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Review Article

Genetics of Bietti Crystalline Dystrophy

Ng, Danny S.C. MPH, FRCS; Lai, Timothy Y.Y. MD, FRCS, FRCOphth; Ng, Tsz Kin PhD; Pang, Chi Pui DPhil

Author Information
Asia-Pacific Journal of Ophthalmology: July/August 2016 - Volume 5 - Issue 4 - p 245-252
doi: 10.1097/APO.0000000000000209
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Abstract

Bietti crystalline dystrophy (BCD) was first described by Bietti1 in 1937 in 3 patients who had tapetoretinal degeneration characterized by glistening, yellow-white intraretinal crystals in the posterior pole, atrophy of the retinal pigment epithelium (RPE), and choroidal sclerosis. Corneal involvement was observed, consisting of crystals in the superficial layer at the limbus. The onset of these changes was in the third decade of life. Two of the patients were brothers, suggesting a familial and inherited disorder. The brothers were subsequently followed 30 years later by Bagolini and Ioli-Spada,2 and further disease progression with marked central vision loss and visual field constrictions were observed. In 1977, Welch3 studied the corneal limbus biopsy from a patient, which revealed that the crystalline deposits were lipid depositions in both fibroblasts and corneal epithelium. Welch3 categorized the distinct disease entity of crystalline retinopathy and corneal involvement by an apparent lipid material and postulated it to be a metabolic disorder. Since then, many cases of this uncommon condition have been reported worldwide. The aim of this review article is to provide a summary and discuss the genetics, biochemical nature, and phenotypic variations of BCD.

PHENOTYPE OF BCD

Epidemiology

Although BCD has been reported worldwide, it is reported to be more common in East Asia, especially in Chinese and Japanese populations.4 An epidemiological survey performed in China estimated a gene frequency of 0.005.5 In a cross-sectional study from Europe, Mataftsi et al6 reported that BCD accounted for approximately 3% of all nonsyndromic retinitis pigmentosa (RP) and 10% of nonsyndromic autosomal recessive RP patients. According to Hartong et al,7 the worldwide prevalence of RP was 1 in 4000, with autosomal recessive RP accounting for 50% to 60% of cases. Thus, the estimated prevalence of BCD is up to 1 in 67,000, representing around 21,000 individuals in China alone.

Symptoms and Onset of BCD

Patients with early-stage BCD may be asymptomatic. As the disease progresses, symptoms of BCD resemble RP, including reduced visual acuity, nyctalopia, floaters, photopsia, color vision impairment, and visual field constriction. The onset of BCD is typically during the second to third decade of life but can vary from the early teens to over age 40. The natural history of BCD is believed to be gradual peripheral visual field loss, followed by reduced visual acuity and central vision, leading to severe visual impairment or legal blindness in the late stage. Nevertheless, there is a considerable amount of variation in disease presentation and progression reported in the literature.

Fundus and Anterior Segment Features of BCD

Classically, the retinal crystals are salient features in BCD.3 These retinal crystals are refractile, polygonal, and are found in all levels of the neurosensory retina, particularly in the perimacular and peripapillary regions (Fig. 1). They are yellowish white and up to 50 μm in diameter.9 Corneal crystals are sometimes present and lie focally or circumferentially in the superficial anterior stroma around the limbus. The corneal crystals are smaller than 15 μm and can easily be missed if not carefully searched for.3,9 Although corneal crystals were described in the original cases, their presence is not required for the diagnosis of BCD. The pure retinal form of BCD is more common in Asians, in particular Chinese and Japanese, compared with whites, suggesting some phenotypic variations of BCD among different ethnic groups.4,10–12

FIGURE 1
FIGURE 1:
Fundus photo of the left eye of a patient with BCD showing multiple refractile crystals of various sizes in the macula and midperiphery. The RPE atrophy is limited within the macular area and is consistent with stage 1 disease based on the classification by Yuzawa et al.8

