Expanding SPG7 dominant optic atrophy phenotype: Infantile nystagmus and optic atrophy without spastic paraplegia.

Spastic paraplegia is a neurodegenerative disorder characterized by progressive leg weakness and spasticity due to degeneration of corticospinal axons. SPG7 encodes paraplegin, and pathogenic variants in the gene cause hereditary spastic paraplegia as an autosomal recessive trait. Various ophthalmological findings including optic atrophy, ophthalmoplegia, or nystagmus have been reported in patients with spastic paraplegia type 7. We report a 15-year-old male patient with a novel heterozygous variant, c.1224T>G:p.(Asp408Glu) in SPG7 (NM_003119.3) causing early onset isolated optic atrophy and infantile nystagmus prior to the onset of neurological symptoms. Therefore, SPG7 should be considered a cause of infantile nystagmus with optic atrophy.

SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization.

Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.

Effect of preoperative eyedrops on cytokine concentrations in aqueous humor of patients undergoing femtosecond laser-assisted cataract surgery.

PURPOSE: To compare the anti-inflammatory activity of preoperatively applied eyedrops, as determined by cytokine concentrations in aqueous humor collected during surgery in patients undergoing femtosecond laser-assisted cataract surgery. METHODS: A total of 120 patients undergoing femtosecond laser-assisted cataract surgery were randomly assigned to four groups of 30 patients each. Groups were administered 0.1% fluorometholone eyedrops, 0.45% ketorolac tromethamine eyedrops, both 0.1% fluorometholone and 0.45% ketorolac tromethamine eyedrops, or no eyedrops. Eyedrops were instilled 1 h, 20 min, and just before surgery. After anterior capsulotomy and nuclear fragmentation using a femtosecond laser, 0.1 cc aqueous humor was obtained using a needle and syringe. Cytokine and prostaglandin E2 (PGE2) concentrations were quantitatively determined. RESULTS: The 120 patients included 59 men and 61 women, of mean age 65.02 years. The mean interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentrations after treatment did not differ significantly in the four groups. The average interleukin-8 (IL-8) concentrations were significantly lower in the fluorometholone (4.80 pg/mL), ketorolac tromethamine (4.84 pg/mL), and fluorometholone + ketorolac tromethamine (4.68 pg/mL) groups than in the control group (6.83 pg/mL). Furthermore, the average PGE2 concentrations were significantly lower in the ketorolac tromethamine (270.04 pg/mL) and fluorometholone + ketorolac tromethamine (239.00 pg/mL) groups, but not in the fluorometholone (393.16 pg/mL) group, than in the control group (472.36 pg/mL). CONCLUSION: Preoperative fluorometholone instillation reduced IL-8, and ketorolac tromethamine instillation reduced IL-8 and PGE2, in aqueous humor of patients undergoing femtosecond laser surgery, with the combination of both eyedrops being more effective than either alone. TRIAL REGISTRATION: KCT0005717.

Aberrant expression of PAX6 gene associated with classical aniridia: identification and functional characterization of novel noncoding mutations.

The PAX6 is essential for ocular morphogenesis and is known to be highly sensitive to changes in gene expression, where neither over- nor under-expression ensures normal ocular development. Two unrelated probands with classical aniridia who were previously considered "PAX6-negative", were studied by whole-genome sequencing. Through the use of multiple in silico deep learning-based algorithms, we identified two novel putative causal mutations, c.-133_-132del in the 5' untranslated region (5'-UTR) and c.-52 + 5G>A in an intron upstream of the PAX6 gene. The luciferase activity was significantly increased and VAX2 binding was disrupted with the former 5'-UTR variant compared with wild-type sequence, which resulted in a striking overexpression of PAX6. The minigene assay showed that the c.-52 + 5G>A mutation caused defective splicing, which resulted in the formation of truncated transcripts.

Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy.

BACKGROUND: Ambroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD. METHODS: ABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed. RESULTS: Enhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2-8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events. CONCLUSIONS: Long-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.

