Clinical characteristics.

Choroideremia (CHM) is characterized by progressive chorioretinal degeneration in affected males and milder signs in heterozygous (carrier) females. Typically, symptoms in affected males evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life. Although carrier females are generally asymptomatic, signs of chorioretinal degeneration can be reliably observed with fundus autofluorescence imaging, and – after age 25 years – with careful fundus examination.

Diagnosis/testing.

The diagnosis of choroideremia is established in a male proband with suggestive findings and a hemizygous pathogenic variant in CHM identified by molecular genetic testing.

Management.

Treatment of manifestations: Surgical correction of retinal detachment and cataract as needed; UV-blocking sunglasses for outdoors; appropriate dietary intake of fresh fruit, leafy green vegetables; antioxidant vitamin supplement as needed; regular intake of dietary omega-3 very-long-chain fatty acids, including docosahexaenoic acid; low vision services as needed; counseling as needed to help cope with depression, loss of independence, fitness for driving, and anxiety over employment issues.

Surveillance: Periodic ophthalmologic examination, kinetic visual field examination, and spectral domain optical coherence tomography (SD-OCT), especially when central vision is affected and cystoid macular edema is suspected.

Agents/circumstances to avoid: UV exposure from sunlight reflected from water and snow; smoking (a major risk factor for macular degeneration).

Genetic counseling.

CHM is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Heterozygous females have a 50% chance of transmitting the variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be symptomatic. Once the CHM pathogenic variant has been identified in an affected family member, carrier testing for at-risk female relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for choroideremia are possible.

Suggestive Findings

The diagnosis of choroideremia (CHM) should be suspected in males with the following clinical, electroretinogram (ERG), and visual field findings, and family history.

Clinical findings

• Defective dark adaptation. Poor vision in the dark is commonly the first symptom in affected males, usually as a preteen.
• Characteristic fundus appearance. Patchy areas of chorioretinal degeneration generally begin in the mid-periphery of the fundus. The areas of chorioretinal degeneration progress to marked loss of the retinal pigment epithelium and choriocapillaris (inner of the two vascular layers of the choroid that is composed largely of capillaries) with preservation of the deep choroidal vessels (Figures 1 and 2).
  Peripapillary atrophy of the RPE occurs early and is progressive [Khan et al 2016].
  The function and anatomy of the central macula are preserved until late in the disease process and can be demonstrated with fundus autofluorescence imaging (Figure 3).

Figure 1.

Fundus collage image from the left eye of an affected male with light pigmentation age 36 years

Figure 2.

Fundus collage image from the left eye an affected male with dark pigmentation age 35 years

Figure 3.

Fundus autofluorescence image from the left eye of an affected male age 35 years.

Electroretinogram (ERG) of affected males may at first show a pattern of rod-cone degeneration, which eventually becomes non-recordable.

Peripheral visual field loss manifests as a ring scotoma and generally follows changes in the fundus appearance. Areas of visual field loss closely match areas of chorioretinal degeneration.

Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of choroideremia is established in a male proband with suggestive findings and a hemizygous pathogenic variant in CHM identified by molecular genetic testing (see Table 1).

Note: Identification of a hemizygous CHM variant of uncertain significance does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of choroideremia has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Affected males. Choroideremia (CHM) is characterized by progressive chorioretinal degeneration in affected males. Typically, symptoms evolve from night blindness to peripheral visual field loss, with central vision preserved until late in life. Males in their 40s have very good visual acuity but only a small visual field. In a large meta-analysis of more than 1,000 eyes, transition from a slow to more rapid decline in vision occurred at age 39 years [Shen et al 2021]. Later, around age 50-70 years, central vision becomes markedly impaired.

Posterior subcapsular cataracts are similar to those observed in retinitis pigmentosa.

Cystoid macular edema has been reported.

