Aicardi syndrome. A cause of infantile seizures.
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Agenesis of Corpus Callosum↗
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Congenital syndrome of anophthalmia-microphthalmia with associated defects in cattle.
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Animals↗
Nanophthalmic uveal effusion syndrome after prophylactic laser treatment.
PURPOSE: We report a case of nanophthalmic uveal effusion syndrome (NUES) with total exudative retinal detachment (RD) after prophylactic argon laser (AL) treatment. The RD subsided and eventually resolved with i.v. steroid therapy. METHODS: A 45-year-old woman was referred to us with NUES and total exudative RD after prophylactic AL treatment for retinoschisis performed elsewhere. The patient had been scheduled for surgical intervention and was given i.v. prednisolone. RESULTS: Two days after starting i.v. prednisolone, the subretinal fluid partially resolved. Intervention had therefore been postponed. After 15 days the RD almost disappeared and vision improved to 20/400. Ten days later the macula was flat and vision was 20/200. At the six-month follow-up visit vision was 20/40. CONCLUSIONS: To our knowledge this is the first report of NUES and total exudative RD following AL treatment that resolved with i.v. steroid therapy alone. Since the AL treatment clearly seemed to play a role in the pathogenesis of the NUES and associated RD we strongly advise careful assessment of the risk/benefit ratio of prophylactic laser treatment in nanophthalmic patients. Although sclerectomy and vortex vein decompression are well-established techniques, we believe steroid therapy might be tried before proceeding to surgery.
Female↗
Environmental risk factors in congenital malformations of the eye.
Developmental eye defects such as coloboma are a significant cause of visual morbidity in children, and are more common in India than elsewhere. The possible role of environmental factors in the aetiology of these conditions was investigated by studying birth order, symptoms of vitamin A deficiency (night blindness), drug use and maternal illness in pregnancy, rubella antibodies and exposure to agricultural chemicals. Through hospital records and community-based rehabilitation programmes in Andhra Pradesh, children with colobomata were recruited from schools for the blind. Eighty-three mothers of affected children were interviewed. The results showed that 43% of parents were consanguineous, that 19% had a positive family history and that the frequency of coloboma was highest in second-born children. Eleven (16%) mothers had a history of night blindness while pregnant with the affected child; seven (8%) took medication during the 1st trimester, abortifacients in two cases; three reported fever in the 1st trimester; and 11 (13%) reported exposure to agricultural chemicals.
Abnormalities, Multiple↗
Congenital toxoplasmosis: eye manifestations in infants and children.
The eye manifestations of congenital toxoplasmosis were investigated in 38 infants and children. Diagnosis of the congenital ocular lesions was established clinically, using also X-ray, computed tomography and ultrasonography, and confirmed by two immunodiagnostic techniques. Infants and children were examined when one or more characteristic manifestations of ophthalmic disorders were present. Typical symptoms and signs can present at birth or appear later in life. The multiplicity of clinical manifestations is characteristic of the disease. The most common symptom was chorioretinitis (92%), associated in 71% of the cases with other ocular lesions, and the second most common symptom was microphthalmia and strabismus. The inflammatory process also involved the anterior segment of the eye: iridocyclitis, cataract, glaucoma. Other rare findings were hydrocephalus, calcification in the brain, paresis, epilepsy and diminished visual acuity. The study showed that transplacental transmission of Toxoplasma to the fetus can have severe clinical consequences and terminate in fatal ocular impairment.
Adolescent↗
Antiserum to rat visceral yolk sac endoderm induced abnormal embryonic development.
The induction of abnormal embryonic development by heterologous tissue antisera has been well established. The underlying mechanism whereby such teratogenesis occurs is not known. There were implications that visceral yolk sac endoderm might be involved. Endoderm was isolated from rat visceral yolk sac of 14th day of gestation using a nonenzymic procedure. The purity of the endoderm preparation was examined by electron microscopy. The preparation contained sheets of single layer of endodermal cells with no apparent contamination by the underlying mesenchyme or basal lamina. The specificity of the antiserum was examined by in vitro immunofluorescent localization studies. The antibodies against the endoderm localized only in the endodermal cells and some of the renal tubular cells. Intraperitoneal injection of the endoderm antiserum into 9-day pregnant rats resulted in congenital malformation, embryonic death, and fetal growth retardation. The effects of the antiserum were dose-dependent. The most frequently observed defects were anophthalmia and microphthalmia. Retarding effect of the antiserum on the growth of the embryo at the egg cylinder stage was also observed. In vivo immunofluorescent localization studies indicated that the endoderm antibodies localized only in the endodermal cells of the visceral yolk sac placenta; no localization was observed in the visceral yolk sac mesenchyme, basal lamina. Reichert's membrane, maternal kidney tissue or the embryo proper.
Animals↗
Combination macrophage-colony stimulating factor and interferon-gamma administration ameliorates the osteopetrotic condition in microphthalmic (mi/mi) mice.
