Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder.

PURPOSE: Pathogenic variants in Kinesin Family Member 1A (KIF1A) are associated with KIF1A-associated neurological disorder (KAND). We report the clinical phenotypes and correlate genotypes of individuals with KAND. METHODS: Medical history and adaptive function were assessed longitudinally. In-person evaluations included neurological, motor, ophthalmologic and cognitive assessments. RESULTS: We collected online data on 177 individuals. Fifty-seven individuals were also assessed in-person. Most individuals had de novo heterozygous missense likely pathogenic/pathogenic KIF1A variants. The most common characteristics were hypotonia, spasticity, ataxia, seizures, optic nerve atrophy, cerebellar atrophy, and cognitive impairment. Mean Vineland Adaptive Behavior Composite score (VABS-ABC) was low (M=62.9, SD=19.1). The mean change in VABS-ABC over time was -3.1 (SD=7.3). The decline in VABS-ABC was associated with the age at first assessment and abnormal electroencephalogram/seizure. There was a positive correlation between Evolutionary Scale Model (ESM) score for the variants and final VABS-ABC (p=0.003). Abnormal electroencephalogram/seizure, neuroimaging result, and ESM explain 34% of the variance in final VABS-ABC (p<0.001). CONCLUSION: In-person assessment confirmed caregiver report and identified additional visual deficits. Adaptive function declined over time consistent with both the neurodevelopmental and neurodegenerative nature of the condition. Using ESM score assists in predicting phenotype across a wide range of unique variants.

Venous Tortuosity in COL4A2-Associated Gould Syndrome.

Mutations in collagen-encoding genes have been linked to numerous systemic diseases. Specifically, pathologic alterations in COL4A2 have been linked to Gould syndrome, a hereditary angiopathy affecting the brain, kidneys, and eyes. However, the ocular phenotype associated with COL4A2-associated disease has yet to be fully characterized. In this report, we describe a novel variant in COL4A2 identified in a 48-year-old woman and her 15-year-old daughter. Funduscopic examination demonstrated significant venous and arteriolar tortuosity. Genetic testing revealed a novel variant, c.2321G>A:p.(Gly774Glu), in COL4A2. This vascular phenotype is similar to the familial retinal arterial tortuosity seen in COL4A2-associated Gould syndrome with additional venous involvement. [Ophthalmic Surg Lasers Imaging Retina 2023;54:536-539.].

Osteopathia striata with cranial sclerosis causing a compressive optic neuropathy.

BACKGROUND: Osteopathia striata combined with cranial sclerosis (OS-CS) is an inherited skeletal dysplasia that manifests with macrocephaly, orofacial abnormalities, thickened craniofacial bones, and vertically oriented radiodensities of the long bones. CASE REPORT: Here, we present a severe case of OS-CS in a 4-year-old girl causing optic neuropathy as shown by radiographic evidence, ophthalmic findings, and histopathology. Previous genetic testing in this patient revealed a de novo heterozygous mutation in AMER1 (c.1057C>T, p.Arg353Ter). Although the patient had a pre-existing, appropriately functioning, ventriculoperitoneal (VP) shunt, a subsequent MRI of the brain and orbits showed narrowing of the bilateral optic nerve canals secondary to osseous thickening causing bilateral optic nerve atrophy, worse on the left. The patient underwent staged bilateral orbital osteotomies, optic canal decompression, and bilateral frontal craniotomy, and at 11 months postoperatively, her vision remained stable. Conclusions: While up to 50% of the patients with OS-CS may experience hearing loss due to cranial nerve compression, we present a case of severe visual loss secondary to OS-CS-associated optic nerve compression.

Indolent Nonprogressive Multifocal Choroidal Lymphoid Lesions: A Clinical-Histopathological Correlation.

