Genetic and Clinical Features of ABCA4-Associated Retinopathy in a Japanese Nationwide Cohort.

PURPOSE: To clarify the genetic and clinical features of Japanese patients with ABCA4-associated retinopathy. DESIGN: Retrospective, multicenter cohort study. METHODS: Patients with retinal degeneration and biallelic ABCA4 variants were recruited from 13 different hospitals. Whole exome sequencing analysis was used for genetic testing. Comprehensive ophthalmic examinations were performed on matched patients. The primary outcome measure was identifying multimodal retinal imaging findings associated with disease progression. RESULTS: This study included 63 patients: 19 with missense/missense, 23 with missense/truncation, and 21 with truncation/truncation genotypes. In total, 62 variants were identified, including 29 novel variants. Six patients had a mild phenotype characterized by foveal-sparing or preserved foveal structure, including 4 with missense/missense and 2 with missense/truncation genotypes. The p.Arg212His variant was the most frequent in patients with mild phenotypes (4/12 alleles). Clinical findings showed a disease duration-dependent worsening of the phenotypic stage. Patients with the truncation/truncation genotype exhibited rapid retinal degeneration within a few years and definite fundus autofluorescence imaging patterns, including hyper autofluorescence at the macula and few or no flecks. CONCLUSIONS: Our results indicate that missense/missense or missense/truncation genotypes, including the p.Arg212His variant, are associated with a relatively mild phenotype. In contrast, the truncation/truncation genotype causes rapid and severe retinal degeneration in Japanese patients with ABCA4-associated retinopathy. These data are vital in predicting patient prognosis, guiding genetic counseling, and stratifying patients for future clinical trials.

Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases.

BACKGROUND: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases. METHODS: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines. RESULTS: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases. CONCLUSION: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.

Intraocular pressure changes at different gaze positions after superior rectus muscle-lateral rectus muscle loop myopexy in highly myopic strabismus.

PURPOSE: To evaluate changes in intraocular pressure (IOP) at different gaze positions before and after superior rectus muscle-lateral rectus muscle (SR-LR) loop myopexy in highly myopic strabismus (HMS). STUDY DESIGN: Nonrandomized clinical, prospective, interventional trial. METHODS: Fourteen patients with HMS (18 eyes) who underwent SR-LR loop myopexy were divided into 3 groups: < 100 prism diopters (PD) (mild esotropia [ET] group), > 100 PD (large ET group), and > 100 PD, and simultaneous recession of the medial rectus (MR) muscle was performed (large ET + MR group). Intraocular pressure was measured preoperatively and postoperatively at the primary, abduction, and adduction positions in each group. RESULTS: Intraocular pressure did not change after surgery in the mild ET group. Intraocular pressure significantly decreased in the abduction position (from 20.0 ± 2.1 to 16.0 ± 1.9 mmHg, P = 0.043) in the large ET group and in the abduction (from 22.2 ± 5.9 to 15.6 ± 4.3 mmHg, P = 0.048) and primary positions (from 15.8 ± 5.0 to 10.2 ± 2.8 mmHg, P = 0.043) in the large ET + MR group. The preoperative significant differences in IOP between the abduction and adduction positions in the large ET group (7.4 ± 3.4 mmHg) and the large ET + MR group (10.0 ± 5.5 mmHg) disappeared postoperatively (3.2 ± 2.8 mmHg and 3.6 ± 1.7 mmHg, respectively). The differences in IOP between abduction and adduction were similar in all the groups. CONCLUSION: SR-LR loop myopexy decreased IOP in patients with HMS in the abduction and primary positions.

The Structural Abnormalities Are Deeply Involved in the Cause of RPGRIP1-Related Retinal Dystrophy in Japanese Patients.

