RTN4IP1-associated non-syndromic optic neuropathy and rod-cone dystrophy.

BACKGROUND: Biallelic variants in RTN4IP1 are a well-established cause of syndromic and nonsyndromic early-onset autosomal recessive optic neuropathy. They have more recently been reported to cause a concomitant but later-onset rod-cone dystrophy with or without syndromic features. METHODS: A comprehensive evaluation was performed that included assessment of visual and retinal function, clinical examination, and retinal imaging. Childhood ophthalmic records as well as the results of genetic testing were evaluated. RESULTS: A 24-year-old female described longstanding reduced visual acuity with more recent subjective impairment of dark adaptation. Visual acuity was subnormal in both eyes. Goldmann kinetic perimetry demonstrated scotomas in a pattern consistent with the presence of both optic neuropathy and rod-cone dystrophy with fundus exam as well as retinal imaging showing corroborating findings. Full-field electroretinography further confirmed the presence of a rod-cone dystrophy. Genetic testing demonstrated biallelic variants in RTN4IP1, one of which was novel, in association with the ocular findings. CONCLUSIONS: RTN4IP1-associated early-onset bilateral optic neuropathy with rod-cone dystrophy is a recently described clinical entity with limited reports available to-date. The present case provides additional support for this dual phenotype and identifies a novel causative variant.

VISUAL AND ANATOMICAL CHANGES AFTER DRUG CESSATION IN PENTOSAN POLYSULFATE SODIUM-ASSOCIATED MACULOPATHY.

PURPOSE: The purpose of this study was to describe a case of development of pentosan polysulfate sodium (PPS)-related maculopathy that exhibited potential improvement in imaging findings after drug cessation. METHODS: This study is a case report. RESULTS: A 66-year-old woman presented with progressive pigmentary maculopathy associated with long-term PPS usage, including development of a choroidal neovascular membrane in her right eye. After discontinuation of PPS, her clinical course was notable for partial subjective and objective improvement in visual acuity, as well as partial improvement in outer retinal architecture on ocular coherence tomography, but persistence of retinal pigment epithelium atrophy and autofluorescence changes. CONCLUSION: The course of retinopathy after discontinuation of PPS has yet to be fully determined and has so far been suggested to be progressive. Anatomical improvements seen in our case suggest that further investigations are warranted to determine whether there is potential for partial reversal of some changes in PPS maculopathy.

Ophthalmic manifestations of MEPAN syndrome.

BACKGROUND: Mitochondrial enoyl CoA reductase protein-associated neurodegeneration (MEPAN) syndrome is an ultra-rare autosomal recessive disorder caused by loss-of-function mutations in the MECR gene. The syndrome is characterized by dystonia in early childhood, basal ganglia signal abnormalities on MRI, and subsequent optic atrophy, with relative sparing of cognition. We characterize the ophthalmic manifestations observed in a patient with MEPAN syndrome, as a detailed account of ocular findings has not been published to date. METHODS: Case study of a patient with genetically confirmed MEPAN syndrome, with full ophthalmic evaluation including slit-lamp exam, sensorimotor exam, fundus photography, retinal ocular coherence tomography (OCT), electroretinography, visual evoked potentials, and visual field testing. RESULTS: The patient exhibited decreased visual acuity of 20/150 in both eyes with moderate dyschromatopsia on pseudoisochromatic plate testing, while peripheral vision was largely intact on Goldmann visual field testing. Fundus exam revealed bilateral optic atrophy with pallor most pronounced temporally, corresponding to OCT findings of diffuse retinal nerve fiber layer thinning most prominent in the papillomacular bundle region and severe ganglion cell layer thinning in the maculae. She also displayed a high frequency horizontal end-gaze nystagmus and symmetric bilateral external ophthalmoplegia. CONCLUSIONS: The pattern of bilateral optic atrophy in our patient with MEPAN syndrome shows predilection for the papillomacular bundle, similar to that seen in other mitochondrial disorders with optic neuropathy, such as Leber Hereditary Optic Neuropathy and Dominant Optic Atrophy. Our patient's external ophthalmoplegia is another neuro-ophthalmic finding that may be seen in patients with heritable mitochondrial disease, either as an isolated ocular phenotype or within a constellation of systemic manifestations.

