Expression of early growth responsive gene-1 in the lateral geniculate body of kittens with amblyopia caused by monocular form deprivation.

OBJECTIVE: The expression of early growth responsive gene-1 (Egr-1) in the lateral geniculate body in the normal kittens and those affected with amblyopia caused by monocular visual deprivation was compared to explore the potential significance of Egr-1 in the pathogenesis of amblyopia. METHODS: A total of 30 healthy kittens were equally and randomly divided into the control (n = 15) and the deprivation group (n = 15). The kittens were raised in natural light and the right eyes of the deprived kittens were covered with a black opaque covering. Pattern visual evoked potential (PVEP) was measured before and 1, 3, and 5 weeks after covering. Five kittens from each group were randomly selected and euthanized with 2% sodium pentobarbital (100 mg/kg) during the 1st, 3rd and 5th week after covering. The expression of Egr-1 in the lateral geniculate body in the two groups was compared by performing immunohistochemistry and in situ hybridization. RESULTS: After three weeks of covering, PVEP detection indicated that the P100 wave latency in the deprivation group was significantly higher than that in the control group (P < 0.05), whereas the amplitude decreased markedly (P < 0.05). The number of the positive cells (P < 0.05) and mean optical density (P < 0.05) of Egr-1 protein expression in the lateral geniculate body of the deprivation group were found to be substantially lower in comparison to the normal group, as well as the number (P < 0.05) and mean optical density of Egr-1 mRNA-positive cells (P < 0.05). However, with increase of age, positive expression of Egr-1 in the control group showed an upward trend (P < 0.05), but this trend was not noted in the deprivation group (P > 0.05). CONCLUSIONS: Monocular form deprivation can lead to substantially decreased expressions of Egr-1 protein and mRNA in the lateral geniculate body, which in turn can affect the normal expression of neuronal functions in the lateral geniculate body, thereby promoting the occurrence and development of amblyopia.

ARC/Arg3.1 expression in the lateral geniculate body of monocular form deprivation amblyopic kittens.

PURPOSE: The present study compared the expression of activity-regulated cytoskeleton-associated protein (ARC/Arg3.1) in the lateral geniculate body between form deprivation amblyopia kittens and normal kittens to examine the significance of ARC/Arg3.1 in the lateral geniculate body in the pathogenesis of amblyopia. METHODS: Twenty kittens were randomly divided into an experimental group (n = 10) and a control group (n = 10). Black opaque covering cloth was used to cover the right eye of kittens in the experimental group. Pattern visual evoked potentials (PVEP) were detected weekly in all kittens. The expression of the ARC/Arg3.1 gene was detected by immunohistochemistry and in situ hybridization, and apoptosis of lateral geniculate body cells was detected by TUNEL. RESULTS: PVEP detection showed that at the age of 5 and 7 weeks, the latency of P100 in the right eye of the experimental group was higher than that of the other three groups (P < 0.05), and the amplitude of P100 was lower than that of the other three groups (P < 0.05). The expression of ARC/Arg3.1 protein (P < 0.05) and mRNA (P < 0.05) in the lateral geniculate body of the experimental group was significantly lower than that of the control group. The level of neuronal apoptosis in the experimental group was higher than that in the control group (P < 0.05). The expression of the ARC/Arg3.1 gene was negatively correlated with the apoptosis level of lateral geniculate body neurons. CONCLUSIONS: The expression of ARC/Arg3.1 is associated with monocular form deprivation amblyopia and apoptosis of lateral geniculate body cells.

Genetic causal inference between amblyopia and perinatal factors.

Amblyopia is a common visual disorder that causes significant vision problems globally. Most non-ocular risk factors for amblyopia are closely related to the intrauterine environment, and are strongly influenced by parent-origin effects. Parent-origin perinatal factors may have a direct causal inference on amblyopia development; therefore, we investigated the causal association between perinatal factors and amblyopia risk using a one-sample Mendelian Randomization (MR) with data from the UK Biobank Cohort Data (UKBB). Four distinct MR methods were employed to analyze the association between three perinatal factors (birth weight [BW], maternal smoking, and breastfeeding) and amblyopia risk, based on the summary statistics of genome-wide association studies in the European population. The inverse variance weighting method showed an inverse causal association between BW and amblyopia risk (odds ratio, 0.48 [95% CI, 0.29-0.80]; p = 0.004). Maternal smoking and breastfeeding were not causally associated with amblyopia risk. Our findings provided a possible evidence of a significant genetic causal association between low BW and increased amblyopia risk. This evidence may highlight the potential of BW as a predictive factor for visual maldevelopment and the need for careful management of amblyopia risk in patients with low BW.

