Choroideremia

Clinical Characteristics
Ocular Features: 

Choroideremia is characterized by a progressive atrophy of photoreceptors, retinal pigment epithelium (RPE) and choroid. Areas of RPE atrophy are present early in the mid-periphery and progress centrally.  This is associated with loss of photoreceptors and the choriocapillaris.

Night blindness is the first symptom often with onset during childhood. A ring-like perimacular scotoma develops that progresses into the periphery during life with corresponding visual field loss (peripheral constriction).  Symptoms and fundus changes are highly variable. Visual acuity is generally well maintained into later stages of the disease but some males are blind by age 30 years whereas others over the age of 50 are symptom-free.  An increased prevalence of myopia has been noted.

Males with choroideremia (and some females) have progressive loss of the choriocapillaris eventually baring the sclera beneath. Female carriers can exhibit patchy areas of RPE atrophy in the periphery and these may enlarge. Female carriers are typically not symptomatic, but there are reports of females being fully affected.  Females may also have visual field changes and defective dark adaptation.  OCT in young women shows dynamic changes and remodeling of the outer retina with time with focal retinal thickening, drusenlike deposits and disruptions in photoreceptor inner and outer segment junctions even in younger individuals.  The phenotype is more severe in older females as well suggesting that the retinal degeneration is progressive in both sexes.

Electroretinography (ERG) initially shows a decreased dark-adapted response with  intact light-adapted responses, indicating general dysfunction of rod photoreceptors. Cone dysfunction, however, develops with progression of the disease.

Systemic Features: 

No general systemic manifestations are associated with choroideremia. This may be explained by systemic expression of REP2, Rab escort protein-2, compensating for the decreased level of REP1.

There are occasional reports of associated deafness and obesity in some families with choroideremia (303110) but it is uncertain if this represents a unique disorder.

Genetics

Choroideremia is an X-linked recessive disorder affecting males and occasional female carriers.  The disorder is caused by mutations in the CHM gene on the X chromosome (Xq21.2) which leads to absence or truncation of the protein Rab escort protein-1 (REP1) that is part of Rab geranylgeranyltransferase, an enzyme complex involved in intracellular vesicular transport. A few patients with chromosomal translocations involving the relevant region of the X chromosome have been reported.

A homozygous mutation in the CYP4V2 gene has been reported to be responsible for a choroideremia-like clinical phenotype.

Treatment
Treatment Options: 

There is presently no effective treatment for the disorder, but visual function can be improved with low vision aids.

Recent early trials using adeno-associated viral vectors containing DNA coding the REP1 protein have documented improved rod and cone function in 6 affected males.

References
Article Title: 

Clinical and Genetic Features of Choroideremia in Childhood

Khan KN, Islam F, Moore AT, Michaelides M. Clinical and Genetic Features of Choroideremia in Childhood. Ophthalmology. 2016 Aug 6. pii: S0161-6420(16)30583-8. doi: 10.1016/j.ophtha.2016.06.051. [Epub ahead of print] PubMed.

PubMed ID: 
27506488

Optical

Jain N, Jia Y, Gao SS, Zhang X, Weleber RG, Huang D, Pennesi ME. Optical
Coherence Tomography Angiography in Choroideremia: Correlating Choriocapillaris
Loss With Overlying Degeneration
. JAMA Ophthalmol. 2016 May 5. doi:
10.1001/jamaophthalmol.2016.0874. [Epub ahead of print].

PubMed ID: 
27149258

References

Khan KN, Islam F, Moore AT, Michaelides M. Clinical and Genetic Features of Choroideremia in Childhood. Ophthalmology. 2016 Aug 6. pii: S0161-6420(16)30583-8. doi: 10.1016/j.ophtha.2016.06.051. [Epub ahead of print] PubMed.

PubMedID: 27506488

Katagiri S, Hayashi T, Gekka T, Tsuneoka H. A novel homozygous CYP4V2 variant (p.S121Y) associated with a choroideremia-like phenotype. Ophthalmic Genet. 2016 Jun 27:1-2.

PubMedID: 27348340

Jain N, Jia Y, Gao SS, Zhang X, Weleber RG, Huang D, Pennesi ME. Optical
Coherence Tomography Angiography in Choroideremia: Correlating Choriocapillaris
Loss With Overlying Degeneration
. JAMA Ophthalmol. 2016 May 5. doi:
10.1001/jamaophthalmol.2016.0874. [Epub ahead of print].

PubMedID: 27149258

Maclaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014 Jan 15. [Epub ahead of print].

PubMedID: 24439297

Huang AS, Kim LA, Fawzi AA. Clinical Characteristics of a Large Choroideremia Pedigree Carrying a Novel CHM Mutation. Arch Ophthalmol. 2012 Sep 1;130(9):1184-9.

PubMedID: 22965595

Coussa RG, Traboulsi EI. Choroideremia: A review of general findings and pathogenesis. Ophthalmic Genet. 33:57-65, 2011.

PubMedID: 22017263

Mura M, Sereda C , Jablonski MM, MacDonald IM; Iannaccone A. Clinical and Functional Findings in Choroideremia Due to Complete Deletion of the CHM Gene. Arch Ophthalmol. 2007;125(8):1107-1113.

PubMedID: 17698759

MacDonald IM, Russell L, Chan CC. Choroideremia: new findings from ocular pathology and review of recent literature. Surv Ophthalmol. 2009 May-Jun;54(3):401-7.

PubMedID: 19422966

Bonilha VL, Trzupek KM, Li Y, Francis PJ, Hollyfield JG, Rayborn ME, Smaoui N, Weleber RG. Choroideremia: analysis of the retina from a female symptomatic carrier. Ophthalmic Genet. 2008 Sep;29(3):99-110.

PubMedID: 18766988