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ABSTRACT Thyroid eye disease (TED) can cause incomitant strabismus with muscle restriction, resulting in diplopia and patient discomfort and discontent. Surgical correction of TED‐associated restrictive strabismus has been attempted, with fixed and adjustable suture success rates varying from 38% to 82%. This paper reviews five articles that explored the utility of the intraoperative relaxed muscle positioning (IRMP) technique in patients with restrictive strabismus due to TED. While IRMP is a useful technique for addressing TED‐related strabismus and is effective in patients with incomitant strabismus, disease reactivation, staged and unplanned surgeries, combined horizontal and vertical deviations, and previous orbital decompression surgeries, it is probable that this approach can be utilized in children with restrictive types of strabismus. Therefore, further studies are required. The intraoperative relaxed muscle positioning technique is a useful surgical tool in treating thyroid eye disease‐related restrictive strabismus.

Background Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are inherited retinal diseases that cause early onset severe visual impairment. An accurate molecular diagnosis can refine the clinical diagnosis and allow gene specific treatments. Methods We developed a capture panel that enriches the exonic DNA of 163 known retinal disease genes. Using this panel, we performed targeted next generation sequencing (NGS) for a large cohort of 179 unrelated and prescreened patients with the clinical diagnosis of LCA or juvenile RP. Systematic NGS data analysis, Sanger sequencing validation, and segregation analysis were utilised to identify the pathogenic mutations. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis. Results Pathogenic mutations for 72 patients (40%) were identified, including 45 novel mutations. Of these 72 patients, 58 carried mutations in known LCA or juvenile RP genes and exhibited corresponding phenotypes, while 14 carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found that homozygous mutations in PRPH2 can cause LCA/juvenile RP. Guided by the molecular diagnosis, we reclassified the clinical diagnosis in two patients. Conclusions We have identified a novel gene and a large number of novel mutations that are associated with LCA/juvenile RP. Our results highlight the importance of molecular diagnosis as an integral part of clinical diagnosis.

Rui Chen and colleagues identify mutations in NMNAT1 as a new cause of Leber congenital amaurosis. They further show that all examined individuals with NMNAT1 mutations have macular colobomas, a condition marked by severe degeneration of the central retina. Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration ( Wld s ) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder.

Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from RPE65 mutations may also have potential for success but only if the retinal photoreceptor layer is intact, as in the early-disease stage-treated animals. Here, we use high-resolution in vivo microscopy to quantify photoreceptor layer thickness in the human disease to define the relationship of retinal structure to vision and determine the potential for gene therapy success. The normally cone photoreceptor-rich central retina and rod-rich regions were studied. Despite severely reduced cone vision, many RPE65-mutant retinas had near-normal central microstructure. Absent rod vision was associated with a detectable but thinned photoreceptor layer. We asked whether abnormally thinned RPE65-mutant retina with photoreceptor loss would respond to treatment. Gene therapy in Rpe65-/-mice at advanced-disease stages, a more faithful mimic of the humans we studied, showed success but only in animals with better-preserved photoreceptor structure. The results indicate that identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in humans with RPE65 mutations and in other retinal degenerative disorders now moving from proof-of-concept studies toward clinical trials.

Nanophthalmos is a rare disorder of eye development characterized by extreme hyperopia (farsightedness), with refractive error in the range of +8.00 to +25.00 diopters. Because the cornea and lens are normal in size and shape, hyperopia occurs because insufficient growth along the visual axis places these lensing components too close to the retina. Nanophthalmic eyes show considerable thickening of both the choroidal vascular bed and scleral coat, which provide nutritive and structural support for the retina. Thickening of these tissues is a general feature of axial hyperopia, whereas the opposite occurs in myopia. We have mapped recessive nanophthalmos to a unique locus at 11q23.3 and identified four independent mutations in MFRP, a gene that is selectively expressed in the eye and encodes a protein with homology to Tolloid proteases and the Wnt-binding domain of the Frizzled transmembrane receptors. This gene is not critical for retinal function, as patients entirely lacking MFRP can still have good refraction-corrected vision, produce clinically normal electroretinograms, and show only modest anomalies in the dark adaptation of photoreceptors. MFRP appears primarily devoted to regulating axial length of the eye. It remains to be determined whether natural variation in its activity plays a role in common refractive errors.

