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Optic Nerve Hypoplasia Is a Pervasive Subcortical Pathology of Visual System in Neonates.

ABSTRACT: Optic nerve hypoplasia (ONH) is the most common cause of childhood congenital blindness in developed nations, yet the fundamental pathobiology of ONH remains unknown. The objective of this study was to employ a 'face validated' murine model to determine the timing of onset and the pathologic characteristics of ONH.Based on the robust linkage between X-linked CASK haploinsufficiency and clinically diagnosed ONH, we hypothesized that heterozygous deletion of CASK (CASK(+/-)) in rodents will produce an optic nerve pathology closely recapitulating ONH. We quantitatively analyzed the entire subcortical visual system in female CASK(+/-) mice using immunohistochemistry, anterograde axonal tracing, toluidine blue staining, transmission electron microscopy, and serial block-face scanning electron microscopy.CASK haploinsuffiency in mice phenocopies human ONH with complete penetrance, thus satisfying the 'face validity'. We demonstrate that the optic nerve in CASK(+/-) mice is not only thin, but is comprised of atrophic retinal axons and displays reactive astrogliosis. Myelination of the optic nerve axons remains unchanged. Moreover, we demonstrate a significant decrease in retinal ganglion cell (RGC) numbers and perturbation in retinothalamic connectivity. Finally, we used this mouse model to define the onset and progression of ONH pathology, demonstrating for the first time that optic nerve defects arise at neonatally in CASK(+/-)mice.Optic nerve hypoplasia is a complex neuropathology of the subcortical visual system involving RGC loss, axonopathy, and synaptopathy and originates at a developmental stage in mice that corresponds to the late third trimester development in humans.

SUBMITTER: Liang C

PROVIDER: S-EPMC5656421 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Optic Nerve Hypoplasia Is a Pervasive Subcortical Pathology of Visual System in Neonates.

Liang Chen C Kerr Alicia A Qiu Yangfengzhong Y Cristofoli Francesca F Van Esch Hilde H Fox Michael A MA Mukherjee Konark K

Investigative ophthalmology & visual science 20171001 12

<h4>Purpose</h4>Optic nerve hypoplasia (ONH) is the most common cause of childhood congenital blindness in developed nations, yet the fundamental pathobiology of ONH remains unknown. The objective of this study was to employ a 'face validated' murine model to determine the timing of onset and the pathologic characteristics of ONH.<h4>Methods</h4>Based on the robust linkage between X-linked CASK haploinsufficiency and clinically diagnosed ONH, we hypothesized that heterozygous deletion of CASK (C ...[more]

PMID: 29067402

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Project description:PurposeTo investigate the optic nerve and macular morphology in patients with optic nerve hypoplasia (ONH) using spectral-domain optical coherence tomography (SD OCT).DesignProspective, cross-sectional, observational study.SubjectsA total of 16 participants with ONH (10 female and 6 male; mean age, 17.2 years; 6 bilateral involvement) and 32 gender-, age-, ethnicity-, and refraction-matched healthy controls.MethodsHigh-resolution SD OCT (Copernicus [Optopol Technology S.A., Zawiercie, Poland], 3 μm resolution) and handheld SD OCT (Bioptigen Inc [Research Triangle Park, NC], 2.6 μm resolution) devices were used to acquire horizontal scans through the center of the optic disc and macula.Main outcome measuresHorizontal optic disc/cup and rim diameters, cup depth, peripapillary retinal nerve fiber layer (RNFL), and thickness of individual retinal layers in participants with ONH and in controls.ResultsPatients with ONH had significantly smaller discs (P < 0.03 and P < 0.001 compared with unaffected eye and healthy controls, respectively), horizontal cup diameter (P < 0.02 for both), and cup depth (P < 0.02 and P < 0.01, respectively). In the macula, significantly thinner RNFL (nasally), ganglion cell layer (GCL) (nasally and temporally), inner plexiform layer (IPL) (nasally), outer nuclear layer (ONL) (nasally), and inner segment (centrally and temporally) were found in patients with ONH compared with the control group (P < 0.05 for all comparisons). Continuation of significantly thicker GCL, IPL, and outer plexiform layer in the central retinal area (i.e., foveal hypoplasia) was found in more than 80% of patients with ONH. Clinically unaffected fellow eyes of patients with ONH showed mild features of underdevelopment. Visual acuity and presence of septo-optic dysplasia were associated with changes in GCL and IPL. Sensitivity and specificity for the detection of ONH based on disc and retinal optical coherence tomography (OCT) parameters were >80%.ConclusionsOur study provides evidence of retinal changes in ONH. In addition to thinning of retina layers mainly involving the RNFL and GCL, signs reminiscent of foveal hypoplasia were observed in patients with ONH. Optic nerve and foveal parameters measured using OCT showed high sensitivity and specificity for detecting ONH, demonstrating their useful for clinical diagnosis.

Project description:ObjectivesTo assess the prevalence of behavioral problems in children with isolated optic nerve hypoplasia, mild to moderate or no visual impairment, and no developmental delay. To identify white matter abnormalities that may provide neural correlates for any behavioral abnormalities identified.Patients and methodsEleven children with isolated optic nerve hypoplasia (mean age 5.9 years) underwent behavioral assessment and brain diffusion tensor imaging, Twenty four controls with isolated short stature (mean age 6.4 years) underwent MRI, 11 of whom also completed behavioral assessments. Fractional anisotropy images were processed using tract-based spatial statistics. Partial correlation between ventral cingulum, corpus callosum and optic radiation fractional anisotropy, and child behavioral checklist scores (controlled for age at scan and sex) was performed.ResultsChildren with optic nerve hypoplasia had significantly higher scores on the child behavioral checklist (p<0.05) than controls (4 had scores in the clinically significant range). Ventral cingulum, corpus callosum and optic radiation fractional anisotropy were significantly reduced in children with optic nerve hypoplasia. Right ventral cingulum fractional anisotropy correlated with total and externalising child behavioral checklist scores (r = -0.52, p<0.02, r = -0.46, p<0.049 respectively). There were no significant correlations between left ventral cingulum, corpus callosum or optic radiation fractional anisotropy and behavioral scores.ConclusionsOur findings suggest that children with optic nerve hypoplasia and mild to moderate or no visual impairment require behavioral assessment to determine the presence of clinically significant behavioral problems. Reduced structural integrity of the ventral cingulum correlated with behavioral scores, suggesting that these white matter abnormalities may be clinically significant. The presence of reduced fractional anisotropy in the optic radiations of children with mild to moderate or no visual impairment raises questions as to the pathogenesis of these changes which will need to be addressed by future studies.

Dataset Information

Optic Nerve Hypoplasia Is a Pervasive Subcortical Pathology of Visual System in Neonates.

Publications

Optic Nerve Hypoplasia Is a Pervasive Subcortical Pathology of Visual System in Neonates.

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