Optical Coherence Tomography Angiography Characteristics and Predictors of Visual Outcomes in Patients With Acute and Chronic Nonarteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND: To investigate the correlation between optical coherence tomography angiography (OCTA) characteristics and visual outcomes in patients with acute and chronic nonarteritic anterior ischemic optic neuropathy (NAION). METHODS: We retrospectively reviewed clinical data and OCTA images of 26 eyes of 26 patients who had been diagnosed with unilateral NAION. OCTA images were acquired from 17 eyes at the acute stage and from 21 eyes at the chronic stage of NAION. We analyzed the peripapillary vessel density (VD) and macular VD in various layers of the retina and choroid for all images. Possible correlations between the OCTA parameters and visual outcomes were investigated. RESULTS: Among the OCTA parameters for the acute stage of NAION, the temporal peripapillary VD was found to be positively correlated with final visual acuity and visual field with statistical significance (P = 0.039 and 0.009, respectively). In the chronic stage of NAION, both peripapillary and superficial macular VDs were positively correlated with visual outcomes. The nasal perifoveal VD in the superficial capillary plexus (SCP) also had a significant correlation with final visual acuity for both acute and chronic stages (the Spearman correlation coefficient = 0.565 and 0.685, respectively). CONCLUSIONS: In patients with NAION, significant correlations were found between OCTA parameters and visual outcomes. The temporal peripapillary VD measured during the acute stage was a significant predictor of final visual outcomes. The decreased nasal perifoveal VD in the SCP was strongly associated with poor visual prognosis.

Neuro-Ophthalmologic Features and Outcomes of Thalamic Infarction: A Single-Institutional 10-Year Experience.

BACKGROUND: Neuro-ophthalmologic deficit after thalamic infarction has been of great concern to ophthalmologists because of its debilitating impacts on patients' daily living. We aimed to describe the visual and oculomotor features of thalamic infarction and to delineate clinical outcomes and prognostic factors of the oculomotor deficits from an ophthalmologic point of view. METHODS: Clinical and neuroimaging data of all participants were retrospectively reviewed. Among the 12,755 patients with first-ever ischemic stroke, who were registered in our Stroke Data Bank between January 2009 and December 2018, 342 were found to have acute thalamic infarcts on MRI, from whom we identified the patients exhibiting neuro-ophthalmologic manifestations including visual, oculomotor, pupillary, and eyelid anomalies. RESULTS: Forty (11.7%) of the 342 patients with thalamic infarction demonstrated neuro-ophthalmologic manifestations, consisting of vertical gaze palsy (n = 19), skew deviation with an invariable hypotropia of the contralesional eye (n = 18), third nerve palsy (n = 11), pseudoabducens palsy (n = 9), visual field defects (n = 7), and other anomalies such as isolated ptosis and miosis (n = 7). Paramedian infarct was the most predominant lesion of neuro-ophthalmologic significance, accounting for 84.8% (n = 28) of all patients sharing the oculomotor features. Although most of the patients with oculomotor abnormalities rapidly improved without sequelae, 6 (18.2%) patients showed permanent oculomotor deficits. Common clinical features of patients with permanent oculomotor deficits included the following: no improvement within 3 months, combined upgaze and downgaze palsy, and the involvement of the paramedian tegmentum of the rostral midbrain. CONCLUSIONS: Thalamic infarction, especially in paramedian territory, can cause a wide variety of neuro-ophthalmologic manifestations, including vertical gaze palsy, skew deviation, and third nerve palsy. Although most oculomotor abnormalities resolve spontaneously within a few months, some may persist for years when the deficits remain unimproved for more than 3 months after stroke.

Copy number variations and multiallelic variants in Korean patients with Leber congenital amaurosis.

