Expert consensus on diagnosis and treatment of choroideremia (2024)_Chinese Journal of Ocular Fundus Diseases

Authors：

 Chinese Hereditary Ocular Disease Diagnosis and Treatment Group , Chinese Hereditary Ocular Disease Alliance

Corresponding author：

Chinese Hereditary Ocular Disease Diagnosis and Treatment Group, Email: hrfsui@163.com

Keywords：

Choroideremia; Diagnosis; Treatment; Expert consensus

DOI：

10.3760/cma.j.cn511434-20240229-00086

Video：

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Choroideremia (CHM) is a rare X-linked recessive genetic retinal degeneration. It mainly affects men, manifested as progressively worsening night blindness, visual field loss, and decreased central vision, which can cause blindness in middle age. Although female carriers typically exhibit mild symptoms, it is essential to understand their clinical features for early diagnosis of patients as well as genetic counseling of family members. The pathogenesis of CHM remains incompletely understood, and currently there is no approved effective treatment. To enhance clinicians’ comprehension of CHM and establish standardized clinical approaches to its diagnosis and management, Chinese Hereditary Ocular Disease Diagnosis and Treatment Group and Chinese Hereditary Ocular Disease Alliance assembled authoritative experts, through in-depth discussion, formed China's standardized suggestions on clinical diagnosis and treatment of CHM. The purpose of this advice is to provide a standardized diagnostic framework, monitoring indicators, and integrated management strategy for clinicians to use in practice to optimize the care and genetic guidance for patients with CHM.