BackgroundX-linked retinitis pigmentosa (XLRP) is the most severe form of retinitis pigmentosa (RP) and accounts for 15–20% of all RP cases. In this study, we investigated the progression of visual acuity loss across age groups in female carriers and compared it to affected males.MethodsA PubMed literature search was conducted, and RP2 cases were included based on specific inclusion criteria. Visual acuity (VA), refractive error spherical equivalent (SE), and retinal findings were recorded. Cross-sectional analyses investigated the relationship between VA and age in carrier females and affected males. Genotype-phenotype VA correlations were studied using t-tests.Results35 carrier females and 28 affected males with confirmed RP2 mutations were collected from 13 studies. The mean age and logMAR VA of carrier females were 44.2 ± 17.4 years, and 0.5 ± 0.5, respectively. 78.8% of carrier females showed abnormal XLRP-related fundus findings and had significantly reduced VA compared to those with normal fundi (0.6 ± 0.5 vs. 0.1 ± 0.1; p = 0.03). Compared to affected males, no statistical correlation was found between logMAR VA and advancing age in carrier females (p = 0.75). Statistically significant linear correlations were found between logMAR VA and SE in each of carrier females (p = 0.01). There were no observed differences in logMAR VA based on mutation type (p = 0.97) or mutation location (p = 0.83). Anisometropia was observed in 38% of carrier females and 68% of affected males; these prevalence numbers are statistically significant between the two groups (1.7 ± 0.3 vs. 3.9 ± 10.9 dioptres; p = 0.03).ConclusionsRP2 carrier females generally maintain good VA throughout their lifetime, as opposed to affected males, whose vision progressively declines. Our study provides important VA prognostic data that is crucial for patient counseling.

BackgroundCockayne syndrome is a rare autosomal recessive neurodegenerative disorder caused by mutations of either the ERCC6/CSB or ERCC8/CSA genes. Here, we describe two sisters with Cockayne syndrome caused by compound heterozygous mutations in the ERCC8 gene using multimodal imaging. Significant ophthalmic and systemic phenotypic variability is discussed.Materials and methodsMultimodal imaging was performed in two affected sisters and included electroretinography, optical coherence tomography, ultra-wide-field confocal scanning laser ophthalmoscopy, fundus autofluorescence and fluorescein angiography, and magnetic resonance imaging. Genetic analyses were performed on the affected sisters, both parents, and three unaffected siblings.ResultsThe older sister (Patient 1) had mental retardation, bilateral hearing loss, ataxia, and decreased visual acuity with retinal dystrophy. Radiographic studies revealed microcephaly, cerebral and cerebellar atrophy, ventriculomegaly, and a diffusely thickened skull. Full-field electroretinography waveforms were severely diminished with attenuation of cone and rod responses. The younger sister (Patient 2) had similar clinical features, including ataxia, bilateral hearing loss, and decreased visual acuity with retinal dystrophy. She also had paranoid schizophrenia. Wide-field fundus autofluorescence showed scattered areas of retinal pigment epithelium atrophy, which was different from her sister. Genetic analysis revealed two mutations in the ERCC8 gene shared by the sisters. These include an unreported missense point mutation: p.Thr328Ser:c.983C > G, and another previously reported pathogenic missense mutation: p.Ala205Pro:c.613G > C. Familial testing showed in trans segregation of these mutations with unaffected siblings inheriting one or neither mutation, but not both.ConclusionThe clinical presentation and genetic studies confirmed a diagnosis of Cockayne syndrome in both sisters caused by compound heterozygous mutations in the ERCC8 gene on chromosome 10. Multimodal ocular imaging and systemic findings revealed wide phenotypic variability between the affected siblings.

KAT6A mutations are associated with intellectual disability, speech delays, dysmorphic facial features, and strabismus. However, detailed ocular findings of such patients have not yet been published. In this case report, the authors present a patient with a KAT6A mutation and optic nerve malformation. [J Pediatr Ophthalmol Strabismus. 2021;58(3):e9–e11.]

Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about onethird (n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families—all from the United States—showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no “region of overlap” among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversionbased exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.