[Diagnostics, clinical aspects and genetics of congenital corneal opacities]. / Diagnostik, Klinik und Genetik kongenitaler Hornhauttrübungen.

BACKGROUND: Congenital corneal opacities are comparatively rare diseases with high amblyogenic potential. PURPOSE: The present work provides an overview of the diagnostics, clinical aspects and genetics of congenital corneal opacities. METHODS: A literature search was carried out to compile an overview and illustration with own clinical case examples. RESULTS: Differentiated diagnostics are of high importance in the treatment of patients with congenital corneal opacities. A close cooperation between the medical departments involved and also the parents is absolutely essential. The structured classification of congenital corneal opacities provides the basis for a targeted treatment. DISCUSSION: The causes and the clinical symptoms of congenital corneal opacities are manifold. The correct diagnosis should be made early and in an interdisciplinary manner. Based on this, conservative and surgical treatment measures can be planned and an impending development of amblyopia can be specifically counteracted.

Visual and ocular findings in a family with X-linked cone dysfunction and protanopia.

Background: Bornholm eye disease (BED) is a rare X-linked cone dysfunction disorder with high myopia, amblyopia, and color vision defects.Materials and methods: Visual and ocular outcomes in a family where two of five siblings had molecularly confirmed BED are reported. Ophthalmological assessments included best-corrected visual acuity (BCVA), color vision test, and optical coherence tomography (OCT). Medical records, electroretinography (ERG), and genetic analyses were re-evaluated.Results: Two male siblings had confirmed BED with myopia and protanopia. The younger brother had high myopia, subnormal BCVA, and ocular fundi that showed tilted discs, crescent shaped peripapillary atrophy, and visible choroidal vessels. OCT confirmed retinal and choroidal atrophy. The older brother was lightly myopic with normal/subnormal BCVA and subtle findings in the fundi. Both brothers had abnormal ERG recordings with a decreased cone response. They also had a structurally intact OPN1LW/OPN1MW gene cluster. The OPN1LW gene was shown to carry a deleterious variant combination in exon 3 known to result in mis-splicing of opsin mRNA and acknowledged as LIAVA amino acid delineation (Leu153-Ile171-Ala174-Val178-Ala180), while the OPN1MW gene exon 3 showed a non-pathogenic variant combination (MVVVA). Another normal-sighted brother carried another wildtype variant combination (LVAIS) in exon 3 of the OPN1LW gene.Conclusions: The two affected brothers demonstrated a large variability in their phenotypes even though the genotypes were identical. They presented a disease-associated haplotype in exon 3 of OPN1LW that has been described as the molecular cause of BED.

Ophthalmic manifestations in patients with Leigh syndrome, French Canadian type.

BACKGROUND: Leigh syndrome, French Canadian type is a rare neurodegenerative disease. To our knowledge, there have been no studies based on ocular findings published for this disease. The purpose of this study is to describe ophthalmic findings in these patients. PATIENTS: Six patients genetically identified as having the syndrome were included in this study. METHODS: Four patients had an ophthalmic examination with an ophthalmologist including evaluation of visual acuity, extraocular motility and lid position, orthoptic workup, evaluation of stereopsis, refraction, evaluation of pupils, color vision, slit-lamp biomicroscopy, measurement of intraocular pressure, and fundoscopy. Two patients had a chart review. RESULTS: Visual acuity ranged from 0.00 logmar to 1.55 logmar. Extraocular motility abnormalities and ptosis were noted in half of the patients. Strabismus was present in the entire cohort, and stereopsis was absent in half of these patients. Amblyopia was noted in 83% of individuals and suppression in 33%. Only one patient had nystagmus. Refraction varied throughout patients. It included severe hyperopia, myopia, astigmatism, and significant anisometropia. Pupils, anterior segment, fundus, and color vision were normal in all patients. Intraocular pressure was slightly elevated in one patient. CONCLUSION: Patients with Leigh syndrome, French Canadian type display a variety of ophthalmic findings, and screening at a young age is recommended.

