Bietti Crystalline Dystrophy Patients Research Articles

Investigating Microperimetric Features in Bietti Crystalline Dystrophy Patients: A Cross-Sectional Longitudinal Study in a Large Cohort.

To assess the clinical and genetic characteristics of patients with Bietti crystalline dystrophy (BCD) with a focus on potential of microperimetry in monitoring macular function. A total of 208 genetically-confirmed BCD patients were enrolled in this retrospective study. The patients were categorized into subgroups based on their fundus characteristics (fovea sparing and fovea involved), optical coherence tomography (OCT) findings (presence/absence of retinal pigment epithelium [RPE] or ellipsoid zone [EZ] line at the fovea/parafovea), and genetic profiles (Mis/Mis, Tru/Mis, Tru/Tru). Fixation patterns were analyzed, and macular sensitivity (MS) parameters were compared among different groups. Longitudinal analysis was performed to calculate the annual changes in MS parameters. Correlation between genotype and phenotype were further investigated by analyzing cumulative incidence of vision impairment among different genotypic groups. Patients with well-preserved RPE or EZ at the foveal/parafoveal region exhibited higher MS. Notably, there was a decline in sensitivity parameters, with a decrease of -2.193dB/year (95% confidence interval [CI] -4.292 to -0.095, P = 0.041) at the fovea and -1.353dB/year (95% CI -2.047 to -0.659, P < 0.001) in average sensitivity. An age-adjusted comparison of sensitivity among genotypic groups and cumulative incidence analyses showed no association between genotypic groups and vision loss. Microperimetry proves to be one of a credible tool for detecting macular functional changes in BCD patients. BCD patients with different genotypes may have similar disease progression.

Targeted lipidomics uncovers oxylipin perturbations and potential circulation biomarkers in Bietti's crystalline dystrophy.

Abnormalities in lipid metabolism have been proposed in Bietti's crystalline dystrophy (BCD). We aim to characterize the lipid profiles in a case-control study. All participants were genetically confirmed by CYP4V2 gene sequencing and underwent chorioretinopathy evaluation by calculating the percentages of AF atrophy (PAFA). Fasting blood samples of BCD patients and controls were collected, and plasma was analyzed for routine lipid profiles. Targeted lipidomic evaluation includes long chain polyunsaturated fatty acids (LCPUFA) and associated eicosanoid metabolites. Routine lipids profiles showed elevated plasma levels of triglyceride (P = 0.043) and low-density lipoprotein cholesterol (P = 0.024) in BCD patients. Lipidomic analysis showed significantly decreased levels of ω-3 LCPUFA including docosahexaenoic acid (DHA, 22:6, P = 0.00068) and eicosapentaenoic acid (EPA, 20:5, P = 0.0016), as well as ω-6 LCPUFA arachidonic acid (ARA, 20:4, P < 0.0001) in BCD patients. Eicosanoid metabolites, either derived from ω-3 and/ or ω-6 LCPUFAs via cyclooxygenase (COX) or lipoxygenase (LOX) pathways, including 5-HEPE, 12-HEPE, 13-HDHA, 15-HETE, 12-HETE, 5-HETE, 6k-PGF1a, PGE2, PGJ2, and TXB2, exhibited significant differences (P < 0.0001) between BCD patients and controls. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites including 5-HETE, 5-HEPE, 12-HEPE and LTB4. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA), as well as their downstream metabolites via the COX and LOX pathways, suggesting that these might be implicated in BCD pathogenesis and could serve as biomarkers and therapeutic targets of the disease. What is known BCD is a vision-threatening hereditary disease the causative gene of which is CYP4V2. Abnormalities in lipid metabolism have been proposed and demonstrated previously in BCD studies. The detailed pathogenesis remains unclear and controversial. What is new We observed prominent lipidomic alterations in the circulation when compared with age, gender, and bodymass index (BMI)-matched healthy controls. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA). Remarkable changes were observed in the downstream metabolites of the LCPUFA via the COX and LOX pathways. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites.

Outer retinal tubulation in Bietti crystalline dystrophy associated with the retinal pigment epithelium atrophy.