Heterozygous females are generally asymptomatic; however, signs of retinal pigment epithelial depigmentation or atrophy can be observed with careful fundus examination. These signs become more readily apparent after the second decade. Night blindness and visual field loss can also develop later in life due to expanding areas of retinal pigment epithelial atrophy.

Symptomatic but mildly affected females are likely underreported in the literature.

Note: The terms "silent carrier" and "manifesting heterozygote" are used in the literature to refer to asymptomatic heterozygous females and symptomatic heterozygous females, respectively. In this GeneReview, the term "heterozygous female" encompasses all females with a CHM pathogenic variant (i.e., silent carriers and manifesting heterozygotes) regardless of the presence or absence of CHM-related symptoms and/or findings.

Heterozygous females may or may not show changes with ERG testing, funduscopic examination, fundus autofluorescence (at a young age, <25 years), color vision testing, and visual field testing.

• The ERG may be normal or reduced. In seven heterozygous females, Renner et al [2006] reported normal ERGs in six and reduced amplitudes in one.
• Fundoscopy may reveal pigmentary stippling and distinct chorioretinal atrophy [Renner et al 2006].
• Color vision defects can be found using the desaturated panel D15 test [Renner et al 2006].
• Visual fields can range from normal in the majority of heterozygous females to distinct field defects that mimic those of affected males [Renner et al 2006].
• Fundus autofluorescence imaging will demonstrate patchy areas of lost fluorescence throughout the fundus [Edwards et al 2015, Jauregui et al 2019] (Figure 4).

Figure 4.

Fundus autofluorescence image from the right eye of a female carrier age 30 years

Heterozygous females who demonstrate clinical findings mimicking those of affected males likely have skewed X-chromosome inactivation.

Genotype-Phenotype Correlations

Genotype-phenotype correlations have not been demonstrated for this disorder.

Prevalence

Prevalence is estimated at between 1:50,000 and 1:100,000 [Khan et al 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with choroideremia (CHM), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Ophthalmologic examination including best corrected visual acuity (BCVA), funduscopic examination, and visual field testing for a baseline
• Spectral domain optical coherence tomography (SD-OCT) to evaluate and monitor the change of macular structure over time, especially ellipsoid zone (EZ), outer retinal tubulations, and chorioretinal atrophy. It is also helpful in identifying any comorbid maculopathy.
• Referral to a low vision specialist or vision rehabilitation clinic may be particularly helpful as central vision declines and/or visual field becomes limited.
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of choroideremia in order to facilitate medical and personal decision making

Treatment of Manifestations

Retinal detachment, which may occur more commonly in individuals with high myopia (as seen in CHM), is treated by conventional surgical techniques by an ophthalmologist.

Cataract surgery may be required for individuals with a posterior subcapsular cataract.

Rare instances of choroidal neovascularization may be treated with intravitreal bevacizumab [Palejwala et al 2014].

UV-blocking sunglasses may have a protective role when an affected individual is outdoors.

Low vision services are designed to benefit those whose ability to function is compromised by vision impairment. Low vision specialists, often optometrists, help optimize the use of remaining vision. Services provided vary based on age and needs.

Counseling from organizations or professionals who work with the blind and visually impaired may help the affected individual cope with issues such as depression, loss of independence, fitness for driving, and anxiety over employment issues.

Nutrition and ocular health have become increasingly topical:

• For those individuals who do not have access to fresh fruit and leafy green vegetables, a supplement with antioxidant vitamins may be important.
• No information is available on the effectiveness of vitamin A supplementation in the treatment of CHM.
• A source of omega-3 very-long-chain fatty acids, including docosahexaenoic acid, may be beneficial, as clinical studies suggest that regular intake of fish is important.

Surveillance

Regular ophthalmologic examination to monitor progression of CHM is recommended, as affected individuals need advice regarding their levels of visual function.

Kinetic visual field examinations provide practical information for both the clinician and the affected individual.

SD-OCT imaging is a fundamental clinical tool to evaluate macular structure, especially when central vision is affected and cystoid macular edema is suspected.

