Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia.

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.

A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene.

Retinal cone photoreceptors mediate fine visual acuity, daylight vision, and color vision. Congenital hereditary conditions in which there is a lack of cone function in humans cause achromatopsia, an autosomal recessive trait, characterized by low vision, photophobia, and lack of color discrimination. Herein we report the identification of mutations in the PDE6C gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase as a cause of autosomal recessive achromatopsia. Moreover, we show that the spontaneous mouse mutant cpfl1 that features a lack of cone function and rapid degeneration of the cone photoreceptors represents a homologous mouse model for PDE6C associated achromatopsia.

The presence of anomalous extraocular bands in Duane retraction syndrome.

PURPOSE: To determine the prevalence of anomalous extraocular bands in patients who underwent surgery for Duane syndrome and to compare the clinical findings in patients with and without bands. METHODS: Thirty-one patients with Duane syndrome who had their first surgery on rectus muscles to correct the primary deviation and abnormal head posture were included in this retrospective study. Patients were divided into two groups depending on the identification of anomalous extraocular bands intraoperatively. Baseline clinical characteristics were compared between the groups. RESULTS: A total of 31 patients were included. Anomalous bands were found in 6 of 19 (32%) patients with esotropic Duane syndrome and 9 of 12 (75%) with exotropic Duane syndrome (P = 0.02). In esotropic Duane syndrome, the bands were localized under the medial rectus muscle in 5 patients and under the lateral rectus muscle in 1 patient. All of the bands in patients with exotropic Duane syndrome were under the lateral rectus muscle. The amount of preoperative primary deviation, globe retraction, and up- or downshoot were similar between groups. All of the bands had distinct tight insertion on the sclera, requiring a sharp dissection for disinsertion. In 7 cases, the anomalous band was a translucent structure that could be identified under the surgical microscope as scleral indentation during forced duction testing. Histological examination of 6 cases revealed only fibrous tissue in 4 and accompanying striated muscle tissue in 2 patients. CONCLUSIONS: The present study highlights the incidence of anomalous bands in Duane syndrome. Repeating forced duction testing after disinsertion of the affected muscle and excision of the anomalous band is helpful for intraoperative identification of these structures.

Acquired Comitant Esotropia in Children and Young Adults: Clinical Characteristics, Surgical Outcomes, and Association With Presumed Intensive Near Work With Digital Displays.

PURPOSE: To describe the clinical characteristics and surgical outcomes of acquired comitant esotropia with symptomatic diplopia. METHODS: The clinical features and surgical outcomes of 27 patients with diplopia due to acquired comitant esotropia were retrospectively reviewed. Exclusion criteria were a history of prematurity, cerebral palsy, head trauma, or febrile illness before the onset of acquired comitant esotropia, incomitant strabismus, accommodative spasm, and divergence paralysis. Neurological evaluation and neuroimaging was normal in all patients. RESULTS: Mean age at onset of esotropia and diplopia was 17.8 ± 10.3 years (range: 6 to 44 years). Eighteen patients had simple myopia (range: -0.25 to -7.75 diopters [D]), 5 patients had hypermetropia (range: 0.50 to 1.50 D), and 4 patients had emmetropia. The angle of deviation prior to surgery was 35.6 ± 10.3 prism diopters (PD) for far and 38.0 ± 10.5 PD for near fixation. Twenty-three patients (85%) were prism responders. A history of excessive near work (≥ 4 hours a day) with digital displays was present in 21 (78%) patients. Diplopia resolved and some level of stereovision was achieved in all patients postoperatively. Three patients had recurrence of esotropia in long-term follow-up. CONCLUSIONS: The differentiation of a serious pathology from a straightforward optically or medically treatable condition in patients with a subacute or chronic history of diplopia is challenging for the clinician. The recognition of acquired comitant esotropia due to presumed intensive near activities with digital display may avoid time-consuming and costly laboratory investigations. Most of the patients in this series were prism responders and surgery for the prism-adapted angle was successful in restoring binocular vision. [J Pediatr Ophthalmol Strabismus. 2020;57(4):251-256.].

Botulinum toxin-A injection in esotropic Duane syndrome patients up to 2 years of age.

