Clinical analysis of eye movement-based data in the medical diagnosis of amblyopia.

Amblyopia is an abnormal visual processing-induced developmental disorder of the central nervous system that affects static and dynamic vision, as well as binocular visual function. Currently, changes in static vision in one eye are the gold standard for amblyopia diagnosis. However, there have been few comprehensive analyses of changes in dynamic vision, especially eye movement, among children with amblyopia. Here, we proposed an optimization scheme involving a video eye tracker combined with an "artificial eye" for comprehensive examination of eye movement in children with amblyopia; we sought to improve the diagnostic criteria for amblyopia and provide theoretical support for practical treatment. The resulting eye movement data were used to construct a deep learning approach for diagnostic and predictive applications. Through efforts to manage the uncooperativeness of children with strabismus who could not complete the eye movement assessment, this study quantitatively and objectively assessed the clinical implications of eye movement characteristics in children with amblyopia. Our results indicated that an amblyopic eye is always in a state of adjustment, and thus is not "lazy." Additionally, we found that the eye movement parameters of amblyopic eyes and eyes with normal vision are significantly different. Finally, we identified eye movement parameters that can be used to supplement and optimize the diagnostic criteria for amblyopia, providing a diagnostic basis for evaluation of binocular visual function.

Clinical and genetic studies for a cohort of patients with Leber congenital amaurosis.

PURPOSE: Leber congenital amaurosis (LCA) is a group of early-onset retinal degenerative disorders, resulting in blindness in children. This study aimed to describe the clinical and genetic characteristics of a cohort of patients with LCA and to investigate the retinal vascular characteristics in LCA patients. METHODS: Fifty-two children with LCA were included in the study. All patients underwent detailed ocular examinations. Electroretinography (ERG) was used to evaluate the retinal function. Optical coherence tomography (OCT) was used to assess the structure change of the retina for those patients who were able to cooperate very well. Panel-based next-generation sequencing was performed to identify pathogenic variants in genes associated with LCA. Diameters of the retinal vessels were measured using the EVision AI screening system with an artificial intelligence (AI) technique. An ultrasound Doppler was used to evaluate hemodynamic parameters, including peak systolic velocity (PSV), resistive index (RI), and pulsatility index (PI), in the ophthalmic, central retinal, posterior ciliary, carotid, and internal carotid as well as external carotid arteries in 12 patients aged from 3 to 14 years. RESULTS: We detected 75 pathogenic variants from ten genes of RPGRIP1, CEP290, GUCY2D, LCA5, AIPL1, CRB1, RPE65, CRX, RDH12, and TULP1, including 29 novel and 36 previously reported variants in 52 affected children with LCA, with the highest detective rate in RPGRIP1 (26.9%). Fundus appearance is diverse in patients with LCA, ranging from normal to severe peripheral or central retinopathy. Retinal vasculature was evaluated in 12 patients with different gene variants, showing narrowed arteries with an average diameter of 43.6 ± 3.8 µm compared to that of 51.7 ± 2.6 µm in the normal controls (P < 0.001, n = 12). Meanwhile, their hemodynamic parameters were changed as well in the ophthalmic artery (OA), with a decreased PSV (P = 0.0132, n = 12) and slightly increased PI (P = 0.0488, n = 12) compared to the normal controls. However, the hemodynamic parameters did not change significantly in the other vessels. CONCLUSIONS: Blood supply to the eyeball is predicted to be reduced in patients with LCA, presumably due to photoreceptor cell degeneration. The novel identified variants will expand the spectrum of variants in LCA-related genes and be useful for studying the molecular mechanisms of LCA.

Analyses of eye movement parameters in children with anisometropic amblyopia.

