. In a recent screening of 187 Chinese patients with high myopia, only a heterozygous variant c.962G > A, p.Arg321His was detected in 1 patient, and it was predicted to be a benign polymorphism.27 Furthermore, it is at present not known whether heterozygous mutations in LRPAP1 might contribute to the risk of RRD or PVR in “nonhereditary” myopic RRD. Thus, further study is needed, analyzing LRPAP1 variants in larger cohorts of patients with myopic RRD with and without PVR. In general, prophylactic treatment of symptomatic retinal breaks must be considered in any patient, whereas no unequivocal conclusion could be reached with regard to
Table 2. Summary of 2 Studies Reporting Rhegmatogenous Retinal Detachment Associated with Autosomal Recessive Nonsyndromic high myopia Study
No. of Patients
Gene
Mutations
Age, yrs
Refraction (D)
Axial Length (mm)
Incidence of RRD
Magliyah et al, current study
12
LRPAP1
14.34.7 yrs
L22.25.1
31.53.2
42%
Mordechai et al4
13
LEPREL1
c.863_864delTC c.605delT c.1523G > T
L12.53.4*
27.51.5y
30.7%
22.2314.5
D ¼ diopters; RRD ¼ rhegmatogenous retinal detachment. *Unavailable and unreliable results were not included. y Unavailable results were not included.
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Ophthalmology Retina Volume -, Number -, Month 2019 prophylactic treatment of asymptomatic retinal breaks.28 In the case of high myopia associated with LRPAP1 mutations, because of the high incidence of childhoodonset RRD and our experience with 1 one-eyed patient who received several rounds of prophylactic laser photocoagulation because of emerging retinal breaks without developing any RRD in that eye (patient 1 in Table 1, Fig 2), we would recommend prophylactic laser photocoagulation for any retinal breaks, in this population.
Conclusions Recessive LRPAP1 mutations confer a high risk of childhood-onset RRD. Such RRD tends to involve the macula and has a high risk of PVR. Recognizing the LRPAP1-related high myopia phenotype is important, and early childhood fundus examination, close follow-up, and prophylactic retinal laser treatment may help patients maintain a good visual outcome. Acknowledgment. The authors thank Adolph Cabanas at Design and Publications, King Khaled Eye Specialist Hospital, for skillful technical assistance with the preparation of Figures 1 and 2. References 1. Johnston T, Chandra A, Hewitt AW. Current understanding of the genetic architecture of rhegmatogenous retinal detachment. Ophthalmic Genet. 2016;37:121e129. 2. Li J, Zhang Q. Insight into the molecular genetics of myopia. Mol Vis. 2017;23:1048e1080. 3. Jiang D, Li J, Xiao X, et al. Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing. Invest Ophthalmol Vis Sci. 2014;56:339e345. 4. Mordechai S, Gradstein L, Pasanen A, et al. High myopia caused by a mutation in LEPREL1, encoding prolyl 3hydroxylase 2. Am J Hum Genet. 2011;89:438e445. 5. Khan AO, Aldahmesh MA, Alkuraya FS. Clinical characterization of LRPAP1-related pediatric high myopia. Ophthalmology. 2016;123:434e435. 6. Muratoglu SC, Belgrave S, Hampton B, et al. LRP1 protects the vasculature by regulating levels of connective tissue growth factor and HtrA1. Arterioscler Thromb Vasc Biol. 2013;33:2137e2146. 7. Aldahmesh MA, Khan AO, Alkuraya H, et al. Mutations in LRPAP1 are associated with severe myopia in humans. Am J Hum Genet. 2013;93:313e320. 8. Bu SC, Kuijer R, van der Worp RJ, et al. Substrate elastic modulus regulates the morphology, focal adhesions, and asmooth muscle actin expression of retinal Müller cells. Invest Ophthalmol Vis Sci. 2015;56:5974e5982. 9. Mitry D, Charteris DG, Fleck BW, et al. The epidemiology of rhegmatogenous retinal detachment: geographical variation and clinical associations. Br J Ophthalmol. 2010;94:678e684.