Purpose: We comprehensively evaluated the mutational spectrum of Leber congenital amaurosis (LCA) and investigated the molecular diagnostic rate and genotype-phenotype correlation in a Korean cohort. Methods: This single-center retrospective case series included 50 Korean patients with LCA between June 2015 and March 2019. Molecular analysis was conducted using targeted panel-based next-generation sequencing, including deep intronic and regulatory variants or whole exome sequencing. The molecular diagnosis was made based on the inheritance pattern, zygosity, and pathogenicity. Results: Among the 50 patients, 27 patients (54%) were male, and 11 (22%) showed systemic features. Genetic variants highly likely to be causative were identified in 78% (39/50) of cases and segregated into families. We detected two pathogenic or likely pathogenic variants in a gene linked to a recessive trait without segregation analysis in three cases (6.0%). GUCY2D (20%), NMNAT1 (18%), and CEP290 (16%) were the most frequently mutated genes in Korean LCA. Copy number variations were found in three patients, which accounted for 6% of LCA cases. A possible dual molecular diagnosis (Senior-Løken syndrome along with Leigh syndrome, and Joubert syndrome with transposition of the great arteries) was made in two patients (4%). Three of 50 patients were medically or surgically actionable: one patient for RPE65 gene therapy and two patients with WDR19 Senior-Løken syndrome for early preparation for kidney and liver transplantations. Conclusions: This study demonstrated that approximately 4% of patients may have dual molecular diagnoses, and 6% were surgically or medically actionable in LCA. Therefore, accurate molecular diagnosis and careful interpretation of next-generation sequencing results can be of great help in patients with LCA.

Difference in myopia progression between dominant and non-dominant eye in patients with intermittent exotropia.

OBJECTIVE: To investigate the difference in the rate of myopia progression between the dominant and non-dominant eye in patients with intermittent exotropia (IXT). METHODS: We retrospectively reviewed the medical records of 33 patients who underwent surgery and later reoperation for IXT. We included only patients whose spherical equivalent refractive errors (SER) were ≤ - 0.50 diopter (D) in at least one eye at the time of reoperation. The main outcome measurement was the rate of myopia progression, which was defined as the mean annual change in SER between the first and second surgery. We classified patients into two groups: group A, which comprised 25 patients whose non-dominant eyes showed a faster myopia progression than their dominant eyes, and group B, which comprised the remaining 8 patients showing the opposite. RESULTS: Mean age of the patients at the time of the initial surgery was 5.64 years. Mean interval between the initial and second surgery was 4.45 years. Mean rate of myopia progression over the interval was - 0.37 D/year in the dominant eyes and - 0.50 D/year in the non-dominant eyes (P < 0.001). Group A had a significantly greater amount of distance deviation (31.0 vs. 25.6 PD, P = 0.020) and near deviation (30.8 vs 26.0 PD, P = 0.039) before the initial surgery and a significantly worse score of distance control (3.05 vs. 2.00, P = 0.023) before the second surgery than group B. CONCLUSIONS: The non-dominant eyes experienced a faster myopia progression than the dominant eyes in patients with IXT. This faster myopia progression demonstrated in the non-dominant eyes was associated with clinically severe exotropia in terms of the amount of deviation and the degree of control.

Clinical and Optic Disc Characteristics of Patients Showing Visual Recovery in Leber Hereditary Optic Neuropathy.

BACKGROUND: The visual prognosis in Leber hereditary optic neuropathy (LHON) is generally poor. However, some individuals can have spontaneous visual recovery (VR) in one or both eyes by a mechanism that is not yet clearly understood. The purpose of this study was to determine whether certain clinical and optic disc features are associated with VR in patients with LHON. METHODS: We retrospectively examined 80 eyes of 40 patients with LHON using clinical databases, fundus photographs, and high-definition spectral-domain optical coherence tomography (OCT) images. VR was defined as a gain of 3 or more lines of logarithm of the minimum angle of resolution (logMAR)-scaled visual acuity from nadir; this represents a doubling of the visual angle. Patients were divided into VR and nonrecovery (NR) groups. Using fundus photographs, we measured optic disc size and evaluated for the presence of optic disc features, including peripapillary telangiectasia, disc hyperemia, and swelling. We also measured the disc area, cup-to-disc ratio, and rim area of the optic disc using OCT. RESULTS: Twenty-one of 80 eyes (26%) had a VR. The VR occurred within 2 years after onset in 81% of cases. The VR group showed younger age at onset (21 vs 29 years, P = 0.017) and better visual acuity at the nadir (1.39 vs 2.16 logMAR, P < 0.001) compared with the NR group. Optic disc features, particularly peripapillary telangiectasia (P = 0.027) and disc hyperemia (P = 0.006), were more prominent in the NR group. The cup-to-disc ratio was significantly smaller (0.64 vs 0.71, P = 0.004) and the rim area was significantly greater (1.17 vs 0.85 mm, P < 0.001) in the VR group compared with the NR group. CONCLUSIONS: A younger age at onset and a less severe reduction of visual acuity at the nadir were associated with a higher probability of VR. Presence of peripapillary telangiectasia and optic disc hyperemia may serve as predictive factors for poor visual prognosis in patients with LHON.

