Choroideremia

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Choroideremia information for patients

Quick links


Overview
The condition
Treatment
Current research in choroideremia
Practical advice
Further information and support

Overview


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The retina of choroideremia patient has advanced degeneration of the retina which gives rise to a whitish appearance while the unaffected normal retina has an red-orange hue.
The retina of a choroideremia patient (top) and the retina of a healthy patient (bottom)

Choroideremia is a rare disease affecting 1 in 50,000 to 100,000 people.[1] It is caused by genetic changes to the CHM gene, resulting in the degeneration of the retina and choroid layers of the eye over time. It begins in early childhood with difficulties in night vision, followed by loss of peripheral vision and then loss of central vision from late middle age onwards. Males are mainly affected due to its X-linked recessive inheritance pattern.


The condition


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Symptoms

The earliest symptom patients notice is difficulty seeing at night (night blindness) starting from early childhood. It then progresses to loss of peripheral vision, leading to “tunnel vision”. Central vision is eventually lost from late middle age onwards. Some patients may experience issues with their colour vision and contrast vision despite having good central vision. The symptoms can vary in severity between patients, even within the same family.

This demonstrates what patients with tunnel vision experience. One picture shows a cow behind a fence in a field while another shows only the face of the cow at the centre of the picture with the rest of the picture all in black, simulating tunnel vision.
Tunnel vision


Cause

Choroideremia is caused by mutations in a single gene called the CHM gene. This gene instructs cells to produce a protein called Rab escort protein 1 (REP-1). REP-1 helps to transport proteins within cells. When the CHM gene is not working properly, proteins cannot reach their correct destination. This malfunction leads to high levels of oxidative stress, which causes damage in the retina and subsequently cell death. This is what causes loss of vision in choroideremia.


How is it diagnosed?

Choroideremia is suspected based on the symptoms, family history and clinical evaluation of the retina. The diagnosis is confirmed with genetic testing by identifying mutations in the CHM gene.


How is it inherited?

  • Affected males
Their sons will not inherit the condition while their daughters will be carriers of the faulty gene.
  • Female carriers
There is a 50% chance of a daughter becoming a carrier and a 50% chance of having a son affected by choroideremia.
These risks apply to every newborn of the affected person.

If you or your child is affected by choroideremia, it is advisable to see a genetic counselor to obtain more information and advice on inheritance and family planning options.


Related links


Treatment


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Is there any treatment?

There is currently no available treatment for choroideremia but researchers are exploring various approaches, some of which have entered clinical trials. In the meantime, here is some useful advice to help limit additional damage to the retina:

  • Have a healthy diet consisting of fresh fruit and vegetables especially those that are green and leafy, and rich in antioxidants
  • Wear UV protected sunglasses in bright light
  • Use blue light screen protectors on mobile devices or computer screens
  • Avoid smoking


How can I be referred for further expert care?

You can ask your GP or ophthalmologist to refer you to the Moorfields Genetic Eye Disease service. It is advisable that you are referred to a specialised genetic eye service for a more comprehensive management of your condition such as genetic testing, genetic counselling and advice on the latest clinical trials.


Current research in choroideremia


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1) Gene therapy

Illustration of how gene therapy works. The normal gene copy is transported by a modified virus to the affected cell. Once inside the cell, the normal gene copy provides the correct instructions for protein production, replacing the mutated gene.
How gene therapy works

Gene therapy aims to halt retinal degeneration by replacing the mutated gene with a normal healthy copy. This enables the affected cells to regain some of their function and produce functioning proteins.

A vector is required to deliver the replacement gene into the affected cells. Viruses are popular vectors due to their ability to penetrate into cells and the adeno-associated virus (AAV) is the most commonly used vector for gene therapy in the eye. Viral vectors are modified initially so that they do not cause any harm when used in humans.

In choroideremia, a normal copy of the CHM gene is “packaged” into the AAV vector and then injected into the retina. This way, the retinal cells with the mutated CHM gene have maximum exposure to the viral vectors.

