Choroideremia Explained

Choroideremia
Synonyms:CHM, Tapetochoroidal dystrophy
Field:Ophthalmology
Symptoms:Progressive vision loss
Onset:Childhood
Duration:Chronic
Causes:Genetic
Diagnosis:Genetic testing, family history, fundus examination

Choroideremia (; CHM) is a rare, X-linked recessive form of hereditary retinal degeneration that affects roughly 1 in 50,000 males. The disease causes a gradual loss of vision, starting with childhood night blindness, followed by peripheral vision loss and progressing to loss of central vision later in life. Progression continues throughout the individual's life, but both the rate of change and the degree of visual loss are variable among those affected, even within the same family.[1]

Choroideremia is caused by a loss-of-function mutation in the CHM gene which encodes Rab escort protein 1 (REP1), a protein involved in lipid modification of Rab proteins. While the complete mechanism of disease is not fully understood, the lack of a functional protein in the retina results in cell death and the gradual deterioration of the retinal pigment epithelium (RPE), photoreceptors and the choroid.[2] [3]

As of 2019, there is no treatment for choroideremia; however, retinal gene therapy clinical trials have demonstrated a possible treatment.[4]

Presentation

Since the CHM gene is located on the X chromosome, symptoms are seen almost exclusively in men. While there are a few exceptions, female carriers have a noticeable lack of pigmentation in the RPE but do not experience any symptoms.[5] Female carriers have a 50% chance of having either an affected son or a carrier daughter, while a male with choroideremia will have all carrier daughters and unaffected sons.

Even though the disease progression can vary significantly,[6] there are general trends. The first symptom many individuals with choroideremia notice is a significant loss of night vision, which begins in youth.[7] Peripheral vision loss occurs gradually, starting as a ring of vision loss, and continuing on to "tunnel vision" in adulthood.[8] Individuals with choroideremia tend to maintain good visual acuity into their 40s, but eventually lose all sight at some point in the 50–70 age range. A study of 115 individuals with choroideremia found that 84% of patients under the age of 60 had a visual acuity of 20/40 or better, while 33% of patients over 60 years old had a visual acuity of 20/200 or worse. The most severe visual acuity impairment (only being able to count fingers or worse) did not occur until the seventh decade of life. The same study found the mean rate of visual acuity loss to be about 0.09 logMAR per 5 years, which is roughly 1 row on a Snellen chart.

Diagnosis

A diagnosis of choroideremia can be made based on family history, symptoms and the characteristic appearance of the fundus. However, choroideremia shares several clinical features with retinitis pigmentosa, a similar but broader group of retinal degenerative diseases, making a specific diagnosis difficult without genetic testing. Because of this choroideremia is often initially misdiagnosed as retinitis pigmentosa.[9] A variety of different genetic testing techniques can be used to make a differential diagnosis.[10] [11]

Management

While nothing currently can be done to stop or reverse the retinal degeneration, there are steps that can be taken to slow the rate of vision loss. UV-blocking sunglasses for outdoors, appropriate dietary intake of fresh fruit and leafy green vegetables, antioxidant vitamin supplements, and regular intake of dietary omega-3 very-long-chain fatty acids are all recommended.[8] One study found that a dietary supplement of lutein increases macular pigment levels in patients with choroideremia. Over a long period of time, these elevated levels of pigmentation "could" slow retinal degeneration.[12] Additional interventions that may be needed include surgical correction of retinal detachment and cataracts, low vision services, and counseling to help cope with depression, loss of independence, and anxiety over job loss.[8]

Gene therapy

See also: Gene therapy of the human retina. Gene therapy is currently not a treatment option, however human clinical trials for both choroideremia and Leber's congenital amaurosis (LCA) have produced somewhat promising results.[13]

Clinical trials of gene therapy for patients with LCA began in 2008 at three different sites.[14] [15] [16] [17] In general, these studies found the therapy to be safe, somewhat effective, and promising as a future treatment for similar retinal diseases.