PAX6 aniridia syndrome: clinics, genetics, and therapeutics.

PURPOSE OF REVIEW: Aniridia is a rare and panocular disorder affecting most of the ocular structures which may have significant impact on vision. The purpose of this review is to describe the clinical features, genetics, and therapeutic options for this disease and to provide an update of current knowledge and latest research findings. RECENT FINDINGS: Aside from the ocular features, a variety of associated systemic abnormalities, including hormonal, metabolic, gastrointestinal, genitourinary, and neurologic pathologies have been reported in children with aniridia. Although mutations in PAX6 are a major cause of aniridia, genetic defects in nearby genes, such as TRIM44 or ELP4, have also been reported to cause aniridia. Recent improvement in genetic testing technique will help more rapid and precise diagnosis for aniridia. A promising therapeutic approach called nonsense suppression therapy has been introduced and successfully used in an animal model. SUMMARY: Aniridia is a challenging disease. The progressive nature of this condition and its potential complications require continuous and life-long ophthalmologic care. Genetic diagnosis for aniridia is important for establishing definitive molecular characterization as well as identifying individuals at high risk for Wilms tumor. Recent advancement in understanding the genetic pathogenesis of this disease offers promise for the approaches to treatment.

The influence of ocular sighting dominance on Fundus torsion in patients with unilateral congenital superior oblique palsy.

PURPOSE: The purpose of our study was to determine whether ocular sighting dominance may influence the ocular torsion in patients with unilateral congenital superior oblique palsy (UCSOP). METHODS: This retrospective study included 22 UCSOP patients with radiologic evidence of unilateral superior oblique muscle hypoplasia on orbital magnetic resonance imaging and 66 healthy individuals with normal ocular motility as controls. Ocular torsion was assessed both quantitatively and qualitatively using digital fundus photography. The disc-fovea angle (DFA) was measured quantitatively using image software on a computer screen. All fundus photographs were qualitatively graded as normal torsion, extorsion, or intorsion in all subjects, based on the location of the optic disc relative to the fovea, according to the Bixenman and von Noorden's criteria. Ocular sighting dominance was assessed by the hole-in-the-card test and the pointing test. The Mann-Whitney U test and Fisher's exact test were used to determine the association between the ocular sighting dominance and the ocular torsion. RESULTS: The median DFA was significantly larger in the eyes of patients with UCSOP (9.1° in the paretic eyes and 9.3° in the non-paretic eyes) than the eyes of the control group (4.3°, p < 0.001 for both). Ocular dominance tests displayed that, among 22 patients, 11 were paretic eye dominant and the other 11 were non-paretic eye dominant. The sighting-dominant eyes demonstrated significantly smaller median DFA than the non-dominant eyes (8.3° and 10.7°, respectively, p = 0.033), regardless of which eyes were paretic. Ten eyes of ten patients had extorsion, none had intorsion, and all the eyes of remaining 12 patients had no abnormal torsion, qualitatively. All the eyes showing extorsion in fundus photography were non-dominant eyes, regardless of whether the eyes were paretic or non-paretic. CONCLUSIONS: Our findings illuminate the importance of considering ocular sighting dominance for properly assessing ocular torsion in patients with UCSOP. Ocular sighting dominance may have an influence on objective ocular torsion in a way that decreases the torsion in the dominant eye, thereby hindering the abnormal ocular torsion from appearing in that eye.

