Bietti Crystalline Corneoretinal Dystrophy

A number sign (#) is used with this entry because of evidence that Bietti crystalline corneoretinal dystrophy (BCD) is caused by homozygous or compound heterozygous mutation in the CYP4V2 gene (608614) on chromosome 4q35.

Description

Bietti crystalline corneoretinal dystrophy is an autosomal recessive retinal dystrophy characterized by numerous tiny glistening yellow-white crystals at the posterior pole of the retina, associated with atrophy of the retinal pigment epithelium (RPE), pigment clumps, and choroidal sclerosis. Most cases have similar crystals at the corneoscleral limbus. The disorder is progressive; most patients develop decreased vision, nyctalopia, and paracentral scotomata between the second and fourth decades of life. Patients later develop peripheral visual field loss and marked visual impairment, usually progressing to legal blindness by the fifth or sixth decade of life. In a series of European patients diagnosed with nonsyndromic retinitis pigmentosa (RP; see 268000), BCD accounted for approximately 3% of all nonsyndromic RP and 10% of nonsyndromic autosomal recessive RP. Histopathology shows advanced panchorioretinal atrophy, with crystals and complex lipid inclusions seen in choroidal fibroblasts, corneal keratocytes, and conjunctival and skin fibroblasts, as well as in circulating lymphocytes, suggesting that BCD may result from a systemic abnormality of lipid metabolism (summary by Li et al., 2004).

Clinical Features

Crystalline retinopathy is a retinal degeneration characterized by innumerable glistening intraretinal dots scattered over the fundus, with degeneration of the retina, sclerosis of the choroidal vessels, progressive night blindness, and constriction of the visual fields. Hu (1983) studied 35 patients (18 male, 17 female) in 25 families and established autosomal recessive inheritance. The average age of onset was 29.3 years.

This disorder was first reported by Bietti (1937, 1937) in 3 patients, 2 of whom were brothers. The fundus is similar to that of retinitis punctata albescens. Bietti (1937) noted crystalline corneal deposits in his cases, and Welch (1977) described associated 'marginal corneal dystrophy.' Bietti dystrophy is a useful designation because of the involvement of both the cornea and the fundus. The 2 brothers originally described by Bietti (1937) were reexamined by Bagolini and Ioli-Spada (1968). Both had suffered a marked decline in central vision and a contraction of visual field. The corneal dystrophy was unchanged but the corneal retinal degeneration had advanced, although the number of crystalline deposits had decreased. The discs were slightly pale and the retinal vessels were narrowed. Hu (1983) did not observe corneal changes.

Harrison et al. (1987) described the first British case. Wilson et al. (1989) described 3 patients, including 2 brothers. Corneal biopsy specimens demonstrated crystals resembling cholesterol or cholesterol ester and complex lipid inclusions in corneal and conjunctival fibroblasts. Similar inclusions were present in circulating lymphocytes, suggesting that Bietti crystalline corneoretinal dystrophy may be a systemic abnormality of lipid metabolism.

Lin et al. (2005) studied 11 unrelated patients with BCD, including 1 Chinese, 2 Middle Eastern, and 8 Japanese individuals, all carrying biallelic mutations in the CYP4V2 gene (see MOLECULAR GENETICS). Seven patients reported night blindness. Visual acuities ranged from normal to severely reduced. Slit-lamp examination revealed peripheral corneal crystalline deposits in 8 patients. Goldmann kinetic visual fields showed a central, paracentral, or ring scotoma in the patients. All had characteristic numerous small retinal crystalline deposits concentrated in the posterior pole. There were varying degrees of retinal pigment epithelium atrophy and attenuation of the choriocapillaris at the posterior pole; these abnormalities sometimes extended to the midperiphery. Full-field electroretinography (ERG) showed variable degrees of cone and rod function, ranging from normal to severely reduced, even among patients carrying the same mutation. Lin et al. (2005) suggested that environmental or additional genetic factors might influence the course of the retinal disease.