To determine the prognostic value of outer retinal tubulation (ORT) in the eyes of a Chinese cohort with Bietti crystalline dystrophy (BCD). This retrospective, multicenter cohort study enrolled forty-two patients with clinically and genetically diagnosed BCD. Eighty eyes with good-quality images of spectral domain optical coherence tomography (SD-OCT) were included. Demographic details and clinical data were collected. The characteristics of ORT, including prevalence, location and morphologic characteristics were analyzed. Forty-two BCD patients harbored potentially CYP4V2 disease-causing mutations. The mutation spectrum comprised 17 unique variants, nine of which were novel. Fifty-two of these 80 eyes demonstrated evidence of ORT. The incidence of ORT is significantly higher in stage 2 than other stages (P<0.001). ORT was mainly bilateral and located at margin of the atrophic area of retinal pigmental epithelial (RPE), and dynamically changed with the progressive RPE atrophy. The process of RPE atrophy was slower in eyes with ORT (P=0.017), with significantly longer intact RPE width in stage 3 (P=0.024). Eyes with ORT had slower vision loss than eyes without ORT (P=0.044). ORT may be a sign of the onset of RPE atrophy in early-stage BCD and may suggest less risk of rapid progression in late-stage BCD.

Vessel density and choroidal vascularity index in patients with Bietti crystalline dystrophy and retinitis pigmentosa

ObjectiveTo evaluate and compare the vessel density (VD) using swept-source optical coherence tomography angiography (OCT-A) and the choroidal vascularity index (CVI) using spectral-domain optical coherence tomography (SD-OCT) in patients with Bietti crystalline dystrophy (BCD) and retinitis pigmentosa (RP). Materials and methodsA cross-sectional retrospective study was conducted on 26 eyes of 13 BCD patients, 26 eyes of 13 RP patients, and 26 eyes of 13 age- and gender-matched healthy individuals. BCD patients were further staged as having early, intermediate, and advanced disease. VD was assessed in five quadrants of the macula (superior, temporal, inferior, nasal, and center) using a modified ETDRS technique with OCT-A. SD-OCT scans were binarized using Niblack's autolocal threshold, and CVI was determined as the ratio of the luminal area to the total choroidal area. ResultsA significant difference was found in VD in all quadrants of the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) slabs among the three groups (p < 0.001). A statistically significant difference was noted in the mean VD of temporal and inferior quadrants of the SCP and between the BCD and RP groups (p = 0.005, p = 0.015, respectively). A statistically significant difference was observed in the mean VD of the temporal, inferior, and nasal quadrants between the BCD and RP groups on DCP slabs (p = 0.002, p = 0.003, p = 0.003, respectively). The mean central choroidal thickness was 214.65±87.10 μm in the BCD group, 351.69±67.94 μm in the RP group, and 320.92±59.26 μm in the control group (p < 0.001). We found that CVI was significantly higher in the control group than BCD group (p < 0.001), and it was significantly lower in the BCD group when compared to the RP group (p < 0.001).There was no difference in CVI between RP and control groups (p = 0.948). Furthermore, the CVI was significantly lower in the intermediate and advanced disease stages than the early disease stage in the subgroup analysis of BCD patients (p < 0.001, p < 0.001, respectively). ConclusionCVI is a novel investigative tool to monitor disease progression. The CVI value was lower in BCD and RP patients than in the healthy subjects, and lower CVI values seem to be related to the disease severity in BCD patients. VD was also significantly lower in BCD patients when compared to RP patients, and VD analysis may help clinicians better understand the disease pathophysiology.

Multimodal Imaging Observation in Different Progressive Types of Bietti Crystalline Dystrophy.