OBJECTIVE: To investigate the characteristics of eye movement in children with anisometropic amblyopia, and to compare those characteristics with eye movement in a control group. METHODS: 31 children in the anisometropic amblyopia group (31 amblyopic eyes in group A, 31 contralateral eyes in group B) and 24 children in the control group (48 eyes in group C). Group A was subdivided into groups Aa (severe amblyopia) and Ab (mild-moderate amblyopia). The overall age range was 6-12 years (mean, 7.83 ± 1.79 years). All children underwent ophthalmic examinations; eye movement parameters including saccade latency and amplitude were evaluated using an Eyelink1000 eye tracker. Data Viewer and MATLAB software were used for data analysis. RESULTS: Mean and maximum saccade latencies, as well as mean and maximum saccade amplitudes, were significantly greater in group A than in groups B and C before and after treatment (P < 0.05). Mean and maximum saccade latencies were significantly different among groups Aa, Ab, and C (P < 0.05). Pupil trajectories in two detection modes suggested that binocular fixation was better than monocular fixation. CONCLUSIONS: Eye movement parameters significantly differed between contralateral normal eyes and control eyes. Clinical evaluation of children with anisometropic amblyopia should not focus only on static visual acuity, but also on the assessment of eye movement.

Thicknesses of the retina and choroid in children with retinitis pigmentosa.

PURPOSE: To compare the retinal thicknesses (RT) and choroidal thicknesses (CT) in retinitis pigmentosa (RP) children with those of healthy children using enhanced depth imaging (EDI) optical coherence tomography (OCT). The RT and CT in different genetic subgroups of autosomal dominant RP (ADRP) and X-linked inheritance RP (XLRP) were further studied to investigate the characteristics of retinal and choroidal changes in the early stages of RP. METHOD: A retrospective analysis was performed on a group of patients with RP who underwent EDI-OCT. Thirty-two children (64 eyes) with RP and 28 age- and refraction-matched healthy children (56 eyes) were included in the study. Seven of the 32 RP children (14 eyes) had X-linked inheritance RP, and 10 (20 eyes) had autosomal dominant inheritance RP. RT and CT were measured by optical coherence tomography and compared between the 32 children with RP and 28 controls and between 7 XLRP and 10 ADRP children. RESULT: Among the 32 children with RP, there were 18 males and 14 females with an average age of 6.6 ± 2.4 years. The mean RT was smaller in the RP group than in the control group at all of the locations. The mean temporal CT was smaller in the RP group (243.76 ± 60.82 µm) than in the control group (275.23 ± 40.92 µm) (P = 0.001), while there was no significant thinning on the foveal or nasal side. The best-corrected visual acuity of the XLRP group (0.40 ± 0.19) was worse than that of the ADRP group (0.68 ± 0.21) (P = 0.001), but the disease duration was the same (P = 0.685). The mean foveal RT was smaller in the XLRP group (173.85 ± 22.87 µm) than in the ADRP group (192.20 ± 9.70 µm) (P = 0.003), while there was no significant thinning at the other locations we studied. The mean temporal CT was smaller in the XLRP group (211.21 ± 69.41 µm) than in the ADRP group (274.45 ± 57.91 µm) (P = 0.007); CT measurements in XLRP children showed a more severe reduction on the temporal side. CONCLUSION: The choroid in RP children was preferentially smaller on the temporal side of the macula, and retinal thinning was relatively extensive. Children with RP have strong clinical and genetic heterogeneity. The XLRP children demonstrated greater RT reduction at the fovea and greater CT reduction at the temporal side of the macula than the ADRP children. Our findings also provide evidence that the changes in thicknesses may be indicative of the greater severity of XLRP versus ADRP in the early stage.

