Autozygome-guided exome-first study in a consanguineous cohort with early-onset retinal disease uncovers an isolated RIMS2 phenotype and a retina-enriched RIMS2 isoform.

Leber congenital amaurosis (LCA) and early-onset retinal degeneration (EORD) are inherited retinal diseases (IRD) characterized by early-onset vision impairment. Herein, we studied 15 Saudi families by whole exome sequencing (WES) and run-of-homozygosity (ROH) detection via AutoMap in 12/15 consanguineous families. This revealed (likely) pathogenic variants in 11/15 families (73%). A potential founder variant was found in RPGRIP1. Homozygous pathogenic variants were identified in known IRD genes (ATF6, CRB1, CABP4, RDH12, RIMS2, RPGRIP1, SPATA7). We established genotype-driven clinical reclassifications for ATF6, CABP4, and RIMS2. Specifically, we observed isolated IRD in the individual with the novel RIMS2 variant, and we found a retina-enriched RIMS2 isoform conserved but not annotated in mouse. The latter illustrates potential different phenotypic consequences of pathogenic variants depending on the particular tissue/cell-type specific isoforms they affect. Lastly, a compound heterozygous genotype in GUCY2D in one non-consanguineous family was demonstrated, and homozygous variants in novel candidate genes ATG2B and RUFY3 were found in the two remaining consanguineous families. Reporting these genes will allow to validate them in other IRD cohorts. Finally, the missing heritability of the two unsolved IRD cases may be attributed to variants in non-coding regions or structural variants that remained undetected, warranting future WGS studies.

Cyclic Esotropia Managed With Botulinum A Toxin Injections: A Report of Four Cases and Literature Review.

Cyclic strabismus is a rare entity and is unique in that patients follow variable but reliable time cycles where they alternate between orthotropia or "straight" eyes and strabismus, most commonly in the form of esotropia. Despite many theories on the underlying etiology and unique features of this diagnosis, none have been proven and its pathophysiology remains unknown. Four cases of cyclic esotropia diagnosed by pediatric ophthalmologists have been included in this report. The ages of the patients ranged from 10 months to eight years. The time duration from the onset of deviation to presentation to an ophthalmologist ranged from 1-52 weeks with three of the four patients presenting in the cyclic phase and the fourth presenting with a constant esotropia after a clear history and photographically documented cyclic esotropia for the preceding two months. All four patients were followed for periods ranging from one to four months to confirm their diagnosis or obtain multiple readings of the maximal deviation on the strabismic days before any intervention. The angle of esotropia when present ranged from 25 to 35 prism diopters and the cycle duration was 48 hours for all four cases (24 hours of esotropia followed by 24 hours of orthotropia). All patients were treated with botulinum toxin A injections to both medial recti, which resulted in an end to their cyclic deviation with excellent alignment obtained during follow-up periods ranging from 12-36 months for all cases. Cyclic esotropia is an elusive diagnosis that can be easily overlooked. When identified, classical treatment is usually extraocular muscle surgery targeting the largest angle of deviation. Many non-surgical treatments have been tried to no avail. However, in recent times, botulinum toxin A has been seen as a viable alternative.

Aberrant regeneration in an international registry of patients with 3rd-nerve palsy.