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10. The Eye Disease Case-Control Study Group. Risk factors for idiopathic rhegmatogenous retinal detachment. Am J Epidemiol. 1993;137:749e757. 11. Miraldi Utz V, Pfeifer W, Longmuir SQ, et al. Presentation of TRPM1-associated congenital stationary night blindness in children. JAMA Ophthalmol. 2018;136:389e398. 12. Meguro A, Ideta H, Ota M, et al. Common variants in the COL4A4 gene confer susceptibility to lattice degeneration of the retina. PLoS One. 2012;7:e39300. 13. Kaartinen V, Warburton D. Fibrillin controls TGF-beta activation. Nat Genet. 2003;33:331e332. 14. Huang SS, Ling TY, Tseng WF, et al. Cellular growth inhibition by IGFBP-3 and TGF-beta1 requires LRP-1. FASEB J. 2003;17:2068e2081. 15. Tseng WF, Huang SS, Huang JS. LRP-1/TbetaR-V mediates TGFbeta1-induced growth inhibition in CHO cells. FEBS Lett. 2004;562:71e78. 16. Gan NY, Lam WC. Retinal detachments in the pediatric population. Taiwan J Ophthalmol. 2018;8:222e236. 17. Stickler GB, Hughes W, Houchin P. Clinical features of hereditary progressive arthro-ophthalmopathy (Stickler syndrome): a survey. Genet Med. 2001;3:192e196. 18. Abeysiri P, Bunce C, da Cruz L. Outcomes of surgery for retinal detachment in children with Stickler syndrome: a comparison of two sequential 20-year cohorts. Graefes Arch Clin Exp Ophthalmol. 2007;245:1633e1638. 19. Maumenee IH. The eye in the Marfan syndrome. Trans Am Ophthalmol Soc. 1981;79:684e733. 20. Alshahrani ST, Ghazi NG, Al-Rashaed S. Rhegmatogenous retinal detachments associated to Stickler syndrome in a tertiary eye care center in Saudi Arabia. Clin Ophthalmol. 2015;10:1e6. 21. Abboud EB. Retinal detachment surgery in Marfan’s syndrome. Retina. 1998;18:405e409. 22. Hollborn M, Birkenmeier G, Saalbach A, et al. Expression of LRP1 in retinal pigment epithelial cells and its regulation by growth factors. Invest Ophthalmol Vis Sci. 2004;45: 2033e2038. 23. Kita T, Hata Y, Arita R, et al. Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target. Proc Natl Acad Sci U S A. 2008;105:17504e17509. 24. Winkler J, Hoerauf H. TGF-ß and RPE-derived cells in taut subretinal strands from patients with proliferative vitreoretinopathy. Eur J Ophthalmol. 2011;21:422e426. 25. Nassar K, Grisanti S, Tura A, et al. A TGF-b receptor 1 inhibitor for prevention of proliferative vitreoretinopathy. Exp Eye Res. 2014;123:72e86. 26. Yokoyama K, Kimoto K, Itoh Y, et al. The PI3K/Akt pathway mediates the expression of type I collagen induced by TGF-b2 in human retinal pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol. 2012;250:15e23. 27. Feng CY, Huang XQ, Cheng XW, et al. Mutational screening of SLC39A5, LEPREL1 and LRPAP1 in a cohort of 187 high myopia patients. Sci Rep. 2017;7:1120. 28. Blindbaek S, Grauslund J. Prophylactic treatment of retinal breaks–a systematic review. Acta Ophthalmol. 2015;93: 3e8.
Magliyah et al
LRPAP1-Associated Retinal Detachment
Footnotes and Financial Disclosures Originally received: August 11, 2019. Final revision: August 13, 2019. Accepted: August 13, 2019. Available online: ---. Manuscript no. ORET-D-19-00102. 1
Ophthalmology Department, Prince Mohammed Medical City, AlJouf, Saudi Arabia.
2
Vitreoretinal Division, King Khalid Eye Specialist Hospital, Riyadh, Saudi Arabia.
3
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 4 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 5
Department of Ophthalmology, Clinical Sciences, Skane County University Hospital, University of Lund, Lund, Sweden.
The abstract of this work entitled “Pediatric Rhegmatogenous Retinal Detachment in Nonsyndromic High Myopia associated with Recessive Mutations in LRPAP1” was accepted for a poster presentation at: the Annual Meeting of the American Academy of Ophthalmology, October 12e15, 2019, San Francisco, California. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Author Contributions: Conception and design: Magliyah, Schatz Data collection: Magliyah, Alsulaiman, Nowilaty, Alkuraya, Schatz Analysis and interpretation: Magliyah, Alsulaiman, Nowilaty, Alkuraya, Schatz Obtained funding: N/A Overall responsibility: Magliyah, Alsulaiman, Nowilaty, Alkuraya, Schatz HUMAN SUBJECTS: Human subjects were included in this study. The human ethics committees at the King Khalid Eye Specialist Hospital approved the study. All research adhered to the tenets of the Declaration of Helsinki. All participants provided informed consent. No animal subjects were used in this study. Abbreviations and Acronyms: OMIM ¼ Online Mendelian Inheritance in Man; PVR ¼ proliferative vitreoretinopathy; RPE ¼ retinal pigment epithelium; RRD ¼ rhegmatogenous retinal detachment; TGF-b ¼ transforming growth factor beta. Correspondence: Patrik Schatz, MD, PhD, Vitreoretinal Division, King Khaled Eye Specialist Hospital, Al-Oruba St., PO Box 7191, Riyadh 11462, Kingdom of Saudi Arabia. E-mail: [email protected].