1.	van Schuppen SM, Talib M, Bergen AA, et al. Long-term follow-up of patients with choroideremia with scleral pits and tunnels as a novel observation[J]. Retina, 2018, 38(9): 1713-1724. DOI: 10.1097/iae.0000000000001844.
2.	Heon E, Alabduljalil T, Iii DB, et al. Visual function and central retinal structure in choroideremia[J]. Invest Ophthalmol Vis Sci, 2016, 57(9): 377-387. DOI: 10.1167/iovs.15-18421.
3.	MacDonald IM, Smaoui N, Seabra MC. Choroideremia[M]//Pagon RA, Bird TD, Dolan CR, et al. Gene Reviews. Seattle WA: University of Washington, Seattle, 1993.
4.	van den Hurk JA, Schwartz M, van Bokhoven H, et al. Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene[J]. Hum Mutat, 1997, 9: 110-117. DOI: 10.1002/(SICI)1098-1004(1997)9:2<110::AID-HUMU2>3.0.CO;2-D.
5.	van Bokhoven H, van den Hurk J A, Bogerd L, et al. Cloning and characterization of the human choroideremia gene[J]. Hum Mol Genet, 1994, 3(7): 1041-1046. DOI: 10.1093/hmg/3.7.1041.
6.	MacDonald IM, Russell L, Chan CC. Choroideremia: new findings from ocular pathology and review of recent literature[J]. Surv Ophthalmol, 2009, 54(3): 401-407. DOI: 10.1016/j.survophthal.2009.02.008.
7.	Han RC, Fry LE, Kantor A, et al. Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?[J]. Expert Opin Orphan Drugs, 2021, 9(1): 13-24. DOI: 10.1080/21678707.2021.1882300.
8.	Zerial M, McBride H. Rab proteins as membrane organizers[J]. Nat Rev Mol Cell Biol, 2001, 2(2): 107-117. DOI: 10.1038/35052055.
9.	Seabra MC, Wasmeier C. Controlling the location and activation of Rab GTPases[J]. Curr Opin Cell Biol, 2004, 16(4): 451-457. DOI: 10.1016/j.ceb.2004.06.014.
10.	Seabra MC, Ho YK, Anant JS. Deficient geranylgeranylation of Ram/Rab27 in choroideremia[J]. J Biol Chem, 1995, 270(41): 24420-24427. DOI: 10.1074/jbc.270.41.24420.
11.	Xue K, Oldani M, Jolly JK, et al. Correlation of optical coherence tomography and autofluorescence in the outer retina and choroid of patients with choroideremia[J]. Invest Ophthalmol Vis Sci, 2016, 57(8): 3674-3684. DOI: 10.1167/iovs.15-18364.
12.	Gordiyenko NV, Fariss RN, Zhi C, et al. Silencing of the CHM gene alters phagocytic and secretory pathways in the retinal pigment epithelium[J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1143-1150. DOI: 10.1167/iovs.09-4117.
13.	Duong TT, Vasireddy V, Ramachandran P, et al. Use of induced pluripotent stem cell models to probe the pathogenesis of choroideremia and to develop a potential treatment[J]. Stem Cell Res, 2018, 27: 140-150. DOI: 10.1016/j.scr.2018.01.009.
14.	Shen LL, Ahluwalia A, Sun M, et al. Long-term natural history of visual acuity in eyes with choroideremia: a systematic review and meta-analysis of data from 1004 individual eyes[J]. Br J Ophthalmol, 2021, 105(2): 271-278. DOI: 10.1136/bjophthalmol-2020-316028.