Agents/Circumstances to Avoid

Avoid the following:

• UV exposure from sunlight reflected from water and snow
• Smoking, a major risk factor for macular degeneration

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Gene replacement therapy using a subretinal delivery of AAV2-REP1 (Nightstar Therapeutics, UK) has been trialed in the UK, Canada, US, and Germany. Reports showed some gain in visual acuity in the treated eye compared to the untreated eye. However, some individuals experienced significant complications such as retinal overstretch and postoperative inflammation. This product is currently in a Phase III trial; results are expected in the coming years [Cehajic Kapetanovic et al 2019].

Another gene augmentation agent that is being trialed uses an intravitreal delivery of 4D-110 (4D Molecular Therapeutics, USA) in individuals with genetically confirmed choroideremia (ClinicalTrials.gov). The trial is estimated to be completed in 2023.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Choroideremia (CHM) is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have CHM nor will he be hemizygous for the CHM pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the CHM pathogenic variant identified in the proband cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo CHM pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/germline mosaicism [van den Hurk et al 2007].
• Evaluation of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Evaluations of the mother include:
  • Molecular genetic testing for the CHM pathogenic variant identified in the proband;
  • Examination of the retina through a dilated pupil to determine if she has signs of chorioretinal degeneration; however, a normal fundus examination at a young age (<25 years) may not be sufficient to exclude carrier status (see Clinical Description, Heterozygous females).

Sibs of a male proband. The risk to the sibs of a male proband depends on the genetic status of the mother:

• If the mother of the proband has a CHM pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected; it is not possible to predict at what age an affected male will start to experience vision problems and how quickly the disease will progress.
  • Females who inherit the pathogenic variant will be heterozygotes and may or may not initially show changes with ERG testing, funduscopic examination, color vision testing, and/or visual field testing; however, with time, areas of decreased fundus autofluorescence will be seen (see Clinical Description, Heterozygous females).
    It is not possible to predict if a heterozygous female will manifest any vision loss. At one time, consensus held that heterozygous females experienced only mild vision disturbances later in life; however, heterozygous females may have vision loss similar to that of affected males because of skewed X-chromosome inactivation.
• If the proband represents a simplex case (i.e., a single occurrence in a family), if the mother has a normal fundus examination, and if the CHM pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism [van den Hurk et al 2007].

Offspring of a male proband. Affected males transmit the pathogenic variant to all of their daughters and none of their sons.

Other family members. The maternal aunts and maternal cousins of an affected male may be at risk of having a CHM pathogenic variant.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote Detection

Molecular genetic testing. Identification of female heterozygotes requires either prior identification of the CHM pathogenic variant in the family or, if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Fundus examination. The retina is examined through a dilated pupil to determine if a female relative has signs of chorioretinal degeneration (see Clinical Description, Heterozygous females).

Note: Females who are heterozygous for this X-linked disorder may not have manifestations of CHM at a young age, but most definitely will have signs after age 25 years (see Clinical Description, Heterozygous females).

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the CHM pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for choroideremia are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

REP-1, the protein encoded by CHM, is a cytosolic protein, present in all cells. REP-1 enables lipid modification by geranylgeranylation of small GTP-binding proteins (Rabs) that are involved in cellular mechanisms of endocytosis, exocytosis, and intracellular trafficking, the processes that primarily become disordered in key pathways within the retinal pigment epithelium, but also the photoreceptors.

Mechanism of disease causation. Loss of function. Nearly all known CHM pathogenic variants are nonsense variants, small deletions or insertions, or splice site alterations that predict or result in truncation of the protein product or its absence (REP-1).

An exception is the CHM pathogenic L1 retrotransposon insertion in exon 6 that results in the direct splicing of exon 5 to exon 7 with maintenance of the reading frame.

