- Clinical phenotype
- Key investigations
- Current research
- Further information and support
- Choroideremia: for patients
|Systemic features||Deletions of X chromosome including the CHM gene may lead to:|
|Molecular diagnosis||Next generation sequencing: |
|Therapies under research||Gene therapy (phase 3)|
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.
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. Female carriers may display mild signs of disease later in life due to X-lyonisation.
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
- Cognitive issues
- Sensorineural deafness
- Cleft lip
- Cleft palate
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%) 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.
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.
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.
FAF imaging of female carriers typically demonstrate fine hypoautofluorescent speckles corresponding to the RPE changes seen on fundoscopy.
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.
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. Presence of CMO and CNV can also be detected with SD-OCT.
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.
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% 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
- 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.
- Genomics England PanelApp for inherited retinal dystrophies
- Clinical genetic testing: for professionals
- 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.
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.
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 clinical trials are underway internationally. Most trials are at the phase 1 or phase 2 stages. Only the AAV2-REP1 therapy (NightstaRx Ltd) is undergoing a phase 3 trial (NCT 03496012).
Here are abstracts of the main gene therapy trials in choroideremia:
AAV2-REP1 therapy (NightstaRx Ltd)
- Xue et al 2018, UK (NCT 01461213)
- Lam et al 2019, USA (NCT 02553135)
- Dimopoulos et al 2018, Canada (NCT 02077361)
AAV2-hCHM therapy (Spark Therapeutics)
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% of the disease-causing mutations in choroideremia. In vitro (human fibroblasts) and in vivo (zebrafish) studies 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.
3) Other potential therapies
- Research Opportunities at Moorfields Eye Hospital UK
- Searching for current clinical research or trials
- Retina UK
- Choroideremia Research Foundation
- Royal National Institute of Blind People (RNIB)
- Guide Dogs for the Blind Association
- Look UK
- Moosajee M, Ramsden SC, Black GC, Seabra MC, Webster AR. Clinical utility gene card for: choroideremia. Eur J Hum Genet. 2014;22(4)
- Jauregui R, Park KS, Tanaka AJ, et al. Spectrum of Disease Severity and Phenotype in Choroideremia Carriers. Am J Ophthalmol. 2019
- Mitsios A, Dubis AM, Moosajee M. Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments. Ther Adv Ophthalmol. 2018;10:2515841418817490
- Schwartz M, Rosenberg T. Prenatal diagnosis of choroideremia. Acta Ophthalmol Scand Suppl. 1996(219):33-36
- 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
- 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
- MacDonald IM, Hume S, Chan S, Seabra MC. Choroideremia. In: GeneReviews®[Internet]. University of Washington, Seattle; 2015
- 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
- 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
- MacDonald IM, Mah DY, Ho YK, Lewis RA, Seabra MC. A practical diagnostic test for choroideremia. Ophthalmology. 1998;105(9):1637-1640