A Case of Candida parapsilosis Stromal Keratitis after Descemet's Membrane Endothelial Keratoplasty: A Case Report and Review of the Literature.

A 68-year-old diabetic male with Fuchs endothelial corneal dystrophy cataract underwent combined DMEK and cataract surgery of the left eye. Post-operative course was complicated by a partial graft detachment on POD 3, treated with a re-bubbling procedure. The patient subsequently developed a corneal infiltrate, cultured by aqueous sample, that was found to be C. parapsilosis. Oral fluconazole and voriconazole, topical voriconazole 1%, and amphotericin B as well as intracameral and intrastromal voriconazole and amphotericin B were employed. By post-operative day 45, symptoms and signs of DMEK stromal C. parapsilosis keratitis had resolved, and a corneal scar remained. Best corrected visual acuity, at post-operative month 4, was 20/25-2 without correction. Post-DMEK fungal stromal keratitis is a rare post-operative complication. We present a case of C. parapsilosis DMEK stromal keratitis and describe diagnostic and therapeutic modalities that allowed for resolution of the infection, without explantation of the patient's graft, and preservation of visual acuity.

Identification of numerous novel disease-causing variants in patients with inherited retinal diseases, combining careful clinical-functional phenotyping with systematic, broad NGS panel-based genotyping.

Purpose: The widespread consensus is that genotyping is essential for patients with inherited retinal disease (IRD). Given the numerous ongoing gene therapy clinical trials for IRDs, identifying the pathogenic mutation in these patients has potential important therapeutic implications. In this study, we demonstrate how we identified with a high degree of confidence numerous novel disease-causing mutations, deletions, and duplications in a large consecutive IRD case series by using a judicious combination of careful, in-depth clinical-functional phenotyping to guide and integrate our genotyping approach. Methods: We conducted a retrospective analysis of data between November 2016 and March 2018 from the Duke Center for Retinal Degenerations and Ophthalmic Genetic Diseases IRD patient database, which encompassed 378 IRD cases that had not yet been previously genotyped. With the exception of some patients who presented with classical clinical-functional phenotypes that allowed for targeted gene testing, all other subjects systematically underwent next-generation sequencing-based broad, IRD-focused panel testing. Most cases were also tested for parental allele phase. Results were reviewed vis-à-vis the clinical-functional phenotypes for reconciliation and potential addition of supplemental testing such as deletion/duplication microarrays or copy number variant (CNV) analysis. Supplemental testing was driven by an IRD specialist-laboratory consensus, and decisions were clinically or genetically driven or both. Results: By judiciously using this two-way approach and leveraging to its full potential the benefits of careful, in-depth clinical-functional phenotyping by an experienced IRD specialist, more than 80% of the cases in this series were successfully genotyped. We also identified with a high degree of confidence 52 novel disease-causing mutations, deletions, and duplications. Conclusions: The combination of meticulous, expert clinical-functional phenotyping studies with systematic next-generation sequencing panel-based genotyping and microarray deletion/duplication testing or CNV analysis as applicable in accordance with the above-mentioned consensus was extremely effective at the diagnostic end, reduced costs, and saved time. IRD specialist-laboratory two-way interactions and case discussions would augment the efficacy of this approach and improve the diagnostic yield in successfully solving and genotyping IRD cases.

PAs reduce rounding interruptions in the pediatric intensive care unit.

OBJECTIVE: We investigated the proportion of encounters that were interrupted during family-centered rounds in the pediatric intensive care unit (PICU) to determine whether the use of a physician assistant (PA) significantly affected the proportion of interrupted encounters. METHODS: We evaluated 2,657 rounding encounters in our 24-bed regional referral unit. The duration of each rounding encounter and total rounding duration were recorded. The presence or absence of a PA during each rounding encounter, the occurrence of an interruption, and other potential predictors of interruptions were recorded. RESULTS: The presence of a PA during PICU rounds was significantly associated (P < .001) with a 35.4% lower likelihood of an interruption. CONCLUSIONS: Family-centered rounds in the PICU are less likely to be interrupted when a PA is present. PAs help physicians and improve rounding efficiency by safely and effectively handling certain interruptions.