Distinct Circuits for Recovery of Eye Dominance and Acuity in Murine Amblyopia.

Degrading vision by one eye during a developmental critical period yields enduring deficits in both eye dominance and visual acuity. A predominant model is that "reactivating" ocular dominance (OD) plasticity after the critical period is required to improve acuity in amblyopic adults. However, here we demonstrate that plasticity of eye dominance and acuity are independent and restricted by the nogo-66 receptor (ngr1) in distinct neuronal populations. Ngr1 mutant mice display greater excitatory synaptic input onto both inhibitory and excitatory neurons with restoration of normal vision. Deleting ngr1 in excitatory cortical neurons permits recovery of eye dominance but not acuity. Reciprocally, deleting ngr1 in thalamus is insufficient to rectify eye dominance but yields improvement of acuity to normal. Abolishing ngr1 expression in adult mice also promotes recovery of acuity. Together, these findings challenge the notion that mechanisms for OD plasticity contribute to the alterations in circuitry that restore acuity in amblyopia.

Ophthalmic findings in Frank-ter Haar syndrome: report of a sibling pair.

Frank-ter Haar syndrome (FTHS) is an autosomal recessive disorder characterized by abnormalities that affect the development of bone, heart, and eyes. We report a sibling pair with FTHS caused by a homozygous, novel mutation pLys133Glnfs*13 in the SH3PXD2B gene: one sibling had bilateral ocular hypertension and unilateral colobomas of iris, choroid and retina; the other, unilateral myelinated nerve fiber layer of the optic disk and papilledema due to idiopathic intracranial hypertension. Both children had refractive amblyopia and megalocornea.

[Amblyopia. Epidemiology, causes and risk factors]. / Amblyopie. Epidemiologie, Ursachen, Risikofaktoren.

BACKGROUND: Amblyopia is the main cause for mostly monocular, impaired vision in childhood. Treatment and prevention of amblyopia is only effective during childhood. Ophthalmological screening of children does not yet exist in Germany. EPIDEMIOLOGY: The prevalence of amblyopia in Germany is 5.6%, which is higher than in reports from studies in Australia; however, the prevalence of amblyopia is not comparable in these studies due to different definitions of amblyopia and the inclusion/exclusion criteria of the study cohorts. At present it is unknown at what age ophthalmological screening should be carried out to prevent amblyopia and the appropriate frequency of screening examinations. CAUSES: Amblyopia is a disorder of the visual cortex that is due to suppression and deprivation of one eye leading to unilateral visual impairment. Approximately 50% of cases of amblyopia are caused by anisometropia, 25% by strabismus and in every sixth person by a combination of both. Other causes, such as unilateral congenital cataracts are relatively rare. RISK FACTORS: A variety of factors, such as ocular pathologies, premature birth, familial disposition and general diseases are associated with an increased risk for amblyopia.

Marfan syndrome: ocular findings and novel mutations-in pursuit of genotype-phenotype associations.

OBJECTIVE: To analyze ocular involvement in patients diagnosed with Marfan syndrome (MFS), study their clinical findings and prognosis based on the type of FBN1 mutation, and evaluate possible genotype-phenotype correlations. DESIGN: Observational single-centre case series. PARTICIPANTS: Eleven patients diagnosed with MFS were included. All subjects met the Ghent criteria of MFS, the diagnosis was confirmed by genetic testing. METHODS: All subjects underwent a complete ophthalmologic examination. We evaluated clinical data, the incidence of ectopia lentis (EL), and other eye disorders. The association of ocular signs with the type of mutation was analyzed. RESULTS: Four of the 11 patients had EL, of which 3 developed secondary glaucoma, and 62.5% of the phakic patients had myopia. Other ocular abnormalities included strabismus, retinal tears, retinal detachment, and amblyopia. The encountered types of mutations were premature termination codon (PTC) in 7 patients, missense in 2 cases, 1 aberration of splicing, and 1 indel mutation. Two novel mutations were found. Of the patients with EL, 2 had a missense, 1 an indel, and 1 a nonsense mutation. CONCLUSIONS: Myopia was the most frequent ocular involvement. Patients with a PTC mutation revealed to have a smaller risk of EL; however, more studies are required to indicate the mechanism of the correlation.