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy. RPGRIP1-related LCA accounts for 5-6% of LCA. We performed whole-exome sequencing and whole-genome sequencing (WGS) on 29 patients with clinically suspected LCA and examined ophthalmic findings in patients with biallelic pathogenic variants of RPGRIP1. In addition to five previously reported cases, we identified five cases from four families with compound heterozygous RPGRIP1 variants using WGS. Five patients had null variants comprising frameshift variants, an Alu insertion, and microdeletions. A previously reported 1339 bp deletion involving exon 18 was found in four cases, and the deletion was relatively prevalent in the Japanese population (allele frequency: 0.002). Microdeletions involving exon 1 were detected in four cases. In patients with RPGRIP1 variants, visual acuity remained low, ranging from light perception to 0.2, and showed no correlation with age. In optical coherence tomography images, the ellipsoid zone (EZ) length decreased with age in all but one case of unimpaired EZ. The retinal structure was relatively preserved in all cases; however, there were cases with great differences in visual function compared to their siblings and a 56-year-old patient who still had a faint EZ line. Structural abnormalities may be important genetic causes of RPGRIP1-related retinal dystrophy in Japanese patients, and WGS was useful for detecting them.

Recovery of stereoacuity after Yokoyama procedure in patients with highly myopic strabismus with good vision.

Purpose: To report stereopsis after bilateral Yokoyama procedure in patients with highly myopic strabismus and good visual acuity. Observations: Five patients aged between 34 and 81 years with best-corrected visual acuity of 20/25 or better were operated on. The preoperative strabismus angle ranged from esotropia of 35-113 prism diopters (PD) at distance and esotropia of 40-113 PD at near. One patient had left hypotropia of 4 PD and excyclotorsion of 15°, and the other had left hypotropia of 10 PD. Their axial lengths were 27.65-33.07 mm, and the posterior globe dislocation angles were between 123 and 148° on coronal magnetic resonance imaging (MRI). Limitations of abduction were between -1 and -2. All patients complained of diplopia, and none of them showed stereopsis. The Yokoyama procedure was performed on both eyes. Postoperative alternate cover testing showed from esotropia of 2 PD to exophoria of 8 PD at distance and from exotropia of 12 PD to esophoria of 10 PD at near.Three patients recovered stereopsis of 100, 50, and 140 sec, respectively. Two cases required unilateral inferior rectus muscle recessions, and their postoperative stereopsis was 25 and 50 sec. Conclusions and Importance: The Yokoyama procedure is effective not only in cases of heavy eye syndrome but also in cases of myopic esotropia associated with a globe dislocation angle of 120° or with little abduction restriction. If visual acuity is good, stereopsis may be restored with improvement in eye deviation.

Steroid-induced ocular hypertensive response in pediatric patients with acute lymphoblastic leukemia.

PURPOSE: To report the characteristics of the steroid-induced ocular hypertensive response in pediatric patients with acute lymphoblastic leukemia (ALL) treated with prednisolone (PSL) during induction therapy and with dexamethasone (DEX) during reinduction therapy. STUDY DESIGN: Retrospective. PATIENTS AND METHODS: This study included pediatric patients diagnosed with B-cell precursor ALL and treated with systemic corticosteroids sometime during the period from 2016 to 2018 at Shizuoka Children's Hospital. Data were extracted from the hematology/oncology records related to the type, dose, and duration of systemic corticosteroids as well as to the ophthalmologic examination findings, intraocular pressure (IOP) data, symptoms of high IOP, and antiglaucoma medications obtained during corticosteroid administration. The maximal IOPs of the PSL and DEX groups were compared. RESULTS: Twenty-eight patients (18 boys and 10 girls; mean age 5.5 years) were treated with systemic corticosteroids. Twelve of the 22 courses of PSL and 33 of the 44 courses of DEX were found to be associated with high IOP. The maximal IOP was higher with the use of DEX than with the use of PSL, including in those who received prophylactic therapy (PSL 25.2 mmHg, DEX 33.6 mmHg; P = 0.02). Antiglaucoma medication was given to 21 patients; 6 patients had symptoms of ocular hypertension. The maximal IOPs were 52.8 mmHg and 70.8 mmHg in the PSL and DEX groups, respectively. Both groups of patients reported severe headache. CONCLUSION: Increased IOP was frequently observed during systemic corticosteroid therapy in pediatric patients with ALL. Although most patients were asymptomatic, they occasionally presented with severe systemic symptoms. Regular ophthalmologic examinations should be included in the treatment guidelines for ALL.

A pediatric case of congenital stromal corneal dystrophy caused by the novel variant c.953del of the DCN gene.

We report a 1-year-old girl with congenital stromal corneal dystrophy confirmed by genetic analysis. The ocular phenotype included diffuse opacity over the corneal stroma bilaterally. We performed a genetic analysis to provide counseling to the parents regarding the recurrence rate. Whole exome sequencing was performed on her and her parents, and a novel de novo variant, NM_001920.5: c.953del, p.(Asn318Thrfs*10), in the DCN gene was identified in the patient.