15.	Han X, Wu S, Li H, et al. Clinical characteristics and molecular genetic analysis of a cohort of Chinese patients with choroideremia[J]. Retina, 2020, 40(11): 2240-2253. DOI: 10.1097/iae.0000000000002743.
16.	Song Y, Chen C, Xie Y, et al. Clinical and genetic findings in a Chinese cohort with choroideremia[J]. Eye (Lond), 2023, 37(3): 459-466. DOI: 10.1038/s41433-022-01950-6.
17.	Krill AE. Atrophic macular changes with emphasis on hereditary aspects[J]. Trans Ophthalmol Soc UK, 1972, 92: 419-447.
18.	Kärnä J. Choroideremia. A clinical and genetic study of 84 Finnish patients and 126 female carriers[J]. Acta Ophthalmol Suppl, 1986, 176: 1-68.
19.	Jauregui R, Park KS, Tanaka AJ, et al. Spectrum of disease severity and phenotype in choroideremia carriers[J]. Am J Ophthalmol, 2019, 207: 77-86. DOI: 10.1016/j.ajo.2019.06.002.
20.	Beaufrère L, Rieu S, Hache JC, et al. Altered rep-1 expression due to substitution at position +3 of the IVS13 splice-donor site of the choroideremia (CHM) gene[J]. Curr Eye Res, 1998, 17(7): 726-729.
21.	Preising MN, Wegscheider E, Friedburg C, et al. Fundus autofluorescence in carriers of choroideremia and correlation with electrophysiologic and psychophysical data[J]. Ophthalmology, 2009, 116(6): 1201-1209. DOI: 10.1016/j.ophtha.2009.01.016.
22.	Mura M, Sereda C, Jablonski MM, et al. Clinical and functional findings in choroideremia due to complete deletion of the CHM gene[J]. Arch Ophthalmol, 2007, 125(8): 1107-1113. DOI: 10.1001/archopht.125.8.1107.
23.	Yusuf IH, MacLaren RE. Choroideremia: toward regulatory approval of retinal gene therapy[J/OL]. Cold Spring Harb Perspect Med, 2023, 13(12): a041279[2023-06-05].https://pubmed.ncbi.nlm.nih.gov/37277205/. DOI: 10.1101/cshperspect.a041279.
24.	Hariri AH, Velaga SB, Girach A, et al. Measurement and reproducibility of preserved ellipsoid zone area and preserved retinal pigment epithelium area in eyes with choroideremia[J]. Am J Ophthalmol, 2017, 179: 110-117. DOI: 10.1016/j.ajo.2017.05.002.
25.	Harvey CM, Whitmore SS, Critser DB, et al. Scleral pits represent degeneration around the posterior ciliary arteries and are signs of disease severity in choroideremia[J]. Eye (Lond), 2020, 34(4): 746-754. DOI: 10.1038/s41433-019-0599-4.
26.	Cunningham CM, Critser DB, Han IC. Swept-source OCT of a scleral tunnel in choroideremia[J]. Ophthalmology, 2018, 125(6): 806. DOI: 10.1016/j.ophtha.2018.03.010.
27.	Hariri AH, Ip MS, Girach A, et al. Macular spatial distribution of preserved autofluorescence in patients with choroideremia[J]. Br J Ophthalmol, 2019, 103(7): 933-937. DOI: 10.1136/bjophthalmol-2018-312620.
28.	Jolly JK, Edwards TL, Moules J, et al. A qualitative and quantitative assessment of fundus autofluorescence patterns in patients with choroideremia[J]. Invest Ophthalmol Vis Sci, 2016, 57(10): 4498-4503. DOI: 10.1167/iovs.15-18362.