Clinical and genetic studies of 17 Han Chinese pedigrees and 31 sporadic patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

Purpose: To investigate the molecular pathogenesis of a large group of Han Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), and to evaluate the correlation between the phenotype and genotype for these patients. Methods: Seventy-six affected individuals, including 45 patients from 17 pedigrees and 31 sporadic patients, were recruited with their family members. All participants underwent complete clinical examinations and were classified as having type I or II based on whether they had premature ovarian failure. The patients' genomic DNA was extracted. A genetic test was performed with direct sequencing of the coding regions of the forkhead transcriptional factor 2 (FOXL2) gene. Variations were analyzed using online databases and programs. Genotype-phenotype correction was investigated. Results: Seventy-six affected and 75 unaffected individuals underwent clinical evaluations and genetic testing. Only one family was diagnosed with type I; the others could not be classified because of a lack of female patients or a definite history of premature ovarian failure. Twenty-seven variations were identified, including 12 novel and 15 previously reported variations. Six variations were detected repeatedly in different nonconsanguineous pedigrees. Four indel variations, located in the alanine/proline-rich region of the FOXL2 gene, presented with a relatively higher frequency. Two rare double variations were detected in two sporadic patients. FOXL2 gene variations were not detected in five sporadic patients. The phenotype varied among different families and patients, although they carried the same variations. Conclusions: We identified 12 novel variations in the FOXL2 gene that would expand the spectrum of the FOXL2 variation database. In addition, we found that the alanine/proline-rich region is a variation hotspot in the FOXL2 gene. The genotype-phenotype correlation is not easy to establish due to clinical and genetic heterogeneity.

Augmented lateral rectus muscle recession for treatment of infantile exotropia.

BACKGROUND: The surgical outcome is usually not satisfactory for treatment of primary infantile exotropia (PIE) with large exodeviation angels of more than 50 prism diopters (PD). Here, we evaluate the effectiveness of augmented bilateral lateral rectus muscle recession (ABLRR) in treatment of PIE with large deviation angles. METHODS: A retrospective analysis was performed for 25 patients with PIE who underwent ABLRR. ABLRR was performed using a hemi-hang-back technique. Ocular alignment, ocular motility and binocular vision were evaluated pre- and postoperatively. RESULTS: Fourteen males and 11 females with PIE were included in this study, with a mean age of (3.92 ± 2.02) years (range, 1-7 years). The average exodeviation angle was (-66.32 ± 7.84) PD (range, -60--80 PD) preoperatively. All patients underwent ABLRR using the hemi-hang-back technique. Three of them underwent bilateral inferior oblique muscle anterior transposition in the same operation. The mean surgical dosage was (11.08 ± 1.19) mm for each lateral rectus muscle. The mean of deviation angel was -2.28 ± 5.08 PD postoperatively (P < 0.05). All patients did not have abduction deficiency after a large amount of lateral rectus recession. Twenty-one of 25 patients (84.0%) achieved orthophoria at the primary gaze position at the final visit, and 13 patients obtained binocular vision. CONCLUSIONS: ABLRR is an effective and safe surgical procedure for treatment of PIE with a large deviation angle.

A randomized trial evaluating efficacy of overminus lenses combined with prism in the children with intermittent exotropia.

BACKGROUND: To evaluate the efficacy of overminus lenses combined with prism spectacles in children of 3 to 6 years of age with intermittent exotropia (IXT). METHODS: Sixty patients with IXT were randomly assigned to the treatment and observation groups. Each group included 30 IXT children aged 3 to 6 years. The treatment group was prescribed overminus lenses of - 2.50 D incorporated with the 2 PD base-in prisms on each side. Ocular alignment, the status of binocular vision, as well as the refraction changes were carried out and followed at 1, 3, 6, and 12 months. A revised form of the Newcastle Control Score (NCS) was used to evaluate the patients' ability to control their IXT. RESULTS: After 12 months, the mean refractive error was 1.42 ± 1.25 D, and 1.43 ± 1.12 D for the observation and the treatment group, respectively (95% CI: - 0.61 to 0.62)); the mean exotropia control score was 5.72 ± 1.28 and 1.75 ± 1.18 in the observation and the treatment group, respectively (95% CI: - 4.63 to - 3.33); the mean near stereoacuity was 2.16 ± 0.42 log arcsec and 1.91 ± 0.26 log arcsec in the observation and the treatment group, respectively (95% CI: - 0.44 to - 0.06). CONCLUSIONS: In our randomized clinical trial, overminus spectacles with prism significantly improved the control of IXT and stereopsis, by reducing the angle of strabismus in children with IXT. This treatment does not appear to cause myopia, at least in the manner used this series. A further randomized trial is warranted to assess the effect of overminus spectacles with prism after the treatment has been discontinued. TRIAL REGISTRATION: This study adheres to CONSORT 2010 guidelines. Chinese Clinical Trial Registry, ChiCTR1900025243 . Registered 17 August 2019.