Objective The aim of the study is to observe the difference in progression between type 1 and type 2 Bietti crystalline dystrophy (BCD) using multimodal imaging. Methods A retrospective clinical study was performed with six BCD patients who underwent multimodal imaging twice in Hebei Provincial Eye Hospital from October 2015 to December 2020. Multimodal imaging includes color fundus photography, fundus autofluorescence (AF), infrared autofluorescence (IRAF), fundus fluorescein angiography (FFA), and spectral domain optical coherence tomography (SD-OCT). The fundus lesion progression difference was observed in 3 patients with type 1 BCD and 3 patients with type 2 BCD. Results In type 1 BCD, the range of hypoautofluorescence (hypo-AF), hypoinfrared autofluorescence (hypo-IRAF), and hypofluorescence in the posterior pole was enlarged, and FFA showed that the lesions in the posterior pole and periphery extended to the middle periphery. SD-OCT revealed retinal and choroidal thinning, progressive loss of the outer nuclear layer and ellipsoid zone, and reduction of the choroid macrovascular diameter. In type 2 BCD, the range of hypo-AF was enlarged, but there was no significant change in the macula area. The uniform hypo-IRAF in the posterior pole showed no significant change. FFA showed no significant change with the progression of the disease in the macula area and the hypofluorescence around it expanded. SD-OCT revealed no obvious change in the macula area. Conclusions The retinal choroid atrophy in the macula area of type 1 BCD continued to worsen, and the choroid great vessels became narrower. The macular lesions of type 2 BCD can remain unchanged for a long time.

Treating Bietti crystalline dystrophy in a high-fat diet-exacerbated murine model using gene therapy.

Lipid metabolic deficiencies are associated with many genetic disorders. Bietti crystalline dystrophy (BCD), a blindness-causing inherited disorder with changed lipid profiles, is more common in Chinese and Japanese than other populations. Our results reveal that mouse models lacking Cyp4v3 have less physiological and functional changes than those of BCD patients with this gene defect. After the administration of a high-fat diet (HFD), the occurrence of retinal lesions were both accelerated and aggregated in the Cyp4v3-/- mouse models, implying that changed lipid levels were not only associated factors but also risk factors to BCD patients. Facilitated by the results, we found that the reduced electroretinography waveforms and retinal thickness observed in the HFD-induced mouse models were effectively recovered after subretinal delivery of a human CYP4V2 gene carried by an adeno-associated virus vector, which demonstrates the potential curability of BCD by gene therapy.

Multimodal Imaging for Differential Diagnosis of Bietti Crystalline Dystrophy

To evaluate the diagnostic usefulness of multimodal imaging in patients with Bietti crystalline dystrophy (BCD). Retrospective cross-sectional study. Patients with chorioretinal dystrophy accompanied by crystalline-like deposits. The right eyes of the patients were analyzed. Fundus photograph, near-infrared reflectance (NIR), fundus autofluorescence (FAF), and OCT images were evaluated. Presence of hyperreflectivity on NIR, well-demarcated areas of decreased FAF, hyperreflective material at or on the retinal pigment epithelium-Bruch's membrane complex, and outer retinal tubulation were graded for each patient. All exons and franking introns of CYP4V2 were screened using Sanger sequencing. Sensitivity and specificity of the findings to discriminate patients with and without CYP4V2 mutation. In total, 33 patients were included in the study. Sanger sequencing revealed homozygous or compound heterozygous CYP4V2 mutations in 20 patients and heterozygous mutations in 2 patients. Among the investigated factors, hyperreflective appearance on NIR imaging yielded 100% sensitivity and 100% specificity in this cohort. The presence of outer retinal tubulation also was sensitive (95%), but specificity was moderate (45%). The revised diagnoses of patients without CYP4V2 mutations included retinitis pigmentosa, late-onset macular dystrophy, and central areolar choroidal dystrophy. Multimodal imaging, especially NIR imaging, is useful to differentiate BCD patients with CYP4V2 mutations from patients with other chorioretinal dystrophies accompanied by crystalline-like retinal deposits.

Whole Exome Sequencing in Eight Thai Patients With Leber Congenital Amaurosis Reveals Mutations in the CTNNA1 and CYP4V2 Genes.

Our goal was to describe the clinical and molecular genetic findings in Thai patients with Leber congenital amaurosis (LCA). Whole exome sequencing (WES) was performed in eight unrelated patients. All genes responsible for inherited retinal diseases (IRDs) based on RetNet were selected for analysis. Potentially causative variants were filtered through a bioinformatics pipeline and validated using Sanger sequencing. Segregation analysis of the causative genes was performed in family members when available. Eleven deleterious variants, six nonsense and five missense, were identified in seven genes: four LCA-associated genes (CEP290, IQCB1, NMNAT1, and RPGRIP1), one gene responsible for syndromic LCA (ALMS1), and two IRDs-related genes (CTNNA1 and CYP4V2). Clinical reassessment supported the diagnosis of syndromic LCA in those patients harboring potentially pathogenic variants in the ALMS1. Interestingly, two causative genes, CTNNA1 and CYP4V2, previously reported to cause butterfly-shaped pigment dystrophy (BSPD) and Bietti's crystalline dystrophy (BCD), respectively, were detected in two other patients. These two patients developed rapid and severe visual loss in contrast to BSPD and BCD patients in previous studies. The results of this study demonstrate that causative variants identified in the CTNNA1 and CYP4V2 genes are also associated with LCA. This is the first report describing the molecular genetics and clinical manifestations of Thai patients with LCA. The present study expands the spectrum of LCA-associated genes, which is a benefit for molecular diagnosis. The identification of mutations in the CTNNA1 and CYP4V2 genes requires further elucidation in larger cohorts with LCA.

