Generation of human induced pluripotent stem cells from peripheral blood mononuclear cells of a Senior-Loken syndrome patient

Senior-Loken syndrome (SLS) is a rare disorder primarily associated with kidney and retinal dysfunction. We generated a human induced pluripotency stem cell (hiPSC) line, designated DKHi005-A, from peripheral blood mononuclear cells of a patient with SLS using a Sendai virus reprogramming method. We confirmed that DKHi005-A cells harbor the same mutation as the patient and show a normal karyotype. DKHi005-A also has pluripotency and the capacity for differentiation into the three germ layers. This cell line is registered and available at the National Stem Cell Bank, Korea National Institute of Health.ope

Generation of a human induced pluripotent stem cell line from a patient with Leber congenital amaurosis

Leber congenital amaurosis (LCA) is an inherited retinal dystrophy that is characterized by severe visual impairment in early infancy. We generated a human induced pluripotent stem cell (hiPSC) line, DKHi090-A, from peripheral blood mononuclear cells (PBMCs) of a patient with LCA, by using a Sendai virus-based gene delivery system. We confirmed that DKHi090-A has a nicotinamide mononucleotide adenyltransferase 1 (NMNAT1) mutation and normal karyotype. DKHi090-A line is pluripotent and is capable of multilineage differentiation. This cell line is registered and is available at the National Stem Cell Bank, Korea National Institute of Health.ope

Missed Heterozygous Deletion in Study of Next-Generation Sequencing for Molecular Diagnosis in Patients With Infantile Nystagmus Syndrome

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Clinical and Genetic Characteristics of Korean Congenital Stationary Night Blindness Patients

In this study, we investigated the clinical and genetic characteristics of 19 Korean patients with congenital stationary night blindness (CSNB) at two tertiary hospitals. Clinical evaluations, including fundus photography, spectral-domain optical coherence tomography, and electroretinography, were performed. Genetic analyses were conducted using targeted panel sequencing or whole exome sequencing. The median age was 5 (3-21) years at the initial examination, 2 (1-8) years at symptom onset, and 11 (5-28) years during the final visit. Genetic mutations were identified as CNGB1 and GNAT1 for the Riggs type (n = 2), TRPM1 and NYX for the complete type (n = 3), and CACNA1F (n = 14) for the incomplete type. Ten novel variants were identified, and best-corrected visual acuity (BCVA) and spherical equivalents (SE) were related to each type of CSNB. The Riggs and TRPM1 complete types presented mild myopia and good BCVA without strabismus and nystagmus, whereas the NYX complete and incomplete types showed mixed SE and poor BCVA with strabismus and nystagmus. This is the first case series of Korean patients with CSNB, and further studies with a larger number of subjects should be conducted to correlate the clinical and genetic aspects of CSNB.ope

Next-generation Sequencing in Inherited Eye Diseases

Next-generation sequencing is widely used in inherited diseases and cancer genetics fields. Next-generation sequencing technology provides accurate diagnosis in genetically heterogeneous disorders such as retinitis pigmentosa, Leber congenital amaurosis, or cone-rod dystrophy. However, the precise interpretation of variants produced by massively parallel sequencing is somewhat difficult to most of ophthalmologists, and misinterpretation of these variants lead to unwanted devastating consequences to the patients and their family. The molecular genetic findings need to be carefully evaluated in the context of the clinical findings to avoid misdiagnosis. Gene therapy trials are already in the market for specific forms of Leber congenital amaurosis. We are in the middle of exiting era of effective treatment for patients with inherited eye diseases, which was considered as incurable in the past. To success such a treatment, molecular diagnosis will become essential.ope

Ophthalmoplegia in Mitochondrial Disease

PURPOSE: To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease. MATERIALS AND METHODS: Among 372 patients with mitochondrial disease who visited our hospital between January 2006 and January 2016, 21 patients with ophthalmoplegia were retrospectively identified. Inclusion criteria included onset before 20 years of age, pigmentary retinopathy, and cardiac involvement. The 16 patients who were finally included in the study were divided into three groups according to disease type: Kearns-Sayre syndrome (KSS), KSS-like, and chronic progressive external ophthalmoplegia (CPEO). RESULTS: The prevalences of clinical findings were as follows: ptosis and retinopathy, both over 80%; myopathy, including extraocular muscles, 75%; lactic acidosis, 71%; and elevated levels of serum creatine kinase, 47%. Half of the patients had normal magnetic resonance imaging findings. A biochemical enzyme assay revealed mitochondrial respiratory chain complex I defect as the most common (50%). The prevalence of abnormal muscle findings in light or electron microscopic examinations was 50% each, while that of large-scale mitochondrial DNA (mtDNA) deletions in a gene study was 25%. We compared the KSS and KSS-like groups with the CPEO patient group, which showed pigmentary retinopathy (p<0.001), cardiac conduction disease (p=0.013), and large-scale mtDNA deletions (p=0.038). KSS and KSS-like groups also had gastrointestinal tract disorders such as abnormal gastrointestinal motility (p=0.013) unlike the CPEO group. CONCLUSION: Patients with KSS had gastrointestinal symptoms, which may indicate another aspect of systemic involvement. The presence of large-scale mtDNA deletions was an objective diagnostic factor for KSS and a gene study may be helpful for evaluating patients with KSS.ope