A case of siblings with juvenile retinitis pigmentosa associated with NEK1 gene variants.

BACKGROUND: Axial spondylometaphyseal dysplasia(axial SMD) is associated with early-onset retinal dystrophy and various skeletal dysplasias of varying severity. NEK1 is the causative gene for short rib polydactyly syndrome and axial SMD. Here, we report a case of siblings with juvenile retinitis pigmentosa (RP) and NEK1 variants not associated with systemic disorders. MATERIALS AND METHODS: The patients were a 7-year-old-girl and a 9-year-old boy with RP, who were followed for 9 years. Whole exome sequencing (WES) was performed on the siblings and their parents, who were not consanguineous. RESULTS: The corrected visual acuity of the girl and the boy at first visit was binocular 20/63 and 20/100 OD and 20/63 OS, respectively. The siblings had narrowing of retinal blood vessels and retinal pigment epithelium atrophy in the fundus and showed an extinguished pattern in electroretinogram. On optical coherence tomography, there was a mottled ellipsoid band with progressive loss in the outer macular, the edges of which corresponded to the ring of hyperautofluorescence on fundus autofluorescence imaging. The siblings showed progressive visual field constriction. Radiological examination did not reveal any skeletal abnormalities. We identified two rare heterozygous NEK1 variants in the patients: c.240 G>A; p.(M80I) and c.634_639dup;p.(V212_L213dup). Heterozygous variants were recognized in the father and mother, respectively. According to the guidelines of the American College of Medical Genetics and Genomics, both variants were classified as likely pathogenic. CONCLUSION: This is the first report of RP patients with NEK1 variants not associated with skeletal abnormalities.

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing.

Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.

Intraocular pressure at different gaze positions in patients with highly myopic strabismus.

PURPOSE: To evaluate intraocular pressure (IOP) at different gaze positions in patients with highly myopic strabismus (HMS). STUDY DESIGN: Nonrandomized, prospective, observational study. METHODS: This study included 18 eyes of 14 patients with HMS and 51 eyes of 51 age-matched controls without strabismus; these were further divided into two groups based on refractive errors: > -6.00 diopter (D) (n = 22 eyes) and ≤ -6.00 D (n = 29 eyes). IOP was measured in primary and side gazes and compared within and among groups. The relationships between IOPs and axial length, angle of globe dislocation measured on magnetic resonance imaging, strabismus angle, and degree of abduction deficit were studied. RESULTS: The HMS group showed higher IOP in abduction (19.3 ± 4.9 mmHg) than in the primary (12.5 ± 4.3 mmHg) and adducting positions (13.0 ± 3.3 mmHg), (p < 0.001). The IOP in the adducting position in the HMS group (13.0 ± 3.3 mmHg) was lower than in the control groups both with (17.6 ± 3.5 mmHg) and without (16.9 ± 4.1 mmHg) high myopia, ; (p < 0.001 and = 0.003). The difference in IOP between abduction and adduction was significantly larger in the HMS group (6.4 ± 4.6 mmHg) compared to others (p < 0.001) and positively correlated with the strabismus angle and the angle of globe dislocation and negatively with abduction deficit. CONCLUSION: The IOP of patients with HMS changes dramatically on side gazes, therefore, care should be taken while measuring IOP.

Coenzyme Q10 in the eye isomerizes by sunlight irradiation.

Photoisomerization of lipids has been well studied. As for the eyes, photoisomerization from 11-cis isomer to all-trans-retinal is well-known as the first step of the visual transduction in the photoreceptors. In addition to that, there would be other ocular lipids that undergo photoisomerization, which may be involved in ocular health and function. To explore any photoisomerizable lipids in the eyes, the nonirradiated and sunlight-irradiated eyeball extracts were subjected to liquid chromatography-mass spectrometry analysis, followed by the identification of the decreased lipid species in the irradiated extracts. Surprisingly, more than nine hundred lipid species were decreased in the irradiated extracts. Three lipid species, coenzyme Q10 (CoQ10), triglyceride(58:4), and coenzyme Q9, were decreased both significantly (p < 0.05) and by more than two-fold, where CoQ10 showed the most significant decrease. Later, photoisomerization was identified as the prominent cause underlying the decrease of CoQ10. Interestingly, CoQ10 in the sunlight-irradiated fresh eyeballs was also isomerized. Both the visible light and ultraviolet radiation were capable of producing CoQ10 isomer, while the latter showed rapid action. This study is believed to enhance our understanding of the biochemistry and photodamage of the eye and can potentially contribute to the advancement of opto-lipidomics.