In 2011, the first gene therapy treatment for choroideremia was administered.[18] The surgery was performed by Robert MacLaren, Professor of Ophthalmology at the University of Oxford and leader of the Clinical Ophthalmology Research Group at the Nuffield Laboratory of Ophthalmology (NLO).[13] [19] [20] In the study, 2 doses of the AAV.REP1 vector were injected subretinally in 12 patients with choroideremia. There study had 2 objectives:

Despite retinal detachment caused by the injection, the study observed initial improved rod and cone function, warranting further study.

In 2016, researchers were optimistic that the positive results of 32 choroideremia patients treated over four and a half years with gene therapy in four countries could be long-lasting.[22]

Preimplantation genetic diagnosis

For women who carry a mutation in the CHM gene, preimplantation genetic diagnosis can be used during the in-vitro fertilization process to select unaffected embryos to implant.[23] This process call be applied to any monogenic disease.

Other potential therapies

While choroideremia is an ideal candidate for gene therapy[2] there are other potential therapies that could restore vision after it has been lost later in life. Foremost of these is stem cell therapy. A clinical trial published in 2014 found that a subretinal injection of human embryonic stem cells in patients with age-related macular degeneration and Stargardt disease was safe and improved vision in most patients. Out of 18 patients, vision improved in 10, improved or remained the same in 7, and decreased in 1 patient, while no improvement was seen in the untreated eyes. The study found "no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue."[24] [25] A 2015 study used CRISPR/Cas9 to repair mutations in patient-derived induced pluripotent stem cells that cause X-linked retinitis pigmentosa.[26] This study suggests that a patient's own repaired cells could be used for therapy, reducing the risk of immune rejection and ethical issues that come with the use of embryonic stem cells.

Research

History

Choroideremia was first described in 1872 by an Austrian ophthalmologist, Ludwig Mauthner.[27] Initially, the condition was thought to be a developmental disorder which caused the absence of a majority of the choroid (hence the probable use of the ancient Greek suffix “eremia,” meaning barren land or desert). After several decades, the non-progressive nature of the disease was called into doubt, eventually being rejected by Paymerer et al. in 1960.[28] The CHM gene was identified and cloned in 1990 by Frans P.M. Cremers.[29]

Basic research

In many inherited retinal diseases the protein affected by the mutation is directly involved in the light sensing function of the eye, however this is not the case in choroideremia. REP1 assists the prenylation of Rab G-proteins by binding and presenting them to the Rab geranylgeranyltransferase subunit.[30] REP1 also escorts prenylated Rabs through the cytoplasm by binding the hydrophobic prenyl groups and carrying them to a specific destination membrane.

In healthy individuals, REP1 is found throughout all of the cells of the body, however patients with choroideremia only experience vision loss, and not broader, systemic symptoms (with the exception of a study that found crystals and fatty acid abnormalities in leukocytes).[31] REP2, a protein that is 75% identical and 90% similar to REP1, is able to significantly compensate for the loss of REP1 outside the eye.[27] [32] It is thought that REP2 is not able to fully compensate for the loss of REP1 in the retina.[27] RAB27A, a Rab that has essential functions in the retina,[33] has been shown to be preferentially prenylated by REP1.[34] Additionally, the Rab27a-REP1 and Rab27a-REP2 complexes have different affinities for the Rab geranylgeranyltransferase enzyme, possibly explaining REP2's inability to fully compensate for REP1 in the retina.[34]

Culture

A number of individuals in public roles are living with choroideremia, and some have been involved in fundraising efforts for the disease. The former UK Labour Member of Parliament Siôn Simon is a known to have the condition.[35] Comic and activist E.J. Scott, partner of Daredevil actress Deborah Ann Woll, also has choroideremia, and is involved in regular fundraising efforts.[36] [37]