7
Rhegmatogenous retinal detachment (RRD) has long been regarded as a mainly age-related disease induced through mechanical changes in the vitreous, associated with myopia. However, during recent years, it has become increasingly clear that there may be strong genetic components influencing the development of syndromic and nonsyndromic forms of myopia and RRD. Approaches to decipher the genetic causes of RRD have included genome-wide association studies of large samples of unrelated patients, as well as clinical and genetic workup of families with hereditary forms of RRD. Such knowledge may lead to novel potential therapeutic targets and to a further understanding of the mechanisms of RRD development and associated pathological processes such as proliferative vitreoretinopathy (PVR), which is the most common reason of failure of surgical repair of RRD. The list of syndromic and nonsyndromic genetic associations with RRD is growing and has been reviewed by Johnston et al.1 Nonsyndromic high myopia may be inherited in autosomal dominant, autosomal recessive, or X-linked recessive 2019 by the American Academy of Ophthalmology Published by Elsevier Inc.
modes.2 To date, autosomal recessive mutations in 3 genesdCathepsin H (CTSH, Online Mendelian Inheritance in Man [OMIM]* 116820), low-density lipoprotein receptorerelated protein-associated protein 1 (LRPAP1, OMIM* 104225), and LEPREL1 (Prolyl 3 Hydroxylase 2, OMIM* 610341)dhave been associated with largely nonsyndromic high myopia.3-7 However, facial dysmorphism was described in CTSH-related myopia, and LEPREL1-related myopia was shown to be associated with vitreoretinal degeneration, early onset cataract, ectopia lentis, and RRD.4,5 By contrast, LRPAP1-related high myopia was not reported to include any of these associated features. Specifically, no RRD was reported in the original cohort of patients with high myopia and recessive LRPAP1 mutations.5 LRPAP1 is a widely expressed gene that encodes lowdensity lipoprotein receptorerelated protein-associated protein 1, a 357 amino acid protein that is thought to act as a chaperone that binds and protects the lipoprotein receptorerelated proteins LRP1 and LRP2. LRPAP1 https://doi.org/10.1016/j.oret.2019.08.005 ISSN 2468-6530/19
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Ophthalmology Retina Volume -, Number -, Month 2019 mutations were described to lead to a deficiency of LRP1, which, in turn, induced upregulation of transforming growth factor beta (TGF-b), leading to disruption of elastic tissues.6 This effect, which is also known to result in vascular elongation and aneurysms in Marfan syndrome, is thought to cause scleral expansion through remodeling of the extracellular matrix.7 Furthermore, high levels of TGF-b are considered to lead to a decrease of retinal elasticity and may increase retinal stiffness through the induction of epithelial mesenchymal transition in which, for example, retinal pigment epithelium (RPE) and Muller cells acquire mesenchymal phenotypes,8 which, in combination with scleral enlargement, could make the retina liable to develop breaks and RRD, even in the absence of any clinically noticeable vitreoretinal degeneration. Therefore, we hypothesized that children with LRPAP1-related high myopia may be at risk of RRD. To test this hypothesis, we retrospectively studied the cohort described by Khan et al5 and an additional 3 children who were identified to have LRPAP1-associated high myopia to determine the frequency, characteristics, and outcomes of any associated RRD in this cohort.
Methods This is a retrospective cohort study including all known children with high myopia associated with autosomal recessive mutations in LRPAP1 gene seen between 2014 and 2018 at King Khaled Eye Specialist Hospital. The patients were recruited from the original cohort of patients in whom the gene was identified,5,7 and a recognizable nonsyndromic high myopia phenotype, which included diffuse severe chorioretinal atrophy and optic nerve head peripapillary conus but no vitreoretinopathy and no RRD, was described.5,7 We also included 3 children who were ascertained by genetic analysis because they had high myopia and RRD. Approval was obtained from the Institutional Review Board at King Khaled Eye Specialist Hospital. The study adhered to the tenets of Declaration of Helsinki. Informed consent was obtained from all patients. Details of ophthalmological examinations, including best-corrected visual acuity, cyclorefraction, axial length measurement, and multimodal retinal imaging were performed (Spectralis OCT, Heidelberg Engineering, Inc., Heidelberg, Germany; and Optos PLC, Dunfermline, UK) for all applicable eyes with clear media. B-scan ultrasonography was performed in case of media opacities. Interventions included prophylactic laser treatment for peripheral retinal breaks with attached retina and retinal surgical repair for RRD with or without PVR. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS Inc., Chicago IL). Data were presented as the mean standard deviation. The chi-square test was used to compare nominal variables such as gender and development of RRDs. Children (eyes) who developed RRD were compared with children (eyes) who did not using the analysis of variance test. Differences were considered significant at P < 0.05.
