Structural and functional phenotypic features and molecular analysis of Indian patients with Bietti crystalline dystrophy

Purpose: Bietti crystalline dystrophy (BCD) is a rare retinal dystrophy, uncommon in Indians. This study describes the various phenotypic features seen in the Indian population. Methods: In this retrospective, descriptive case series, records of patients with either clinical or molecular diagnosis of BCD from 2009 to 2020 were perused. Phenotypic and genotype information was collected and analyzed. Results: This study included 58 patients of BCD (31 males) aged 21–79 years (mean: 47 ± 14 years). The age at onset ranged from 7 to 41 years (mean: 28.8 ± 5.1 years). Vision ranged from 20/20 to counting fingers. There were 18 (31%) patients with stage 1 with crystals and mild retinochoroidal atrophy, 22 (38%) with stage 2 with atrophy extending beyond arcades, and 18 (31%) with absent crystals and extensive atrophy of stage 3. Choroidal neovascular membrane was seen in four patients. The optical coherence tomography showed retinochoroidal thinning (84.6%), outer retinal tubulations (71.8%), and paradoxical foveal thickening with interlaminar bridges (7.7%). Electrophysiology and visual fields showed reduced responses in advanced retinochoroidal changes. Molecular confirmation was available in five patients; five mutations were seen in the CYP4V2. Conclusion: A wide variation is seen in the phenotypic picture of BCD. A molecular diagnosis is helpful in differentiating from other retinal dystrophies. The OCT shows the peculiar feature of the interlaminar bridge in early cases with photoreceptor loss. Further investigations into this OCT feature may provide insights into the pathogenesis of BCD. A genotype–phenotype correlation could not be done.

Analysis of Radial Peripapillary Capillary Density in Patients with Bietti Crystalline Dystrophy by Optical Coherence Tomography Angiography / 生物医学与环境科学（英文）

OBJECTIVE@#We wanted to investigate the radial peripapillary capillary (RPC) network in patients with Bietti crystalline dystrophy (BCD).@*METHODS@#We compared RPC densities in the disk and different peripapillary regions, obtained using optical coherence tomography angiography in 22 patients with BCD (37 eyes) and 22 healthy subjects (37 eyes). The BCD group was then divided into Stage 2 and Stage 3 subgroups based on Yuzawa staging, comparing the RPC densities of the two.@*RESULTS@#The disk area RPC density was 38.8% ± 6.3% in the BCD group and 49.2% ± 6.1% in the control group ( P < 0.001), and peripapillary region RPC density was significantly lower in the BCD group than in the control group (49.1% ± 4.7% and 54.1% ± 3.0%, respectively, P < 0.001). There were no significant RPC density differences between the tempo quadrant and inside disk of Stages 2 and 3 subgroups; the other areas showed a significantly lower RPC density in Stage 3 than in Stage 2 BCD.@*CONCLUSION@#The BCD group RPC density was significantly lower than the control group. The reduction of RPC density in the tempo quadrant occurred mainly in the Stage 1 BCD. In contrast, the reduction of RPC density in superior, inferior, and nasal quadrants occurred mainly in Stage 2.

Identify pathogenic mutations of <i>CYP4V2</i> gene in Bietti crystalline corneoretinal dystrophy / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To identify pathogenic mutations of <i>CYP4V2</i> gene in two Chinese families with Bietti crystalline corneoretinal dystrophy(BCD)by Sanger sequencing. <p>METHODS: The relevant clinical examination of BCD patients were collected. Peripheral blood of patients and their family members was collected. Then DNA was extracted from peripheral blood, and Sanger sequencing was used to identify mutation sites.<p>RESULTS: Two probands of BCD from different families were collected. All the probands showed progressive decrease of visual acuity and typical crystal-like material deposition could be seen in the fundus. Sanger sequencing showed that proband 1 and her brother and sister all had homozygous mutation of c.802-8_810del17insGC in <i>CYP4V2</i> gene. On the other hand, proband 2 had a compound heterozygous mutation of c.219T>A(p.F73L)and c.802-8_810del17insGC in <i>CYP4V2</i> gene. <p>CONCLUSION: The most common mutation was c.802-8_810del17insGC in Chinese BCD patients. The homozygous c.802-8_810del17insGC mutation was the cause of BCD in the proband 1 family. On the other hand, proband 2 had c.802-8_810del17insGC heterozygous mutation and c. 219T>A(p.F73L)heterozygous missence mutation, all of which affected the normal coding of <i>CYP4V2</i> gene and led to disease.