The clinical course of BCD is marked by the progressive atrophy of the RPE-choriocapillaris complex. Retinal pigment epithelium atrophy begins in the posterior pole with gradual peripheral involvement. As the RPE atrophy progresses, the visibility of crystalline deposits may diminish because the increased paleness of light reflected from the fundi can mask the retinal crystals. Bernauer et al9 demonstrated that, using a moving light source, the glistening reflex from the retinal crystals may be visible even with extensive chorioretinal atrophy in the background. Typical features of RP fundi such as “bone spicules” due to RPE hypertrophy and attenuated and sclerosed retinal vessels are also commonly seen in BCD patients. However, waxy pallor of the optic disc has rarely been observed in BCD. Yuzawa et al8 previously classified BCD into early, intermediate, and advanced stages. Early-stage BCD is characterized by the presence of white crystalline deposits in the posterior pole and midperiphery of the retina and mild RPE atrophy in the posterior pole. In the intermediate stage, areas of RPE atrophy are enlarged and crystalline deposits begin to diminish in the posterior pole but remain visible in the midperiphery. The late stage of BCD is characterized by diffuse RPE and choriocapillaris atrophy and the disappearance of most crystalline deposits. Bietti crystalline dystrophy can be associated with other sight-threatening complications, including cystoid macular edema, choroidal neovascularization, and macular hole.13–21

Fluorescein and Indocyanine Green Angiography Findings

Fluorescein angiography changes correlate well with clinical findings and progression in BCD.12,22,23 In the early stage of BCD, hyperfluorescence due to window defects appears in areas of RPE atrophy with intact choriocapillaris. Retinal crystals do not result in blocked fluorescence. As the disease progresses, lobular hypofluorescent islands appear, corresponding to areas of chorioretinal atrophy with nonperfusion of choriocapillaris. During the early phase on indocyanine green angiography (ICGA), there is delayed choroidal filling followed by lobular pattern of hypofluorescence.6 Late-phase ICGA shows variable hyperfluorescent areas that appear amid the hypofluorescent lesions. Findings on ICGA also correspond well to the stage and severity of BCD and might be superior to fluorescein angiography in outlining areas of chorioretinal atrophy and the true extent of choroidal circulatory impairment.24,25

Optical Coherence Tomography Findings

Spectral domain optical coherence tomography (SD-OCT) is able to provide detailed imaging of the retinal architectural changes in patients with BCD.26–31 A myriad of hyperreflective spots of various configurations are present in SD-OCT sections of patients with BCD.27,32 These multiple hyperreflective retinal dots have been observed in all retinal layers, including the inner retina and on top of the Bruch membrane. There has been controversy as to the location within the retina of the crystalline deposits in BCD. Some investigators have reported hyperreflective spots located on the RPE/Bruch membrane complex on SD-OCT, whereas others have reported similar looking hyperreflective spots throughout the neurosensory retina and choroid, which has been interpreted as crystal deposition occurring throughout the retina and choroid.32–34 By using SD-OCT with coregistration of lesions on near-infrared images, Halford et al32 observed that the majority of crystals were situated on or in the RPE/Bruch membrane complex, with a small number of crystals located elsewhere in the retina but not in the choroid. These hyperreflective dots may be related to inflammatory cells, protein deposits, a glial response to retinal degeneration, or even artifacts.33

One of the OCT features in BCD patients is outer retinal tabulation located in the outer nuclear layer of the retina and appearing as round or ovoid hyporeflective spaces with hyperreflexive borders.28,29 Outer retinal tabulation represents the rearrangement of the photoreceptor layer in response to retinal injury and has been observed in a variety of retinal diseases such as choroidal neovascularization secondary to age-related macular degeneration, angioid streaks, multifocal choroiditis, and inherited retinal dystrophies.35 Outer retinal tabulations seem to be relatively more commonly described in BCD when compared with other retinal dystrophies, such as RP and cone dystrophy.28,29

Li et al17 proposed the evolution of SD-OCT features as the severity of BCD progresses. In the early stage, there is loss of interdigitation zone and localized disruption of the ellipsoid zone. Disappearance of the outer retina and RPE layers occurs as the clinical severity increases. With the use of enhanced depth imaging SD-OCT, thinning of the choroidal layer is also found as the clinical course of BCD advances.17 Cystoid macular edema has also been observed in a few reported cases of BCD.17,26,36