Nogo Receptor 1 Limits Ocular Dominance Plasticity but not Turnover of Axonal Boutons in a Model of Amblyopia.

The formation and stability of dendritic spines on excitatory cortical neurons are correlated with adult visual plasticity, yet how the formation, loss, and stability of postsynaptic spines register with that of presynaptic axonal varicosities is unknown. Monocular deprivation has been demonstrated to increase the rate of formation of dendritic spines in visual cortex. However, we find that monocular deprivation does not alter the dynamics of intracortical axonal boutons in visual cortex of either adult wild-type (WT) mice or adult NgR1 mutant (ngr1-/-) mice that retain critical period visual plasticity. Restoring normal vision for a week following long-term monocular deprivation (LTMD), a model of amblyopia, partially restores ocular dominance (OD) in WT and ngr1-/- mice but does not alter the formation or stability of axonal boutons. Both WT and ngr1-/- mice displayed a rapid return of normal OD within 8 days after LTMD as measured with optical imaging of intrinsic signals. In contrast, single-unit recordings revealed that ngr1-/- exhibited greater recovery of OD by 8 days post-LTMD. Our findings support a model of structural plasticity in which changes in synaptic connectivity are largely postsynaptic. In contrast, axonal boutons appear to be stable during changes in cortical circuit function.

Postnatal visual deprivation in rats regulates several retinal genes and proteins, including differentiation-associated fibroblast growth factor-2.

Little is known about the retinal cellular basis of amblyopia, which is a developmental disease characterized by impaired visual acuity. This study examined the retinal transcripts associated with experimentally induced unilateral amblyopia in rats. Surgical tarsorrhaphy of the eyelids on one side was performed in pups prior to eye opening at postnatal day 14, thereby preventing any visual experience. This condition was maintained for over 2 months, after which electroretinograms (ERGs) were recorded, the retinal ganglion cell (RGC) arrangement and number were determined using neuroanatomical tracing, the retinal transcripts were studied using microarray analysis, regulated mRNAs were confirmed with quantitative reverse-transcriptase PCR, and proteins were stained using Western blotting and immunohistochemistry. An attenuated ERG was found in eyes that were deprived of visual experience. Retrograde neuroanatomical staining disclosed a larger number of RGCs within the retina on the visually deprived side compared to the non-deprived, control side, and a multilayered distribution of RGCs. At the retinomic level, several transcripts associated with retinal differentiation, such as fibroblast growth factor 2 (FGF-2), were either up- or downregulated. Most of the transcripts could be verified at the mRNA level. To unravel the role of a differentiation-associated protein, we tested FGF-2 in dissociated postnatal retinal cell cultures and found that FGF-2 is a potent factor triggering ganglion cell differentiation. The data suggest that visual experience shapes the postnatal retinal differentiation, whereas visual deprivation induces changes at the functional, cellular and molecular levels within the retina.

Deprivation amblyopia and congenital hereditary cataract.

Amblyopia is a neurodevelopmental disorder of vision associated with decreased visual acuity, poor or absent stereopsis, and suppression of information from one eye.(1,2) Amblyopia may be caused by strabismus (strabismic amblyopia), refractive error (anisometropic amblyopia), or deprivation from obstructed vision (deprivation amblyopia). 1 In the developed world, amblyopia is the most common cause of childhood visual impairment, 3 which reduces quality of life 4 and also almost doubles the lifetime risk of legal blindness.(5, 6) Successful treatment of amblyopia greatly depends on early detection and treatment of predisposing disorders such as congenital cataract, which is the most common cause of deprivational amblyopia. Understanding the genetic causes of congenital cataract leads to more effective screening tests, early detection and treatment of infants and children who are at high risk for hereditary congenital cataract.

Clinical and molecular analysis of children with central pulverulent cataract from the Arabian Peninsula.

