choroidal sclerosis

Bietti Crystalline Corneoretinal Dystrophy

Clinical Characteristics
Ocular Features: 

The retina contains refractile glistening intraretinal crystals at all levels and choroidal vessels are said to be sclerosed.  The RPE atrophies and often forms pigment clumps.  The yellow-white crystals may be seen in the peripheral cornea and in the limbus.  Symptoms of night blindness and early vision loss begin about the third decade.  Night blindness is progressive as is the narrowing of the visual fields but this is highly variable between patients.  The visual field may show paracentral scotomas at some stage.  Central acuity can be normal until late in the disease when it becomes markedly impaired. Legal blindness can occur by the 5th decade of life. 

The ERG may show lack of rod and cone responses late in the disease and color vision may be lost.  However, the ffERG and mfERGs show decreases in amplitude of scotopic and photopic responses in all patients, even younger ones.  The EOG becomes abnormal in late stages.  The degree of involvement may be asymmetrical.  Complex lipid inclusions can be seen histologically in choroidal, conjunctival and skin fibroblasts, as well as in keratocytes and lymphocytes.

Crystalline deposits have been detected mostly in the proximal portions of RPE cells adjacent to degenerated retinal  areas.  Most common are circular hyperrefractive structures in the outer nuclear layer adjacent to areas of degeneration.  Some patients have cystoid macular edema. Others in late stages have fundus changes that resemble choroideremia.

Systemic Features: 

No other organ disease has been reported.

Genetics

This is an autosomal recessive disorder caused by mutations in the CYP4V2 gene (4q35.1) involved in fatty acid metabolism.

A homozygous CYP4V2 mutation has also been reported in patients with a choroideremia-like clinical phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond low vision aids is available.

References
Article Title: 

Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2

Li A, Jiao X, Munier FL, Schorderet DF, Yao W, Iwata F, Hayakawa M, Kanai A, Shy Chen M, Alan Lewis R, Heckenlively J, Weleber RG, Traboulsi EI, Zhang Q, Xiao X, Kaiser-Kupfer M, Sergeev YV, Hejtmancik JF. Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2. Am J Hum Genet. 2004 May;74(5):817-26. Epub 2004 Mar 23.

PubMed ID: 
15042513

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.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Visual function can be improved with low vision aids.  Recent early trials using adeno-associated viral vectors containing DNA coding for normal REP1 protein have documented improved rod and cone function with better visual acuity in affected males.

References
Article Title: 

CHANGES IN RETINAL SENSITIVITY AFTER GENE THERAPY IN CHOROIDEREMIA


Fischer MD, Ochakovski GA, Beier B, Seitz IP, Vaheb Y, Kortuem C, Reichel FFL, Kuehlewein L, Kahle NA, Peters T, Girach A, Zrenner E, Ueffing M, MacLaren RE, Bartz-Schmidt K, Wilhelm B. CHANGES IN RETINAL SENSITIVITY AFTER GENE THERAPY IN CHOROIDEREMIA. Retina. 2018 Oct 9. doi: 10.1097/IAE.0000000000002360. [Epub ahead of print].
 

PubMed ID: 
30308560

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
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