Results A total of 24 eyes of 12 patients with homozygous LRPAP1 mutations were observed during 4.6 (mean) 1.9 (standard deviation) years (Table 1). Some 42% of children (5 children [6 eyes]) developed RRD at the age of 10.430.97 years. Of these, 1 child developed bilateral total RRDs. Four of the eyes developed
2
total RRDs, and 2 eyes developed subtotal macular-involving RRD. All RRDs were associated with primary PVR. Male gender and the presence of the c.863_864delTC mutation were more common in patients with RRD; however, the effect was not statistically significant in this small cohort (P ¼ 0.171 and P ¼ 0.52, respectively). Slightly higher refractive errors (25.31.54 vs. 21.865.3) and axial length measurements (32.72.26 mm vs. 31.15 3.4 mm) were observed in eyes with RRD with insignificant risks (P ¼ 0.265 and P ¼ 0.314, respectively). Bestcorrected visual acuity at presentation and at most recent visit were significantly poorer in eyes with RRD compared with eyes that did not develop any RRD (P < 0.001 for both). Two total RRDs were deemed inoperable with extensive PVR and bare to no light perception at presentation. Two total RRDs and 1 subtotal RRD had grade C PVR and were repaired by pars plana vitrectomy with silicone oil implantation, whereas 1 subtotal RRD that had grade A PVR was initially repaired by cryopexy with scleral buckle. All 4 repaired eyes (100%) developed recurrent RRD with PVR, requiring further surgical intervention in 3 of the 4 eyes (Table 1, Fig 1). One of these eyes was deemed as inoperable with extensive PVR. The 3 reoperated eyes were reattached throughout 6 months of follow-up with 2 eyes maintaining 20/300 vision and 1 maintaining 20/400. One eye of one child who developed a total inoperable RRD in the other eye was managed successfully with repeated prophylactic laser only for emerging retinal breaks and did not develop any RRD during more than 4 years of follow-up (Table 1, Fig 2). One eye of 1 child presented with optic atrophy, without developing any RRD, and was presumed to have had congenital glaucoma (Table 1). Most of the patients in this study had the homozygous c.863_864delTC mutation in LRPAP1 (Table 1). A subgroup analysis of all patients with this specific mutation was subsequently carried out, comparing the children who developed RRD with those who did not develop any RRD in the search of factors that could contribute to a variable expressivity of RRD among patients with the homozygous recessive c.863_864delTC mutation. There was no significant difference regarding the age of the children with RRD compared with those who did not develop any RRD nor was the observation period longer for the children who developed RRD compared with those who did not. However, the axial length was significantly longer in eyes that developed RRD (mean 32.671.88 mm) compared with those without any RRD (mean 30.92.36 mm, P < 0.05).
Discussion We observed 24 eyes of 12 patients with homozygous LRPAP1 mutations during 4.6 years (Table 1). Six eyes developed RRD, amounting to an annual average incidence of 6 RRDs per 12 patients per 5 years, which is equal to 0.25. Although 3 of the children in this cohort were ascertained by genetic testing because of RRD, implying that the rate of RRD in a population of children with LRPAP1 mutations may be somewhat lower, this number (0.25) is considerably higher than that reported for RRD in the general population, which is approximately 10/100 000, which is equal to 0.0001.9 By adjusting for high myopia more than 3 diopters in the general
Table 1. Characteristics of Patients with Nonsyndromic High Myopia Associated with Recessive Mutations in LRPAP1
Patient 1
Age at Most Recent Visit 11
Eye
Refraction (D)
AL (mm)
Retinal Break
First Retinal Detachment and Degree of PVR (Age)
c.863_864delTC
4
R
N/A
31.57
Yes
L
20.75
36.14
Yes
Total RRD with grade C PVR (10) No
c.605delT
4
R L
N/A N/A
39.92 37.11
No Yes
3
9
c.863_864delTC
1
R
26.00
32.43
Yes
4
13
c.863_864delTC
6
L R
25.00 26.00
30.87 32.40
No Yes
No Total RRD with grade C PVR (11)
L
N/A
30.60
Yes
R L R L R L R L R L R L
9.00 10.00 21.75 16.00 25.00 25.00 20.00 20.00 25.00 26.00 23.50 24.00
26.37 26.85 30.15 29.72 35.22 34.89 28.40 29.12 29.52 29.88 31.78 32.09
No No No No No No No No No No No Yes
R L R L
27.50 27.00 23.50 23.00
31.55 30.95 29.64 29.80