Currently, most gene therapy trials in choroideremia are at phase 1 or phase 2 stages. The AAV2-REP1 therapy (NightstaRx) is currently undergoing a phase 3 trial. Below are links to completed gene therapy trials in choroideremia:

AAV2-REP1 therapy (NightstaRx Ltd)


AAV2-hCHM therapy (Spark Therapeutics)


Related links


2) Nonsense suppression therapy

Nonsense suppression therapy is a new drug-based treatment targeting conditions caused by nonsense mutations. A nonsense mutation introduces an abnormal “stop” signal into a gene that halts protein production prematurely, resulting in a protein which is too short and not functional. A drug called ataluren (Translarna™) modifies the affected cell to “ignore” these abnormal “stop” signals and produce normal full-length functioning protein. [2]

About 30% [3] of choroideremia patients have nonsense mutations. Ataluren has shown to reduce oxidative stress, prevent retinal cell death and regain function in animal and human cell models of choroideremia. However, it has not been studied in patients yet. If proven to be beneficial in clinical trials, ataluren could potentially offer a non-surgical alternative to gene therapy for choroideremia patients.


Related links


3) Other potential therapies


Finding out current clinical research/trials for choroideremia

www.ClinicalTrials.gov is a useful resource on international clinical studies provided by the US National Library of Medicine. Not all listed studies are trials; some are natural history studies identifying the genetic basis and outcomes of disease. ClinicalTrials.gov can be searched by the name of the disease, name of disease-causing gene if known or by drug or device name, by names of investigators, or by country, or combinations of these terms.

The database includes trials completed, underway and some yet to start. Some trials are unsuccessful and are never published.

A word of warning is necessary. The presence of a study on ClinicalTrials.gov does not mean that the study has been evaluated by an ethics committee or given approval. Several women went blind after an unproven intervention, listed as a “stem cell trial” on ClinicalTrials.gov. If you are interested in a particular trial, it is important that you seek advice from your doctor on whether they think it is reputable and ethically approved.


Practical advice


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Living with choroideremia

Patients are still able to lead a fairly independent life through maximising their available vision and having access to social support. Here are some ideas:

  • Attending the low vision clinic which provides access to low vision specialists, Eye Care Liaison Officers (ECLO), visual aids and visual rehabilitation services
  • Contacting the local council’s social services department for access to rehabilitation services and assessment of your individual needs to help you remain independent
  • Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI)
  • Registering as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
  • Getting in touch with national or local charities for advice and peer support


Related links


Further information and support


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References

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  1. Orphanet. Choroideremia. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=180. Published 2011. Updated 27 October 2019.
  2. Richardson R, Smart M, Tracey-White D, Webster AR, Moosajee M. Mechanism and evidence of nonsense suppression therapy for genetic eye disorders. Exp Eye Res. 2017;155:24-37
  3. Moosajee M, Ramsden SC, Black GC, Seabra MC, Webster AR. Clinical utility gene card for: choroideremia. Eur J Hum Genet. 2014;22(4)

Choroideremia information for doctors

Quick links


Overview
Clinical phenotype
Genetics
Key investigations
Diagnosis
Differential diagnoses
Management
Current research
Further information for patients

Overview


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Choroideremia (OMIM: #303100) is an X-linked recessive chorioretinal dystrophy caused by mutation in the CHM gene. It is characterised by progressive degeneration of the photoreceptors, retinal pigment epithelium (RPE) and choriocapillaris. Patients tend to experience nyctalopia from early childhood, which then progresses to visual field loss and eventually central vision loss from late middle age onwards. It has a prevalence of 1:50,000-100,000 [1] affecting males, however female carriers may display signs of disease later in life due to X-lyonisation.[2]


Clinical phenotype


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Left and right eye of a patient with choroideremia showing advanced degeneration of the retina, giving a whitish appearance.
Fundi of a patient with advanced choroideremia. Note the advanced peripheral chorioretinal atrophy with relative sparing of the central macula island

Inter- and intra-familial phenotypic variability exists (in terms of severity), although affected individuals tend to have relatively symmetrical fundal appearances. These include RPE mottling and patchy scalloped areas of chorioretinal atrophy in the mid-periphery early in the disease.[2] The atrophic process progresses over time and starts encroaching a central retinal island at the macula, which is eventually lost.[2] Large choroidal vessels and sclera tend to be visible in areas of chorioretinal atrophy. Other abnormalities include posterior sub-capsular cataract, choroidal neovascularisation (CNV) and cystoid macular oedema (CMO).

Nyctalopia is usually the first presenting symptom in early childhood due to loss of rod photoreceptors. This is followed by visual field loss due to progression of the chorioretinal atrophy and eventually central vision loss as the fovea is damaged. Affected individuals could also experience photophobia, reduced contrast sensitivity and colour vision defects. Given it is an X-linked condition, males are predominantly affected but there are cases of females presenting with severe disease phenotype.[3]

Although primarily an ocular condition, there are reported cases of choroideremia associated with cognitive issues, sensorineural deafness, cleft lip and cleft palate. This is due to complete or partial deletions of the X chromosome involving the CHM gene.[4][5]


Genetics


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Genes involved: CHM (OMIM 300390)

The CHM gene, located on the X chromosome (Xq 21.2) encodes Rab escort protein 1 (REP-1). REP-1 supports intracellular trafficking of Rab proteins and modification of their lipid membranes (prenylation).