Characteristics of Optic Neuritis in South Korean Children and Adolescents: A Retrospective Multicenter Study

Purpose: To analyze the clinical characteristics and prognosis of optic neuritis (ON) in pediatric patients aged <19 years in South Korea. Methods: This multicenter retrospective cohort study included 127 pediatric patients (median age: 10.3 (IQR: 7.3-14.2) years; female, 62.2%) who experienced ON for the first time between January 2004 and January 2018, with data obtained from five tertiary university-based hospitals in Korea. When ON was bilateral, the worse eye was selected for analysis. The baseline clinical characteristics and prognoses of patients, as well as the associations between these parameters, were analyzed. Results: The baseline clinical characteristics of the patients were as follows: best-corrected visual acuity (BCVA) < 20/200, 65.9%; pain on eye movement, 47.2%; optic disc swelling, 66.9%; and bilateral involvement, 41.7%. Among 101 patients who were followed up for ≥6 months, 48 (47.5%), 12 (11.9%), 19 (18.8%), 13 (12.9%), and 9 (8.9%) had been diagnosed with isolated ON, recurrent ON, multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and acute disseminated encephalomyelitis (ADEM)-related ON, respectively. At the latest visit, 81.9% and 71.1% had achieved BCVA of ≥20/40 and ≥ 20/25, respectively. Only disc swelling at presentation was associated with poor baseline BCVA (coefficient: 0.31, P=0.004) and greater improvement in BCVA (coefficient: 0.49, P = 0.001P=0.001); there were no significant associations between the baseline factors and final BCVA. Conclusions: This study demonstrated pediatric ON-related clinical characteristics and visual outcomes in South Korea. Within this cohort, in about 40.6% of patients, ON was associated with other demyelinating diseases, namely, MS, NMOSD, and ADEM.ope

Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study

Purpose: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). Design: Multicenter, observational study. Participants: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). Methods: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. Main outcome measures: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). Results: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. Conclusions: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.ope

Genetic Characteristics and Phenotype of Korean Patients with Stickler Syndrome: A Korean Multicenter Analysis Report No. 1

Stickler syndrome is an inherited connective tissue disorder of collagen. There are relatively few reports of East Asian patients, and no large-scale studies have been conducted in Korean patients yet. In this study, we retrospectively analyzed the genetic characteristics and clinical features of Korean Stickler syndrome patients. Among 37 genetically confirmed Stickler syndrome patients, 21 types of gene variants were identified, of which 12 were novel variants. A total of 30 people had variants in the COL2A1 gene and 7 had variants in the COL11A1 gene. Among the types of pathogenic variants, missense variants were found in 11, nonsense variants in 8, and splice site variants in 7. Splicing variants were frequently associated with retinal detachment (71%) followed by missense variants. This is the first large-scale study of Koreans with Stickler syndrome, which will expand the spectrum of genetic variations of Stickler syndrome.ope

Comparison of surgical outcomes between lateral rectus recession and medial rectus advancement for postoperative consecutive exotropia

To compare the surgical outcomes of medial rectus advancement and lateral rectus recession in postoperative consecutive exotropia with single-stage adjustable suture surgery.Among 1003 patients who underwent bilateral medial rectus recession between November 1996 and March 2013, the patients who required surgery for consecutive exotopia were retrospectively reviewed. Nineteen patients underwent medial rectus advancement and 15 patients underwent lateral rectus recession. All patients underwent single-stage adjustable surgery under topical anesthesia and were followed up for at least 12 months.The mean follow-up duration was 2.4 years. At final follow-up, a successful surgical outcome was found in 12 patients (63.0%) in the medial rectus advancement group and 14 patients (93.3%) in the lateral rectus recession group (P = .039). The change in ocular deviation was correlated with the amount of recession (P = .008) and preoperative angle (P < .001) in the lateral rectus recession group.Lateral rectus recession showed a higher success rate with predictable and easily performed procedure than medial rectus advancement for the treatment of postoperative consecutive exotropia with adjustable suture.ope