First-ever optic neuritis: distinguishing subsequent neuromyelitis optica from multiple sclerosis.

To identify factors distinguishing subsequent neuromyelitis optica (NMO) from multiple sclerosis (MS) after first-ever optic neuritis (ON), we compared ophthalmic findings and MRI features of 24 NMO and 55 MS patients who initially presented with ON. The female-to-male ratio was higher, and bilateral ON was more common in NMO patients than in MS patients (p = 0.044 and p = 0.020, respectively). The visual acuity (VA) score was higher in NMO patients (p = 0.034), and a greater proportion of NMO patients had a VA score ≥ 5 (p = 0.003). The frequency of patients without pattern-reversal and flash visual evoked potentials was higher in the NMO group (p = 0.015). Brain MRI abnormalities were more common in the MS group (p = 0.001). The optic chiasm was affected in 25 % of NMO patients and was unaffected in MS patients, although it did not reach statistical significance (p = 0.096). There were no differences with respect to the severity of swelling and enhancement of the optic nerve. In conclusion, severe optic nerve damage at the first ON attack was associated with subsequent development of NMO, whereas presence of brain MRI abnormalities was associated with developing MS.

Digital therapeutics using virtual reality-based visual perceptual learning for visual field defects in stroke: A double-blind randomized trial.

INTRODUCTION: Visual field defects (VFDs) represent a debilitating poststroke complication, characterized by unseen parts of the visual field. Visual perceptual learning (VPL), involving repetitive visual training in blind visual fields, may effectively restore visual field sensitivity in cortical blindness. This current multicenter, double-blind, randomized, controlled clinical trial investigated the efficacy and safety of VPL-based digital therapeutics (Nunap Vision [NV]) for treating poststroke VFDs. METHODS: Stroke outpatients with VFDs (>6 months after stroke onset) were randomized into NV (defective field training) or Nunap Vision-Control (NV-C, central field training) groups. Both interventions provided visual perceptual training, consisting of orientation, rotation, and depth discrimination, through a virtual reality head-mounted display device 5 days a week for 12 weeks. The two groups received VFD assessments using Humphrey visual field (HVF) tests at baseline and 12-week follow-up. The final analysis included those completed the study (NV, n = 40; NV-C, n = 35). Efficacy measures included improved visual area (sensitivity ≥6 dB) and changes in the HVF scores during the 12-week period. RESULTS: With a high compliance rate, NV and NV-C training improved the visual areas in the defective hemifield (>72 degrees2) and the whole field (>108 degrees2), which are clinically meaningful improvements despite no significant between-group differences. According to within-group analyses, mean total deviation scores in the defective hemifield improved after NV training (p = .03) but not after NV-C training (p = .12). CONCLUSIONS: The current trial suggests that VPL-based digital therapeutics may induce clinically meaningful visual improvements in patients with poststroke VFDs. Yet, between-group differences in therapeutic efficacy were not found as NV-C training exhibited unexpected improvement comparable to NV training, possibly due to learning transfer effects.

Clinician-Driven Reanalysis of Exome Sequencing Data From Patients With Inherited Retinal Diseases.