PURPOSE: To present the clinicopathologic correlation of indolent nonprogressive multifocal choroidal lesions, clinically presumed to be lymphoid in nature, using multimodal imaging and histopathological analysis of a donor eye. DESIGN: Case study and clinicopathological correlation. PARTICIPANTS: A 77-year-old man of Caucasian ancestry with indolent, nonprogressive, multifocal, choroidal infiltration of his right eye, presumed to be lymphocytic in nature based on the appearance of the lesions, was followed up for 19 years. METHODS: Multimodal imaging, including fundus photography, B-scan ultrasonography, OCT, fluorescein angiography, and indocyanine green angiography, was performed throughout the 19 years of follow-up before the patient's death. The involved eye was preserved 21 hours postmortem and analyzed using standard histopathological and immunohistochemical techniques. MAIN OUTCOME MEASURES: Correlation of findings on multimodal imaging with histopathological and immunohistochemical findings in the involved eye. RESULTS: Clinical examination over the course of 19 years showed no deterioration in the visual acuity of the involved eye. Multimodal imaging revealed yellow-orange choroidal lesions that showed no appreciable progression during the 19 years of follow-up. These areas stained minimally on fluorescein angiography. Indocyanine green angiography revealed tortuous choroidal vessels and fluorescence blockage. Enhanced-depth imaging OCT revealed hyporeflective, homogenous choroidal thickening. Light microscopy, histopathology, and immunohistochemistry showed that the lesions were composed of small, mature-appearing B cells that spared the choriocapillaris. The findings were most consistent with extranodal marginal-zone lymphoma of the mucosa-associated lymphoid tissue (MALT). CONCLUSIONS: Indolent, nonprogressive, multifocal, choroidal lymphoid lesions in this patient remained confined to the choroid, as determined based on the clinical examination and imaging for almost 2 decades, with no clinical evidence of extension into the retina. Light microscopy, histopathology, and immunohistochemistry postmortem showed that the lesions were composed of small, mature-appearing B cells that spared the choriocapillaris. The findings were consistent with extranodal marginal-zone lymphoma of the MALT. This entity is distinct from more aggressive uveal and choroidal lymphomas and is expected to remain relatively stationary on long-term clinical follow-up, with a good visual prognosis.

IPSILATERAL BULLOUS EXUDATIVE RETINAL DETACHMENT ASSOCIATED WITH EXTRACORPOREAL MEMBRANE OXYGENATION.

PURPOSE: To describe the first known case of an extracorporeal membrane oxygenation (ECMO)-related complication in an adult. METHODS: Case report. RESULTS: A 34-year-old man awaiting a lung transplant for interstitial lung disease was connected to an ECMO circuit as a bridge to lung transplant, with a drainage catheter attached to his right internal jugular vein. Shortly after he was cannulated, he developed blurred vision in his right eye and was found to have a progressively worsening bullous exudative retinal detachment. After receiving a lung transplant and getting decannulated from ECMO, his bullous detachment rapidly improved. The patient's clinical course as well as his ophthalmic testing showed findings inconsistent with alternative diagnoses such as central serous chorioretinopathy. His findings were best explained as a complication of ECMO cannulation. CONCLUSION: Extracorporeal membrane oxygenation may be associated with bullous exudative retinal detachment in rare cases where there is a possible anatomical or physiological predisposition.

ARE THERE TWO FORMS OF MULTIPLE EVANESCENT WHITE DOT SYNDROME?

PURPOSE: To analyze the nature of multiple evanescent white dot syndrome (MEWDS) and differentiate an idiopathic or primary form of MEWDS from a secondary form that is seen in association with other clinical conditions affecting the posterior segment of the eye. METHODS: Clinical and multimodal imaging findings including color fundus photography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral-domain optical coherence tomography, and optical coherence tomography angiography of patients with secondary MEWDS are presented. RESULTS: Twenty consecutive patients with secondary MEWDS were evaluated. Fifteen patients were female. Most were young adults aged between 20 to 40 years with myopia (less than -6 diopters). Pathologic conditions associated with the secondary MEWDS reaction were high myopia (greater than -6 diopters) in two eyes, previous vitreoretinal surgery for rhegmatogenous retinal detachment in 2 eyes, and manifestations of multifocal choroiditis in 18 eyes. In all eyes, the MEWDS lesions followed a course of progression and resolution independent from the underlying condition. CONCLUSION: Secondary MEWDS seems to be an epiphenomenon ("EpiMEWDS") that may be seen in association with clinical manifestations disruptive to the choriocapillaris-Bruch membrane-retinal pigment epithelium complex.

DIFFERENTIAL RESPONSE TO GLUCOCORTICOID IMMUNOSUPPRESSION OF TWO DISTINCT INFLAMMATORY SIGNS ASSOCIATED WITH PUNCTATE INNER CHOROIDOPATHY.