Deletions (25-50%) and nonsense (30%)[1] mutations of the CHM gene causes loss-of-function to REP-1, affecting protein transport within the photoreceptor cells and phagocytosis of shed outer segments by the RPE.[6] This results in high levels of oxidative stress and subsequent cell death.

X-lyonisation and X-autosome translocation have been implicated in affected females. Syndromic presentations of choroideremia can be attributed to complete or partial gene deletions in the X chromosome including the Xq 21.2 locus.[7]


Key investigations


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1) Fundus autofluorescence imaging (FAF)

Progression of choroideremia as shown on fundus autofluorescence imaging, with a reduction in size of the central hyperfluorescent macular island.
Choroideremia as shown on FAF with central area of hyperautofluorescence. Note the size of the central hyperfluorescent area 7 years apart, signifying disease progression
It shows the difference between the retina of a choroideremia patient and its corresponding fundus autofluorescence appearance and a related female carrier.
Difference between the fundal appearance and FAF findings of a proband (A,B) and a related female carrier (C,D). Note subtle yellow spots at the inferior arcade and the macula in C corresponding to hypoautofluorescent areas in D

A central island of hyperautofluorescence with sharply demarcated edges represent the surviving RPE cells. This is surrounded by large areas of hypoautofluorescence due to chorioretinal atrophy. The central island progressively shrinks over time eventually encroaching the fovea. This measure can be used to monitor disease progression.[6]

FAF imaging of female carriers typically demonstrate a patchy pattern of hypoautofluorescent speckles corresponding to the RPE changes observed in the fundus.[3]


2) Spectral-domain optical coherence tomography (SD-OCT)

OCT findings in choroideremia. There is extrafoveal loss of ellipsoid zone and thinning of the outer nuclear layer. Multiple outer retinal tubulations are highlighted by blue arrows.
SD-OCT findings in choroideremia
Note the extrafoveal loss of the EZ and ELM accompanied with thinning of the ONL in both images A & B. Outer retinal tubulations (blue arrows) are clearly visible in B.
Comparison of OCT image of the same patient 5 years apart, showing ellipsoid zone shortening, signifying disease progression.
EZ length as marker of disease progression
SD-OCT scans of a patient 5 years apart showing shortening of the EZ length, correlating with disease progression seen on FAF

At borders of the surviving retinal island, the outer nuclear layer (ONL) thickness sharply declines in addition to termination of the external limiting membrane (ELM) and ellipsoid zone (EZ).[6] Further beyond in areas of hypoautofluorescence, outer retinal tubulations (ORT) can be observed. ORT is thought to be due to remodelling of degenerating photoreceptors from primary RPE dysfunction.[6] Measurement of the preserved EZ area or EZ length can be used to monitor disease progression over time.[8][9]

Central foveal thickness is increased in early childhood and remains normal before it gradually decreases at around late middle age, correlating with deterioration of central vision. Presence of CMO should be noted as this is a common finding in choroideremia patients, which can result in increased central foveal thickness.[10]

Compared to healthy individuals, sub-foveal choroidal thickness is reduced in choroideremia patients when measured on enhanced depth imaging (EDI) mode.[6]


3) Electrophysiology

Electrophysiology is usually performed to determine level of visual function and to support the diagnosis. An early pattern of rod-cone degeneration is first noted which progressively deteriorates with age.


4) Standard perimetry

Constrictive visual field loss that begins in the mid-periphery. Areas of reduced sensitivity corresponds to observed areas of chorioretinal atrophy.


5) Other modalities

In deep phenotyping research studies, OCT angiography (OCT-A) has been utilised to assess the choriocapillaris (CC) blood flow and density. These could potentially serve as markers for natural history and interventional studies in the future.