Evaluation of the iris thickness changes for the Chinese families with GPR143 gene mutations.

PURPOSE: Pathogenic variants of the G-protein coupled receptor 143 (GPR143) gene may result in Ocular albinism type I (OA1). In this study, we describe the clinical features and investigate the GPR143 gene mutations in six Chinese families with OA1 and evaluate the thickness changes of iris for the affected males and female carriers. METHODS: Families were ascertained, and patients underwent complete ophthalmologic examinations, including the best corrected visual acuity (BCVA), anterior segment of the eyes, vitreous and fundus changes. Spectral domain optical coherence tomography (SD-OCT) was used to measure the full iris thickness, the stroma/anterior border (SAB) layer, and the posterior epithelial layer (PEL) at the pupillary and ciliary regions. DNA was extracted from the peripheral blood vessels after confirmed consent information. GPR143 gene was directly sequenced by the Sanger method. RESULTS: The affected males had variable reduced visual acuity, nystagmus and macular hypoplasia. Four novel frameshift mutations and two previously reported missense/nonsense mutations in the GPR143 gene were detected in these families. The thickness of the iris was significantly reduced at the ciliary region in the affected males, compared with that in the normal controls and the female carriers. CONCLUSIONS: Pathogenic variants in the GPR143 gene may disturb the normal melanogenesis in the pigmented tissues of the eye, result in macular hypoplasia, and alter the thickness of the iris.

Differences of ocular oscillations and neuro-retinal structures in patients with nystagmus caused by GPR143 and FRMD7 gene variants.

PURPOSE: Mutations of G protein-coupled receptor 143 (GPR143) and FERM domain containing 7 (FRMD7) may result in congenital nystagmus (CN) in the first 6 months of life. We aimed to compare the differences in ocular oscillations between patients with these two gene mutations as well as the functional and structural changes in their retinas and visual pathways. METHODS: Medical records were retrospectively reviewed to identify patients of congenital nystagmus with confirmed mutations in either GPR143 or FMRD7 genes from January 2018 to May 2023. The parameters of the ocular oscillations were recorded using Eyelink 1000 Plus. The retinal structure and function were evaluated using optical coherence tomography and multi-focal electroretinography (mERG). The visual pathway and optical nerve projection were evaluated using visual evoked potentials. The next-generation sequencing technique was used to identify the pathogenic variations in the disease-causing genes for CN. RESULTS: Twenty nystagmus patients of GPR143 and 21 patients of FMRD7 who had been confirmed by molecular testing between January 2018 and May 2023 were included. Foveal hypoplasia was detected only in patients with the GPR143 pathogenic variant. mERG examination showed a flat response topography in the GPR143 group compared to the FRMD7 group. VEP showed that bilateral amplitude inconsistency was detected only in the patients with GPR143 gene mutation. The amplitude and frequency of the ocular oscillations were not found to differ between patients with two different genetic mutations. CONCLUSIONS: Although the etiology and molecular mechanisms are completely different between CN patients, they may have similar ocular oscillations. A careful clinical examination and electrophysiological test will be helpful in making a differential diagnosis. Our novel identified variants will further expand the spectrum of the GPR143 and FRMD7 variants.

Effect of graded partial inferior rectus muscle tenotomy in treatment for superior oblique paralysis.

