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.

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.

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.

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.