CHM-specific laboratory technical considerations. When a clinical diagnosis of choroideremia is suspected, and no CHM pathogenic variant from gene-targeted testing can be identified, RNA and western blot analysis of CHM expression may be considered if available in a clinical laboratory. When a lack of CHM expression is identified, other variants (e.g., intronic, promoter, retrotransposon insertion, and large duplications) should be suspected. These variants may be incidentally detected by routine gene-targeted testing, for example, when the PCR product is larger than expected [Vaché et al 2019] or there is a drop in coverage of next-generation sequencing data within exon 2 of CHM [Jones et al 2020].

Author Notes

Ian M MacDonald, MSc, MD, CM, is Professor Emeritus in the Department of Ophthalmology and Visual Sciences, University of Alberta, and past Chair of the department for 20 years. Prior to becoming Chair in Edmonton, he was a career scientist of the Ontario Ministry of Health at the University of Ottawa. From 2007 to 2008, he served as Branch Chief of Ophthalmic Genetics and Visual Function at the National Eye Institute of the National Institutes of Health. Dr MacDonald trained in genetics as an undergraduate and postgraduate student at McGill University, Montreal. His ophthalmology residency and clinical genetics fellowship training occurred at the University of Ottawa, Queen's University, Kingston, and the Hospital for Sick Children, Toronto.

Dr MacDonald's areas of interest are inherited ocular disorders, in particular maculopathies and choroideremia. In 2009, in recognition of his work in Canada to foster the development of academic ophthalmology, he was elected as a Fellow of the Canadian Academy of Health Sciences. The Canadian College of Medical Geneticists honored him with a Lifetime Achievement Award.

CHM Gene Therapy at University of Alberta website: chmgenetherapy.ca

Acknowledgments

Grant funding from Fighting Blindness Canada is gratefully acknowledged. Past grant funding: CIHR, Alberta Innovates, Choroideremia Research Foundation Inc. Dr Yi Zhai received a fellowship award from the Choroideremia Research Foundation. Dr Manlong Xu received fellowship support from a grateful patient, Pat Krawchuk.

Natural History of the Progression of Choroideremia (NIGHT NCT03359551) and SOLSTICE NCT03584165 was supported by Nightstar Therapeutics and Biogen Study Group.

The choroideremia natural history study (NCT02994368) was supported by funding from 4D Molecular Therapeutics, Inc (Emeryville, CA as sponsor) and Roche Pharma AG.

Author History

Stephanie Hoang, MSc, CGC, CCGC; University of Alberta Hospital (2015-2021)
Stacey Hume, PhD (2015-present)
Ian M MacDonald, MD, CM (2003-present)
Kerry McTaggart, MSc; University of Alberta (2003-2007)
Meira R Meltzer, MA, MS, CGC; National Eye Institute (2007-2010)
Miguel C Seabra, MD, PhD; Imperial College School of Medicine (2003-2021)
Christina Sereda, MSc; University of Alberta (2003-2007)
Nizar Smaoui, MD; GeneDx (2007-2015)
Manlong Xu, MD, PhD (2021-present)
Yi Zhai, MD, PhD (2021-present)

Revision History

• 4 March 2021 (bp) Comprehensive update posted live
• 26 February 2015 (me) Comprehensive update posted live
• 3 June 2010 (me) Comprehensive update posted live
• 28 May 2008 (cd) Revision: duplication/deletion analysis available clinically
• 3 May 2007 (me) Comprehensive update posted live
• 29 December 2004 (me) Comprehensive update posted live
• 2 January 2004 (im) Revision: testing
• 7 May 2003 (im) Revision: Molecular genetic testing; prenatal diagnosis
• 21 February 2003 (me) Review posted live
• 2 December 2002 (im) Original submission

Published Guidelines / Consensus Statements

• American Academy of Ophthalmology Task Force on Genetic Testing. Recommendations for genetic testing of inherited eye diseases – 2014. Available online. 2014. Accessed 11-9-21. [PubMed: 22944025]

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