29.	Dimopoulos IS, Freund PR, Knowles JA, et al. The natural history of full-field stimulus threshold decline in choroideramia[J]. Retina, 2018, 38(9): 1731-1742. DOI: 10.1097/iae.0000000000001764.
30.	Jolly JK, Groppe M, Birks J, et al. Functional defects in color vision in patients with choroideremia[J]. Am J Ophthalmol, 2015, 160(4): 822-831. DOI: 10.1016/j.ajo.2015.06.018.
31.	Seitz IP, Jolly JK, Dominik Fischer M, et al. Colour discrimination ellipses in choroideremia[J]. Graefe's Arch Clin Exp Ophthalmol, 2018, 256(4): 665-673. DOI: 10.1007/s00417-018-3921-0.
32.	Edwards TL, Groppe M, Jolly JK, et al. Correlation of retinal structure and function in choroideremia carriers[J]. Ophthalmology, 2015, 122(6): 1274-1276. DOI: 10.1016/j.ophtha.2014.12.036.
33.	Syed R, Sundquist SM, Ratnam K, et al. High-resolution images of retinal structure in patients with choroideremia[J]. Invest Ophthalmol Vis Sci, 2013, 54(2): 950-961. DOI: 10.1167/iovs.12-10707.
34.	McTaggart KE, Tran M, Mah DY, et al. Mutational analysis of patients with the diagnosis of choroideremia[J]. Hum Mutat, 2002, 20(3): 189-196. DOI: 10.1002/humu.10114.
35.	van den Hurk JA, van de Pol DJ, Wissinger B, et al. Novel types of mutation in the choroideremia (CHM) gene: a full-length L1 insertion and an intronic mutation activating a cryptic exon[J]. Hum Genet, 2003, 113(3): 268-275. DOI: 10.1007/s00439-003-0970-0.
36.	Chi JY, MacDonald IM, Hume S. Copy number variant analysis in CHM to detect duplications underlying choroideremia[J]. Ophthalmic Genet, 2013, 34(4): 229-233. DOI: 10.3109/13816810.2012.752016.
37.	Zhou Q, Yao F, Han X, et al. Rep1 copy number variation is an important genetic cause of choroideremia in Chinese patients[J]. Exp Eye Res, 2017, 164: 64-73. DOI: 10.1016/j.exer.2017.07.016.
38.	Poloschek CM, Kloeckener-Gruissem B, Hansen LL, et al. Syndromic choroideremia: sublocalization of phenotypes associated with Martin-Probst deafness mental retardation syndrome[J]. Invest Ophthalmol Vis Sci, 2008, 49(9): 4096-4104. DOI: 10.1167/iovs.08-2044.
39.	Kmoch S, Majewski J, Ramamurthy V, et al. Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness[J]. Nat Commun, 2015, 6: 5614. DOI: 10.1038/ncomms6614.
40.	Kabunga P, Lau AK, Phan K, et al. Systematic review of cardiac electrical disease in Kearns–Sayre syndrome and mitochondrial cytopathy[J]. Int J Cardiol, 2015, 181: 303-310. DOI: 10.1016/j.ijcard.2014.12.038.
41.	Richardson R, Smart M, Tracey-White D, et al. Mechanism and evidence of nonsense suppression therapy for genetic eye disorders[J]. Exp Eye Res, 2017, 155: 24-37. DOI: 10.1016/j.exer.2017.01.001.
42.	Moosajee M, Tracey-White D, Smart M, et al. Functional rescue of REP1 following treatment with PTC124 and novel derivative PTC-414 in human choroideremia fibroblasts and the nonsense-mediated zebrafish model[J]. Hum Mol Genet, 2016, 25(16): 3416-3431. DOI: 10.1093/hmg/ddw184.