PURPOSE: To evaluate the surgical outcomes for patients with superior oblique paralysis (SOP) who underwent the inferior oblique weakening and the graded partial inferior rectus muscle tenotomy in the contralateral eye. METHODS: Medical records were retrospectively reviewed for those SOP patients who had hyperdeviation of 4△ -20△ in the primary position and 8△ -25△ in the downgaze position. Patients were subdivided into three subgroups according to their vertical deviation angle in the downgaze position. They underwent an ipsilateral inferior oblique muscle recession and a graded partial tenotomy of the contralateral inferior rectus muscle. The vertical deviation angles, abnormal head position, and fundus torsion were compared statistically before and after operations. All patients were followed up at least 1 year. RESULTS: Forty-seven patients were included in this study. The mean follow-up period was 17.2 months after surgery (ranging from 12 to 28 months). The vertical deviation angle was averaged preoperatively to 7.74△ ± 3.23△ in the primary position and 15.30△ ± 5.92△ in the downgaze position and reduced postoperatively to 0.85△ ± 1.15△ in the primary position and 1.53△± 1.49△ in the downgaze position (P < 0.001). All patients had an abnormal head position preoperatively and had improved significantly postoperatively. Fundus extorsion had been improved significantly postoperatively. CONCLUSION: The surgical procedure of IO weakening combined with contralateral graded partial inferior rectus muscle tenotomy is a successful intervention for the correction of small deviation in primary position of SOP.

Clinical and genetic studies for a cohort of patients with congenital stationary night blindness.

BACKGROUND: Congenital stationary night blindness (CSNB) is an inherited retinal disorder. Most of patients have myopia. This study aims to describe the clinical and genetic characteristics of fifty-nine patients with CSNB and investigate myopic progression under genetic cause. RESULTS: Sixty-five variants were detected in the 59 CSNB patients, including 32 novel and 33 reported variants. The most frequently involved genes were NYX, CACNA1F, and TRPM1. Myopia (96.61%, 57/59) was the most common clinical finding, followed by nystagmus (62.71%, 37/59), strabismus (52.54%, 31/59), and nyctalopia (49.15%, 29/59). An average SE of -7.73 ± 3.37 D progressed to -9.14 ± 2.09 D in NYX patients with myopia, from - 2.24 ± 1.53 D to -4.42 ± 1.43 D in those with CACNA1F, and from - 5.21 ± 2.89 D to -9.24 ± 3.16 D in those with TRPM1 during the 3-year follow-up; the TRPM1 group showed the most rapid progression. CONCLUSIONS: High myopia and strabismus are distinct clinical features of CSNB that are helpful for diagnosis. The novel variants identified in this study will further expand the knowledge of variants in CSNB and help explore the molecular mechanisms of CSNB.

Novel pathogenic variants of SLC38A8 gene and literature review.

PURPOSE: This study aimed to analyze the clinical and genetic characteristics of 6 Chinese patients with foveal hypoplasia (FH) caused by the variants of solute carrier family 38 member 8 (SLC38A8), and to describe the genotype and phenotype of SLC38A8 variants from previous literature. METHODS: All subjects underwent comprehensive ophthalmic examinations. Optical coherence tomography (OCT) was performed to evaluate the structural grade of FH. Pathogenic variants of SLC38A8 gene were identified using panel-based next-generation sequencing and direct Sanger sequencing techniques. Further, all previously reported cases of SLC38A8 variants were re-analyzed together with the novel ones identified in this study. RESULTS: Nystagmus and FH were present in 6 patients with variants of SLC38A8 gene, accompanied by a normal anterior segment. Grade 4 FH was identified in 4 patients. A total of 12 variants of SLC38A8 gene were identified, including 9 novel variants. Systematical analysis revealed that half of the variants (30/60) were missense, the majority of which (23/30) were distributed in the transmembrane (TM) domains. Grade 4 FH was detected in the majority of patients (66%, 23/35). There was no statistical difference in the clinical features between the subgroups of patients with 0, 1 and 2 missense variants. CONCLUSION: Severe arrest of foveal development was identified in patients with variants of SLC38A8. This study provides a brief summary of the clinical and genetic characteristics of the pathogenic SLC38A8 variants, which is helpful in the differentiation diagnosis of FH.