Importance: Despite advances in next-generation sequencing (NGS), a significant proportion of patients with inherited retinal disease (IRD) remain undiagnosed after initial genetic testing. Exome sequencing (ES) reanalysis in the clinical setting has been suggested as one method for improving diagnosis of IRD. Objective: To investigate the association of clinician-led reanalysis of ES data, which incorporates updated clinical information and comprehensive bioinformatic analysis, with the diagnostic yield in a cohort of patients with IRDs in Korea. Design, Setting, and Participants: This was a multicenter prospective cohort study involving 264 unrelated patients with IRDs, conducted in Korea between March 2018 and February 2020. Comprehensive ophthalmologic examinations and ES analyses were performed, and ES data were reanalyzed by an IRD specialist for single nucleotide variants, copy number variants, mobile element insertions, and mitochondrial variants. Data were analyzed from March to July 2023. Main Outcomes and Measures: Diagnostic rate of conventional bioinformatic analysis and clinician-driven ES reanalysis. Results: A total of 264 participants (151 [57.2%] male; mean [SD] age at genetic testing, 33.6 [18.9] years) were enrolled, including 129 patients (48.9%) with retinitis pigmentosa and 26 patients (9.8%) with Stargardt disease or macular dystrophy. Initial bioinformatic analysis diagnosed 166 patients (62.9%). Clinician-driven reanalysis identified the molecular cause of diseases in an additional 22 patients, corresponding to an 8.3-percentage point increase in diagnostic rate. Key factors associated with new molecular diagnoses included clinical phenotype updates (4 patients) and detection of previously overlooked variation, such as structural variants (9 patients), mitochondrial variants (3 patients), filtered or not captured variants (4 patients), and noncanonical splicing variants (2 patients). Among the 22 patients, variants in 7 patients (31.8%) were observed in the initial analysis but not reported to patients, while those in the remaining 15 patients (68.2%) were newly detected by the ES reanalysis. Conclusions and Relevance: In this cohort study, clinician-centered reanalysis of ES data was associated with improved molecular diagnostic yields in patients with IRD. This approach is important for uncovering missed genetic causes of retinal disease.

Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.

BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase 2 trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥ 3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hrs for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22±5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥ 20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSION: Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.

Comparison of OCT measurements between high myopic and low myopic children.

PURPOSE: To compare the peripapillary retinal nerve fiber layer (RNFL) thickness, macular thickness, and total macular volume of high myopic eyes with those of low myopic eyes in children younger than 10 years. METHODS: Prospective, randomized, comparative study. Time-domain optical coherence tomography (OCT) (Stratus OCT; Carl Zeiss Meditec) was performed on 15 children with high myopia (refractive error greater than or equal to -6.0 diopters [D], group 1) and 20 children with low myopia (0 less than refractive error from -0.25 to -3.0 D, group 2). Fast RNFL scan and a fast macular scan with OCT were performed in both groups. The authors compared the data between the two groups. RESULTS: The mean age of the patients with high myopia was 7.8 years and that of those with low myopia was 7.2 years. The mean overall thickness of the peripapillary RNFL was 100.8 µm in the high myopes and 110.5 µm in the low myopes. There was a statistically significant difference in the overall RNFL thickness between the two groups (p < 0.05). In addition, peripapillary RNFL thinning was especially prominent in the inferior quadrant in children with high myopia (p = 0.021). The mean values of macula thickness and volume for high myopes were also significantly smaller than the mean values for low myopes (p < 0.05). CONCLUSIONS: The inferior quadrant and the overall peripapillary RNFL were significantly thinner in high myopic children relative to low myopic children. High myopic children had significantly thinner macular thickness and lower macular volumes. These structural differences should be considered in the clinical assessment of high myopic children.

Clinical and Genetic Features of Korean Patients with Achromatopsia.

This multicenter study aimed to characterize Korean patients with achromatopsia. The patients' genotypes and phenotypes were retrospectively evaluated. Twenty-one patients (with a mean age at the baseline of 10.9 years) were enrolled and followed up for a mean of 7.3 years. A targeted gene panel or exome sequencing was performed. The pathogenic variants of the four genes and their frequencies were identified. CNGA3 and PDE6C were equally the most prevalent genes: CNGA3 (N = 8, 38.1%), PDE6C (N = 8, 38.1%), CNGB3 (N = 3, 14.3%), and GNAT2 (N = 2, 9.5%). The degree of functional and structural defects varied among the patients. The patients' age exhibited no significant correlation with structural defects. During the follow-up, the visual acuity and retinal thickness did not change significantly. In CNGA3-achromatopsia patients, a proportion of patients with a normal foveal ellipsoid zone on the OCT was significantly higher than that of patients with other causative genes (62.5% vs. 16.7%; p = 0.023). In PDE6C-achromatopsia patients, the same proportion was significantly lower than that of patients with other causative genes (0% vs. 58.3%; p = 0.003). Korean patients with achromatopsia showed similar clinical features but a higher prevalence of PDE6C variants than those of other ethnic groups. The retinal phenotypes of the PDE6C variants were more likely to be worse than those of other genes.