PURPOSE: To describe the differential response of two distinct inflammatory signs occurring in eyes with punctate inner choroidopathy. METHODS: Retrospective, observational case series using multimodal imaging. RESULTS: Four eyes of 4 myopic female patients (mean age of 35 years, range 31-42 years) presenting with retinal manifestations of punctate inner choroidopathy. All study eyes had 2 distinct signs of active disease: 1) acute focal hyperreflective lesions splitting the retinal pigment epithelium/Bruch membrane complex on optical coherence tomography which appeared hypoautofluorescent on fundus autofluorescence and 2) more diffuse areas of outer retinal disruption limited to the ellipsoid zone and interdigitation zone on optical coherence tomography and corresponding to hyperautofluorescence on fundus autofluorescence. All patients were treated with oral prednisone and demonstrated prompt regression of the retinal pigment epithelium/Bruch membrane complex lesions with a concurrent, paradoxical centrifugal expansion of outer retinal disruption. The outer retinal disruption eventually resolved in all eyes (mean time of 6 weeks, range 4-10 weeks). CONCLUSION: In patients with punctate inner choroidopathy, two distinct inflammatory signs observed with multimodal imaging display a differential response to systemic corticosteroids. Although focal inflammatory lesions splitting the retinal pigment epithelium/Bruch membrane complex seem to respond rapidly, the more diffuse, transient outer retinal disruption shows little response. This difference in treatment response may reflect different immunological phenomena with independent natural history.

Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency.

BACKGROUND: Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. MATERIALS AND METHODS: Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. RESULTS: We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. CONCLUSIONS: We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

Resident physician exposure to novel coronavirus (2019-nCoV, SARS-CoV-2) within New York City during exponential phase of COVID-19 pandemic: Report of the New York City Residency Program Directors COVID-19 Research Group.

Background From March 2-April 12, 2020, New York City (NYC) experienced exponential growth of the COVID-19 pandemic due to novel coronavirus (SARS-CoV-2). Little is known regarding how physicians have been affected. We aimed to characterize COVID-19 impact on NYC resident physicians. Methods IRB-exempt and expedited cross-sectional analysis through survey to NYC residency program directors (PDs) April 3-12, 2020, encompassing events from March 2-April 12, 2020. Findings From an estimated 340 residency programs around NYC, recruitment yielded 91 responses, representing 24 specialties and 2,306 residents. 45.1% of programs reported at least one resident with confirmed COVID-19: 101 resident physicians were confirmed COVID-19-positive, with additional 163 residents presumed positive for COVID-19 based on symptoms but awaiting or unable to obtain testing. 56.5% of programs had a resident waiting for, or unable to obtain, COVID-19 testing. Two COVID-19-positive residents were hospitalized, with one in intensive care. Among specialties with >100 residents represented, negative binomial regression indicated that infection risk differed by specialty (p=0.039). Although most programs (80%) reported quarantining a resident, with 16.8% of residents experiencing quarantine, 14.9% of COVID-19-positive residents were not quarantined. 90 programs, encompassing 99.2% of the resident physicians, reported reuse or extended mask use, and 43 programs, encompassing 60.4% of residents, felt that personal protective equipment (PPE) was suboptimal. 65 programs (74.7%) have redeployed residents elsewhere to support COVID-19 efforts. Interpretation Many resident physicians around NYC have been affected by COVID-19 through direct infection, quarantine, or redeployment. Lack of access to testing and concern regarding suboptimal PPE are common among residency programs. Infection risk may differ by specialty. Funding AHA, MPB, RWSC, CGM, LRDG, and JDH are supported by NEI Core Grant P30EY019007, and unrestricted grant from RPB. ACP and JS are supported by Parker Family Chair. SXX is supported by University of Pennsylvania.

New York City COVID-19 resident physician exposure during exponential phase of pandemic.