Ift172 conditional knock-out mice exhibit rapid retinal degeneration and protein trafficking defects.

Intraflagellar transport (IFT) is a bidirectional transport process that occurs along primary cilia and specialized sensory cilia, such as photoreceptor outersegments. Genes coding for various IFT components are associated with ciliopathies. Mutations in IFT172 lead to diseases ranging from isolated retinal degeneration to severe syndromic ciliopathies. In this study, we created a mouse model of IFT172-associated retinal degeneration to investigate the ocular disease mechanism. We found that depletion of IFT172 in rod photoreceptors leads to a rapid degeneration of the retina, with severely reduced electroretinography (ERG) responses by 1 month and complete outer-nuclear layer (ONL) degeneration by 2 months. We investigated molecular mechanisms of degeneration and show that IFT172 protein reduction leads to mislocalization of specific photoreceptor outersegment (OS) proteins (RHO, RP1, IFT139), aberrant light-driven translocation of alpha transducin and altered localization of glioma-associated oncogene family member 1 (GLI1). This mouse model exhibits key features of the retinal phenotype observed in patients with IFT172-associated blindness and can be used for in vivo testing of ciliopathy therapies.

Gene therapy for inherited retinal degenerations: initial successes and future challenges.

Inherited retinal degenerations are a clinically and genetically heterogeneous group of conditions that have historically shared an untreatable course. In recent years, however, a wide range of therapeutic strategies have demonstrated efficacy in preclinical studies and entered clinical trials with a common goal of improving visual function for patients affected with these conditions. Gene therapy offers a particularly elegant and precise opportunity to target the causative genetic mutations underlying these monogenic diseases. The present review will provide an overview of gene therapy with particular emphasis on key clinical results to date and challenges for the future.

The Effect of Family Presence on Rounding Duration in the PICU.

BACKGROUND AND OBJECTIVE: The incorporation of family-centered rounds has become standard in PICUs across the United States. We compared rounding times in our institution, with and without family members present, to determine the effect on total rounding time and work flow. METHODS: This observational study of a convenience sample was conducted over a 17-month period (May 2014-October 2015), accounting for typical seasonal variation in the PICU. The individual patient rounding times for 2657 encounters were recorded. The presence of family members, intubation status, physician assistant participation, interruptions during rounds, attending physician's full- or part-time status, and patient census were documented. The effect of family presence on per-patient rounding time was analyzed, while controlling for influential variables. RESULTS: Family members were present during 1743 of 2657 (66%) rounding encounters. The average per-patient rounding time with and without family members present was 8.6 minutes and 7.3 minutes, respectively, a difference of 1.3 minutes per patient. In statistical models that accounted for other influential variables, the presence of family members was associated with a highly significant (20.4%, P < .001) increase in the per-patient rounding time. CONCLUSIONS: The presence of family members increases per-patient rounding times in the PICU. Family presence on rounds may have benefits that outweigh the additional time required to complete each patient interaction.

Single-Cell Migration as Studied by Scanning Electrochemical Microscopy.

Scanning electrochemical microscopy (SECM) was used to study the migration of single live head and neck cancer cells (SCC25). The newly developed graphite paste ultramicroelectrode (UME) showed significantly less fouling in comparison to a 10 µm Pt-UME and thus could be used to monitor and track the migration pattern of a single cell. We also used SECM probe scan curves to measure the morphology (height and diameter) of a single live cancer cell during cellular migration and determined these dimensions to be 11 ± 4 µm and 40 ± 10 µm, respectively. The migration study revealed that cells within the same cell line had a heterogeneous migration pattern (migration and stationary) with an estimated migration speed of 8 ± 3 µm/h. However, serum-starved synchronized cells of the same line were found to have a non-heterogeneous cellular migration pattern with a speed of 9 ± 3 µm/h. Thus, this non-invasive SECM-based technique could potentially be expanded to other cell lines to study cellular biomechanics for improved understanding of the structure-function relationship at the level of a single cell.