Further reading

External links

Notes and References

  1. Kärnä. J. Choroideremia. A clinical and genetic study of 84 Finnish patients and 126 female carriers.. Acta Ophthalmologica Supplement. 1986. 176. 1–68. 3014804.
  2. Roberts. MF. Fishman. GA. Roberts. DK. Heckenlively. JR. Weleber. RG. Anderson. RJ. Grover. S. Retrospective, longitudinal, and cross sectional study of visual acuity impairment in choroideraemia.. The British Journal of Ophthalmology. June 2002. 86. 6. 658–62. 12034689. 10.1136/bjo.86.6.658. 1771148.
  3. Aleman. TS. Han. G. Serrano. LW. Fuerst. NM. Charlson. ES. Pearson. DJ. Chung. DC. Traband. A. Pan. W. Ying. GS. Bennett. J. Maguire. AM. Morgan. JI. Natural History of the Central Structural Abnormalities in Choroideremia: A Prospective Cross-Sectional Study.. Ophthalmology. 13 December 2016. 10.1016/j.ophtha.2016.10.022. 27986385. 124. 3. 5319901. 359–373.
  4. Abigail Beall, 2014, "Gene therapy restores sight in people with eye disease," New Scientist (online), January 16, 2014, see https://www.newscientist.com/article/dn24879-gene-therapy-restores-sight-in-people-with-eye-disease.html#.VTkaJTf_SOJ, accessed 21 January 2017.
  5. Dugel. Pravin U.. Zimmer. Cheryl N.. Shahidi. Ayda M.. A case study of choroideremia carrier – Use of multi-spectral imaging in highlighting clinical features. American Journal of Ophthalmology Case Reports. July 2016. 2. 18–22. 10.1016/j.ajoc.2016.04.003. 29503891. 5757363.
  6. Book: Strunnikova. N. Zein. WM. Silvin. C. MacDonald. IM. Retinal Degenerative Diseases. Serum Biomarkers and Trafficking Defects in Peripheral Tissues Reflect the Severity of Retinopathy in Three Brothers Affected by Choroideremia. Advances in Experimental Medicine and Biology. 2012. 723. 381–7. 22183356. 10.1007/978-1-4614-0631-0_49. 978-1-4614-0630-3.
  7. Khan. Kamron N.. Islam. Farrah. Moore. Anthony T.. Michaelides. Michel. Clinical and Genetic Features of Choroideremia in Childhood. Ophthalmology. October 2016. 123. 10. 2158–2165. 10.1016/j.ophtha.2016.06.051. 27506488. Submitted manuscript.
  8. MacDonald. Ian M.. Hume. Stacey. Chan. Stephanie. Seabra. Miguel C.. Choroideremia. GeneReviews. February 26, 2015. University of Washington, Seattle. 20301511 .
  9. Guo. Hui. Li. Jisheng. Gao. Fei. Li. Jiangxia. Wu. Xinyi. Liu. Qiji. Whole-exome sequencing reveals a novel CHM gene mutation in a family with choroideremia initially diagnosed as retinitis pigmentosa. BMC Ophthalmology. 28 July 2015. 15. 1. 85. 10.1186/s12886-015-0081-4. 26216097. 4517409 . free .
  10. Sanchez-Alcudia. Rocio. Garcia-Hoyos. Maria. Lopez-Martinez. Miguel Angel. Sanchez-Bolivar. Noelia. Zurita. Olga. Gimenez. Ascension. Villaverde. Cristina. Rodrigues-Jacy da Silva. Luciana. Corton. Marta. Perez-Carro. Raquel. Torriano. Simona. Kalatzis. Vasiliki. Rivolta. Carlo. Avila-Fernandez. Almudena. Lorda. Isabel. Trujillo-Tiebas. Maria J.. Garcia-Sandoval. Blanca. Lopez-Molina. Maria Isabel. Blanco-Kelly. Fiona. Riveiro-Alvarez. Rosa. Ayuso. Carmen. Janecke. Andreas R.. A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice. PLOS ONE. 12 April 2016. 11. 4. e0151943. 10.1371/journal.pone.0151943. 27070432. 4829155. 2016PLoSO..1151943S. free.
  11. Furgoch. MJ. Mewes-Arès. J. Radziwon. A. Macdonald. IM. Molecular genetic diagnostic techniques in choroideremia.. Molecular Vision. 25 April 2014. 20. 535–44. 24791138. 4000712.