Evaluation of Photoreceptors in Bietti Crystalline Dystrophy with CYP4V2 Mutations Using Adaptive Optics Scanning Laser Ophthalmoscopy

To evaluate photoreceptors in Bietti crystalline dystrophy patients with CYP4V2 mutations using high-resolution images of the macula obtained with adaptive optics scanning laser ophthalmoscopy (AO-SLO). Prospective observational case series with comparison to healthy controls. Seven eyes of 7 Bietti crystalline dystrophy patients with CYP4V2 mutations and 12 normal eyes of 12 age- and axial length-matched healthy volunteers were studied. All participants underwent ophthalmologic examinations and AO-SLO assessments. All patients underwent spectral-domain optical coherence tomography, fundus autofluorescence, Humphrey field analysis, and electroretinography. AO-SLO images were analyzed 0.5 mm and 1.0 mm from the center of the fovea in the superior, inferior, nasal, and temporal quadrants. Mean ± standard deviation cone density (cells/mm(2)) 0.5 mm from the center of the fovea was 17,209 ± 2276 in patients and 20 493 ± 2758 in controls, which was statistically different (P = .001); however, mean cone density 1.0 mm from the center of the fovea was 15 685 ± 2302 in patients and 15 705 ± 1848 in controls, which was not statistically different (P = .20). There was no correlation between cone density and mean deviation measured using a Humphrey field analysis or visual acuity in patients. In Bietti crystalline dystrophy patients with CYP4V2 mutations, cone density remained for visual dysfunction by evaluation using high-resolution AO-SLO. These findings support the theory that disorder of the retinal pigment epithelium and the photoreceptors in the patients are the primary and secondary pathologic changes, respectively. This is consistent with results from previous basic studies.

Novel insights into the molecular pathogenesis of CYP4V2-associated Bietti's retinal dystrophy.

Bietti's crystalline dystrophy (BCD) is a rare, autosomal recessive retinal degenerative disease associated with mutations in CYP4V2. In this study, we describe the genetic and clinical findings in 19 unrelated BCD patients recruited from five international retinal dystrophy clinics. Patients underwent ophthalmic examinations and were screened for CYP4V2 mutations by Sanger sequencing and quantitative polymerase chain reaction (qPCR) copy number variation screening. Eight CYP4V2 mutations were found in 10/19 patients, including three patients in whom only monoallelic mutations were detected. Four novel mutations were identified: c.604G>A; p.(Glu202Lys), c.242C>G; p.(Thr81Arg), c.604+4A>G; p.(?), and c.1249dup; p.(Thr417Asnfs*2). In addition, we identified a heterozygous paternally inherited genomic deletion of at least 3.8 Mb, encompassing the complete CYP4V2 gene and several other genes, which is novel. Clinically, patients demonstrated phenotypic variability, predominantly showing choroidal sclerosis, attenuated vessels, and crystalline deposits of varying degrees of severity. To our knowledge, our study reports the first heterozygous CYP4V2 deletion and hence a novel mutational mechanism underlying BCD. Our results emphasize the importance of copy number screening in BCD. Finally, the identification of CYP4V2-negative patients with indistinguishable phenotypes from CYP4V2-positive patients might suggest the presence of mutations outside the coding regions of CYP4V2, or locus heterogeneity, which is unreported so far.