Fundus Autofluorescence Findings

Fundus autofluorescence (FAF) imaging with confocal scanning laser ophthalmoscope imaging is derived from lipofuscin within the RPE, allowing noninvasive visualization of the RPE layer in BCD patients.35 In the early stage of BCD, FAF reveals widespread hypoautofluorescence corresponding to areas of RPE atrophy and multiple hyperautofluorescent speckles in the fundus (Fig. 2). It is unlikely that the hyperautofluorescent speckles correspond to the retinal crystals because normal autofluorescence is observed in the peripheral retina even in the presence of retinal crystals. The lack of autofluorescence associated with the retinal crystals is consistent with suggestions that the crystals in BCD may represent collections of cholesterol esters from abnormal lipid metabolism.22 Instead, the hyperautofluorescent speckles may be due to RPE hyperplasia or stress in concordance with histopathologic findings in BCD patients.12 As the severity of BCD progresses, hypoautofluorescent patches enlarge and become confluent and can extend beyond the posterior pole.

FIGURE 2
FIGURE 2:
Multimodal imaging of the right eye of a patient with BCD. A, Infrared imaging of the right eye showing multiple white dots due to intraretinal crystals. B, Fundus autofluorescence showing multiple patches of oval-shaped reduced autofluorescence due to RPE atrophy. The RPE atrophy extends beyond the posterior pole and is consistent with stage 2 disease based on the classification by Yuzawa et al.8

Visual Electrophysiology Findings

Unlike most inherited retinal dystrophies, visual electrophysiological testing is not essential for diagnosing BCD. However, visual electrophysiological tests are helpful for monitoring the severity and extent of the retinal damage. In early stages of BCD, full-field electroretinogram (ffERG) can be normal.33 With disease progression, phototransduction becomes increasingly affected, and various ffERG abnormalities occur, including decreased oscillatory potential amplitude, reduced a- and b-wave scotopic bright flash and photopic flash ffERG amplitudes, reduced amplitude of 30 Hz flicker ffERG, and abnormal S-cone response.10,22,37,38 The progression of BCD follows a rod-cone dystrophy pattern.10,38 The amplitudes of the responses on ffERG are more significantly affected than the implicit times.37 In end-stage BCD, ffERG response may become completely extinct.6

Multifocal ERG provides topographical information on the electrophysiological responses from the retina and helps identify areas of retinal dysfunction more precisely than ffERG.39 Reduced central multifocal ERG responses with preserved peripheral responses have been reported in patients with BCD.10 Multifocal ERG also shows amplitudes to be more significantly affected than implicit times, as in ffERG. P1 amplitudes and implicit times are more significantly affected than N1 responses.37

CYP4V2 GENE

Cytochrome P450

Bietti crystalline dystrophy has long been thought to be an autosomal recessive inherited disorder due to familial clustering in siblings and offspring of consanguineous marriage.2,22,40,41 Genetic linkage analysis first identified the BCD locus to be located on human chromosome 4q35.42 Fine mapping of this locus identified CYP4V2 as the gene responsible for BCD.42 The CYP4V2 gene encodes a 525 amino acid hemethiolate protein and is 1 of the 57 functional cytochrome P450 genes identified in the human genome, acting as an enzyme for fatty acid metabolism.43–45 Even before the identification of the CYP4V2 gene as the mutation causing BCD, abnormal lipid metabolism had been postulated in the pathogenesis of BCD.3,45 Lee et al45 reported the absence of a 32-kDa fatty acid–binding protein with a high affinity for 3 fatty acids, including docosahexaenoic acid (DHA; 22:6n-3), α-linolenic acid (18:3n-3), and palmitic acid (16:0), in the lymphocytes of patients with BCD compared with controls. Furthermore, metabolic studies of fibroblasts and lymphocytes cultured from individuals with BCD exhibited altered lipid metabolism, with decreased synthesis of ω-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (20:5n-3), and DHA from α-linolenic acid compared with controls.46

Role of CYP4V2 in Fatty Acid Metabolism

Nakano et al47 studied the substrate specificity of CYP4V2 and found that it is a fatty acid ω-hydroxylase of both saturated and unsaturated fatty acids. CYP4V2 exhibited ω-hydroxylase activity toward eicosapentaenoic acid (C20:5) and DHA, and the rates of ω-hydroxylation were similar to CYP4F2, an established hepatic PUFA hydroxylase.48–50 Because DHA is a major constituent of ocular membranes, the CYP4V2 protein is likely to be localized in the eye.50

Further to the development of a selective polyclonal antibody against recombinant CYP4V2, the immunocytochemical signal of recombinant CYP4V2 protein was localized in the endoplasmic reticulum of human RPE cell line ARPE-19.49 Moreover, immunohistochemical signal of the CYP4V2 protein was observed in the RPE cells of human retina.49 Weak staining was also observed in the ganglion cells and internal and external nuclear layers in the retina and moderate reactivity in corneal epithelial cells.49 Gene expression analysis demonstrated that CYP4V2 is the dominantly expressed cytochrome P450 gene in ARPE-19 cells, followed by CYP1B1.49 These experiments demonstrated that CYP4V2, as a fatty acid ω-hydroxylase, is expressed in RPE cells that are the major target for BCD.