  12. Duncan. JL. Aleman. TS. Gardner. LM. De Castro. E. Marks. DA. Emmons. JM. Bieber. ML. Steinberg. JD. Bennett. J. Stone. EM. MacDonald. IM. Cideciyan. AV. Maguire. MG. Jacobson. SG. Macular pigment and lutein supplementation in choroideremia.. Experimental Eye Research. March 2002. 74. 3. 371–81. 10.1006/exer.2001.1126. 12014918.
  13. Pallab Ghosh, 2011, "Health: Gene therapy used in a bid to save a man's sight," at BBC News (online), October 27, 2011, see https://www.bbc.com/news/health-15446912, accessed 23 April 2015.
  14. Cideciyan A. V. . Hauswirth W. W. . Aleman T. S. . Kaushal S. . Schwartz S. B. . Boye S. L. . Windsor E. A. M. . 2009 . Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year . Human Gene Therapy . 20 . 9. 999–1004 . 10.1089/hum.2009.086 . 19583479 . 2829287. etal.
  15. Simonelli F. . Maguire A. M. . Testa F. . Pierce E. A. . Mingozzi F. . Bennicelli J. L. . Rossi S. . 2010 . Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration . Molecular Therapy . 18 . 3. 643–650 . 10.1038/mt.2009.277 . 19953081 . 2839440. etal.
  16. Maguire A. M. . High K. A. . Auricchio A. . Wright J. F. . Pierce E. A. . Testa F. . Mingozzi F. . 2009 . Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial . Lancet . 374 . 9701. 1597–1605 . 10.1016/S0140-6736(09)61836-5 . 19854499. etal . 4492302.
  17. Bainbridge J. W. B. . Smith A. J. . Barker S. S. . Robbie S. . Henderson R. . Balaggan K. . Viswanathan A. . 2008 . Effect of gene therapy on visual function in Leber's congenital amaurosis . The New England Journal of Medicine . 358 . 21. 2231–2239 . 10.1056/NEJMoa0802268 . 18441371 . etal. 10.1.1.574.4003 .
  18. MacLaren. RE. Groppe. M. Barnard. AR. Cottriall. CL. Tolmachova. T. Seymour. L. Clark. KR. During. MJ. Cremers. FP. Black. GC. Lotery. AJ. Downes. SM. Webster. AR. Seabra. MC. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial.. Lancet. 29 March 2014. 383. 9923. 1129–37. 24439297. 10.1016/s0140-6736(13)62117-0. 4171740.
  19. Abigail Beall, 2014, "Gene therapy restores sight in people with eye disease," New Scientist (online), January 16, 2014, see https://www.newscientist.com/article/dn24879-gene-therapy-restores-sight-in-people-with-eye-disease.html#.VTkaJTf_SOJ, accessed 23 April 2015.
  20. Ewen Callaway, 2008, "Gene therapy success 'reverses' blindness," New Scientist (online), April 28, 2008, see https://www.newscientist.com/article/dn13783-gene-therapy-success-reverses-blindness.html#.VTkaXDf_SOI and http://www.nature.com/news/2008/080428/full/news.2008.786.html and http://www.nejm.org/doi/full/10.1056/NEJMoa0802315, accessed 23 April 2015.
  21. CT.gov, 2014, "Gene Therapy for Blindness Caused by Choroideremia (Sponsor:University of Oxford): NCT01461213," at ClinicalTrials.gov, see https://clinicaltrials.gov/ct2/show/NCT01461213, accessed 23 April 2015.
  22. News: Ghosh. Pallab. Gene therapy reverses sight loss and is long-lasting. 29 April 2016. BBC News, Science & Environment. 28 April 2016.
  23. Web site: Preimplantation Genetic Diagnosis: (PGD). www.americanpregnancy.org. 23 June 2018. 2012-04-24.
  24. Schwartz. SD. Regillo. CD. Lam. BL. Eliott. D. Rosenfeld. PJ. Gregori. NZ. Hubschman. JP. Davis. JL. Heilwell. G. Spirn. M. Maguire. J. Gay. R. Bateman. J. Ostrick. RM. Morris. D. Vincent. M. Anglade. E. Del Priore. LV. Lanza. R. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies.. Lancet. 7 February 2015. 385. 9967. 509–16. 25458728. 10.1016/s0140-6736(14)61376-3. 85799.