Wang et al. (2012) examined 22 members of a 4-generation Chinese family in which 4 sisters had congenital cataract, high myopia, and thin corneas, as well as retinal findings consistent with retinitis pigmentosa. All 4 sisters reported high myopia from about 10 years of age, with visual acuity decreasing progressively to only light perception by the sixth decade of life. Funduscopic examination and fluorescein angiography revealed peripheral pigmentation, retinal choroidal atrophy, and retinal vascular attenuation, and there was retinal atrophy on optical coherence tomography (OCT). Electroretinography demonstrated no detectable cone or rod responses. Punctate opacities of the lens were seen under slit-lamp examination, and the patients' corneas were thinner than those of unaffected members of the family. In addition, B-scan ultrasonography showed posterior scleral staphyloma, indicating high myopia. Wang et al. (2012) stated that they did not observe crystalline deposits in these patients.

Diagnosis

Mataftsi et al. (2004) examined 214 consecutive index patients diagnosed with retinitis pigmentosa or related chorioretinal disorders, and found an estimated BCD prevalence of 10% among nonsyndromic autosomal recessive RP patients (3 of 31 patients). The authors stated that BCD is a rare and underdiagnosed form of RP, noting that the characteristic marginal crystalline keratopathy, which consists of refringent subepithelial limbal deposits smaller than 15 micrometers, can easily be missed even by an experienced ophthalmologist. In their series of patients, the percentage of peripheral lymphocytes containing crystals tended to increase with age, and Mataftsi et al. (2004) suggested that this might serve as a diagnostic criterion for BCD in advanced cases, which are sometimes indistinguishable from choroideremia (see 303100) or other conditions involving diffuse choroidal sclerosis.

Population Genetics

Although patients with BCD have been reported from most parts of the world, the disorder appears to be most common in East Asia, especially in Chinese and Japanese populations. From the frequency of first-cousin parents in his series of patients with BCD, Hu (1983) estimated the frequency of the BCD gene in China to be 0.005. He pointed out that 3 of the 21 cases reported in the West (Grizzard et al., 1978; Welch, 1977) were in patients of Oriental extraction.

Biochemical Features

A number of findings point to the existence of systemic abnormalities of lipid metabolism in BCD (Lee et al., 1998). Abnormally high levels of triglycerides and cholesterol storage are seen in cultured cells from patients with BCD, whereas metabolism of labeled fatty acid precursors is decreased in BCD. Lee et al. (1998) showed that lymphocytes from patients with BCD lack 2 fatty acid-binding activities.

Mapping

In a study of 10 families with BCD, Jiao et al. (2000) reported linkage of the disease to chromosome 4q35-qter (maximum lod = 5.31 with D4S2299 at theta = zero). Using haplotype and linkage analyses, Li et al. (2004) refined the critical region for the BCD locus to a region of 4q35.1 flanked centromerically by D4S2924.

Molecular Genetics

In 23 of 25 unrelated patients with BCD, Li et al. (2004) identified 13 mutations in the CYP4V2 gene (see, e.g., 608614.0001-608614.0006).

Lin et al. (2005) screened the CYP4V2 gene in 11 unrelated patients with BCD, including 1 Chinese, 2 Middle Eastern, and 8 Japanese individuals, and identified homozygous or compound heterozygous mutations in all of them (see, e.g., 608614.0006-608614.0008).

In 4 Chinese sisters with congenital cataract, high myopia, thin corneas, and retinal findings consistent with RP, who were negative for mutation in 8 genes associated with autosomal recessive RP, Wang et al. (2012) performed exome sequencing and identified compound heterozygosity for 2 mutations in the CYP4V2 gene (608614.0005-608614.0006) that segregated fully with disease in the family. Both mutations had previously been identified in homozygosity or compound heterozygosity in patients with BCD.

Fu et al. (2013) screened 31 unrelated Chinese families with a diagnosis of autosomal recessive RP for mutations in 163 retinal disease genes, and identified compound heterozygosity for mutations in the CYP4V2 gene (see 608614.0005-608614.0006 and 608614.0009) in 2 probands. Reexamination of 1 proband was not possible because of dense cataracts in both eyes; however, reevaluation of affected individuals in the other family revealed yellowish shiny crystals in the proband's younger sister, although none were observed in the proband. Fu et al. (2013) stated that in their experience, the crystals seen in BCD may vanish as patients age and the disease progresses; thus, they clinically rediagnosed the patients in the latter family with BCD.