It is a physiological requirement for an efficient lipid recycling system in the photoreceptors and RPE to regenerate disc membranes, given that rod and cone outer segments are constantly shed.51 The tip of the photoreceptor outer segment is shed and then phagocytized, whereas the lipids from processed membranes enter into RPE cells by endocytosis.51 Polyunsaturated fatty acids including DHA are taken up by RPE cells and further transferred to photoreceptor inner segments for the biosynthesis of new disc membranes.52 Mutations in CYP4V2 can lead to deficient PUFA-hydroxylase catalytic activity, contributing to RPE dysfunction in BCD patients. However, the exact molecular mechanism underlying CYP4V2 involvement in crystal accumulation and RPE atrophy in the eye remains to be elucidated. Biochemical tracer studies indicated a potential cellular defect in the anabolism of ω-3 PUFA in BCD patients.46 By performing comparative modeling, Kumar et al53 demonstrated that CYP4V2 has 4 possible fatty acid substrates, including caprylic, lauric, myristic, and palmitic acids. We previously analyzed the total fatty acids in the plasma of BCD patients and revealed significantly altered fatty acid concentrations compared with controls. Specifically, stearic acid (18:0) was elevated and oleic acid (18:1n-9) was reduced in patients with BCD.54 Furthermore, the CYP4V2 gene is expressed ubiquitously in human tissues, including brain, placenta, lung, liver, and kidney.49,55 Interestingly, clinical symptoms of BCD remain only in the eyes. The link between altered lipid profiles and the development of BCD-associated ocular crystals therefore remains unclear.54

Recently, a Cyp4v3 (the murine ortholog to human CYP4V2) knockout mouse was created.56 The Cyp4v3−/− mouse recapitulates the characteristic features of corneoretinal crystal accumulation and systemic dyslipidemia observed in BCD patients.57 Furthermore, some PUFA-derived metabolites, such as resolvin and protectin, possess anti-inflammatory and immunoregulatory signaling properties and may be disrupted in BCD patients.58

CYP4V2 MUTATIONS IN BCD

Known Mutations for BCD

Currently, CYP4V2 is the only known gene that causes BCD. CYP4V2 spans 21.7 kilobase pairs and comprises 11 exons.55 Around 60 mutations in the CYP4V2 gene have now been described in individuals with BCD (Table 1).10,11,17,27,32,36,55,57,59–79 At least 1 pathogenic variant has been reported in each of the 11 exons of CYP4V2. The most common mutation observed in BCD is the insertion-deletion mutation at intron 6-exon 7 junction (IVS6-8del17bp/insGC or c.802-8del17bp/insGC).57 A number of nonsense mutations, such as R320X and W340X, and missense mutations, such as I111T, H331P, and R400H, have also been identified in multiple patient groups. Small insertions, deletions, and splicing mutations have also been reported.59 In our previously reported Chinese cohort, the heterozygote carrier frequency of IVS6-8del17bp/insGC and H331P mutations in unrelated control subjects was 0.5%,11 indicating a hidden mutation in the general population.