BACKGROUND/AIMS: To describe the patterns of pre-operative aberrant regeneration and motility outcomes reported in an international registry of patients with 3rd-nerve palsy treated with nasal transposition of the split lateral rectus muscle (NTSLR). METHODS: This cross-sectional study used data from an international, multicentre registry of patients with 3rd-nerve palsy treated with NTSLR. Patients with aberrant regeneration were identified, and patterns of innervation described. Demographics and postoperative success defined as horizontal alignment ≤15 PD were compared based on the presence, and type, of aberrant regeneration using Wilcoxon rank sum and Fisher's exact tests. RESULTS: Aberrant regeneration was reported in 16% (21/129) of patients. Age at diagnosis, sex, and aetiology of palsy were not significantly associated with aberrant regeneration. Abnormal movements were triggered by adduction in 52% (11/21), infraduction in 23% (5/21), and supraduction in 23% (5/21) of cases. Presentation patterns involved rectus muscle innervation in 29% (6/21) and levator muscle innervation in 71% (15/21) of cases. Although patients with aberrant regeneration had similar probability of success in comparison to those without following NTLSR (76% vs. 69%, p = 0.5), those with abnormal innervation of a rectus muscle had a lower success rate than those with abnormal innervation of the levator palpebrae superioris muscle (17% vs. 93%; p = 0.002). CONCLUSION: Successful treatment of a 3rd nerve palsy with NTSLR was not influenced by aberrant regeneration involving the levator muscle. Alternative surgical interventions should be considered when aberrant regeneration alters rectus muscle function given its adverse impact on motor outcomes with NTSLR.

Nasal Transposition of the Split Lateral Rectus Muscle for Strabismus Associated With Bilateral 3rd-Nerve Palsy.

PURPOSE: To determine the success rate and complications associated with nasal transposition of the split lateral rectus muscle (NTSLR) for treating bilateral 3rd-nerve palsy. DESIGN: Retrospective, interventional case series. METHODS: An international, multicenter registry was used for the study. The study population was all patients with bilateral 3rd-nerve palsy treated with NTSLR. Sensorimotor evaluations were conducted before and 6 months after unilateral or bilateral NTSLR. Outcome measures were postoperative horizontal alignment ≤15 prism diopters (PD), intraoperative technical difficulties, and vision-threatening complications. The association of patient demographics and surgical technique with each outcome was analyzed using multivariable logistic regression. RESULTS: A total of 34 patients were included, with a median age of 46 years (interquartile range [IQR] = 25-54 years) at surgery. The most common etiologies were ischemic (29%), neoplastic (15%), and congenital (12%). NTSLR performed unilaterally with alternative surgery on the opposite eye (65%) resulted in a median postoperative exotropia of 18 PD (IQR = 7-35 PD), and when performed bilaterally (35%) resulted in postoperative exotropia of 14 PD (IQR = 5-35 PD). Success was achieved in 50% of cases, intraoperative technical difficulties were reported in 18%, and vision-threatening complications occurred in 21%. Attachment of the lateral rectus muscle ≥10 mm posterior to the medial rectus insertion was associated with increased vision-threatening complications (odds ratio = 9.0; 95% CI = 1.3-99). CONCLUSIONS: NTSLR can address the large-angle exotropia associated with bilateral 3rd-nerve palsy. Surgeons should be aware that posterior placement of the lateral rectus muscle may increase the risk of vision-threatening complications, particularly serous choroidal effusion.

Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement.

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.

Accuracy of formulae for secondary intraocular lens power calculations in pediatric aphakia.

PURPOSE: To compare the accuracy of axial length vergence formulas versus refractive vergence formulas for secondary intraocular lens (IOL) implantation in pediatric aphakia. METHODS: This retrospective comparative study, evaluated 31 eyes of 31 patients aged ≤3.5 years, who had undergone secondary IOL implantation. The median absolute error (MedAE) was compared between axial length vergence formulas (Hoffer Q, Holladay I, SRK II, and SRK/T) and refractive vergence formulas (Lanchulev, Holladay R, Mackool, and Khan) as well as between formulas within the same vergence. RESULTS: There was a significant difference (P = 0.010) between MedAE for axial length vergence formulas [1.19 Diopter(D)] and MedAE for refractive vergence formulas (2.48 D). The MedAE of axial length vergence formulas were comparable as to Hoffer (1.59 D), Holladay (1.27 D), SRK/T (1.23 D), and SRK II (1.30 D). Among refractive vergence formulas, Lanchulev (5.00 D) and Holladay R (2.51 D) had significantly larger MedAE as compared to Khan (2.06 D) and Mackool (2.15 D). CONCLUSION: Axial length vergence formulas performed significantly better than refractive vergence formulas; however, axial length vergence formulas were comparable within the same vergence.