AIM: To clinically and genetically characterise central pulverulent cataract in a consecutive cohort of children from the Arabian Peninsula who were referred for ophthalmic evaluation. METHODS: Ophthalmic examination, homozygosity mapping in a consanguineous family and candidate gene analysis. RESULTS: All 16 children (4-16 years old, mean 9 years; seven girls and nine boys from 10 families) had bilateral central nuclear dust-like lenticular opacities. Two patients (one family) had cortical riders and six had associated strabismus. Cycloplegic retinoscopy was usually hyperopic (13/16; right eye spherical equivalent +0.50 to +6.25 dioptres, mean +3.50) but was sometimes myopic (3/16; right eye spherical equivalent -0.50 to -11.75, mean -6.50). In children with amblyopia (5/16), the cause was significant uncorrected ametropias rather than the lens opacities. Three patients had uncomplicated unilateral cataract surgery suggested by an outside second opinion that did not improve best-corrected visual acuity. Homozygosity mapping for one consanguineous family suggested the candidate gene CRYBB1. Sequencing of this gene revealed a homozygous c.171del mutation (p.N58Tfs*107) with a shared haplotype in all 16 children. In asymptomatic carrier parents from five of the six families available for careful slit-lamp examination, occasional central dot lenticular opacities were documented. CONCLUSIONS: Central pulverulent cataract in this consanguineous population does not significantly impact visual acuity during early childhood, can be associated with significant ametropias (with amblyopia and/or strabismus) and is specific for a homozygous CRYBB1 founder mutation. Primary management in children is typically spectacle correction based on cycloplegic retinoscopy to treat significant refractive error rather than paediatric cataract surgery.

Thirty-Year follow-up of an African American family with macular dystrophy of the retina, locus 1 (North Carolina macular dystrophy).

PURPOSE: To describe clinical characteristics, including visual acuity (VA), genetic analysis, and management of complications, over a 30-year period in an African American family with macular dystrophy of the retina, locus 1 (MCDR1), commonly referred to as "North Carolina macular dystrophy." DESIGN: Observational, cohort study. PARTICIPANTS: Twelve family members from a 4-generation pedigree. METHODS: A total of 12 African American patients in an affected family were examined. Clinical examination was documented during 2 different follow-up periods from 1979 to 1982 in 10 patients and from 2005 to 2009 in 11 patients. Genetic analysis was performed in 4 affected members during this time. Foveal microperimetry, fundus autofluorescence, and spectral domain optical coherence tomography (OCT) data were also obtained. MAIN OUTCOME MEASURES: Change in VA of 8 members followed over 3 decades and clinical data and management of complications for all patients. RESULTS: Nine of 11 living family members had classic findings ranging from disease grade 2 (confluent foveal drusen, 8 eyes) to grade 3 (central coloboma-like lesion, 10 eyes). Two members developed choroidal neovascularization (CNV) requiring laser ablation, and 1 member developed non-clearing vitreous hemorrhage and underwent 25-gauge pars plana vitrectomy. Another family member developed exotropia and amblyopia in 1 eye by age 7 years. Those without CNV had no significant change in VA over 30 years. Linkage studies of 4 affected family members showed the same short tandem repeats on markers spanning D6S249 and D6S283 within the MCDR1 region of chromosome 6q16. Microperimetry analysis of an affected member with grade 3 MCDR1 revealed absent function in the region of the central coloboma-like lesions, corresponding to photoreceptor absence on OCT, although there were preserved foveal function and intact photoreceptors adjacent to the lesion. CONCLUSIONS: This African American family shares similar clinical findings as other MCDR1 pedigrees and the same haplotype as the originally described family from North Carolina. Clinical characteristics, including retinal features and stable VA in the absence of amblyopia and CNV, are similar to those in other reports. Eccentric viewing around impaired photoreceptors may explain good VA in patients with clinically severe-appearing macular lesions. Sequencing of the MCDR1 interval may help identify a protein responsible for early macular development. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

[Neuro-ophthalmological and ophthalmological findings in Joubert syndrome]. / Neuroophthalmologische und ophthalmologische Befunde beim Joubert-Syndrom.