Generation and characterization of Cyp4v3 gene knockout mice / 北京大学学报(医学版)

OBJECTIVE@#Bietti crystalline dystrophy (BCD) is a rare degenerative eye disease caused by mutations in the CYP4V2 gene, and Cyp4v3 is the murine ortholog to CYP4V2. To better understand the molecular pathogenesis of this disease and to explore the potential treatment we have established a Cyp4v3 knock-out mouse model.@*METHODS@#Cyp4v3-/- mice were generated by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 in embryonic stem cells of C57BL/6J mice. Ocular morphologic characteristics were evaluated via fundus imaging, histologic analysis of rods and cones via immunofluorescence, and phalloidin stain to observe retinal pigment epithelium (RPE) in whole-mounts, electroretinogram (ERG) was also conducted to examine the retinal function.@*RESULTS@#The characteristic features of BCD recurred in the Cyp4v3-/- mice, including retinal crystalline deposits, atrophy and degeneration of RPE cells, and ERG amplitude decline of dark and light adapted a- and b- wave; however, the immunofluorescence stain of rod and cone cells did not show obvious differences when compared with the wild type (WT) mice. In the early stage of the disease, no crystal-like deposits were found in the fundus, ERG detection of the retinal function did not find a significant decline, and the morphological structure and quantity of the neural retina and RPE did not change significantly. Crystalline deposits occurred and converged when the Cyp4v3-/- mice at the end of 6 months, and the deposits disappeared when the Cyp4v3-/- mice at the end of 12 months. The ERG amplitude started to decline when the Cyp4v3-/- mice at the end of 6 months and deteriorated at the end of 12 months. The RPE cells of the 12-month old Cyp4v3-/- mice showed irregular shape by phalloidin staining of F-actin. The Cyp4v3-/- mice behaved normally and were viable and fertile when maintained under specific pathogen-free (SPF) housing conditions.@*CONCLUSION@#Just like BCD patients, the disease progress of Cyp4v3-/- mouse is correlated with the age, which provides a good model for pathogenesis and gene therapy study in the future. The atrophy and degeneration of RPE take the lead in progressing of the disease, but the mechanism is not clear yet.

Clinical manifestation and gene mutation of Bietti crystalline corneoretinal dystrophy / 中华实验眼科杂志

Objective@#To analyze the clinical manifestation and CYP4V2 mutations of Bietti crystalline corneoretinal dystrophy( BCD) families.@*Methods@#Total of 234 patients (173 families) diagnosed as BCD were recruited in Peking University Third Hospital from 2010 to 2018.All of the subjects underwent comprehensive eye examinations to observe the clinical manifestations.Blood samples were collected and genomic DNA was extracted.The Sanger sequencing or high- throughput sequencing was applied for CYP4V2 gene mutation analysis.This study was approved by the Ethics Committee of Peking University Third Hospital (NO.2012093). All patients and their family members signed informed consent.@*Results@#Some patients manifested the typical phenotype of BCD characterized by yellowish-white crystalline deposits throughout the fundus.However, some patients in advanced stage were easily misdiagnosed as other inherited retinal degeneration because the crystalline deposits diminished or even disappeared.Forty-nine probands in our cohort were misdiagnosed as other inherited retinal degeneration at first visit, with a misdiagnosis rate of 28.3%.Genetic diagnosis results showed that 161 patients carried CYP4V2 mutation, and the positive rate was 93.1%.Eight novel mutations were obtained.The three known mutations c. 802-8 _810del17bp, c.1091-2 A>G and c. 992 A>C accounted for 73.5% of the mutations, which were hotspots in Chinese Han populations for BCD.@*Conclusions@#Patients with BCD have characteristic fundus manifestation, but are easily misdiagnosed in advanced stage.Molecular diagnosis is valuable in clinical diagnosis of the disease, thus contribute to the prevention and treatment of the disease.A single hybrid mutation is not enough to lead to BCD.No apparent genotype- phenotype correlation between the CYP4V2 gene and occurrence of BCD is identified.

Clinical manifestation and gene mutation of Bietti crystalline corneoretinal dystrophy / 中华实验眼科杂志