Jain et al reported that CC density is significantly lower in choroideremia patients compared to female carriers and healthy controls.[11] In both affected patients and carriers, it was also noted that CC density is higher in areas with preserved EZ compared to areas absent of EZ (areas of atrophy).[11] The former finding is reflected when Abbouda et al utilised OCT-A to measure areas with flow in the superficial retinal vessel network (SRVN) and the CC layer. It showed choroideremia patients not only have significantly fewer areas with SRVN and CC flow when compared to female carriers and healthy controls, but also the area of flow is negatively correlated with age in the choroideremia cohort.[12]

Microperimetry has also been used in research to assess macular sensitivity although there is still a high rate of test-retest variability among choroideremia patients.[13]


Diagnosis


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Patients should be referred to an ophthalmologist specialising in genetic eye disease for genetic testing. They should be screened for causative mutations in the CHM gene with a multi-gene retinal dystrophy panel; ~95%[7] of pathogenic mutations can be identified using this method.

If choroideremia is strongly suspected but no mutation is found on panel testing, western blot analysis of patients’ leukocytes to detect the presence or absence of REP-1 can be performed.[14] Whole genome sequencing can be undertaken to identify mutations in intronic regions of CHM, novel genes or non-coding regulatory elements.

In atypical cases, chromosomal microarray can be considered to detect large contiguous deletions that include the CHM gene or karyotyping to detect X-autosome translocation in symptomatic females.[7]


Related links


Differential diagnoses


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Both X-linked[15][16] (RPGR and RP2) and RPE65 autosomal dominant variants[17][18] of retinitis pigmentosa have been reported as phenocopies.

Conditions Genes involved Mode of inheritance Distinguishing features
Gyrate atrophy OAT AR
  • Elevated plasma ornithine levels
Bietti's crystalline dystrophy CYP4V2 AR
  • Disease onset typically at second to third decade of life; variable
  • Numerous glistening yellow-white crystals scattered on posterior pole; occasionally found on corneal limbus [19]
  • Hyper-reflective dots in the RPE-Bruch membrane complex corresponds to crystal deposits [20]
Thioridazine hydrochloride toxicity N/A N/A
  • History of thioridazine usage, particularly for psychiatric disorders
  • Visual function might improve if detected early and drug is discontinued [21]
  • Progressive atrophic fundal appearance despite drug cessation [21]


Management


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Patient management

There is currently no treatment for choroideremia and management is mainly supportive. These include:

  • Direct patients to supporting organisations
  • Avoid smoking
  • UV sunglasses wear
  • Using a blue light screen filter on mobile devices
  • Encourage adequate intake of fruits and green leafy vegetables
  • Monitoring for complications (CNV, CMO and cataracts) and treat appropriately


Family management and counselling

Choroideremia is inherited in an X-linked recessive pattern. Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation diagnosis.


Emotional and social support

Eye Care Liaison Officers (ECLO) act as an initial point of contact for newly diagnosed patients in clinic. They provide emotional and practical support to help patients deal with their diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.


Referral to a specialist service

You can refer patients to the Moorfields Genetic Eye Disease service. Patients will have access to genetic testing, genetic counselling and advice on the latest clinical trials


Related links


Current research


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1) Gene therapy

Gene therapy works by replacing a mutated gene in target cells with a normal healthy copy, enabling the cells to produce the correct protein. The normal gene copy is carried by a viral vector, usually adeno-associated virus (AAV) and is delivered through sub-retinal injections via vitrectomy or intravitreal injections.

In choroideremia, the normal CHM gene is transduced by AAV with several clinical trials underway internationally. Most trials are at the phase 1 or phase 2 stages. AAV2-REP1 therapy (NightstaRx Ltd) is currently undergoing a phase 3 trial.

Here are abstracts of the main gene therapy trials in choroideremia:

AAV2-REP1 therapy (NightstaRx Ltd)


AAV2-hCHM therapy (Spark Therapeutics)


Related links


2) Nonsense suppression therapy

Nonsense suppression therapy is a new drug-based genetic treatment that can override the effect of nonsense mutations within the coding region of a gene. It promotes “read-through” of premature termination codons (PTC) during translation to continue protein production.

Nonsense mutations account for up to 30%[1] of the disease-causing mutations in choroideremia. In vitro (human fibroblasts) and in vivo (zebrafish) studies[22] of a drug called ataluren (or Translarna™) have shown prevention of retinal degeneration onset and recovery of REP-1 protein function. There are no current clinical trials in choroideremia yet.


Related links


3) Other potential therapies


Finding out current clinical research/trials for choroideremia

This can be found on www.ClinicalTrials.gov.

It is important to note that the presence of a study on ClinicalTrials.gov does not mean that the study has been evaluated by an ethics committee or given approval. Several women went blind after an unproven intervention, listed as a “stem cell trial” on ClinicalTrials.gov.


