Choroideremia
Summary
Clinical characteristics.
Choroideremia (CHM) is characterized by progressive chorioretinal degeneration in affected males and milder signs in 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 observed with careful fundus examination. These signs become more readily apparent after the second decade.
Diagnosis/testing.
The diagnosis of CHM can be made clinically, based on the fundus examination and family history consistent with X-linked inheritance. The diagnosis is confirmed with the identification of a pathogenic variant in CHM which encodes the protein REP-1.
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 job loss.
Surveillance: Periodic ophthalmologic examination and Goldmann visual field examinations to monitor progression.
Agents/circumstances to avoid: UV exposure from sunlight reflected from water and snow.
Genetic counseling.
CHM is inherited in an X-linked manner. An affected male transmits the pathogenic variant to all of his female offspring and none of his male offspring. A carrier female has a 50% chance of passing the pathogenic variant to her offspring: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Carrier testing for at-risk female relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variant has been identified in an affected family member.
Diagnosis
Suggestive Findings
Diagnosis of choroideremia (CHM) should be suspected in individuals with the following findings.
Affected males. The diagnosis of choroideremia (CHM) can be made if the following are present [Roberts et al 2002]:
- A history of defective dark adaptation. Poor vision in the dark is commonly the first symptom in affected males. Males may not note such symptoms until their early teens.
- 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, as demonstrated by intravenous fluorescein angiography. The function and anatomy of the central macula is preserved until late in the disease process.
- Peripheral visual field loss. 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.
- Electroretinogram (ERG) of affected males that may at first show a pattern of rod-cone degeneration, which eventually becomes non-recordable.
- Family history consistent with X-linked inheritance
Carrier females
- Fundus appearance. Carrier females have fundus changes that are similar to those in affected males and follow a similar pattern of progression.
- No visual complaints. Carrier females do not experience significant visual impairment and in general are asymptomatic.
- Test results. Carrier females may show changes with ERG, dark adaptation, and visual field testing.
- The ERG may be normal in obligate carriers or in carriers with characteristic fundus changes. Sieving et al [1986] demonstrated that although abnormal responses may be recorded in female carriers with a dim blue flash, a dark-adapted white flash, or a flickering stimulus, no one test consistently predicted carrier status.
- Fundus autofluorescence may demonstrate in female carriers patchy areas of loss of fluorescence throughout the fundus [Preising et al 2009].
- Carrier females age 21-65 years had no change in the Arden ratio of the electrooculogram [Yau et al 2007].
Establishing the Diagnosis
The diagnosis of choroideremia is established in a proband with the identification of a pathogenic variant in CHM (see Table 1).
Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
- Single-gene testing
- Sequence analysis of CHM is performed first, followed by deletion/duplication analysis if no pathogenic variant is found.
- Targeted analysis for pathogenic variants is performed first in individuals of Finnish ancestry.
- A multigene panel that includes CHM and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of CHM. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
For individuals with atypical findings (see Genetically Related Disorders), a different testing strategy should be considered.
- For males presenting with choroideremia in addition to cognitive issues, and/or hearing loss, testing should begin with a chromosomal microarray (CMA) to look for a large contiguous deletion that includes CHM.
- For symptomatic females in whom a CHM pathogenic variant is not identified, a karyotype may be considered to look for an X:autosome translocation resulting in a disruption of CHM.
Table 1.
Molecular Genetic Testing Used in Choroideremia
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant Detectable by Method | |
|---|---|---|---|
| Affected Males | Carrier Females | ||
| CHM | Sequence analysis 2 | 95% 3, 4 | Unknown 3, 5 |
| Deletion/duplication analysis 6 | Unknown | ||
| Targeted analysis for pathogenic variants 7 | Most pathogenic variants in the Finnish population | ||
- 1.
See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.
- 2.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 3.
van den Hurk et al [1997]; Fujiki et al [1999]; McTaggart et al [2002]; van den Hurk et al [2003]; Freund, MSc thesis, University of Alberta, unpublished
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.
- 5.
Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.
- 6.
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
- 7.
Targeted analysis that detects c.1609+2dupT [Sankila et al 1992] for individuals of Finnish ancestry. Note: Pathogenic variants included in a panel may vary by laboratory.
Clinical Characteristics
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. Later, around age 50-70 years, the central vision is lost.
A study of 115 males with CHM confirmed the typically slow rate of visual acuity loss and the generally good prognosis for central visual acuity retention until the seventh decade [Roberts et al 2002]. In that study, 84% of males under age 60 years had visual acuity of 20/40 or better and 35% of individuals over age 60 years had a visual acuity of 20/200 or worse.
Posterior subcapsular cataracts are found in 31% of males.
Cystoid macular edema (CME) has been identified in individuals with choroideremia. Genead & Fishman [2011] reviewed 16 affected individuals without lesions by fundus examination; ten (62.5%) showed a degree of CME on spectral-domain optical coherence tomography.
Carrier females. Carrier females are generally asymptomatic; however, signs of chorioretinal degeneration can be observed with careful fundus examination. These signs become more readily apparent after the second decade. Night blindness and field loss can also develop later in life due to expanding areas of choroioretinal atrophy in females. Females who demonstrate clinical findings that mimic those of affected males likely have skewed X-chromosome inactivation.Symptomatic but mildly affected females are likely underreported in the literature.