TABLE 1
TABLE 1:
Reported Mutations in the CYP4V2 Gene Causing BCD

The CYP4V2 protein is composed of 18 helices and β-strands, in which the heme group (the porphyrin ring) is coordinated by the I, K, and L helices. From our previous gene screening analysis, we identified 9 mutations, including 2 splice-site, 1 nonsense, and 6 missense mutations (Y219H, D324V, H331P, P396C, R400C, and R400H).11 All these 6 amino acid substitutions are located around the heme-coordinating region (Fig. 3), indicating that they are important for structural and/or functional roles of the CYP4V2 protein. The positively charged R400, located in the β-strand after K helix, is considered a hotspot for gene mutations, as substitutions for C and H have been reported in this residue and they have been predicted to alter heme coordination.10,26,57,60,62,63 In addition, the D324V substitution in the central I helix neutralizes the negative charge in this residue and will alter the local isoelectric point (pI) around the active site. Furthermore, insertion or deletion of a proline residue has been predicted to influence the stability of the protein heme coordination–dependent secondary structures, which explains why H331P (in the central I helix) and P396L (in the β-strand after K helix) are the causative mutations in BCD. Despite the similar aromaticity and steric hindrance between tyrosine and histidine, Y219H could possibly influence the interaction of F helix with other secondary structures by introducing a charge from histidine into this position, depending on the local pI.

FIGURE 3
FIGURE 3:
The location of 6 selected missense mutations in the CYP4V2 protein. The CYP4V2 protein structure (1BU7) was obtained from Swiss-Pdb Viewer. The structure surrounding the porphyrin ring (the heme group), composed of the central I, K, and L helices, is shown. Six missense mutations (Y219H, D324V, H331P, P396L, R400C, and R400H) identified from our previous study are signified.

Genotype and Phenotype Correlation in BCD

Genotype-phenotype correlation studies in BCD are mostly derived from small case series.10,32,36,61,63,69 Our group has previously evaluated the genotype-phenotype correlation in a group of 18 Chinese patients in 13 families and showed that BCD with homozygous IVS6-8del17bp/insGC (c.802-8del17bp/insGC) or compound heterozygous IVS6-8del17bp/insGC and IVS8-2A_G (c1091-2A>G) mutations seemed to have a more severe disease phenotype based on electrophysiological testing.10 Deletion at the exon 7 splice acceptor site causes an in-frame deletion of exon 7, resulting in the expression of a truncated protein.55 Halford et al32 also reported that patients with these deletions had worse visual acuity. Exon-skipping mutations may predict more severe forms of the disease than missense mutations, which lead to homozygous or heterozygous amino acid substitutions. In addition, Halford et al32 pooled our data to perform Kaplan-Meier survival analysis and found that a missense mutation, p.M66R, seemed to be associated with earlier onset of symptoms.

In contrast, Rossi et al61 described the clinical and genetic features of 15 Italian patients with BCD and illustrated that there was a large range of genotypic and phenotypic variations, stressing the lack of an explicit genotype-phenotype correlation. Astuti et al63 also reported considerable phenotypic variability in 19 BCD patients and found no clear genotypic-phenotypic correlations.

The high degree of phenotypic variability in BCD may suggest that environmental factors affecting lipid metabolism, such as diet, may influence the disease manifestation and progression.

FUTURE DIRECTIONS FOR BCD

Bietti crystalline dystrophy is a progressive condition characterized by gradual peripheral visual field defect, increasing severity of nyctalopia, and irreversible vision loss. Periodic clinical monitoring with retinal imaging and visual function tests are useful in determining the severity and rate of progression in patients with BCD. Multimodal imaging with SD-OCT, FAF, and more recently, adaptive optics scanning laser ophthalmoscopy (AOSLO) is useful in delineating the severity and rate of progression of BCD in concordance with visual acuity and other functional parameters from perimetry and ERG.27,80 The confocal AOSLO system enables enface images in any plane, and ultrahigh-resolution imaging has the ability to reveal individual cone photoreceptors in vivo. Using AOSLO to image the retina in BCD patients, Miyata et al80 observed significant reductions in cone density at 0.5 mm from the center of the fovea, but not at 1.0 mm from the fovea despite significant RPE atrophy. This finding suggests that the RPE is the primary site of pathology in BCD, with the photoreceptors being the secondary site of degeneration.80 This implies that in the earlier stages of BCD, most of the photoreceptors can maintain structural integrity, and thus, these patients might be ideal candidates for possible future gene therapy. Gene therapy might be a reality in the near future for patients with BCD, as a murine model of BCD is now available.

Genetic counseling is also imperative for individuals and families with BCD to obtain information regarding the nature, inheritance, and implications of their eye conditions. This will be helpful for determining risk of inheritance, clarifying carrier status, and prenatal testing for family planning.

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— Ernest Hemingway

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Keywords:

Bietti crystalline dystrophy; retinal dystrophy; CYP4V2; genetics

© 2016 by Asia Pacific Academy of Ophthalmology