No No No No
Total RRD with grade C PVR (11) No No No No No No No No No No No Subtotal RRD with Grade A PVR (10) No No No No
5
23
c.605delT
5
6
13
c.605delT
5
7
15
c.863_864delTC
5
8
22
c.863_864delTC
7
9
9
c.863_864delTC
6
10
11
c.863_864delTC
1
11
15
c.863_864delTC
6
12
11
c.863_864delTC
6
No Total RRD with grade C PVR (12) Subtotal RRD with grade C PVR (9)
None
LP (irreparable RRD)
Prophylactic laser (several sessions) None PPV þ MP þ SO
20/80
1. PPV þ MP þ SO, 2. PPV þ MP þ SO þ SB 3. PPV þ MP þ SO None 1. PPV þ MP þ SO þ SB 2. PPV þ MP þ SO 3. PPV þ MP þ SO None None None None None None None None None None None None 1. Cryopexy þ SB 2. PPV þ MP þ SO None None None None
NLP (optic atrophy) LP (irreparable RRD) 20/400 (flat under SO) 20/80 20/300 (flat under SO) LP 20/40 20/60 20/40 20/60 20/50 20/100 20/125 20/160 20/50 20/40 20/40 20/300 (flat under SO) 20/40 20/50 20/50 20/60
AL ¼ axial length; L ¼ left; LP ¼ light perception; MP ¼ membrane peeling; MSO ¼ silicone oil; N/A ¼ unable to get good red reflex for cyclorefraction; NLP ¼ no light perception; PPV ¼ pars plana vitrectomy; PVR ¼ proliferative vitreoretinopathy; R ¼ right; RRD ¼ rhegmatogenous retinal detachment; SB ¼ scleral buckling; SO ¼ silicone oil. All mutations are homozygous. Patients 4e12 were included in the article by Khan et al,5 whereas patients 1e3 have not been reported previously.
LRPAP1-Associated Retinal Detachment
20
Outcome
2
Interventions
Magliyah et al
Mutation
Follow-up Duration (yrs)
3
Ophthalmology Retina Volume -, Number -, Month 2019
Figure 1. Fundus of the right eye of a 9-year-old female child (patient 3 in Table 1) with the homozygous mutation c.863_864delTC in the LRPAP1 gene who presented 1 year earlier after undergoing pars plana vitrectomy with silicone oil tamponade, with a macula-involving rhegmatogenous retinal detachment (RRD) in the right eye, with a large inferior break (A) and retinal folds compatible with grade C proliferative vitreoretinopathy (PVR). She underwent scleral buckle, pars plana vitrectomy, membrane peeling, and silicone oil injection and the inferior retina subsequently redetached under silicone oil (B). A third pars plana vitrectomy with silicone oil injection followed and shows attached retina (C) after the procedure. The axial length was >32 mm.
population, which was reported to yield a 10-fold increased risk for RRD,10 the number would be 0.001, which is still less by a factor of 250 compared with the incidence of RRD in our cohort of patients with LRPAP1 mutations. Thus, according to available literature on the risk of RRD in relation to high myopia in the general population, the risk seems to be considerably higher in patients with homozygous LRPAP1 mutations, which would suggest that the RRD risk in these children is caused by other factors in addition to high myopia. On the other hand, there are no data from the general population regarding the RRD risk in patients with a comparable degree of extremely high myopia as seen in LRPAP1 mutations, so the pathogenesis of RRD in these patients requires further study. A different approach could be to compare with another well-defined population with a genetically induced childhood-onset high myopia, such as that seen in congenital stationary night blindness due to recessive TRPM1 mutations. To date, no RRD has been reported in these patients, including a recent study by Miraldi Utz et al11 in which 7 patients were followed for 11 years, and our own patients (n ¼ 4) who have been observed for 4 to 10 years (Al-Hujaili et al. submitted manuscript, 2019). A PubMed search for “TRPM1 rhegmatogenous retinal detachment” (https://www.ncbi.nlm.nih.gov/pubmed/?term ¼trpm1þrhegmatogenousþretinalþdetachment, conducted on August 11, 2019), yielded no results. Khan et al5 reported the clinical appearance of children with LRPAP1-related myopia. The retina was typical for very high myopia with diffuse severe chorioretinal atrophy and optic nerve head peripapillary conus, but neither lacquer cracks nor neovascularization was seen. Vitreopathy was not observed. None of the patients were described to have any RRD-predisposing peripheral degeneration, such as lattice degeneration.5 None of the patients in the original description of the high myopia phenotype associated with LRPAP1 mutations by Khan et al5 were noted to have had any RRD at the time of that publication. However, 2 of the patients included in the