Malignant osteopetrosis is a fatal congenital bone disorder characterized by defective osteoclastic function. Death frequently occurs within the first decade of life. The precise molecular defect(s) that causes osteopetrosis is not known. The possibility that osteoclasts, like macrophages, are controlled by interactions with cytokines suggests that these agents may provide a means of increasing osteoclastic function. Macrophage-colony stimulating factor (M-CSF), a cytokine known to enhance macrophage and osteoclast generation, and recombinant human interferon-gamma (rIFN), a cytokine known to stimulate superoxide generation by white cells, were administered to microphthalmic (mi/mi) mice in an attempt to improve the osteopetrotic condition. Each cytokine was administered separately and in combination to neonatal mi/mi mice for 7 consecutive d. Bone turnover, osteoclast numbers, superoxide generation by white cells, and hematocrit were assessed. rIFN, M-CSF, and a combination of the cytokines stimulates oxygen-derived free radical production by white cells and increased bone resorption. rIFN resulted in a reduction in the number of osteoclasts. This reduction in number was ameliorated by M-CSF. M-CSF alone and in combination with rIFN resulted in improved hematopoietic function, increased weight gain, and increased physical activity of the affected mutants.
Animals↗
Molecular genetics and neurobiology of neurodegenerative and neurodevelopmental disorders.
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Age of Onset↗
Genetic rescue of cell number in a mouse model of microphthalmia: interactions between Chx10 and G1-phase cell cycle regulators.
Insufficient cell number is a primary cause of failed retinal development in the Chx10 mutant mouse. To determine if Chx10 regulates cell number by antagonizing p27(Kip1) activity, we generated Chx10, p27(Kip1) double null mice. The severe hypocellular defect in Chx10 single null mice is alleviated in the double null, and while Chx10-null retinas lack lamination, double null retinas have near normal lamination. Bipolar cells are absent in the double null retina, a defect that is attributable to a requirement for Chx10 that is independent of p27(Kip1). We find that p27(Kip1) is abnormally present in progenitors of Chx10-null retinas, and that its ectopic localization is responsible for a significant amount of the proliferation defect in this microphthalmia model system. mRNA and protein expression patterns in these mice and in cyclin D1-null mice suggest that Chx10 influences p27(Kip1) at a post-transcriptional level, through a mechanism that is largely dependent on cyclin D1. This is the first report of rescue of retinal proliferation in a microphthalmia model by deletion of a cell cycle regulatory gene.
Animals↗
Roles of cell-adhesion molecules nectin 1 and nectin 3 in ciliary body development.
Nectins are Ca2+-independent immunoglobulin-like cell-cell-adhesion molecules consisting of four members. Nectins homophilically and heterophilically trans-interact to form a variety of cell-cell junctions, including cadherin-based adherens junctions in epithelial cells and fibroblasts in culture, synaptic junctions in neurons, and Sertoli cell-spermatid junctions in the testis, in cooperation with, or independently of, cadherins. To further explore the function of nectins, we generated nectin 1-/- and nectin 3-/-)mice. Both nectin 1-/- and nectin 3-/- mice showed a virtually identical ocular phenotype, microphthalmia, accompanied by a separation of the apex-apex contact between the pigment and non-pigment cell layers of the ciliary epithelia. Immunofluorescence and immunoelectron microscopy revealed that nectin 1 and nectin 3, but not nectin 2, localized at the apex-apex junctions between the pigment and non-pigment cell layers of the ciliary epithelia. However, nectin 1-/- and nectin 3-/- mice showed no impairment of the apicolateral junctions between the pigment epithelia where nectin 1, nectin 2 and nectin 3 localized, or of the apicolateral junctions between the non-pigment epithelia where nectin 2 and nectin 3, but not nectin 1, localized. These results indicate that the heterophilic trans-interaction between nectin 1 and nectin 3 plays a sentinel role in establishing the apex-apex adhesion between the pigment and non-pigment cell layers of the ciliary epithelia that is essential for the morphogenesis of the ciliary body.
Animals↗
Diverse gap junctions modulate distinct mechanisms for fiber cell formation during lens development and cataractogenesis.
Different mutations of alpha3 connexin (Cx46 or Gja8) and alpha8 connexin (Cx50 or Gja8), subunits of lens gap junction channels, cause a variety of cataracts via unknown mechanisms. We identified a dominant cataractous mouse line (L1), caused by a missense alpha8 connexin mutation that resulted in the expression of alpha8-S50P mutant proteins. Histology studies showed that primary lens fiber cells failed to fully elongate in heterozygous alpha8(S50P/+) embryonic lenses, but not in homozygous alpha8(S50P/S50P), alpha8-/- and alpha3-/- alpha8-/- mutant embryonic lenses. We hypothesized that alpha8-S50P mutant subunits interacted with wild-type alpha3 or alpha8, or with both subunits to affect fiber cell formation. We found that the combination of mutant alpha8-S50P and wild-type alpha8 subunits specifically inhibited the elongation of primary fiber cells, while the combination of alpha8-S50P and wild-type alpha3 subunits disrupted the formation of secondary fiber cells. Thus, this work provides the first in vivo evidence that distinct mechanisms, modulated by diverse gap junctions, control the formation of primary and secondary fiber cells during lens development. This explains why and how different connexin mutations lead to a variety of cataracts. The principle of this explanation can also be applied to mutations of other connexin isoforms that cause different diseases in other organs.