Clinical and Molecular Characterization of AIPL1-Associated Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy.

PURPOSE: This study aimed to characterize the clinical features, genetic findings, and genotype-phenotype correlations of patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD) harboring biallelic AIPL1 pathogenic variants. DESIGN: Retrospective case series. METHODS: This study consecutively enrolled 51 patients from 47 families with a clinical diagnosis of LCA/EOSRD harboring disease-causing variants in the AIPL1 gene, from October 2021 to September 2023. Molecular genetic findings, medical history, and ophthalmic evaluation including visual acuity (VA), multimodal retinal imaging, and electrophysiologic assessment were reviewed. RESULTS: Of the 51 patients (32 with LCA and 19 with EOSRD), 27 (53%) were females, and age at last review ranged from 0.5 to 58.4 years. We identified 28 disease-causing AIPL1 variants, with 18 being novel. In patients with EOSRD, the mean (range) VA was 1.3 (0.7-2.7) logMAR and 1.3 (0.5-2.3) logMAR for right and left eyes respectively, with an average annual decline of 0.03 logMAR (R2 = 0.7547, P < .01). For patients with LCA, the VA ranged from light perception to counting fingers. Optical coherence tomography imaging demonstrated preservation of foveal ellipsoid zone in the 5 youngest EOSRD patients and 9 LCA children. Electroretinography showed severe cone-rod patterns in 78.6% (11/14) of patients with EOSRD, while classical extinguished pattern was documented in all patients with LCA available for the examination. The most common mutation was the nonsense variants of c.421C>T, with an allele frequency of 53.9%. All patients with EOSRD carried at least one missense mutation, of whom 13 identified with c.152A>G and 5 with c.572T>C. Twenty-six patients with LCA harbored two null AIPL1 variants, while 18 were homozygous for c.421C>T and 6 were heterozygous for c.421C>T with another loss-of-function variant. CONCLUSIONS: This study reveals distinct clinical features and variation spectrum between AIPL1-associated LCA and EOSRD. Patients harboring at least one nonnull mutation, especially c.152A>G and c.572T>C, were significantly more likely to have a milder EOSRD phenotype than those with two null mutations. Residual foveal outer retinal structure observed in the youngest proportion of patients suggests an early window for gene augmentation therapy.

Plasminogen activator inhibitor-1 4G/5G polymorphism and retinopathy risk in type 2 diabetes: a meta-analysis.

BACKGROUND: Mounting evidence has suggested that plasminogen activator inhibitor-1 (PAI-1) is a candidate for increased risk of diabetic retinopathy. Studies have reported that insertion/deletion polymorphism in the PAI-1 gene may influence the risk of this disease. To comprehensively address this issue, we performed a meta-analysis to evaluate the association of PAI-1 4G/5G polymorphism with diabetic retinopathy in type 2 diabetes. METHODS: Data were retrieved in a systematic manner and analyzed using Review Manager and STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. RESULTS: Nine studies with 1, 217 cases and 1, 459 controls were included. Allelic and genotypic comparisons between cases and controls were evaluated. Overall analysis suggests a marginal association of the 4G/5G polymorphism with diabetic retinopathy (for 4G versus 5G: OR 1.13, 95%CI 1.01 to 1.26; for 4G/4G versus 5G/5G: OR 1.30, 95%CI 1.04 to 1.64; for 4G/4G versus 5G/5G + 4G/5G: OR 1.26, 95%CI 1.05 to 1.52). In subgroup analysis by ethnicity, we found an association among the Caucasian population (for 4G versus 5G: OR 1.14, 95% CI 1.00 to 1.30; for 4G/4G versus 5G/5G: OR 1.33, 95%CI 1.02 to 1.74; for 4G/4G versus 5G/5G + 4G/5G: OR 1.41, 95%CI 1.13 to 1.77). When stratified by the average duration of diabetes, patients with diabetes histories longer than 10 years have an elevated susceptibility to diabetic retinopathy than those with shorter histories (for 4G/4G versus 5G/5G: OR 1.47, 95%CI 1.08 to 2.00). We also detected a higher risk in hospital-based studies (for 4G/4G versus 5G/5G+4G/5G: OR 1.27, 95%CI 1.02 to 1.57). CONCLUSIONS: The present meta-analysis suggested that 4G/5G polymorphism in the PAI-1 gene potentially increased the risk of diabetic retinopathy in type 2 diabetes and showed a discrepancy in different ethnicities. A higher susceptibility in patients with longer duration of diabetes (more than 10 years) indicated a gene-environment interaction in determining the risk of diabetic retinopathy.