4
original cohort subsequently developed RRD during further follow-up (patients 4 and 10, Table 1). Furthermore, none of the patients in this study developed any lattice degeneration throughout follow-up. This is in keeping with a different mechanism for the development of lattice degeneration compared with LRPAP1-high myopia and RRD. The pathogenesis of lattice degeneration has been associated with variants in COL4A4 gene, which codes for the alpha-4 chain of type IV collagen, involved in the development of basement membranes.12 The mechanism of RRD in children with LRPAP1 mutations may be partially related to the high myopia, which is known to be an independent risk factor for RRD.1 Additionally, a postulated TGF-beinduced scleral wall remodeling, similar to Marfan syndrome, combined with loss of retinal elasticity, could contribute considerably to the risk of RRD.6-8 This similarity with Marfan syndrome regarding these aspects may be due to a convergence of some of the pathomechanisms in Marfan syndrome and LRPAP1-related disease: Marfan syndrome is caused by loss of function mutations in Fibrillin-1, a protein that binds and immobilizes TGF-b, thus controlling its activation.13 Likewise, LRP1 was reported to be required for mediating a normal, growth inhibitory response of TGF-b by binding to it.14,15 Mordechai et al4 reported RRD in 30.7% of a cohort with recessive LEPREL1 mutations associated with nonsyndromic high axial myopia and vitreoretinal degeneration. However, the pathogenesis of ocular enlargement and LEPREL1-associated RRD occurs through defective collagen hydroxylation in the sclera, similar to Stickler syndrome. Thus, the pathogenesis of RRD in these 2 nonsyndromic forms of RRD (LEPREL1 vs. LRPAP1) differs, even if the risk of RRD seems to be comparable (Table 2). The observed risk of RRD in LRPAP1-related high myopia was comparable to Stickler syndrome (10%e73%) but higher than in Marfan syndrome (5%e11%).14,16 Rhegmatogenous retinal detachment in LRPAP1-related high myopia tended to develop at early childhood (9e12 years), earlier than Stickler syndrome17,18 and Marfan syndrome.19 One eye of
Magliyah et al
LRPAP1-Associated Retinal Detachment
Figure 2. Fundus of the left eye of an 11-year-old male child (patient 1 in Table 1) with the homozygous c.863>864delTC mutation in the LRPAP1 gene who presented 4 years earlier with an inoperable RRD in the right eye (not shown) and received prophylactic retinal laser in the left eye at the same time. A, At the age of 9 years, the patient presented with a new superior break. The break was treated with indirect laser photocoagulation under general anesthesia. B, Subsequently, another 2 superonasal breaks, further nasally compared with the original break, developed during the following 2 years, which were treated with laser at the slit-lamp. The retina remained attached until the most recent follow-up. The axial length of the left eye was >36 mm.
1 of the children who developed a total inoperable RRD in the other eye was managed successfully with repeated prophylactic laser only, for emerging retinal breaks. Taken together, this suggests that dilated fundus examination including the retinal periphery with periodic monitoring is necessary from early childhood for these children. Primary retinal repairs for RRD in children with LRPAP1 mutations had limited success rates, mainly due to PVR, which is similar to Stickler and Marfan syndromes.20,21 The high incidence and aggressive nature of PVR in this cohort of patients with LRPAP1 mutations could be induced by an uncontrolled RPE proliferation because of a deficiency of LRP1, which has been shown to regulate RPE proliferation.22 Furthermore, TGF-beinduced contraction of vitreous gel collagen and epithelial mesenchymal transition of RPE and Muller cells could contribute to PVR.23,24 Our study suggests that LRP1 may be a therapeutic target for PVR, and therefore, an approach toward controlling the potential role of LRP1 in the PVR process may be more powerful than attempting to control TGF-b, which has been attempted previously.25,26 However, to date, there is no clinically available, approved pharmacologic approach to prevent or manage PVR.