BACKGROUND: Joubert syndrome (JS) belongs to the ciliopathies and is a mostly autosomal recessively inherited disease (in the case of OFD1 mutations, JS is an X-linked trait). It is characterised by midbrain-hindbrain malformations with developmental delay, hypotonia and ataxia and a broad spectrum of other facultative findings. The aim of our study was to examine the ophthalmological and neuro-ophthalmological features of JS in our patients and to compare our findings to those of other studies. METHODS: In a retrospective study we evaluated the ophthalmological and neuro-ophthalmological findings of 9 consecutive patients who met the diagnostic criteria of JS. RESULTS: All patients had abnormalities of ocular motility, 4/9 used head thrusts to shift gaze (oculomotor apraxia OMA). In 6/8 patients, the optokinetic reflex (OKN) was absent. Furthermore, 8/9 children showed nystagmus, mostly see-saw nystagmus. Manifest strabismus was found in 8/9 while 3/9 had a retinopathy with either abnormal ERG and/or fundus appearance with or without visual impairment. Chorioretinal colobomata were present in 5/9 cases. Two patients showed a unilateral congenital ptosis, one a facial nerve paresis. CONCLUSIONS: The early neuro-ophthalmological findings in JS are not pathognonomic, but may lead to the diagnosis of JS. The syndrome should be suspected in patients with nystagmus, especially see-saw nystagmus, and abnormal OKN and/or OMA, and/or colobomata of the fundus, and further paediatric examinations should be initiated.

Discordant refraction in male monozygotic twins.

As part of the Genes In Myopia (GEM) Study, the authors describe a pair of monozygotic twins who presented with discordant hypermetropia. Both twins also reported amblyopia, but the cause differed. The phenomenon of refractive discordance in twins is rare, with this case representing only the second to ever be reported.

Monocular visual deprivation in macaque monkeys: a profile in the gene expression of lateral geniculate nucleus by laser capture microdissection.

PURPOSE: Amblyopia is the most common cause of visual impairment in children. Early detection of amblyopia and subsequent intervention are vital in preventing visual loss. Understanding the molecular pathogenesis of amblyopia would greatly facilitate development of therapeutic interventions. An animal model of amblyopia induced by monocular vision deprivation has been extensively studied in terms of anatomic and physiologic alterations that affect visual pathways. However, the molecular events underlying these changes are poorly understood. This study aimed to characterize changes of gene expression profiles in the lateral geniculate nucleus (LGN) associated with amblyopia induced by monocular visual deprivation. METHODS: Monocular vision deprivation was generated by either opaque dark contact lens or tarsorrhaphy of newborn rhesus monkeys. LGN was harvested at two or four months following induction of vision deprivation. Laser capture microdissection was used to obtain individual LGN layers for total RNA isolation. Linear T7-based in vitro RNA amplification was used to obtain sufficient RNA to conduct DNA microarray studies. The resulting Affymetrix GeneChip Expression data were analyzed using Affymetrix GeneChip Operating Software. Real-time quantitative polymerase chain reaction and in situ hybridization were used to further analyze expression of selected genes. RESULTS: Using 52,699 microarray probe sets from a Rhesus array, we identified 116 transcripts differentially expressed between deprived and nondeprived parvocellular layers: 45 genes were downregulated and 71 genes were upregulated in deprived parvocellular layers. We also observed substantial changes in deprived magnocellular laminae: 74 transcripts exhibited altered expression, 42 genes were downregulated, and 32 genes were upregulated. The genes identified in this study are involved in many diverse processes, including binding (calcium ion binding, nucleic acid binding, and nucleotide binding), catalytic activity, and signal transducer activity. CONCLUSIONS: There were significant differences in gene expression profiles between deprived and nondeprived parvocellular layers and magnocellular laminae of LGN. These alterations in gene expression may play a critical role in the molecular pathogenesis of amblyopia. The genes identified in this study may provide potential targets for therapeutic intervention of this disease.

Critical period revisited: impact on vision.

Neural circuits are shaped by experience in early postnatal life. The permanent loss of visual acuity (amblyopia) and anatomical remodeling within primary visual cortex following monocular deprivation is a classic example of critical period development from mouse to man. Recent work in rodents reveals a residual subthreshold potentiation of open eye response throughout life. Resetting excitatory-inhibitory balance or removing molecular 'brakes' on structural plasticity may unmask the potential for recovery of function in adulthood. Novel pharmacological or environmental interventions now hold great therapeutic promise based on a deeper understanding of critical period mechanisms.