Clinical Diagnosis

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.

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

• Family history consistent with X-linked inheritance

Carrier females

• Carrier females have fundus changes that are similar to those in affected males and follow a similar pattern of progression.

• Carrier females do not experience significant visual impairment and in general are asymptomatic.

• 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].

Testing

Chromosome analysis. A high-resolution karyotype may reveal deletion of Xq21 in males with a contiguous gene deletion or an X;autosome translocation in symptomatic females.

Immunoblot analysis. Affected males show absence of the REP-1 protein by Western analysis of protein from peripheral blood lymphocytes or cell lines using anti-REP-1 antibody [MacDonald et al 1998]. Such testing is available on a research basis only.

Molecular Genetic Testing

Gene. CHM is the only gene known to be associated with choroideremia.

Clinical testing

• Targeted mutation analysis. A recurrent mutation (exon 13, donor splice site, insertion T) accounts for most mutations in the Finnish population [MacDonald et al 2004].

• Sequence analysis. Sequence analysis of the 15 exons and adjacent splice sites detects mutations in approximately 60%-95% of affected males [van den Hurk et al 1997, Fujiki et al 1999, McTaggart et al 2002, van den Hurk et al 2003].

• Duplication/deletion analysis. CHM deletions involving multiple and single exons, and even the entire gene, have been reported. See HGMD.

Research testing. If sequence analysis and duplication/deletion analysis together fail to identify a mutation, reverse transcriptase PCR, northern blot analysis, or protein truncation testing can be employed on a research basis to detect aberrantly spliced products and/or check protein integrity [MacDonald et al 2004].

Table 1. Summary of Molecular Genetic Testing Used in Choroideremia

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Affected Males	Carrier Females
CHM	Sequence analysis	Sequence variants 2	~60%-95% 3	60%-95%	Clinical
	Sequence analysis	Whole- and partial-gene deletions	~60%-95% 3	0% 4
	Duplication / deletion analysis 5	Whole- and partial-gene deletions	Not needed 6	4%-25% 3
	Targeted mutation analysis	Exon 13, donor splice site, insertion T	Most mutations in the Finnish population	Most mutations in the Finnish population

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Small intragenic deletions/insertions, missense, nonsense, and splice site mutations

3. van den Hurk et al [1997], Fujiki et al [1999], McTaggart et al [2002], van den Hurk et al [2003]

4. Sequence analysis of genomic DNA cannot detect exonic or whole-gene deletions on the X chromosome in carrier females.

5. Testing that identifies duplications/deletions not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), and array GH may be used.

6. Sequence analysis can detect putative exonic and whole-gene deletions on the X chromosome in affected males based on lack of amplification by PCR.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

• Clinical examination, in general, suggests a putative diagnosis of choroideremia in an affected male.

• Sequence analysis is the first step to confirm the diagnosis.

• When the clinical diagnosis is consistent with choroideremia, but no mutation is found by sequence analysis, duplication/deletion analysis is the next step.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

(1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

CHM is typically an isolated finding; rarely, it may be part of a contiguous gene syndrome involving Xq21.

• Males with large interstitial deletions involving Xq21 and additional X-chromosome material may have CHM, severe cognitive deficits, and birth defects such as cleft lip and palate and agenesis of the corpus callosum [Schwartz & Rosenberg 1996].

• Males with smaller deletions of Xq21 only may have CHM, mixed sensorineural and conductive hearing loss from stapes fixation with perilymphatic gusher caused by deletion of the POU3F4 gene (locus name DFN3), and varying degrees of cognitive deficits caused by deletion of the RSK4 gene [Yntema et al 1999].

• The presence of premature ovarian failure (POF) and mixed conductive and sensorineural deafness in the female with a de novo X;4 translocation reported by Lorda-Sanchez et al [2000] is consistent with a contiguous gene deletion of Xq21.

Natural History

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 (age 50-70 years) the central vision is lost.

A recent study in 115 males (mean age 39 years) 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, common in individuals with retinitis pigmentosa (RP), is not seen in individuals with CHM.

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.

Females are occasionally severely affected with findings that mimic those of affected males because of skewed X-chromosome inactivation or the presence of an X;autosome chromosome translocation involving Xq21 [Lorda-Sanchez et al 2000]. In the latter instance, CHM results from either disruption of the gene at the site of the translocation or from a submicroscopic deletion of multiple genes resulting in a continuous gene deletion syndrome.