Serum proteins for monitoring and predicting visual function in patients with recent optic neuritis.

It is unclear whether serum proteins can serve as biomarkers to reflect pathological changes and predict recovery in inflammation of optic nerve. We evaluated whether serum proteins could monitor and prognosticate optic neuritis (ON). We prospectively recruited consecutive patients with recent ON, classified as ON with anti-aquaporin-4 antibody (AQP4-ON), ON with anti-myelin oligodendrocyte glycoprotein antibody (MOG-ON), and double-seronegative ON (DSN-ON). Using ultrasensitive single-molecule array assays, we measured serum neurofilament light chain and glial fibrillary acidic protein (GFAP), and brain-derived neurotrophic factor (BDNF). We analyzed the markers according to disease group, state, severity, and prognosis. We enrolled 60 patients with recent ON (15 AQP4-ON; 14 MOG-ON; 31 DSN-ON). At baseline, AQP4-ON group had significantly higher serum GFAP levels than did other groups. In AQP4-ON group, serum GFAP levels were significantly higher in the attack state than in the remission state and correlated with poor visual acuity. As a prognostic indicator, serum BDNF levels were positively correlated with follow-up visual function in the AQP4-ON group (r = 0.726, p = 0.027). Serum GFAP reflected disease status and severity, while serum BDNF was identified as a prognostic biomarker in AQP4-ON. Serum biomarkers are potentially helpful for patients with ON, particularly those with AQP4-ON.

Comparison between aniridia with and without PAX6 mutations: clinical and molecular analysis in 14 Korean patients with aniridia.

PURPOSE: To describe clinical and molecular characteristics of Korean patients with aniridia and to compare the clinical phenotype between those having an identifiable PAX6 mutation and those not. DESIGN: Comparative case series. PARTICIPANTS: A total of 14 Korean patients from 10 families with aniridia. METHODS: Complete ophthalmologic examinations were performed for all patients. PAX6 analysis included direct sequencing of all coding regions and multiplex ligation-dependent probe amplification (MLPA) to detect large deletions when the sequencing was negative. If the PAX6 analysis failed to reveal any identifiable mutations, genomic copy number variation analysis via array comparative genomic hybridization (CGH) and candidate gene PITX3 and FOXE3 sequencing were then performed. MAIN OUTCOME MEASURES: Severity of ocular abnormalities and genetic findings. RESULTS: Sequencing of PAX6 exhibited 5 different heterozygous mutations in 8 patients from 5 families; 2 (p.Ser43Phe, IVS8-9C>G) were novel, and 3 (p.Arg208Trp, p.Arg317X, and p.X423L) have been previously reported. Among the remaining 6 patients in whom the PAX6 sequencing was negative, MLPA identified large deletions in 2 sporadic patients. However, the array CGH and candidate gene sequencing found no genomic or genetic abnormalities. The mutation detection rate was therefore 70%. Patients harboring an identifiable mutation in PAX6 had either a severe or a mild variant phenotype depending on the type of mutations. Likewise, among patients without an identifiable PAX6 mutation, their phenotypes varied widely from severe to very mild. CONCLUSIONS: This study adds 2 novel PAX6 mutations to those previously reported, providing further evidence for genetic and phenotypic heterogeneity in aniridic ocular malformation. There was no difference in the clinical phenotype between patients with and without detectable mutations in the PAX6 gene. The wide variability of ocular phenotype regardless of the presence or absence of PAX6 mutations calls for a further appreciation of the complexity in the molecular diagnosis of aniridia and suggests that this ocular malformation may be better regarded as a group of heterogeneous disorders, rather than a single disease entity, associated with mutations in PAX6 and/or other genes located elsewhere in the human genome. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.