The characterization of functional disturbances in Chinese patients with Bietti’s crystalline dystrophy at different fundus stages

The aim of this study was to characterize the functional and clinical disturbances and screen the optimal functional tests in assessing Bietti's crystalline dystrophy (BCD) patients by a cross-sectional method. The clinical characteristics of BCD were studied in 15 Chinese patients using fundoscopy, fundus fluorescein angiography (FFA), and autofluorescence (AF). The functional features were evaluated by full-field electroretinography (fERG), 85º and 30º perimetry, multifocal ERG (mERG), and chromatic pupillometry. The 15 patients were separated into three clinical stages according to their fundus features. fERG- and mERG- showed reduced reponses in the early stages. Substages could be further defined according to the fERG results in the intermediate stages. Reduced pupillary light reflex (PLR) activities with blue-and white-light stumili existed in all patients. The most reduced PLR activities were elicited in the advanced stage of patients who had other nonresponsive functional tests. This study identified the most sensitive functional methods for assessing BCD patients, and the significance of PLR in the advanced stages. In addition, the defined-substages can help us understand the disease more clearly.

Genotype–Phenotype Analysis of Bietti’s Crystalline Dystrophy in Patients withCYP4V2Mutations

To evaluate the genotypic and phenotypic correlations of Bietti's crystalline dystrophy (BCD) in patients with the CYP4V2 gene by mutation screening and clinical and electrophysiological assessment. Eighteen Chinese patients in 13 families with BCD were recruited for full ophthalmic examinations, optical coherence tomography (OCT), and visual electrophysiological tests, including electrooculography (EOG), full-field electroretinography (ERG), and multifocal electroretinography (mfERG). Peripheral venous blood was obtained from all index patients and their family members for genomic DNA extraction and CYP4V2 sequence screening by direct sequencing. All 18 patients with BCD had mutations in the CYP4V2 gene: five were novel (Y219H, W244X, D324V, P396L, and R400C) and four had been reported. A common mutation occurred at the splice site IVS6-8del17bp/insGC of 12 patients, four being homozygous. OCT showed the presence of intraretinal crystals in all patients. Patients with more severe thinning of the retina had worse visual acuity, and there was moderate correlation between the OCT central foveal thickness and visual acuity (Spearman rho = 0.46, P = 0.005). Patients with splice site mutations (i.e., homozygous IVS6-8del17bp/insGC or compound heterozygous IVS6-8del17bp/insGC and IVS8-2A>G) had lower EOG Arden index (P = 0.014) and were more likely to have a nonrecordable scotopic full-field ERG (P = 0.003) and nonrecordable 30-Hz flicker ERG (P = 0.043). BCD patients with homozygous IVS6-8del17bp/insGC or compound heterozygous IVS6-8del17bp/insGC and IVS8-2A>G mutations appeared to have more severe disease phenotype based on electrophysiological testing. The level of visual loss in BCD is related to the severity of retinal thinning.

Characterization of Bietti Crystalline Dystrophy Patients withCYP4V2Mutations

Mutations of the CYP4V2 gene, a novel family member of the cytochrome P450 genes on chromosome 4q35, have recently been identified in patients with Bietti crystalline dystrophy (BCD). The aim of this study was to investigate the spectrum of mutations in this gene in BCD patients from Singapore, and to characterize their phenotype. Nine patients with BCD from six families were recruited into the study. The 11 exons of the CYP4V2 gene were amplified from genomic DNA of patients by polymerase chain reaction and then sequenced. Detailed characterization of the patients' phenotype was performed with fundal photography, visual field testing, fundal fluorescein angiography, and electroretinography (ERG). Three pathogenic mutations were identified; two mutations, S482X and K386T, were novel and found in three patients. The third mutation, a previously identified 15-bp deletion that included the 3' splice site for exon 7, was found in all nine patients, with six patients carrying the deletion in the homozygous state. Haplotype analysis in patients and controls indicated a founder effect for this deletion mutation in exon 7. Clinical heterogeneity was present in the patients. Compound heterozygotes for the deletion in exon 7 seemed to have more severe disease compared to patients homozygous for the deletion. There was good correlation between clinical stage of disease and ERG changes, but age did not correlate with disease severity. This study identified novel mutations in the CYP4V2 gene as a cause of BCD. A high carrier frequency for the 15-bp deletion in exon 7 may exist in the Singapore population. Phenotype characterization showed clinical heterogeneity, and age did not correlate with disease severity.