CHM gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: Rab escort protein 1 (REP-1)
  • Expressed ubiquitously throughout the body
  • Supports intracellular trafficking of Rab proteins and modification of their lipid membranes (prenylation)
  • Dysfunction of REP-1 affects protein transport within the photoreceptor cells and phagocytosis of shed outer segments by the RPE
Clinical phenotype
(OMIM phenotype no.)
Inheritance
  • X-linked recessive
SignsMale patients
  • Progressive diffuse chorioretinal atrophy encroaching the fovea
  • Sclera may be visible in advanced cases
  • Cataract
  • Choroidal neovascularization
  • Cystoid macular oedema
Female carriers
  • Range of severity
  • Patchy areas of RPE mottling (mild; common)
  • Smaller, localized areas of chorioretinal atrophy (intermediate)
  • Diffuse chorioretinal atrophy similar to male patients (severe)
  • Earlier onset disease tends to have more severe phenotype
Visual function
  • Onset of nyctalopia in early childhood
  • Progressive peripheral scotoma over time
  • VA is usually preserved till the late stages before foveal atrophy ensues
  • Legal blindness in the 4th or 5th decade of life
  • Female carriers are usually mildly affected (later disease onset) due to X-inactivation but there are some cases of severe phenotype similar to male patients
Systemic featuresComplete/partial deletion of the X chromosome involving the CHM gene can result in:
  • Cognitive issues
  • Sensorineural deafness
  • Cleft lip/palate
Key investigations
  • FAF: Small island of central hyper-AF with sharply-demarcating borders represent surviving retinal tissue; surrounded by large hypo-AF areas due to chorioretinal atrophy
  • FAF in female carriers with mild disease show fine speckles of hypo-AF throughout the posterior pole
  • OCT: Loss of outer retinal layers and RPE in areas of chorioretinal atrophy; ellipsoid zone is preserved centrally
  • Progressive shortening of EZ length as disease progresses
  • Electrophysiology: rod-cone dystrophy can be observed early in the disease; both responses progressively deteriorate over time
  • Standard perimetry
Molecular diagnosis
  • Targeted gene panels (retinal) as primary investigation
  • Western blot analysis of leukocytes for REP-1 protein if panel testing is negative and choroideremia is still suspected
  • Whole genome sequencing
  • Cytogenetic testing (microarray or karyotyping) for atypical cases to detect chromosomal deletion
Management
Therapies under research
Further information

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References

  1.  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
  2.  Mitsios A, Dubis AM, Moosajee M. Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments. Ther Adv Ophthalmol. 2018;10:2515841418817490.
  3.  Jauregui R, Park KS, Tanaka AJ, et al. Spectrum of Disease Severity and Phenotype in Choroideremia Carriers. Am J Ophthalmol. 2019;207:77-86.
  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.  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
  7.  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
  8.  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 November 30, 2020
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