  25. Web site: Duffy. Maureen. Updated Stem Cell Clinical Trial Results for Stargardt Disease and Dry Macular Degeneration - VisionAware Blog - VisionAware. www.visionaware.org. 21 October 2014. 23 January 2017. en.
  26. Bassuk. Alexander G.. Zheng. Andrew. Li. Yao. Tsang. Stephen H.. Mahajan. Vinit B.. Precision Medicine: Genetic Repair of Retinitis Pigmentosa in Patient-Derived Stem Cells. Scientific Reports. 27 January 2016. 6. 19969. 10.1038/srep19969. 26814166. 4728485. 2016NatSR...619969B.
  27. Barnard. A. R.. Groppe. M.. MacLaren. R. E.. Gene Therapy for Choroideremia Using an Adeno-Associated Viral (AAV) Vector. Cold Spring Harbor Perspectives in Medicine. 30 October 2014. 5. 3. a017293. 10.1101/cshperspect.a017293. 25359548. 4355255.
  28. Pameyer. J. K.. Waardenburg. P. J.. Henkes. H. E.. CHOROIDEREMIA. The British Journal of Ophthalmology. 1 December 1960. 44. 12. 724–738. 510030. 0007-1161. 10.1136/bjo.44.12.724. 13732369.
  29. Cremers. Frans P. M.. van de Pol. Dorien J. R.. van Kerkhoff. Liesbeth P. M.. Wieringa. Berend. Ropers. Hans-Hilger. Cloning of a gene that is rearranged in patients with choroideraemia. Nature. 18 October 1990. 347. 6294. 674–677. 10.1038/347674a0. 2215697. 1990Natur.347..674C. 4347627.
  30. Pylypenko. O. Rak. A. Reents. R. Niculae. A. Sidorovitch. V. Cioaca. MD. Bessolitsyna. E. Thomä. NH. Waldmann. H. Schlichting. I. Goody. RS. Alexandrov. K. Structure of Rab escort protein-1 in complex with Rab geranylgeranyltransferase.. Molecular Cell. February 2003. 11. 2. 483–94. 12620235. 10.1016/s1097-2765(03)00044-3. free.
  31. Zhang AY, Mysore N, Vali H, Koenekoop J, Cao SN, Li S, Ren H, Keser V, Lopez-Solache I, Siddiqui SN, Khan A, Mui J, Sears K, Dixon J, Schwartzentruber J, Majewski J, Braverman N, Koenekoop RK. 2015 . Choroideremia is a systemic disease With lymphocyte crystals and plasma lipid and RBC membrane abnormalities . Invest Ophthalmol Vis Sci . 56 . 13. 8158–8165 . 10.1167/iovs.14-15751 . 26720468 . 4699407 .
  32. Cremers. FP. Armstrong. SA. Seabra. MC. Brown. MS. Goldstein. JL. REP-2, a Rab escort protein encoded by the choroideremia-like gene.. The Journal of Biological Chemistry. 21 January 1994. 269. 3. 2111–7. 10.1016/S0021-9258(17)42142-9. 8294464. free.
  33. Tolmachova. T. Ramalho. JS. Anant. JS. Schultz. RA. Huxley. CM. Seabra. MC. Cloning, mapping and characterization of the human RAB27A gene.. Gene. 18 October 1999. 239. 1. 109–16. 10571040. 10.1016/s0378-1119(99)00371-6.
  34. Larijani. B. Hume. AN. Tarafder. AK. Seabra. MC. Multiple factors contribute to inefficient prenylation of Rab27a in Rab prenylation diseases.. The Journal of Biological Chemistry. 21 November 2003. 278. 47. 46798–804. 12941939. 10.1074/jbc.m307799200. free.
  35. News: BBC NEWS UK Politics Sion Simon. news.bbc.co.uk. 2017-01-20. 2002-10-21.
  36. Bill Dwyre, 2013, "Though going blind, E.J. Scott keeps looking ahead, moving forward," L.A. Times (online), January 11, 2013, see https://www.latimes.com/sports/la-xpm-2013-jan-11-la-sp-dwyre-20130112-story.html, accessed 23 April 2015.
  37. E.J. Scott, 2015, "This is my 40: Running 7 continents in 1 year, blindfolded," at Crowdrise (online crowdsourcing), undated, see https://www.crowdrise.com/ThisisMY40/fundraiser/ejscott, accessed 23 April 2015.

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