Objective To analyze the clinical manifestation and CYP4V2 mutations of Bietti crystalline corneoretinal dystrophy( BCD) families. Methods Total of 234 patients (173 families) diagnosed as BCD were recruited in Peking University Third Hospital from 2010 to 2018. All of the subjects underwent comprehensive eye examinations to observe the clinical manifestations. Blood samples were collected and genomic DNA was extracted. The Sanger sequencing or high- throughput sequencing was applied for CYP4V2 gene mutation analysis. This study was approved by the Ethics Committee of Peking University Third Hospital (NO. 2012093). All patients and their family members signed informed consent. Results Some patients manifested the typical phenotype of BCD characterized by yellowish-white crystalline deposits throughout the fundus. However,some patients in advanced stage were easily misdiagnosed as other inherited retinal degeneration because the crystalline deposits diminished or even disappeared. Forty-nine probands in our cohort were misdiagnosed as other inherited retinal degeneration at first visit, with a misdiagnosis rate of 28. 3％. Genetic diagnosis results showed that 161 patients carried CYP4V2 mutation,and the positive rate was 93. 1％. Eight novel mutations were obtained. The three known mutations c. 802-8 _810del17bp, c. 1091-2 A>G and c. 992 A>C accounted for 73. 5％ of the mutations, which were hotspots in Chinese Han populations for BCD. Conclusions Patients with BCD have characteristic fundus manifestation, but are easily misdiagnosed in advanced stage. Molecular diagnosis is valuable in clinical diagnosis of the disease,thus contribute to the prevention and treatment of the disease. A single hybrid mutation is not enough to lead to BCD. No apparent genotype-phenotype correlation between the CYP4V2 gene and occurrence of BCD is identified.

Multimodal imaging of Bietti's crystalline dystrophy

Bietti's crystalline dystrophy (BCD) is a rare autosomal recessive retinal dystrophy characterized by deposition of crystals in the retina. The purpose of this article is to describe retinal abnormalities in BCD using multimodal imaging. An 18-year-old girl presented with decrease of vision and nyctalopia. She was assessed with color fundus picture, red-free photographs, short-wave autofluorescence, spectral-domain optical coherence tomography (OCT) and en face OCT and was diagnosed to have BCD based on typical presentation. Retinal crystals were better visualized on en face OCT as compared to conventional B scan OCT.

Research progress in Bietti crystalline corneoretinal dystrophy / 中华实验眼科杂志

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal degenerative disease characterized by crystalline deposits in the retina,followed by progressive atrophy of retinal pigment epithelium (RPE),choriocapillaris and photoreceptors.CYP4V2 has been identified as causative gene for BCD.At present,multiple gene mutation sites have been found in BCD patients.CYP4V2 gene belongs to cytochrome P450,it participates in the ω-hydroxylase activity of polyunsaturated fatty acids (PUFAs).CYP4V2 proteins are mainly distributed in the RPE,docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) as specific catalytic substrates,and play an important role in ocular physiological lipid recycling system.CYP4V2 gene mutations can disrupt the endogenous fatty acids or steroid synthesis and decomposition approach.The treatment of BCD always refers to retinitis pigmentosa (RP),and the study of mutation sites have provided the possibility for future gene therapy.Understanding the mechanism of molecular genetics and the pathophysiology of disease will be useful for the genetic diagnosis of BCD and potential development of genetic therapy in the future.This article reviewed the molecular genetic mechanism of BCD,in vivo expression and role of CYP4V2 in lipid metabolism and the treatment of BCD.

Three Cases of Outer Retinal Tubulation in Bietti's Crystalline Dystrophy

PURPOSE: To report the prevalence and the characteristics of outer retinal tubulation (ORT) in Bietti's crystalline dystrophy in 6 eyes of 3 patients. CASE SUMMARY: Three patients with Bietti's crystalline dystrophy were examined using color fundus photography, fundus autofluorescence picture, spectral domain optical coherence tomography (SD-OCT), fluorescein angiography, electroretinogram and electrooculogram. ORT was detected in 3 of 3 (100%) Bietti's crystalline dystrophy patients. SD-OCT B-scan revealed hyperreflective material inside the hyporeflective internal space with hyperreflective border. ORT was observed under the fovea or outside the fovea and on the outer nuclear layer in the retina. ORTs were no greater than 70 x 140 microm in size when measured using SD-OCT B-scan image. CONCLUSIONS: ORT was observed frequently in patients with Bietti's crystalline dystrophy. These findings can potentially predict the extensive photoreceptor abnormalities in retinal pigment epithelial atrophy.