BACKGROUNDFrom March 2, 2020, to April 12, 2020, New York City (NYC) experienced exponential growth of the COVID-19 pandemic due to novel coronavirus (SARS-CoV-2). Little is known regarding how physicians have been affected. We aimed to characterize the COVID-19 impact on NYC resident physicians.METHODSIRB-exempt and expedited cross-sectional analysis through survey to NYC residency program directors April 3-12, 2020, encompassing events from March 2, 2020, to April 12, 2020.RESULTSFrom an estimated 340 residency programs around NYC, recruitment yielded 91 responses, representing 24 specialties and 2306 residents. In 45.1% of programs, at least 1 resident with confirmed COVID-19 was reported. One hundred one resident physicians were confirmed COVID-19-positive, with an additional 163 residents presumed positive for COVID-19 based on symptoms but awaiting or unable to obtain testing. Two COVID-19-positive residents were hospitalized, with 1 in intensive care. Among specialties with more than 100 residents represented, negative binomial regression indicated that infection risk differed by specialty (P = 0.039). In 80% of programs, quarantining a resident was reported. Ninety of 91 programs reported reuse or extended mask use, and 43 programs reported that personal protective equipment (PPE) was suboptimal. Sixty-five programs (74.7%) redeployed residents elsewhere to support COVID-19 efforts.CONCLUSIONMany resident physicians around NYC have been affected by COVID-19 through direct infection, quarantine, or redeployment. Lack of access to testing and concern regarding suboptimal PPE are common among residency programs. Infection risk may differ by specialty.FUNDINGNational Eye Institute Core Grant P30EY019007; Research to Prevent Blindness Unrestricted Grant; Parker Family Chair; University of Pennsylvania.

Unique histopathologic features of the eyelid dermatofibroma.

Purpose: Dermatofibromas are common cutaneous lesions, but rarely occur in the eyelid skin. The reason for the low incidence in the palpebral skin has not been elucidated. In this study, we analyze the histopathologic features of an illustrative case of dermatofibroma and review previously published cases to determine whether eyelid dermatofibroma develops differently from the prototypical dermatofibroma. Methods: Histopathologic analysis of a new illustrative case of eyelid dermatofibroma and retrospective review of published cases. Results: The distinguishing features of the illustrative lesion included a rounder gross appearance, nonacanthotic epithelium, basophilic staining, cellular character, and a paucity of "collagen trapping." These features deviated from the typical features associated with classic dermatofibroma. Review of the 11 previously published cases of eyelid dermatofibroma revealed that they were more similar in appearance to the illustrative lesion than to classic dermatofibroma. Discussion: The rarity and histological deviations of the eyelid dermatofibroma suggest that the dermal substrate from which the lesion develops differs from that of the classic dermatofibroma. This difference may be explained microanatomically based on the fact that the dermis of the eyelid is predominantly papillary, whereas the dermis of extrapalpebral skin where dermatofibromas are more common is predominantly reticular. Conclusions: Although related, eyelid dermatofibromas appear to be histologically distinct from classic dermatofibromas, owing to the unique dermal composition of the site of origin.

Gene Therapy Restores Mfrp and Corrects Axial Eye Length.

Hyperopia (farsightedness) is a common and significant cause of visual impairment, and extreme hyperopia (nanophthalmos) is a consequence of loss-of-function MFRP mutations. MFRP deficiency causes abnormal eye growth along the visual axis and significant visual comorbidities, such as angle closure glaucoma, cystic macular edema, and exudative retinal detachment. The Mfrp rd6 /Mfrp rd6 mouse is used as a pre-clinical animal model of retinal degeneration, and we found it was also hyperopic. To test the effect of restoring Mfrp expression, we delivered a wild-type Mfrp to the retinal pigmented epithelium (RPE) of Mfrp rd6 /Mfrp rd6 mice via adeno-associated viral (AAV) gene therapy. Phenotypic rescue was evaluated using non-invasive, human clinical testing, including fundus auto-fluorescence, optical coherence tomography, electroretinography, and ultrasound. These analyses showed gene therapy restored retinal function and normalized axial length. Proteomic analysis of RPE tissue revealed rescue of specific proteins associated with eye growth and normal retinal and RPE function. The favorable response to gene therapy in Mfrp rd6 /Mfrp rd6 mice suggests hyperopia and associated refractive errors may be amenable to AAV gene therapy.

Retinal reattachment and ERG recovery after ophthalmic artery chemosurgery for advanced retinoblastoma in eyes with minimal baseline retinal function.