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.

Individuals with full deletions of the CHM gene seem to be no more adversely affected than those with point mutations; all point mutations characterized thus far are nonsense mutations that result in a truncated unstable protein, which is rapidly degraded. Thus, functionally, full-gene deletions and point mutations both result in absence of the REP-1 protein.

Nomenclature

Choroideremia, the only diagnostic term used for this condition, has consistently been applied for over 130 years.

Prevalence

Prevalence is estimated to be 1:50,000. This estimation is supported by the assumption that if the prevalence of RP is 1:3500, and about 6% of individuals diagnosed with RP-related disorders actually have CHM, it is likely that approximately 1:58,000 individuals have CHM.

Evaluations Following Initial Diagnosis

To establish the extent of disease 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

• Family history

• Electroretinogram

• Funduscopic examination

Treatment of Manifestations

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.

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.

Surveillance

Periodic 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.

Agents/Circumstances to Avoid

UV exposure from sunlight reflected from water and snow should be avoided.

Testing 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 may be a future possibility. 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]. CHM is a likely target for gene therapy with defined clinical parameters that may guide when to intervene and how to monitor the outcome [Jacobson et al 2006].

Note: A gene therapy trial for CHM is currently planned but not yet registered with www.clinicaltrials.gov. No public information is available [Author, personal communication].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

A small short-term study of lutein oral supplementation (20 mg/day) showed that macular lutein was increased in individuals with CHM who received the supplement [Duncan et al 2002]; however, whether or not such supplementation provides a long-term protective effect is unknown.

A small study of 30 persons, including individuals with CHM, concluded that individuals with CHM already have normal levels of macular carotenoids (e.g., lutein and zeaxanthin). Therefore, diet supplementation is unlikely to alter the clinical course of the disease [Zhao et al 2003].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• The father of an affected male will not have CHM nor will he be a carrier of the disease-causing mutation.

• In a family with more than one affected male, the mother of an affected male is an obligate carrier.

• If pedigree analysis reveals that the proband is the only affected family member, it is appropriate to examine the retina of the mother through a dilated pupil to determine if she has evidence of carrier status.

• Possible genetic explanations for a male proband with no family history of CHM (i.e., a simplex case) are:

  • The proband has a de novo mutation. In this instance, the proband's mother does not have a germline mutation and does not have the retinal changes seen in carriers. The only other family members at risk are the offspring of the proband.

  • The proband's mother has a de novo gene mutation and may or may not have the retinal changes seen in carriers. One of two types of de novo gene mutations may be present in the mother:

    a.

    A germline mutation that was present at the time of her conception, is present in every cell of her body, and is detectable in her DNA
    
    OR

    b.

    A mutation that is present only in her ovaries (termed "germline mosaicism") and is not detectable in the DNA from her leukocytes

  • Germline mosaicism has not been reported in individuals with CHM but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members. In both instances a) and b), each offspring of the proband's mother has a risk of inheriting the mutation; none of the sibs of the proband's mother, however, is at risk of inheriting the altered gene.

Sibs of a proband

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

• If the mother has the mutation, the chance of transmitting the CHM mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.

• When the mother has a normal fundus examination, the risk to the sibs of a proband appears to be low. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a male proband. Affected males transmit the disease-causing mutation to all of their female offspring and none of their male offspring.

Family members of a proband. If a parent of the proband also has a disease-causing mutation, his or her female family members may be at risk of being carriers (asymptomatic or symptomatic) and his or her male family members may be at risk of being affected, depending on their genetic relationship to the proband.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the mutation has been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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 carriers, or are at risk of being carriers.