1. van Schuppen SM, Talib M, Bergen AA, et al. Long-term follow-up of patients with choroideremia with scleral pits and tunnels as a novel observation[J]. Retina, 2018, 38(9): 1713-1724. DOI: 10.1097/iae.0000000000001844.
2. Heon E, Alabduljalil T, Iii DB, et al. Visual function and central retinal structure in choroideremia[J]. Invest Ophthalmol Vis Sci, 2016, 57(9): 377-387. DOI: 10.1167/iovs.15-18421.
3. MacDonald IM, Smaoui N, Seabra MC. Choroideremia[M]//Pagon RA, Bird TD, Dolan CR, et al. Gene Reviews. Seattle WA: University of Washington, Seattle, 1993.
4. van den Hurk JA, Schwartz M, van Bokhoven H, et al. Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene[J]. Hum Mutat, 1997, 9: 110-117. DOI: 10.1002/(SICI)1098-1004(1997)9:2<110::AID-HUMU2>3.0.CO;2-D.
5. van Bokhoven H, van den Hurk J A, Bogerd L, et al. Cloning and characterization of the human choroideremia gene[J]. Hum Mol Genet, 1994, 3(7): 1041-1046. DOI: 10.1093/hmg/3.7.1041.
6. MacDonald IM, Russell L, Chan CC. Choroideremia: new findings from ocular pathology and review of recent literature[J]. Surv Ophthalmol, 2009, 54(3): 401-407. DOI: 10.1016/j.survophthal.2009.02.008.
7. Han RC, Fry LE, Kantor A, et al. Is subretinal AAV gene replacement still the only viable treatment option for choroideremia?[J]. Expert Opin Orphan Drugs, 2021, 9(1): 13-24. DOI: 10.1080/21678707.2021.1882300.
8. Zerial M, McBride H. Rab proteins as membrane organizers[J]. Nat Rev Mol Cell Biol, 2001, 2(2): 107-117. DOI: 10.1038/35052055.
9. Seabra MC, Wasmeier C. Controlling the location and activation of Rab GTPases[J]. Curr Opin Cell Biol, 2004, 16(4): 451-457. DOI: 10.1016/j.ceb.2004.06.014.
10. Seabra MC, Ho YK, Anant JS. Deficient geranylgeranylation of Ram/Rab27 in choroideremia[J]. J Biol Chem, 1995, 270(41): 24420-24427. DOI: 10.1074/jbc.270.41.24420.
11. Xue K, Oldani M, Jolly JK, et al. Correlation of optical coherence tomography and autofluorescence in the outer retina and choroid of patients with choroideremia[J]. Invest Ophthalmol Vis Sci, 2016, 57(8): 3674-3684. DOI: 10.1167/iovs.15-18364.
12. Gordiyenko NV, Fariss RN, Zhi C, et al. Silencing of the CHM gene alters phagocytic and secretory pathways in the retinal pigment epithelium[J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1143-1150. DOI: 10.1167/iovs.09-4117.
13. Duong TT, Vasireddy V, Ramachandran P, et al. Use of induced pluripotent stem cell models to probe the pathogenesis of choroideremia and to develop a potential treatment[J]. Stem Cell Res, 2018, 27: 140-150. DOI: 10.1016/j.scr.2018.01.009.
14. Shen LL, Ahluwalia A, Sun M, et al. Long-term natural history of visual acuity in eyes with choroideremia: a systematic review and meta-analysis of data from 1004 individual eyes[J]. Br J Ophthalmol, 2021, 105(2): 271-278. DOI: 10.1136/bjophthalmol-2020-316028.
15. Han X, Wu S, Li H, et al. Clinical characteristics and molecular genetic analysis of a cohort of Chinese patients with choroideremia[J]. Retina, 2020, 40(11): 2240-2253. DOI: 10.1097/iae.0000000000002743.
16. Song Y, Chen C, Xie Y, et al. Clinical and genetic findings in a Chinese cohort with choroideremia[J]. Eye (Lond), 2023, 37(3): 459-466. DOI: 10.1038/s41433-022-01950-6.
17. Krill AE. Atrophic macular changes with emphasis on hereditary aspects[J]. Trans Ophthalmol Soc UK, 1972, 92: 419-447.
18. Kärnä J. Choroideremia. A clinical and genetic study of 84 Finnish patients and 126 female carriers[J]. Acta Ophthalmol Suppl, 1986, 176: 1-68.
19. Jauregui R, Park KS, Tanaka AJ, et al. Spectrum of disease severity and phenotype in choroideremia carriers[J]. Am J Ophthalmol, 2019, 207: 77-86. DOI: 10.1016/j.ajo.2019.06.002.
20. Beaufrère L, Rieu S, Hache JC, et al. Altered rep-1 expression due to substitution at position +3 of the IVS13 splice-donor site of the choroideremia (CHM) gene[J]. Curr Eye Res, 1998, 17(7): 726-729.
21. Preising MN, Wegscheider E, Friedburg C, et al. Fundus autofluorescence in carriers of choroideremia and correlation with electrophysiologic and psychophysical data[J]. Ophthalmology, 2009, 116(6): 1201-1209. DOI: 10.1016/j.ophtha.2009.01.016.
22. Mura M, Sereda C, Jablonski MM, et al. Clinical and functional findings in choroideremia due to complete deletion of the CHM gene[J]. Arch Ophthalmol, 2007, 125(8): 1107-1113. DOI: 10.1001/archopht.125.8.1107.