Changes of serum lipids in patients with Bietti crystalline dystrophy / 中华实验眼科杂志

Background Bietti crystalline dystrophy (BCD) is a congenital and autosomal recessive hereditary eye disease characterized by multiple glistening intraretinal crystals scattered over the fundus.Studies determined abnormality of fatty acid metabolism probably is associated with BCD.However,the study on the alteration of blood lipid level in BCD patients is rare.Objective This trail was to study the change of serum lipids in BCD patients.Methods A total of 50 patients with bilateral BCD and 50 matched healthy volunteers were included from November 2011 to March 2013 in Beijing Tongren Eye Center with the approval of Ethic Committee of Beijing Tongren Hospital.Written informed consent was obtained from each subject before any medial examination.Peripheral blood of 3 ml was collected from the subjects.The serum concentrations of triglyceride (TG),total cholesterol (TC),low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were measured and analyzed.The examination outcome was identified based on the criteria of China Adult Dyslipidemia Prevention Guideline (Version 2007).Results Abnormality of serum lipid content was detected in 58.00％ patients (29/50),and hypertriglyceridemia and hypercholesteremia were in 34.48％ (10/29),respectively,and mixed hyperlipidaemia was in 27.59 ％ (8/29).The serum levels of TG,TC and LDL-C were (1.63± 1.19) mmol/L,(5.10±1.05) mmol/L and (3.27±0.97) mmol/L in the BCD group,which were significantly higher than (0.93± 0.33) mmol/L,(4.33 ±0.56) mmol/L,(2.63 ±0.51) mmol/L of the normal group (t =4.036,4.496,4.095,all at P=0.000).Conclusions The serum lipid levels elevate in BCD patients,which might be related to the occurrence of BCD.

Progress in mechanism of CYP4V2 gene mutations for Bietti crystalline corneoretinal dystrophy / 中华实验眼科杂志

Bietti crystalline corneoretinal dystrophy (BCD) is a common form of hereditary retinal degeneration in Chinese.Mutation of the cytochrome P450 4V2 (CYP4V2) gene,a novel family member of the cytochrome P450 genes on chromosome 4q35,has been identified in BCD patients,with the common mutation locus at c.802-8 _ 810dell7insGC (Exon7del),c.992A ＞ C (p.H331 P) and c.1091-2A ＞ G (Exon 9del).CYP4V2 is responsible for oxidation of various substrates in the metabolic pathway,especially ω-hydroxylase activity towards ω-3 polyunsaturated fatty acids (PUFAs).CYP4V2 appears to be the only CYP4 memeber at significant levels in retinal cells,and it may be a prominent contributor to local metabolism of PUFAs,mainly DHA (C22:6n-3),in retinal cells.To understand and investigate the main mechanism of CYP4V2 gene mutation causing BCD is important in the study of genetic diagnosis and genetic management of BCD.This review summarized the current advance in the genetic mechanism of BCD and function of CYP4V2 gene,elucidated the substrate specificity and unraveled the biochemical pathways that may impact function of CYP4V2 in BCD patients.

Acetazolamide for Cystoid Macular Oedema in Bietti Crystalline Retinal Dystrophy

Bietti crystalline retinal dystrophy is a rare, inherited disorder whose hallmark is the presence of retinal crystal deposits associated with later chorioretinal degeneration. This condition may rarely be complicated by the development of cystoid macular oedema leading to rapid visual decline. Currently, treatment options for this complication of Bietti dystrophy are limited and the visual prognosis is poor. Here, we present a case of cystoid macular oedema associated with Bietti dystrophy that was successfully diagnosed using multimodal imaging techniques including optical coherence tomography and fluorescein angiography. These modalities confirmed the diagnosis of macular oedema and excluded other possible causes of oedema such as choroidal neovascularisation. In this patient, cystoid macular oedema was resolved with oral acetazolamide therapy, a treatment that has not been previously reported in this context. Acetazolamide treatment resulted in oedema resolution and improvement in visual function, and can be considered a therapeutic option for other patients with Bietti dystrophy who develop cystoid macular oedema.

Ranibizumab for choroidal neovascular membrane in a rare case of Bietti's crystalline dystrophy: A case report.

We report a rare case of Bietti's crystalline dystrophy presenting with choroidal neovascular membrane (CNVM) which was treated with three injections of intravitreal ranibizumab. The CNVM underwent scarring after the injections with stabilization of visual acuity at a follow-up period of 12 months suggesting that intravitreal ranibizumab may have a role in the management of CNVM in these rare cases.

Two Female Siblings With Bietti Crystalline Retinopathy Without Corneal Dystrophy

PURPOSE: To report clinical and functional results in two female siblings with Bietti crystalline retinopathy. CASE SUMMARY: Recently, a 48-year-old female with bilateral intraretinal depositions presented with a complaint of decreased visual acuity and night blindness in both eyes. Several tiny glistening yellow intraretinal crystalline depositions were observed. Fluorescein angiography showed a well-demarcated choriocapillaris filling defect and pigment epithelial window defect. Electrophysiologic tests showed decreased amplitude and OCT scans showed fine intraretinal lesions with increased signal intensity. In addition, a 50-year-old female sibling presented with bilateral yellow, intraretinal crystalline depositions. A choriocapillaris filling defect and pigment epithelial window defect in a fluorescein angiography was observed. Electrophysiologic tests showed severely decreased amplitude. CONCLUSIONS: Two female siblings with Bietti crystalline retinopathy are reported.