Specific risk issues. 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. It is also not possible to know if a carrier female will manifest any vision loss. At one time, consensus held that carrier females experienced only mild vision disturbances later in life; however, manifesting carriers may have vision loss similar to that of affected males because of skewed X-chromosome inactivation. It is important to note, however, that manifesting carriers are rare.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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2. Duncan JL, Aleman TS, Gardner LM, De Castro E, Marks DA, Emmons JM, Bieber ML, Steinberg JD, Bennett J, Stone EM, MacDonald IM, Cideciyan AV, Maguire MG, Jacobson SG. Macular pigment and lutein supplementation in choroideremia. Exp Eye Res. 2002;74:371–81. [PubMed: 12014918]
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4. Jacobson SG, Cideciyan AV, Sumaroka A, Aleman TS, Schwartz SB, Windsor EA, Roman AJ, Stone EM, MacDonald IM. Remodeling of the human retina in choroideremia: rab escort protein 1 (REP-1) mutations. Invest Ophthalmol Vis Sci. 2006;47:4113–20. [PubMed: 16936131]
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7. Lorda-Sanchez IJ, Ibanez AJ, Sanz RJ, Trujillo MJ, Anabitarte ME, Querejeta ME, Rodriguez de Alba M, Gimenez A, Infantes F, Ramos C, Garcia-Sandoval B, Ayuso C. Choroideremia, sensorineural deafness, and primary ovarian failure in a woman with a balanced X-4 translocation. Ophthalmic Genet. 2000;21:185–9. [PubMed: 11035551]
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11. Preising MN, Wegscheider E, Friedburg C, Poloschek CM, Wabbels BK, Lorenz B. Fundus autofluorescence in carriers of choroideremia and correlation with electrophysiologic and psychophysical data. Ophthalmology. 2009;116:1201–9. [PubMed: 19376587]
12. Rak A, Pylypenko O, Niculae A, Pyatkov K, Goody RS, Alexandrov K. Structure of the Rab7:REP-1 complex: insights into the mechanism of Rab prenylation and choroideremia disease. Cell. 2004;117:749–60. [PubMed: 15186776]
13. Roberts MF, Fishman GA, Roberts DK, Heckenlively JR, Weleber RG, Anderson RJ, Grover S. Retrospective, longitudinal, and cross sectional study of visual acuity impairment in choroideraemia. Br J Ophthalmol. 2002;86:658–62. [PMC free article: PMC1771148] [PubMed: 12034689]
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17. van den Hurk JA, Schwartz M, van Bokhoven H, van de Pol TJ, Bogerd L, Pinckers AJ, Bleeker-Wagemakers EM, Pawlowitzki IH, Ruther K, Ropers HH, Cremers FP. Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene. Hum Mutat. 1997;9:110–7. [PubMed: 9067750]
18. van den Hurk JA, van de Pol DJ, Wissinger B, van Driel MA, Hoefsloot LH, de Wijs IJ, van den Born LI, Heckenlively JR, Brunner HG, Zrenner E, Ropers HH, Cremers FP. Novel types of mutation in the choroideremia (CHM) gene: a full-length L1 insertion and an intronic mutation activating a cryptic exon. Hum Genet. 2003;113:268–75. [PubMed: 12827496]
19. Yau RJ, Sereda CA, McTaggart KE, Sauve Y, MacDonald IM. Choroideremia carriers maintain a normal electro-oculogram (EOG). Doc Ophthalmol. 2007;114:147–51. [PubMed: 17333094]
20. Yntema HG, van den Helm B, Kissing J, van Duijnhoven G, Poppelaars F, Chelly J, Moraine C, Fryns JP, Hamel BC, Heilbronner H, Pander HJ, Brunner HG, Ropers HH, Cremers FP, van Bokhoven H. A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation. Genomics. 1999;62:332–43. [PubMed: 10644430]
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Suggested Reading

1. MacDonald IM, Russell L, Chan CC. Choroideremia: new findings from ocular pathology and review of recent literature. Surv Ophthalmol. 2009;54:401–7. [PMC free article: PMC2679958] [PubMed: 19422966]
2. Sandberg MA, Gaudio AR. Reading speed of patients with advanced retinitis pigmentosa or choroideremia. Retina. 2006;26:80–8. [PubMed: 16395143]
3. Cremers FPM, Ropers H-H. Choroideremia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 236. Available at www.ommbid.com. Accessed 11-17-09.

Author History

Ian M MacDonald, MD, CM (2003-present)
Kerry McTaggart, MSc; University of Alberta (2003-2007)
Meira R Meltzer, MA, MS, CGC (2007- 2010)
Miguel C Seabra, MD, PhD (2003-present)
Christina Sereda, MSc; University of Alberta (2003-2007)
Nizar Smaoui, MD (2007-present)

Revision History

• 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 to live Web site

• 29 December 2004 (me) Comprehensive update posted to live Web site

• 2 January 2004 (im) Revision: testing

• 7 May 2003 (im) Revision: Molecular genetic testing; prenatal diagnosis

• 21 February 2003 (me) Review posted to live Web site

• 2 December 2002 (im) Original submission