Although the numbers are small, the risk of RRD with the 2 observed homozygous mutations (which both lead to frame shifts and subsequent termination of the transcript; c.605delA, p.Asn202Thrfs*8; c.863_864del, p.Ile288Argfs*118) may differ depending on genotype. Four of the patients who presented with RRD or retinal breaks had the homozygous mutation c.863_864delTC in LRPAP1, whereas only 1 patient had the homozygous c.605delT mutation. It also remains to be determined if any of these mutations may play a role in high myopia or RRD in other populations. In a recent screening of 187 Chinese patients with high myopia, only a heterozygous variant c.962G > A, p.Arg321His was detected in 1 patient, and it was predicted to be a benign polymorphism.27 Furthermore, it is at present not known whether heterozygous mutations in LRPAP1 might contribute to the risk of RRD or PVR in “nonhereditary” myopic RRD. Thus, further study is needed, analyzing LRPAP1 variants in larger cohorts of patients with myopic RRD with and without PVR. In general, prophylactic treatment of symptomatic retinal breaks must be considered in any patient, whereas no unequivocal conclusion could be reached with regard to
Table 2. Summary of 2 Studies Reporting Rhegmatogenous Retinal Detachment Associated with Autosomal Recessive Nonsyndromic high myopia Study
No. of Patients
Gene
Mutations
Age, yrs
Refraction (D)
Axial Length (mm)
Incidence of RRD
Magliyah et al, current study
12
LRPAP1
14.34.7 yrs
L22.25.1
31.53.2
42%
Mordechai et al4
13
LEPREL1
c.863_864delTC c.605delT c.1523G > T
L12.53.4*
27.51.5y
30.7%
22.2314.5
D ¼ diopters; RRD ¼ rhegmatogenous retinal detachment. *Unavailable and unreliable results were not included. y Unavailable results were not included.
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Ophthalmology Retina Volume -, Number -, Month 2019 prophylactic treatment of asymptomatic retinal breaks.28 In the case of high myopia associated with LRPAP1 mutations, because of the high incidence of childhoodonset RRD and our experience with 1 one-eyed patient who received several rounds of prophylactic laser photocoagulation because of emerging retinal breaks without developing any RRD in that eye (patient 1 in Table 1, Fig 2), we would recommend prophylactic laser photocoagulation for any retinal breaks, in this population.
Conclusions Recessive LRPAP1 mutations confer a high risk of childhood-onset RRD. Such RRD tends to involve the macula and has a high risk of PVR. Recognizing the LRPAP1-related high myopia phenotype is important, and early childhood fundus examination, close follow-up, and prophylactic retinal laser treatment may help patients maintain a good visual outcome. Acknowledgment. The authors thank Adolph Cabanas at Design and Publications, King Khaled Eye Specialist Hospital, for skillful technical assistance with the preparation of Figures 1 and 2. References 1. Johnston T, Chandra A, Hewitt AW. Current understanding of the genetic architecture of rhegmatogenous retinal detachment. Ophthalmic Genet. 2016;37:121e129. 2. Li J, Zhang Q. Insight into the molecular genetics of myopia. Mol Vis. 2017;23:1048e1080. 3. Jiang D, Li J, Xiao X, et al. Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing. Invest Ophthalmol Vis Sci. 2014;56:339e345. 4. Mordechai S, Gradstein L, Pasanen A, et al. High myopia caused by a mutation in LEPREL1, encoding prolyl 3hydroxylase 2. Am J Hum Genet. 2011;89:438e445. 5. Khan AO, Aldahmesh MA, Alkuraya FS. Clinical characterization of LRPAP1-related pediatric high myopia. Ophthalmology. 2016;123:434e435. 6. Muratoglu SC, Belgrave S, Hampton B, et al. LRP1 protects the vasculature by regulating levels of connective tissue growth factor and HtrA1. Arterioscler Thromb Vasc Biol. 2013;33:2137e2146. 7. Aldahmesh MA, Khan AO, Alkuraya H, et al. Mutations in LRPAP1 are associated with severe myopia in humans. Am J Hum Genet. 2013;93:313e320. 8. Bu SC, Kuijer R, van der Worp RJ, et al. Substrate elastic modulus regulates the morphology, focal adhesions, and asmooth muscle actin expression of retinal Müller cells. Invest Ophthalmol Vis Sci. 2015;56:5974e5982. 9. Mitry D, Charteris DG, Fleck BW, et al. The epidemiology of rhegmatogenous retinal detachment: geographical variation and clinical associations. Br J Ophthalmol. 2010;94:678e684.