Inherited KIF21A and PAX6 gene mutations in a boy with congenital fibrosis of extraocular muscles and aniridia.

BACKGROUND: Mutations in the KIF21A gene are detected in the patients with congenital fibrosis of the extraocular muscles. Mutations in the PAX6 gene are detected in the patients with congenital aniridia. CASE PRESENTATION: Herein we report a boy with both congenital fibrosis of extraocular muscles and aniridia. Sequence analysis of his KIF21A and PAX6 genes reveals a 1-bp deletion (c.745delC) in the PAX6 gene and a missense mutation of c.2860C > T (p.Arg954Trp) in KIF21A. CONCLUSIONS: This study demonstrates that the occurrence of independent mutations in more than a single gene in a patient may lead to a complex phenotype.

Identification of the forkhead transcriptional factor 2 (FOXL2) gene mutations in four Chinese families with blepharophimosis syndrome.

PURPOSE: To determine the genetic origin of disease in four Chinese families with blepharophimosis syndrome. METHODS: Four Han Chinese families with blepharophimosis syndrome were ascertained and patients underwent complete physical and ophthalmic examinations. Blood samples were collected and genomic DNA was extracted. Sequence analysis of the forkhead transcriptional factor 2 (FOXL2) gene was performed by direct sequencing and mutations were analyzed. RESULTS: Three mutations in FOXL2 were found in four families, including c.672_701dup30 (p.Ala224_Ala234dup10), c.313C>A (p.N105H), and c.430G>T (p.R144W). The c.672_701dup30 (p.Ala224_Ala234dup10) mutation was reported previously and predicted to result in expansions of the polyalanine tract. The mutations of c.313C>A (p. N105H) and c.430G>T (p.R144W) are two novel missense mutations. CONCLUSIONS: Our study further supports the view that the expansion of the polyalanine tract is the hotspot of mutations within FOXL2. The two novel missense mutations detected in this study will expand the mutation spectrum of the FOXL2 gene and contribute to the research on the molecular pathogenesis of FOXL2.

Diversity of clinical phenotypes in a cohort of Han Chinese patients with PAX6 variants.

The PAX6 gene plays an important role in ocular development. Mutations of the PAX6 gene may result in a series of ocular abnormalities, including congenital aniridia, anterior segment dysgenesis (ASD), progressive corneal opacification, glaucoma, and hypoplasia of the fovea and optic nerve, leading to reduced visual acuity and even blindness. This study aimed to describe the diversity of clinical features caused by PAX6 pathogenic variants in 45 Han Chinese patients from 23 unrelated families. All patients underwent detailed clinical assessment. Genetic testing was performed to identify pathogenic variations in the PAX6 gene by next-generation sequencing, minigene splicing assay, RT-qPCR, and long-range PCR. Twenty pathogenic variations were detected in the PAX6 gene from 12 pedigrees and 11 sporadic patients, of which 12 were previously reported and 8 were novel. The clinical phenotypes obtained as a result of the PAX6 gene mutations were complicated and vary among patients, even among those who carried the same variants. Genetic testing is helpful for differential diagnosis. Our genetic findings will expand the spectrum of pathogenic variations in the PAX6 gene. PAX6 pathogenic variants not only cause defects in ocular tissues, such as the iris and retina, but also lead to maldevelopment of the whole eye, resulting in microphthalmia.

