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Choroideremia: for professionals


Overview

Prevalence1:50,000-100,000[1]
Inheritance
  • X-linked recessive
Genes involved
(OMIM no.)
Symptoms
  • Nyctalopia (early childhood)
  • Visual field loss
  • Central vision loss (end stage)
  • Colour vision defect
  • Reduced contrast sensitivity
  • Photophobia
Ocular features
  • Progressive chorioretinal atrophy encroaching fovea
  • Cataract
  • CNV
  • Cystoid macular oedema (CMO)
Systemic featuresDeletions of X chromosome including the CHM gene may lead to:
  • Cognitive impairment
  • Sensorineural deafness
  • Cleft lip/palate
Key investigations
  • FAF: Central hyperautofluorescence with surrounding hypoautofluorescence
  • OCT: Progressive outer retinal thinning
  • OCT and FAF can monitor progression
Molecular diagnosisNext generation sequencing:
  • Targeted gene panel (retinal)
  • Whole genome sequencing
Management
  • Avoid smoking
  • UV sunglasses
  • Blue light screen filter on devices
  • Fruits and green leafy vegetables
  • Monitor for CNV, cataract and CMO
Therapies under researchGene therapy (phase 3)

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Clinical phenotype

Presenting features

Patients typically present with nyctalopia in early childhood from rod photoreceptor loss. Over time, peripheral scotomas start to develop due to progression of chorioretinal atrophy and eventually, the fovea is affected as well in the late stages causing central vision loss. Other associated symptoms include photophobia, reduced contrast sensitivity and colour vision defects. Males are predominantly affected but cases of severe phenotypes in female carriers have been reported.[2]

Fundal appearance

The severity of the phenotype varies between and within families, but affected individuals tend to have relatively symmetrical fundal features. Early in the disease, there is retinal pigment epithelium (RPE) mottling and patchy areas of chorioretinal atrophy in the periphery. These atrophic areas coalesce over time and starts encroaching the central macula, leaving a small island of viable retina which is eventually lost.[3] Female carriers may display mild signs of disease later in life due to X-lyonisation.[3]

The retina labeled A has multiple foci of white patches in the periphery indication retinal degeneration. The retinal labeled B only has 1 remaining island of healthy tissue in the middle while the rest appears white due to progressive damage.
Fundal appearance of choroideremia in the early (A) and advanced stages (B)

Other ocular features

Apart from chorioretinal dystrophy, patients may present with the following ocular features: 

  • Posterior sub-capsular cataract
  • Cystoid macular oedema (CMO)
  • Choroidal neovascularisation (CNV)

Associated extraocular features

Rarely, patients might have extraocular features due to complete or partial deletions of the X chromosome involving the CHM gene.[4][5] These include: 

  • Cognitive issues
  • Sensorineural deafness
  • Cleft lip
  • Cleft palate 

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Genetics

Gene: CHM (Xq 21.2)

OMIM no.: #300390

Protein: Rab escort protein (REP-1)

Location of expression: Expressed ubiquitously throughout the body

Function: 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]

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]

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Key investigations

1) Fundus autofluorescence imaging (FAF)

A small central island of hyperautofluorescence with sharply-demarcating borders represent the surviving retina. There is usually diffuse peripheral hypoautofluorescence due to chorioretinal atrophy. The island of viable retina progressively shrinks over time and eventually dissipates in end-stage disease. As a result, serial FAF imaging is essential to monitor disease progression.[6]

The central bright area demarcating relatively healthy retina has reduced in size after 7 years, signifying disease progression.
Progression of choroideremia as seen on FAF

FAF imaging of female carriers typically demonstrate fine hypoautofluorescent speckles corresponding to the RPE changes seen on fundoscopy.[2]

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)

2) Optical coherence tomography (OCT)

Centrally within the border of hyperautofluorescence, the foveal lamination is intact while at the border, the ellipsoid zone (EZ) and external limiting membrane (ELM) are absent along with thinning of the outer nuclear layer (ONL). RPE atrophy can be observed in here as well, evidenced by the increased choroidal reflectance.

Frequently, rosette-like structures called outer retinal tubulations (ORT) due to remodelling of degenerating photoreceptors are seen in atrophic areas.[6]

A cross section scan of the macula showing marked thinning of the retina. Some whorl-like appearance are pointed out. These are outer retinal tabulations.
Extrafoveal outer retinal loss and RPE atrophy (evidenced by increased choroidal reflectance) in both images. Outer retinal tubulations are clearly seen as well (blue arrows)

As the condition progresses, the fovea undergoes atrophic changes as well leading to further visual deterioration. SD-OCT can be used in conjunction with FAF in monitoring disease progression by measuring preserved EZ area or EZ length.[8][9] Presence of CMO and CNV can also be detected with SD-OCT.

Comparison of OCT image of the same patient 5 years apart, showing ellipsoid zone shortening, signifying disease progression.
OCT scans of a patient 5 years apart showing shortening of the EZ length, correlating with disease progression seen on FAF

3) Electrophysiology

Full-field and pattern electroretinograms (ERG) are performed to determine level of visual function and to support the diagnosis. An early pattern of rod-cone dystrophy 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.

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Diagnosis

Genetic testing should be performed by an ophthalmologist specialising in genetic eye disease to confirm the diagnosis. This may be conducted with the following methods:

  • Targeted retinal gene panels (~95%[7] detection rate)
  • Western blot analysis of leukocytes to detect the presence of REP-1 if no mutation is found on panel testing and choroideremia is still strongly suspected[10]
  • 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

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Management

Ocular

Supportive management:

  • Referral to low vision services
  • Direct patients to supporting organisations
  • Consider registration if criteria met
  • 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

*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.

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 Clinic Liaison Officers (ECLOs) 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.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

In the UK, patients with confirmed biallelic RPE65 mutations can be referred to one of the four Luxturna centres to evaluate if they are suitable for treatment.

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Current research in choroideremia

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 or intravitreal injections.

In choroideremia, the normal CHM gene is transduced by AAV and injected sub-retinally. Several multicentre international clinical trials were undertaken for choroideremia. The most advanced was the phase 3 STAR study run by Biogen 2021, USA (NCT03496012). This was based on promising earlier phase 1/2 data, but the investigational treatment (timrepigene emparvovec) failed to meet the primary and secondary endpoints.

Here are links to papers related to the development and testing of AAV-REP1 gene therapy:

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.

Nonsense mutations account for up to 30%[1] of the disease-causing mutations in choroideremia. 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.

Recent study in zebrafish

3) Other potential therapies

Related links

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Further information and support

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References

  1.  Moosajee M, Ramsden SC, Black GC, Seabra MC, Webster AR. Clinical utility gene card for: choroideremia. Eur J Hum Genet. 2014;22(4)
  2.  Jauregui R, Park KS, Tanaka AJ, et al. Spectrum of Disease Severity and Phenotype in Choroideremia Carriers. Am J Ophthalmol. 2019
  3.  Mitsios A, Dubis AM, Moosajee M. Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments. Ther Adv Ophthalmol. 2018;10:2515841418817490
  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.  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.  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.  MacDonald IM, Mah DY, Ho YK, Lewis RA, Seabra MC. A practical diagnostic test for choroideremia. Ophthalmology. 1998;105(9):1637-1640

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Updated on September 29, 2023
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