Genotype-Phenotype Correlations
Genotype-phenotype correlations have not yet been demonstrated for this disorder.
Nomenclature
Choroideremia, the only diagnostic term used for this condition, has consistently been applied for more than 130 years.
Prevalence
Prevalence is estimated at 1:50,000.
Differential Diagnosis
Laboratory analysis may not always support the clinical diagnosis of choroideremia (CHM). For instance, a study identified 13 individuals who had a clinical diagnosis of CHM without a lab test confirmation [Lee et al 2003]. On reassessment of available clinical data, alternate diagnoses were suggested for eight of the 13 affected individuals. Specifically, CHM needs to be distinguished from the following retinal dystrophies:
- Retinitis pigmentosa (RP) is a group of inherited disorders in which abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) of the retina lead to progressive visual loss. The symptoms of RP (i.e., "night blindness" and constriction of peripheral visual field) are similar to those of CHM. In the later stages of CHM, when the loss of choroid and retina are significant, the fundus appearance may be confused with end-stage RP; however, the degree of migration of pigment into the retina that typifies RP is not seen in individuals with CHM. Diagnosis of RP relies on electroretinography (ERG) and visual field testing. RP can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Pathogenic variants in RPGR and RP2 are the most common causes of X-linked RP, accounting for 70%-90% and 10%-20%, respectively, of X-linked RP. The pattern of autofluorescence retinal imaging in carriers of X-linked RP is distinct from that of CHM carriers [Preising et al 2009].
- Usher syndrome type 1 is characterized by congenital, bilateral, profound hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. Unless fitted with a cochlear implant, individuals do not typically develop speech. Retinitis pigmentosa develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity. The diagnosis is established on clinical grounds using electrophysiologic and subjective tests of hearing and retinal function. Usher syndrome type 1 may be confused with the contiguous gene deletion syndrome, CHM and deafness with perilymphatic gusher. The scalloped areas of significant chorioretinal degeneration with preservation of the choroidal vessels, typical of CHM, are not seen in Usher syndrome type 1. Usher syndrome type I is inherited in an autosomal recessive manner. Mutation of genes at a minimum of nine different loci causes Usher syndrome type I. Genes at six of these loci – MYO7A (USH1B), USH1C, CDH23 (USH1D), PCDH15 (USH1F), USH1G, and CIB2 (USH1J) – have been identified.
- Gyrate atrophy of choroid and retina (OMIM 258870). The progressive nature of scalloped areas of chorioretinal atrophy seen in gyrate atrophy of the choroid and retina may be confused with CHM. Gyrate atrophy of the choroid and retina is an autosomal recessive condition caused by pathogenic variants in the gene encoding ornithine aminotransferase. Individuals with gyrate atrophy of the choroid and retina have elevated plasma concentration of ornithine, which is not seen in individuals with CHM.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with choroideremia (CHM), the following evaluations are recommended:
- Ophthalmologic examination including visual acuity and Goldmann visual field testing for a baseline
- Electroretinogram
- Funduscopic examination
- Optical coherence tomography (OCT)
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Retinal detachment which may occur more commonly in patients 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.
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 be needed to help the affected individual cope with issues such as depression, loss of independence, fitness for driving, and anxiety over job loss.
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 a regular intake of fish is important.
Prevention of Secondary Complications
Rare cases of choroidal neovascularization may be treated with intravitreal bevacizumab [Palejwala et al 2014]
Surveillance
Regular ophthalmologic examination to monitor progression of CHM is recommended as affected individuals need advice regarding their levels of visual function. Goldmann visual field examinations provide practical information for both the clinician and the affected individual.
Spectral domain-OCT (SD-OCT) is useful during therapeutic trials to measure macular thickness and the presence of cystoid macular edema [Genead & Fishman 2011].
Agents/Circumstances to Avoid
UV exposure from sunlight reflected from water and snow should be avoided.
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 therapy for individuals with CHM has been considered an achievable goal. Introduction of adenovirus containing the CHM coding region can restore in vitro protein levels and REP-1 activity in CHM-deficient lymphocytes and fibroblasts [Anand et al 2003].
Vasireddy et al [2013] reported encouraging preclinical results using induced pluripotent stem cells from patients with CHM as in vitro models as well as normal-sighted mice as in vivo models. Delivery of CHM cDNA via a recombinant adeno-associated viral vector (AAV2) did not induce cytotoxicity in either model, suggesting that a human clinical trial for this condition is possible. To date, a safety trial of AAV2-mediated gene therapy in human subjects with CHM has been completed [MacLaren et al 2014]. Despite the requirement for submacular placement of the vector through microsurgical techniques, no serious adverse events were noted.
Morgan et al [2014] provided supporting evidence that the retinal pigment epithelium and photoreceptor layers should be the primary targets for experimental therapies based on their high resolution retinal imaging studies.
Other preclinical studies suggest that AAV8 may also be a candidate vector for choroideremia human gene therapy trials [Black et al 2014].
Note: Gene therapy trials for CHM are currently planned or underway and are registered with www.clinicaltrials.gov.
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.
Other
Genead et al [2012] studied the use of 2% topical dorzolamide ophthalmic solution to treat two patients with CHM who had cystoid macular edema. Clear improvements in retinal thickness were identified though changes to visual acuity, retinal sensitivity and other functional measures were not clinically significant.