Alterations of large-scale functional network connectivity in patients with infantile esotropia before and after surgery.

BACKGROUND: Growing evidences have indicated neurodevelopmental disorders in infantile esotropia (IE). However, few studies have analyzed the characteristics of large-scale functional networks of IE patients or their postoperative network-level alterations. METHODS: Here, individuals with IE (n = 32) and healthy subjects (n = 30) accomplished the baseline clinical examinations and resting-state MRI scans. A total of 17 IE patients also underwent corrective surgeries and completed the longitudinal clinical assessments and resting-state MRI scans. Linear mixed effects models were applied for cross-sectional and longitudinal network-level analyses. Correlation analysis was performed to assess the relationship between longitudinal functional connectivity (FC) alterations and baseline clinical variables. RESULTS: In cross-sectional analyses, network-level FC were apparently aberrant in IE patients compared to controls. In longitudinal analyses, intra- and internetwork connectivity were observed with significant alterations in postoperative IE patients compared to the preoperative counterparts. Longitudinal FC changes are negatively correlated to the age at surgery in IE. CONCLUSIONS: Obviously, altered network-level FC benefiting from the corrective surgery serves as the neurobiological substrate of the observed improvement of stereovision, visuomotor coordination, and emotional management in postoperative IE patients. Corrective surgery should be performed as early as possible to obtain more benefits for IE in brain function recovery.

[Recurrent N1173K mutation in FBN1 gene in a Chinese family with ectopia lentis].

OBJECTIVE: To study the disease-causing gene mutation in a Chinese family with ectopia lentis. METHODS: The phenotype of each family member in a Chinese family with ectopia lentis was identified by detailed clinical examination. The inheritance mode in this family was ascertained by the pedigree analysis. Linkage analysis was performed by microsatellite markers on chromosome 15 and LOD Score was calculated by Mlink program. Gene mutations were detected by sequence analysis to the whole coding region and exon-intron boundaries of the candidate gene. RESULTS: A significant LOD score of 3.01 was obtained at D15S978 on chromosome 15q21.1, where FBN1 gene was located. A C3519G change in exon 29 of FBN1 gene, resulting in asparagine change to lysine at codon 1173, was detected by direct sequence analysis. This mutation was absent in the normal family members and 100 normal controls. CONCLUSIONS: Our results indicate that c.C3519G (p.N1173K) mutation in FBN1 gene is the underlying molecular pathogenesis of this family with ectopia lentis.

[R954 mutations in KIF21A gene in Chinese patients with congenital fibrosis of extraocular muscles].

OBJECTIVE: Screening KIF21A gene mutation in 9 families with congenital fibrosis of extraocular muscles and 7 sporadic cases. METHODS: Families were ascertained and patients underwent complete ophthalmological examinations. The probands of 9 families with CFEOM and 7 sporadic patients were recruited for this study after informed consent. Genomic DNA was isolated from 5 ml peripheral blood samples according to the standard methods. Direct sequencing was performed after PCR amplification to genomic DNA for detection of KIF21A gene mutation. RESULTS: We identified heterozygous KIF21A mutations in 14 of sixteen patients. Twelve of them harbor the most common mutation, c.2860C > T (p.R954W) and two of them harbor the second most common mutation, c2861G > A(p.R954Q). The R954 mutations account for 87.5% (14/16), in which 75% (12/16) are R954W, 12.5% (2/16) are R954Q. CONCLUSION: The R954 mutations are also hotspots in Chinese patients with CFEOM.