Likely pathogenic structural variants in genetically unsolved patients with retinitis pigmentosa revealed by long-read sequencing.

Despite the successful identification of causative genes and genetic variants of retinitis pigmentosa (RP), many patients have not been molecularly diagnosed. Our recent study using targeted short-read sequencing showed that the proportion of carriers of pathogenic variants in EYS, the cause of autosomal recessive RP, was unexpectedly high in Japanese patients with unsolved RP. This result suggested that causative genetic variants, which are difficult to detect by short-read sequencing, exist in such patients. Using long-read sequencing technology (Oxford Nanopore), we analysed the whole genomes of 15 patients with RP with one heterozygous pathogenic variant in EYS detected in our previous study along with structural variants (SVs) in EYS and another 88 RP-associated genes. Two large exon-overlapping deletions involving six exons were identified in EYS in two patients with unsolved RP. An analysis of an independent patient set (n=1189) suggested that these two deletions are not founder mutations. Our results suggest that searching for SVs by long-read sequencing in genetically unsolved cases benefits the molecular diagnosis of RP.

Exophthalmos associated with chronic progressive external ophthalmoplegia.

PURPOSE: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease characterized by slowly progressive ptosis and limitations in ocular motility. Although exophthalmos is not considered to be a common feature of CPEO, this study focused on the incidence of exophthalmos in patients with CPEO. STUDY DESIGN: Retrospective observational case series METHODS: We reviewed the clinical charts of patients who received a diagnosis of CPEO sometime during the period between January 2010 and December 2018. CPEO was diagnosed on the basis of detection of a deletion of mitochondrial DNA (mtDNA) from saliva, buccal mucosa, or extraocular muscle specimens obtained during strabismus surgery. Horizontal MRI/CT images or Hertel ophthalmometry was used in determining exophthalmos. RESULTS: Seven patients (4 males) were identified. The mean age at diagnosis was 32.6 years (range 13-53 years). mtDNA deletion mutations were detected in the buccal mucous membrane DNA in 5 patients and in the saliva and extraocular muscle DNA in 2 patients. MRI/CT was recorded in 6 patients, four of whom showed exophthalmos (cases 1-4), and case 5 was determined as exophthalmos on the basis of a Hertel ophthalmometer reading. Exophthalmos was bilateral in 4 of the patients (cases 1, 2, 4, and 5) and unilateral in 1 patient (case 3). Exophthalmos was the chief concern of 2 of the patients; however, it was not clinically significant in the other patients. CONCLUSIONS: Although exophthalmos may not be recognized by either the patient or the clinician, it may be one of the common features of CPEO. A large multiethnic study should be performed.

De novo heterozygous variants in KIF5B cause kyphomelic dysplasia.

Kyphomelic dysplasia is a heterogeneous group of skeletal dysplasias characterized by severe bowing of the limbs associated with other variable findings, such as narrow thorax and abnormal facies. We searched for the genetic etiology of this disorder. Four individuals diagnosed with kyphomelic dysplasia were enrolled. We performed whole-exome sequencing and evaluated the pathogenicity of the identified variants. All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val). All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress. Short stature was observed in three individuals. Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy. Our findings suggest that heterozygous KIF5B deleterious variants cause a specific form of kyphomelic dysplasia. Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies.

Medial Rectus Muscle Resection Versus Plication: A Comparison of Conjunctival-Scleral Thickness Measured by AS-OCT.