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10. The Eye Disease Case-Control Study Group. Risk factors for idiopathic rhegmatogenous retinal detachment. Am J Epidemiol. 1993;137:749e757. 11. Miraldi Utz V, Pfeifer W, Longmuir SQ, et al. Presentation of TRPM1-associated congenital stationary night blindness in children. JAMA Ophthalmol. 2018;136:389e398. 12. Meguro A, Ideta H, Ota M, et al. Common variants in the COL4A4 gene confer susceptibility to lattice degeneration of the retina. PLoS One. 2012;7:e39300. 13. Kaartinen V, Warburton D. Fibrillin controls TGF-beta activation. Nat Genet. 2003;33:331e332. 14. Huang SS, Ling TY, Tseng WF, et al. Cellular growth inhibition by IGFBP-3 and TGF-beta1 requires LRP-1. FASEB J. 2003;17:2068e2081. 15. Tseng WF, Huang SS, Huang JS. LRP-1/TbetaR-V mediates TGFbeta1-induced growth inhibition in CHO cells. FEBS Lett. 2004;562:71e78. 16. Gan NY, Lam WC. Retinal detachments in the pediatric population. Taiwan J Ophthalmol. 2018;8:222e236. 17. Stickler GB, Hughes W, Houchin P. Clinical features of hereditary progressive arthro-ophthalmopathy (Stickler syndrome): a survey. Genet Med. 2001;3:192e196. 18. Abeysiri P, Bunce C, da Cruz L. Outcomes of surgery for retinal detachment in children with Stickler syndrome: a comparison of two sequential 20-year cohorts. Graefes Arch Clin Exp Ophthalmol. 2007;245:1633e1638. 19. Maumenee IH. The eye in the Marfan syndrome. Trans Am Ophthalmol Soc. 1981;79:684e733. 20. Alshahrani ST, Ghazi NG, Al-Rashaed S. Rhegmatogenous retinal detachments associated to Stickler syndrome in a tertiary eye care center in Saudi Arabia. Clin Ophthalmol. 2015;10:1e6. 21. Abboud EB. Retinal detachment surgery in Marfan’s syndrome. Retina. 1998;18:405e409. 22. Hollborn M, Birkenmeier G, Saalbach A, et al. Expression of LRP1 in retinal pigment epithelial cells and its regulation by growth factors. Invest Ophthalmol Vis Sci. 2004;45: 2033e2038. 23. Kita T, Hata Y, Arita R, et al. Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target. Proc Natl Acad Sci U S A. 2008;105:17504e17509. 24. Winkler J, Hoerauf H. TGF-ß and RPE-derived cells in taut subretinal strands from patients with proliferative vitreoretinopathy. Eur J Ophthalmol. 2011;21:422e426. 25. Nassar K, Grisanti S, Tura A, et al. A TGF-b receptor 1 inhibitor for prevention of proliferative vitreoretinopathy. Exp Eye Res. 2014;123:72e86. 26. Yokoyama K, Kimoto K, Itoh Y, et al. The PI3K/Akt pathway mediates the expression of type I collagen induced by TGF-b2 in human retinal pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol. 2012;250:15e23. 27. Feng CY, Huang XQ, Cheng XW, et al. Mutational screening of SLC39A5, LEPREL1 and LRPAP1 in a cohort of 187 high myopia patients. Sci Rep. 2017;7:1120. 28. Blindbaek S, Grauslund J. Prophylactic treatment of retinal breaks–a systematic review. Acta Ophthalmol. 2015;93: 3e8.
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LRPAP1-Associated Retinal Detachment
Footnotes and Financial Disclosures Originally received: August 11, 2019. Final revision: August 13, 2019. Accepted: August 13, 2019. Available online: ---. Manuscript no. ORET-D-19-00102. 1
Ophthalmology Department, Prince Mohammed Medical City, AlJouf, Saudi Arabia.
2
Vitreoretinal Division, King Khalid Eye Specialist Hospital, Riyadh, Saudi Arabia.
3
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 4 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 5
Department of Ophthalmology, Clinical Sciences, Skane County University Hospital, University of Lund, Lund, Sweden.
The abstract of this work entitled “Pediatric Rhegmatogenous Retinal Detachment in Nonsyndromic High Myopia associated with Recessive Mutations in LRPAP1” was accepted for a poster presentation at: the Annual Meeting of the American Academy of Ophthalmology, October 12e15, 2019, San Francisco, California. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Author Contributions: Conception and design: Magliyah, Schatz Data collection: Magliyah, Alsulaiman, Nowilaty, Alkuraya, Schatz Analysis and interpretation: Magliyah, Alsulaiman, Nowilaty, Alkuraya, Schatz Obtained funding: N/A Overall responsibility: Magliyah, Alsulaiman, Nowilaty, Alkuraya, Schatz HUMAN SUBJECTS: Human subjects were included in this study. The human ethics committees at the King Khalid Eye Specialist Hospital approved the study. All research adhered to the tenets of the Declaration of Helsinki. All participants provided informed consent. No animal subjects were used in this study. Abbreviations and Acronyms: OMIM ¼ Online Mendelian Inheritance in Man; PVR ¼ proliferative vitreoretinopathy; RPE ¼ retinal pigment epithelium; RRD ¼ rhegmatogenous retinal detachment; TGF-b ¼ transforming growth factor beta. Correspondence: Patrik Schatz, MD, PhD, Vitreoretinal Division, King Khaled Eye Specialist Hospital, Al-Oruba St., PO Box 7191, Riyadh 11462, Kingdom of Saudi Arabia. E-mail: [email protected].
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