Hypomorphic variants in inherited retinal and ocular diseases: A review of the literature with clinical cases.

Hypomorphic variants decrease, but do not eliminate, gene function via a reduction in the amount of mRNA or protein product produced by a gene or by production of a gene product with reduced function. Many hypomorphic variants have been implicated in inherited retinal diseases (IRDs) and other genetic ocular conditions; however, there is heterogeneity in the use of the term "hypomorphic" in the scientific literature. We searched for all hypomorphic variants reported to cause IRDs and ocular disorders. We also discuss the presence of hypomorphic variants in the patient population of our ocular genetics department over the past decade. We propose that standardized criteria should be adopted for use of the term "hypomorphic" to describe gene variants to improve genetic counseling and patient care outcomes.

Identification of the Vibrational Optical Coherence Tomography Corneal Cellular Peak.

Purpose: Our team previously identified the presence of five corneal resonant frequency (RF) peaks in healthy volunteers using vibrational optical coherence tomography (VOCT). Prior studies have suggested that the ≤100 Hz RF peak represents the cellular element of tissue. The aim of this study was to confirm that this peak reflects the human corneal cellular component using VOCT and histological analysis. Methods: Two human research globes were obtained from the same donor, and VOCT measurements were collected from the full-thickness corneas. A microkeratome was then used to create serial-free corneal caps from each cornea, with VOCT performed on the residual stromal bed after each excision. All lamellar sections from both globes were sent for histological analysis to determine cellularity. Cell counts on the specimens were performed by two independent observers. Results: The average of the normalized ≤100 Hz peak values before lamellar sectioning was significantly higher than the average of this peak values after the first, second, and third cuts (P = 0.023), which was 33.9% less than before any cuts. The cell count values in the first slice were significantly higher than the average cell count values of the three deeper slices (P < 0.001), and the cell count dropped 84.4% after the first slice was removed. Conclusions: The findings of this study suggest that the ≤100 Hz corneal peak identified by VOCT corresponds to the cellular component of the cornea. Translational Relevance: This work furthers our understanding of the origin of the corneal ≤100 Hz peak identified using VOCT.

Signal Peptide Variants in Inherited Retinal Diseases: A Multi-Institutional Case Series.

Signal peptide (SP) mutations are an infrequent cause of inherited retinal diseases (IRDs). We report the genes currently associated with an IRD that possess an SP sequence and assess the prevalence of these variants in a multi-institutional retrospective review of clinical genetic testing records. The online databases, RetNet and UniProt, were used to determine which IRD genes possess a SP. A multicenter retrospective review was performed to retrieve cases of patients with a confirmed diagnosis of an IRD and a concurrent SP variant. In silico evaluations were performed with MutPred, MutationTaster, and the signal peptide prediction tool, SignalP 6.0. SignalP 6.0 was further used to determine the locations of the three SP regions in each gene: the N-terminal region, hydrophobic core, and C-terminal region. Fifty-six (56) genes currently associated with an IRD possess a SP sequence. Based on the records review, a total of 505 variants were present in the 56 SP-possessing genes. Six (1.18%) of these variants were within the SP sequence and likely associated with the patients' disease based on in silico predictions and clinical correlation. These six SP variants were in the CRB1 (early-onset retinal dystrophy), NDP (familial exudative vitreoretinopathy) (FEVR), FZD4 (FEVR), EYS (retinitis pigmentosa), and RS1 (X-linked juvenile retinoschisis) genes. It is important to be aware of SP mutations as an exceedingly rare cause of IRDs. Future studies will help refine our understanding of their role in each disease process and assess therapeutic approaches.

Enucleations, Eviscerations, and Exenterations at a Supratertiary-care Hospital in Puerto Rico: A Retrospective Study.

OBJECTIVE: To provide a descriptive analysis of the indications and the intraoperative and postoperative complications of eye enucleations and eviscerations, and orbital exenterations performed at the only academic institution in Puerto Rico providing supratertiary care. METHODS: A retrospective medical record review of patients who underwent enucleations, eviscerations, and exenterations from January 2015 through June 2020 was conducted. The data were analyzed to generate a descriptive profile of the demographic characteristics of the patients, their clinical indications and surgical complications, and a histopathological diagnosis per type of eye-removal procedure. RESULTS: A total of 118 eyes were removed via enucleation, evisceration, or exenteration over the 66-month study period. The average patient age was 64 (±17.5) years and 63.8% of the patients were male. The most frequently performed eye-removal procedure was enucleation (73.7%), followed by evisceration (18.6%) and exenteration (7.6%). The main clinical indications for enucleations and eviscerations were infectious processes, namely panophthalmitis, endophthalmitis, and/or perforated corneal ulcers, that failed medical management. In our sample, squamous cell carcinoma was the most common diagnosis (both clinically and histopathologically) leading to exenteration. Postoperative complications in our patient cohort were minimal. CONCLUSION: At our institution, enucleations predominate over eviscerations. Retrospective reviews published in recent years indicate that the rate of eviscerations at our institution is comparatively low. The results of this study, the first of its kind at our institution, may encourage a re-evaluation of the indications for evisceration versus enucleation in our patient population.

In Vivo Determination of the Human Corneal Elastic Modulus Using Vibrational Optical Coherence Tomography.

Purpose: To determine the in vivo elastic modulus of the human cornea using vibrational optical coherence tomography (VOCT). Methods: Vibrational analysis coupled with optical coherence tomography (OCT) was used to obtain the resonant frequency (RF) and elastic modulus of corneal structural components. VOCT corneal thickness values were measured using OCT images and correlated with corneal thickness determined with Pentacam (Oculus, Wetzlar, Germany). Moduli were obtained at two locations: central cornea (CC) and inferior cornea (IC). Measurements were obtained with and without anesthetic eye drops to assess their effect on the modulus measurements. Results: VOCT thickness values correlated positively (R2 = 0.97) and linearly (y = 1.039x-16.89) with those of Pentacam. Five RF peaks (1-5) were present, although their presence was variable across eyes. The RF for peaks 1 to 5 in the CC and IC ranged from 73.5 ± 4.9 to 239 ± 3 Hz and 72.1 ± 6.3 to 238 ± 4 Hz, respectively. CC and IC moduli for peaks 1 to 5 ranged from 1.023 ± 0.104 to 6.87 ± 0.33 MPa and 0.98 ± 0.15 to 6.52 ± 0.79 MPa, respectively. Topical anesthesia did not significantly alter the modulus (P > 0.05 for all), except for peak 2 in the CC (P < 0.05). Conclusions: This pilot study demonstrates the utility of VOCT as an in vivo, noninvasive technology to measure the elastic modulus in human corneas. The structural origin of these moduli is hypothesized based on previous reports, and further analyses are necessary for confirmation. Translational Relevance: This work presents VOCT as a novel approach to assess the in vivo elastic modulus of the cornea, an indicator of corneal structural integrity and health.