PURPOSE: To compare conjunctival-scleral thickness measured with anterior segment optical coherence tomography before and after medial rectus muscle resection and plication for exotropia. METHODS: In this prospective observational study, patients with exotropia aged 5 years and older who underwent medial rectus muscle resection or plication through limbal incision of the conjunctiva between April 2016 and June 2018 were enrolled. Conjunctivalscleral thickness was measured with anterior segment optical coherence tomography before and 3 and 6 months after surgery at 1.5 mm (limbus), 4 mm (insertion), and 5.5 mm (tendon) posterior to the scleral spur. One examiner made measurements twice blinded for the initial data. Conjunctival-scleral thickness was compared between groups using the Mann-Whitney U test. RESULTS: Twenty participants were divided into two groups: resection (n = 11) and plication (n = 9). The respective conjunctival-scleral thicknesses before and 3 and 6 months after surgery in the resection group were as follows: 0.76, 0.90, and 0.86 mm at the limbus; 0.86, 1.18, and 1.12 mm at the insertion; and 1.04, 1.41, and 1.33 mm at the tendon. Corresponding values in the plication group were as follows: 0.74, 0.87, and 0.81 mm at the limbus; 0.84, 1.16, and 1.08 mm at the insertion; and 1.00, 1.39, and 1.27 mm at the tendon. No between-group differences were observed at any location or time. CONCLUSIONS: No differences in conjunctival-scleral thickness were observed between the resection and plication groups before surgery or at 3 months and 6 months postoperatively. [J Pediatr Ophthalmol Strabismus. 2022;59(4):274-278.].

Retinitis pigmentosa with optic neuropathy and COQ2 mutations: A case report.

PURPOSE: To report the clinical findings of a Japanese patient presenting with retinitis pigmentosa (RP) together with optic neuropathy and COQ2 mutations. OBSERVATIONS: The patient had experienced night blindness and photophobia since his 20s. At 27 years of age, he experienced sudden vision loss in his left eye. We performed comprehensive ophthalmic examinations. Trio-based whole-exome sequencing was performed to identify the candidate variants, which were confirmed by Sanger sequencing. Fundus examination revealed typical RP findings with an additional Leber hereditary optic neuropathy (LHON). The patient's visual acuity was severely affected, and the visual field showed central scotoma. Electroretinograms were non-recordable under scotopic condition and showed reduced response under photopic conditions. Genetic analysis revealed compound heterozygous COQ2 variants in the patient: c.469C > T [p.(P157S], and c.518G > A [p.(R173H)]. Co-segregation analysis in the unaffected parents confirmed that the two variants were in trans. During the 4-year follow-up period, his visual acuity and central scotoma gradually improved. CONCLUSION: This is the first description of a case of RP together with LHON harboring COQ2 mutations. Additional cases are necessary to more accurately determine the clinical course and mutation spectrum in this condition.

Maternal Uniparental Isodisomy of Chromosome 4 and 8 in Patients with Retinal Dystrophy: SRD5A3-Congenital Disorders of Glycosylation and RP1-Related Retinitis Pigmentosa.

PURPOSE: Uniparental disomy (UPD) is a rare chromosomal abnormality. We performed whole-exosome sequencing (WES) in cases of early-onset retinal dystrophy and identified two cases likely caused by UPD. Herein, we report these two cases and attempt to clarify the clinical picture of retinal dystrophies caused by UPD. METHODS: WES analysis was performed for two patients and their parents, who were not consanguineous. Functional analysis was performed in cases suspected of congenital disorders of glycosylation (CDG). We obtained clinical case data and reviewed the literature. RESULTS: In case 1, a novel c.57G>C, p.(Trp19Cys) variant in SRD5A3 was detected homozygously. Genetic analysis suggested a maternal UPD on chromosome 4, and functional analysis confirmed CDG. Clinical findings showed early-onset retinal dystrophy, intellectual disability, and epilepsy. In case 2, an Alu insertion (c.4052_4053ins328, p.[Tyr1352Alafs]) in RP1 was detected homozygously. Maternal UPD on chromosome 8 was suspected. The clinical picture was consistent with RP1-related retinitis pigmentosa. Although the clinical features of retinal dystrophy by UPD may vary, most cases present with childhood onset. CONCLUSIONS: There have been limited reports of retinal dystrophy caused by UPD, suggesting that it is rare. Genetic counseling may be encouraged in pediatric cases of retinal dystrophy.

Clinical findings of acute acquired comitant esotropia in young patients.