23. Yusuf IH, MacLaren RE. Choroideremia: toward regulatory approval of retinal gene therapy[J/OL]. Cold Spring Harb Perspect Med, 2023, 13(12): a041279[2023-06-05].https://pubmed.ncbi.nlm.nih.gov/37277205/. DOI: 10.1101/cshperspect.a041279.
24. Hariri AH, Velaga SB, Girach A, et al. Measurement and reproducibility of preserved ellipsoid zone area and preserved retinal pigment epithelium area in eyes with choroideremia[J]. Am J Ophthalmol, 2017, 179: 110-117. DOI: 10.1016/j.ajo.2017.05.002.
25. Harvey CM, Whitmore SS, Critser DB, et al. Scleral pits represent degeneration around the posterior ciliary arteries and are signs of disease severity in choroideremia[J]. Eye (Lond), 2020, 34(4): 746-754. DOI: 10.1038/s41433-019-0599-4.
26. Cunningham CM, Critser DB, Han IC. Swept-source OCT of a scleral tunnel in choroideremia[J]. Ophthalmology, 2018, 125(6): 806. DOI: 10.1016/j.ophtha.2018.03.010.
27. Hariri AH, Ip MS, Girach A, et al. Macular spatial distribution of preserved autofluorescence in patients with choroideremia[J]. Br J Ophthalmol, 2019, 103(7): 933-937. DOI: 10.1136/bjophthalmol-2018-312620.
28. Jolly JK, Edwards TL, Moules J, et al. A qualitative and quantitative assessment of fundus autofluorescence patterns in patients with choroideremia[J]. Invest Ophthalmol Vis Sci, 2016, 57(10): 4498-4503. DOI: 10.1167/iovs.15-18362.
29. Dimopoulos IS, Freund PR, Knowles JA, et al. The natural history of full-field stimulus threshold decline in choroideramia[J]. Retina, 2018, 38(9): 1731-1742. DOI: 10.1097/iae.0000000000001764.
30. Jolly JK, Groppe M, Birks J, et al. Functional defects in color vision in patients with choroideremia[J]. Am J Ophthalmol, 2015, 160(4): 822-831. DOI: 10.1016/j.ajo.2015.06.018.
31. Seitz IP, Jolly JK, Dominik Fischer M, et al. Colour discrimination ellipses in choroideremia[J]. Graefe's Arch Clin Exp Ophthalmol, 2018, 256(4): 665-673. DOI: 10.1007/s00417-018-3921-0.
32. Edwards TL, Groppe M, Jolly JK, et al. Correlation of retinal structure and function in choroideremia carriers[J]. Ophthalmology, 2015, 122(6): 1274-1276. DOI: 10.1016/j.ophtha.2014.12.036.
33. Syed R, Sundquist SM, Ratnam K, et al. High-resolution images of retinal structure in patients with choroideremia[J]. Invest Ophthalmol Vis Sci, 2013, 54(2): 950-961. DOI: 10.1167/iovs.12-10707.
34. McTaggart KE, Tran M, Mah DY, et al. Mutational analysis of patients with the diagnosis of choroideremia[J]. Hum Mutat, 2002, 20(3): 189-196. DOI: 10.1002/humu.10114.
35. van den Hurk JA, van de Pol DJ, Wissinger B, et al. Novel types of mutation in the choroideremia (CHM) gene: a full-length L1 insertion and an intronic mutation activating a cryptic exon[J]. Hum Genet, 2003, 113(3): 268-275. DOI: 10.1007/s00439-003-0970-0.
36. Chi JY, MacDonald IM, Hume S. Copy number variant analysis in CHM to detect duplications underlying choroideremia[J]. Ophthalmic Genet, 2013, 34(4): 229-233. DOI: 10.3109/13816810.2012.752016.
37. Zhou Q, Yao F, Han X, et al. Rep1 copy number variation is an important genetic cause of choroideremia in Chinese patients[J]. Exp Eye Res, 2017, 164: 64-73. DOI: 10.1016/j.exer.2017.07.016.
38. Poloschek CM, Kloeckener-Gruissem B, Hansen LL, et al. Syndromic choroideremia: sublocalization of phenotypes associated with Martin-Probst deafness mental retardation syndrome[J]. Invest Ophthalmol Vis Sci, 2008, 49(9): 4096-4104. DOI: 10.1167/iovs.08-2044.
39. Kmoch S, Majewski J, Ramamurthy V, et al. Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness[J]. Nat Commun, 2015, 6: 5614. DOI: 10.1038/ncomms6614.
40. Kabunga P, Lau AK, Phan K, et al. Systematic review of cardiac electrical disease in Kearns–Sayre syndrome and mitochondrial cytopathy[J]. Int J Cardiol, 2015, 181: 303-310. DOI: 10.1016/j.ijcard.2014.12.038.
41. Richardson R, Smart M, Tracey-White D, et al. Mechanism and evidence of nonsense suppression therapy for genetic eye disorders[J]. Exp Eye Res, 2017, 155: 24-37. DOI: 10.1016/j.exer.2017.01.001.
42. Moosajee M, Tracey-White D, Smart M, et al. Functional rescue of REP1 following treatment with PTC124 and novel derivative PTC-414 in human choroideremia fibroblasts and the nonsense-mediated zebrafish model[J]. Hum Mol Genet, 2016, 25(16): 3416-3431. DOI: 10.1093/hmg/ddw184.

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