North Carolina Macular Dystrophy Is Caused by Dysregulation of the Retinal Transcription Factor PRDM13.

PURPOSE: To identify specific mutations causing North Carolina macular dystrophy (NCMD). DESIGN: Whole-genome sequencing coupled with reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression in human retinal cells. PARTICIPANTS: A total of 141 members of 12 families with NCMD and 261 unrelated control individuals. METHODS: Genome sequencing was performed on 8 affected individuals from 3 families affected with chromosome 6-linked NCMD (MCDR1) and 2 individuals affected with chromosome 5-linked NCMD (MCDR3). Variants observed in the MCDR1 locus with frequencies <1% in published databases were confirmed using Sanger sequencing. Confirmed variants absent from all published databases were sought in 8 additional MCDR1 families and 261 controls. The RT-PCR analysis of selected genes was performed in stem cell-derived human retinal cells. MAIN OUTCOME MEASURES: Co-segregation of rare genetic variants with disease phenotype. RESULTS: Five sequenced individuals with MCDR1-linked NCMD shared a haplotype of 14 rare variants spanning 1 Mb of the disease-causing allele. One of these variants (V1) was absent from all published databases and all 261 controls, but was found in 5 additional NCMD kindreds. This variant lies in a DNase 1 hypersensitivity site (DHS) upstream of both the PRDM13 and CCNC genes. Sanger sequencing of 1 kb centered on V1 was performed in the remaining 4 NCMD probands, and 2 additional novel single nucleotide variants (V2 in 3 families and V3 in 1 family) were identified in the DHS within 134 bp of the location of V1. A complete duplication of the PRDM13 gene was also discovered in a single family (V4). The RT-PCR analysis of PRDM13 expression in developing retinal cells revealed marked developmental regulation. Next-generation sequencing of 2 individuals with MCDR3-linked NCMD revealed a 900-kb duplication that included the entire IRX1 gene (V5). The 5 mutations V1 to V5 segregated perfectly in the 102 affected and 39 unaffected members of the 12 NCMD families. CONCLUSIONS: We identified 5 rare mutations, each capable of arresting human macular development. Four of these strongly implicate the involvement of PRDM13 in macular development, whereas the pathophysiologic mechanism of the fifth remains unknown but may involve the developmental dysregulation of IRX1.

Closed-globe injuries of the ocular surface associated with combat blast exposure.

PURPOSE: To describe closed-globe conjunctival and corneal injuries and endothelial cell abnormalities associated with blast exposure and their relationships to other closed-globe injuries and blast-event characteristics. DESIGN: Observational cross-sectional study. PARTICIPANTS: Veterans with a history of blast-related traumatic brain injury (TBI). METHODS: History and ocular examination, including slit-lamp biomicroscopy, gonioscopy, specular microscopy. MAIN OUTCOME MEASURES: Type and location of blast injuries to the conjunctiva and cornea. RESULTS: Ocular surface injuries were present in 25% (16 of 65) of blast-exposed veterans with TBI. Injuries included partial-thickness anterior stromal corneal scars (15 eyes), Descemet membrane ruptures (6 eyes), and conjunctival or corneal foreign bodies (7 eyes). Based on normative information from an age-matched comparison group, endothelial cell abnormalities were identified in 37% of participants. Eyes with ocular surface injury were more likely to have lower endothelial cell density, higher coefficient of variation of cell area, and lower percentage of hexagonal cells compared with eyes without injury. Presence of ocular surface injury or endothelial cell abnormalities was associated with elevated rates of other anterior and posterior segment injuries, as well as impairment of visual acuity. We found no relationship between ballistic eyewear use or severity level of TBI and presence of ocular surface injuries from blast. CONCLUSIONS: Independent of TBI severity or use of protective eyewear, ocular surface injuries and endothelial cell abnormalities were found in significant numbers of veterans with blast-related brain injury. Descemet membrane ruptures from blast exposure were described. Ocular surface trauma was associated with other ocular injuries throughout the globe. Potential mechanisms for the types and locations of ocular injuries seen were discussed. Any corneal or conjunctival injury in a blast survivor should prompt a thorough ocular trauma examination, including gonioscopy and specular microscopy, with appropriate follow-up for associated injuries. Longitudinal studies are required to determine long-term visual outcomes after blast exposure.

Central retinal artery occlusion without retrobulbar hemorrhage after retrobulbar anaesthesia

Four patients had central retinal artery occlusions after retrobulbar anaesthesia with lidocaine HCl was administered before photocoagulation. One of these four had two separate episodes of closure. Only one had permanent visual loss and none had evidence of retrobulbar hemorrhage. Each patient had a severe hematologic or vascular disorder. We think that direct trauma to the central retinal artery behind the globe, the pharmacologic or compressive effects of the injected solution,or both caused the occlusions in these patients. (AU)