Further information for patients


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Here are some supporting organisations for choroideremia:


References

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  1. 1.0 1.1 1.2 Moosajee M, Ramsden SC, Black GC, Seabra MC, Webster AR. Clinical utility gene card for: choroideremia. Eur J Hum Genet. 2014;22(4)
  2. 2.0 2.1 2.2 Mitsios A, Dubis AM, Moosajee M. Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments. Ther Adv Ophthalmol. 2018;10:2515841418817490
  3. 3.0 3.1 Jauregui R, Park KS, Tanaka AJ, et al. Spectrum of Disease Severity and Phenotype in Choroideremia Carriers. Am J Ophthalmol. 2019
  4. Schwartz M, Rosenberg T. Prenatal diagnosis of choroideremia. Acta Ophthalmol Scand Suppl. 1996(219):33-36
  5. Yntema HG, van den Helm B, Kissing J, et al. A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation. Genomics. 1999;62(3):332-343
  6. 6.0 6.1 6.2 6.3 6.4 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. Invest Ophthalmol Vis Sci. 2016;57(8):3674-3684.
  7. 7.0 7.1 7.2 MacDonald IM, Hume S, Chan S, Seabra MC. Choroideremia. In: GeneReviews®[Internet]. University of Washington, Seattle; 2015
  8. 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. Am J Ophthalmol. 2017;179:110-117.
  9. Aleman TS, Han G, Serrano LW, et al. Natural History of the Central Structural Abnormalities in Choroideremia: A Prospective Cross-Sectional Study. Ophthalmology. 2017;124(3):359-373
  10. Genead MA, Fishman GA. Cystic macular oedema on spectral-domain optical coherence tomography in choroideremia patients without cystic changes on fundus examination. Eye (Lond). 2011;25(1):84-90
  11. 11.0 11.1 Jain N, Jia Y, Gao SS, et al. Optical Coherence Tomography Angiography in Choroideremia: Correlating Choriocapillaris Loss With Overlying Degeneration. JAMA Ophthalmol. 2016;134(6):697-702
  12. Abbouda A, Dubis AM, Webster AR, Moosajee M. Identifying characteristic features of the retinal and choroidal vasculature in choroideremia using optical coherence tomography angiography. Eye (Lond). 2018;32(3):563-571.
  13. Dimopoulos IS, Tseng C, MacDonald IM. Microperimetry as an Outcome Measure in Choroideremia Trials: Reproducibility and Beyond. Invest Ophthalmol Vis Sci. 2016;57(10):4151-4161.
  14. MacDonald IM, Mah DY, Ho YK, Lewis RA, Seabra MC. A practical diagnostic test for choroideremia. Ophthalmology. 1998;105(9):1637-1640.
  15. Jayasundera T, Branham KE, Othman M, et al. RP2 phenotype and pathogenetic correlations in X-linked retinitis pigmentosa. Arch Ophthalmol. 2010;128(7):915-923.
  16. Nanda A, Salvetti AP, Martinez-Fernandez de la Camara C, MacLaren RE. Misdiagnosis of X-linked retinitis pigmentosa in a choroideremia patient with heavily pigmented fundi. Ophthalmic Genet. 2018;39(3):380-383.
  17. Jauregui R, Park KS, Tsang SH. Two-year progression analysis of RPE65 autosomal dominant retinitis pigmentosa. Ophthalmic Genet. 2018;39(4):544-549.
  18. Bowne SJ, Humphries MM, Sullivan LS, et al. A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. Eur J Hum Genet. 2011;19(10):1074-1081.
  19. Saatci AO, Doruk HC, Yaman A, Oner FH. Spectral domain optical coherence tomographic findings of bietti crystalline dystrophy. J Ophthalmol. 2014;2014:739271
  20. Kojima H, Otani A, Ogino K, et al. Outer retinal circular structures in patients with Bietti crystalline retinopathy. Br J Ophthalmol. 2012;96(3):390-393
  21. 21.0 21.1 Shah GK, Auerbach DB, Augsburger JJ, Savino PJ. Acute thioridazine retinopathy. Arch Ophthalmol. 1998;116(6):826-827
  22. 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. Hum Mol Genet. 2016;25(16):3416-3431.


ability to distinguish an object from its background

harmful oxygen molecules in the cells

Random and permanent inactivation of one X chromosome in female somatic cells so that only one functional copy is present in each cell

A thread-like structure in our cells that contains all our genetic characteristics

A segment of a chromosome or the whole chromosome is attached to or interchanged with another whole chromosome or a segment of it. This can be either balanced (no apparent net gain or loss of chromosomal material) or unbalanced.