PURPOSE: To evaluate the role of botulinum toxin-A (BTX) injection as the primary treatment for patients with esotropic Duane retraction syndrome ≤2 years of age. METHODS: The medical records of patients with esotropic Duane syndrome who underwent unilateral or bilateral BTX injection to the medial rectus muscle at or before 2 years of age were reviewed retrospectively. The following data were extracted from the record: laterality, age at the time of injection, primary position deviation, duction deficit, anomalous head posture, globe retraction before and after injection, further surgeries, and complications. Success was defined as permanent resolution of esotropia and head turn in primary position at final follow-up. RESULTS: A total of 15 patients (14 unilateral, 1 bilateral) were included. Before BTX injection the mean primary esotropia at near with full cycloplegic refraction was 29.3Δ ± 14.4Δ; the mean head turn, 23° ± 11°. Mean duration of follow-up was 37 ± 29 months (range, 7-96 months). Orthotropia and resolution of head turn was achieved in 7 patients (46.7%). In subgroup analysis, success rate gradually decreased from 100% in patients ≤7 months of age to 33.3% in patients 8-12 months of age, and 20% in patients >12 months of age. Seven patients (46.7%) required surgery (medial rectus recession and/or superior rectus transposition) because of residual head turn and esodeviation following BTX. CONCLUSIONS: In this patient cohort, orthotropia in primary position and correction of head turn were achieved with a single BTX injection in about half of the patients ≤2 years of age and all patients ≤7 months of age. BTX injection early in infancy can obviate the need for surgery in esotropic Duane syndrome.

Superior or inferior rectus transposition in esotropic Duane syndrome: a longitudinal analysis.

PURPOSE: To evaluate the results of superior rectus transposition (SRT) or inferior rectus transposition (IRT) in esotropic Duane syndrome. METHODS: The medical records of patients with esotropic Duane syndrome who underwent ciliary vessel-sparing SRT or IRT by a single surgeon in private practice were included. Pre- and postoperative head posture, primary position deviation, fundus torsion, collapse in pattern, and improvement in ductions were analyzed between groups. RESULTS: A total of 21 patients were included: 7 had a V-pattern esotropia and/or larger abduction deficiency in downgaze compared to upgaze and underwent IRT; 14 underwent SRT of which 6 had A pattern and/or larger abduction deficiency in upgaze compared to downgaze. Orthotropia within 10Δ of esotropia was achieved in 10 patients (71.4%) with SRT and 4 patients (57.1%) with IRT. Pattern was reduced and abduction improved in all patients. The improvement in abduction was slightly better in elevation after SRT compared with IRT (1.7 ± 1 vs 1.4 ± 0.7; P = 0.4) and in depression after IRT compared to SRT (2 ± 1.2 vs 1.1 ± 0.7; P = 0.05). CONCLUSIONS: Both SRT and IRT procedures effectively correct the head posture and primary position deviation in esotropic Duane patients. SRT can be advantageous in patients with an A pattern or more limitation of abduction in elevation; IRT, in patients with a V pattern or more limitation of abduction in depression.

Clinical and sensorial characteristics of microtropia.

PURPOSE: To investigate the clinical characteristics and sensory mechanism of microtropia. METHODS: Twenty patients with primary microtropia were studied. The patients were evaluated by the visuscope, Irvine prism test, Bagolini striated glasses test, Worth 4-dot test (W4D), TNO, and stereo-fly plate of the Titmus test. RESULTS: The patients who had positive cover test and eccentric fixation showed wandering eccentric fixation. The Irvine prism test was positive in all the patients by using prisms of different strengths and positions. All the patients had abnormal fusion at near. At distance, 15 patients had abnormal fusion by the Bagolini glasses and 8 patients had abnormal fusion by the Worth test. Ten patients had gross stereopsis and the remaining 10 had no measurable stereopsis. CONCLUSIONS: The type of microtropia with eccentric fixation without identity is mainly due to the wandering eccentric fixation. All patients with microtropia have abnormal fusion without fixation point scotoma because positive prism test response does not change to normal by using prisms of different strengths and positions. Differences in fusion results are mainly due to the weakness of abnormal fusion rather than fixation point scotoma. With occlusion treatment, amblyopia can be improved, whereas binocular defects of microtropia cannot be improved.