AIM: To report retinal function outcomes after ophthalmic artery chemosurgery (OAC) for advanced retinoblastoma (RB) in eyes with minimal pretreatment retinal function. METHODS: For 72 advanced RB eyes with baseline electroretinograms (ERGs) indistinguishable from noise ('extinguished') or flicker ERG amplitudes <25 µV ('poor'), ERGs were obtained before OAC and at 3 months, 1 year and 2 years after OAC. Presence of baseline retinal detachments (RDs) and their subsequent resolution or persistence was also noted. RESULTS: At 3 months, 1 year and 2 years post-OAC, 'extinguished' eyes showed 9/15, 4/11 and 2/6 detectable ERGs, respectively, and 'poor' eyes showed 19/55, 14/30 and 8/18 ERGs exceeding 25 µV, respectively. Correlations between baseline and post-OAC ERGs were poor; however, good correlation (R2) existed between ERGs post-OAC at 3 months and 1 year (0.749), at 3 months and 2 years (0.773) and at 1 year and 2 years (0.771). Overall, 49/70 eyes presented with RD; 29 RDs resolved 3 months post-OAC, with an average ERG change of +20.6 µV. Eyes with persistent RD had an average ERG change of -2.2 µV. No eyes underwent ≥25 µV change without RD resolution. CONCLUSIONS: Minimal baseline ERGs do not preclude significant recovery of retinal function after OAC. Good correlation exists between ERG outcomes at 3 months and those at subsequent follow-ups, suggesting that ERG amplitudes at 3-month post-OAC can prognosticate longer term retinal function, and that improvement is durable. For eyes presenting with RD, RD resolution is necessary but not sufficient for significant (≥25 µV) increases in ERG amplitudes.

Structural correlates of rotavirus cell entry.

Cell entry by non-enveloped viruses requires translocation into the cytosol of a macromolecular complex--for double-strand RNA viruses, a complete subviral particle. We have used live-cell fluorescence imaging to follow rotavirus entry and penetration into the cytosol of its ∼ 700 Šinner capsid particle ("double-layered particle", DLP). We label with distinct fluorescent tags the DLP and each of the two outer-layer proteins and track the fates of each species as the particles bind and enter BSC-1 cells. Virions attach to their glycolipid receptors in the host cell membrane and rapidly become inaccessible to externally added agents; most particles that release their DLP into the cytosol have done so by ∼ 10 minutes, as detected by rapid diffusional motion of the DLP away from residual outer-layer proteins. Electron microscopy shows images of particles at various stages of engulfment into tightly fitting membrane invaginations, consistent with the interpretation that rotavirus particles drive their own uptake. Electron cryotomography of membrane-bound virions also shows closely wrapped membrane. Combined with high resolution structural information about the viral components, these observations suggest a molecular model for membrane disruption and DLP penetration.

The AAA+ ClpX machine unfolds a keystone subunit to remodel the Mu transpososome.

A hyperstable complex of the tetrameric MuA transposase with recombined DNA must be remodeled to allow subsequent DNA replication. ClpX, a AAA+ enzyme, fulfills this function by unfolding one transpososome subunit. Which MuA subunit is extracted, and how complex destabilization relates to establishment of the correct directionality (left to right) of Mu replication, is not known. Here, using altered-specificity MuA proteins/DNA sites, we demonstrate that transpososome destabilization requires preferential ClpX unfolding of either the catalytic-left or catalytic-right subunits, which make extensive intersubunit contacts in the tetramer. In contrast, ClpX recognizes the other two subunits in the tetramer much less efficiently, and their extraction does not substantially destabilize the complex. Thus, ClpX targets the most stable structural components of the complex. Left-end biased Mu replication is not, however, determined by ClpX's intrinsic subunit preference. The specific targeting of a stabilizing "keystone subunit" within a complex for unfolding is an attractive general mechanism for remodeling by AAA+ enzymes.

Unique contacts direct high-priority recognition of the tetrameric Mu transposase-DNA complex by the AAA+ unfoldase ClpX.

Clp/Hsp100 ATPases remodel and disassemble multiprotein complexes, yet little is known about how they preferentially recognize these complexes rather than their constituent subunits. We explore how substrate multimerization modulates recognition by the ClpX unfoldase using a natural substrate, MuA transposase. MuA is initially monomeric but forms a stable tetramer when bound to transposon DNA. Destabilizing this tetramer by ClpX promotes an essential transition in the phage Mu recombination pathway. We show that ClpX interacts more tightly with tetrameric than with monomeric MuA. Residues exposed only in the MuA tetramer are important for enhanced recognition--which requires the N domain of ClpX--as well as for a high maximal disassembly rate. We conclude that an extended set of potential enzyme contacts are exposed upon assembly of the tetramer and function as internal guides to recruit ClpX, thereby ensuring that the tetrameric complex is a high-priority substrate.