PURPOSE: This study aimed to identify the characteristics of acute acquired comitant esotropia (AACE) in young patients from a single institution; and clarify their relationship with the excess use of digital devices. STUDY DESIGN: Retrospective, observational. METHODS: We extracted the clinical charts of patients aged between 5 and 35 years who presented at the Hamamatsu University Hospital with AACE symptoms from January 1, 2015 to December 31, 2018. The age of onset, angle of deviation, refractive errors, history of near work, including excess smartphone use, and treatment modality were retrieved. Patients were divided into three groups: CHILD (aged 5-12 years), JUNIOR (aged 13-17 years), and ADULT (aged 18-35 years) and statistically analyzed with Kruskal-Wallis test. RESULTS: Forty-one patients were retrieved, with a mean age at onset of 15.8 (5-28) years; eight in the CHILD group, 23 in the JUNIOR group, and 10 in the ADULT group. Refractive errors and age of patients were correlated, but were not significantly different among groups. The mean angle of deviation at distance was 28.0 ± 12.8 prism diopters (PD) and 28.6 ± 17.2 PD at near. The CHILD group showed the largest near-distant dissociation. History of excessive near work was found in all groups. CONCLUSION: AACE was most commonly found in the JUNIOR group, especially those aged 15-16 years. AACE may encompass multiple diseases; using common diagnostic criteria and asking common questions regarding digital device usage is necessary to clarify the influence of digital device usage, and a multicenter prospective study is recommended.

Identification of susceptibility loci for light-induced visual impairment in rats.

Bright light exposure in animals results in the selective degeneration of the outer retina, known as "retinal photic injury" (RPI). The susceptibility to RPI differs among rat strains. WKY rats display susceptibility to RPI with extensive retinal degeneration observed in the sagittal eye specimen, whereas LEW strain rats are resistant to it, showing only slight or no degeneration. In the present study, we first established an ethological screening method using the Morris water maze to discern differential susceptibility among the living rats. WKY and LEW were crossed to produce the first filial generation (F1) offspring. Maze-trained individuals were exposed to bright, white light. The screening test results demonstrated that the susceptibility to light-induced visual impairment in rats is a dominant Mendelian susceptibility trait, as F1 rats were susceptible to visual impairment like WKY rats. Therefore, F1 rats were backcrossed with recessive LEW to produce the first backcross offspring (BC1). Subsequent recurrent backcrossing while selecting for the susceptibility, indicated a segregation ratio of ca. 24% in BC1 and BC2 generations, indicating the involvement of two or more genes in the susceptibility. Further, microsatellite analysis of BC1-to-BC4 individuals using microsatellite markers mapped two susceptibility loci on chromosome segments 5q36 and 19q11-q12, named RPI susceptibility (Rpi)1 and Rpi2, respectively. This study provides an insight into mechanisms underlying differential susceptibility, which could help decipher the mechanism underlying the onset/progression of human age-related macular degeneration.

Retinal Features of Family Members With Familial Exudative Vitreoretinopathy Caused By Mutations in KIF11 Gene.

Purpose: To determine the clinical characteristics of patients and family members with familial exudative vitreoretinopathy (FEVR) caused by mutations in the KIF11 gene. Methods: Twenty-one patients from 10 FEVR families with mutations in the KIF11 gene were studied. The retinal and systemic features were examined. The genetic analyses performed included Sanger sequencing of the KIF11 gene, whole exome sequencing, as well as array comparative genomic hybridization (CGH) analysis and multiple ligation probe assay (MLPA). Results: Sequence analysis revealed seven different KIF11 mutations. Array CGH with MLPA revealed two different exon deletions. All probands had advanced FEVR with retinal detachments (RDs) and microcephaly with or without developmental disabilities. Patients with bilateral RDs were more frequently associated with developmental disabilities (P = 0.023). Multimodal imaging of the family members revealed that six of nine patients without RDs (66%) had varying degrees of chorioretinopathy. The retinal folds in FEVR patients were associated with severe retinal avascularization. However, funduscopic changes in the peripheral retina were unremarkable in family members without RDs. A score representing the peripheral vascular anomalies determined from the fluorescein angiograms was lower than that of control eyes of patients with mutations of the Wnt signaling genes (P = 0.0029). Conclusions: The probands with KIF11 mutations were associated with severe ocular and systemic pathologies, whereas affected family members showed highly variable clinical manifestations. Peripheral vascular anomalies can often be unremarkable in eyes without RDs. Translational Relevance: These findings highlight more diverse mechanisms that underlie the pathological changes in patients with FEVR.