Animals↗
Analysis of lens cell fate and eye morphogenesis in transgenic mice ablated for cells of the lens lineage.
Transgenic mice carrying the diphtheria toxin A gene driven by mouse gamma 2-crystallin promoter sequences manifest microphthalmia due to ablation of fiber cells in the ocular lens. Here we map ablation events in the lens by crossing animals hemizygous for the ablation construct with transgenic mice homozygous for the in situ lacZ reporter gene driven by identical gamma 2-crystallin promoter sequences. By comparing the spatial distribution of lacZ-expressing cells and the profile of gamma-crystallin gene expression in the lenses of normal and microphthalmic offspring, the contributions of specific cell types to lens development were examined. The results suggest that phenotypically and developmentally distinct populations of lens fiber cells are able to contribute to the lens nucleus during organogenesis. We also show that dosage of the transgene and its site of integration influence the extent of ablation. In those mice homozygous for the transgene and completely lacking cells of the lens lineage, we show that the sclera, cornea, and ciliary epithelium are reduced in size but, otherwise, reasonably well formed. In contrast, the anterior chamber, iris, and vitreous body are not discernible while the sensory retina is highly convoluted and extensively fills the vitreous chamber.
Animals↗
Overlapping effects of different members of the FGF family on lens fiber differentiation in transgenic mice.
Fibroblast growth factors (FGFs), such as FGF-1, have been shown to induce differentiation of lens epithelial cells both in tissue culture and in transgenic mice. In the present study, using the alpha A-crystallin promoter, we generated transgenic mice that express different FGFs (FGF-4, FGF-7, FGF-8, FGF-9) specifically in the lens. All four FGFs induced changes in ocular development. Microphthalmic eyes were evident in transgenic mice expressing FGF-8, FGF-9 and some lines expressing FGF-4. A developmental study of the microphthalmic eyes revealed that, by embryonic day 15, expression of these FGFs induced lens epithelial cells to undergo premature fiber differentiation. In less severely affected lines expressing FGF-4 or FGF-7, the lens epithelial cells exhibited a premature exit from the cell cycle and underwent a fiber differentiation response later in development, leading to cataract formation. The responsiveness of lens cells to different FGFs indicates that these proteins stimulate the same or overlapping downstream signalling pathway(s). These overlapping effects of different FGFs on a common cell type indicate that the normal developmental roles for these genes are determined by the temporal and spatial regulation of their expression patterns. The fact that any of these FGFs can induce ocular defects and loss of lens transparency implies that it is essential for the normal eye to maintain very specific spatial control over FGF expression in order to prevent cataract induction.
Animals↗
The role of bone morphogenetic proteins in the differentiation of the ventral optic cup.
The ventral region of the chick embryo optic cup undergoes a complex process of differentiation leading to the formation of four different structures: the neural retina, the retinal pigment epithelium (RPE), the optic disk/optic stalk, and the pecten oculi. Signaling molecules such as retinoic acid and sonic hedgehog have been implicated in the regulation of these phenomena. We have now investigated whether the bone morphogenetic proteins (BMPs) also regulate ventral optic cup development. Loss-of-function experiments were carried out in chick embryos in ovo, by intraocular overexpression of noggin, a protein that binds several BMPs and prevents their interactions with their cognate cell surface receptors. At optic vesicle stages of development, this treatment resulted in microphthalmia with concomitant disruption of the developing neural retina, RPE and lens. At optic cup stages, however, noggin overexpression caused colobomas, pecten agenesis, replacement of the ventral RPE by neuroepithelium-like tissue, and ectopic expression of optic stalk markers in the region of the ventral retina and RPE. This was frequently accompanied by abnormal growth of ganglion cell axons, which failed to enter the optic nerve. The data suggest that endogenous BMPs have significant effects on the development of ventral optic cup structures.
Animals↗
Complicated colobomatous microphthalmia in the microphthalmic (mi/mi) mouse.
A study of the development of the eye in the cinnamon mouse, homozygous for the gene for microphthalmia (mi), has shown that the microphthalmia is due to failure of secondary vitreous formation associated with a coloboma. The retina is dystrophic but there is a residual population of large ganglion cells and the optic nerve also contains ganglion cells. All these ganglion cells have cytoplasm similar to the retinal ganglion cells in the normal controls. It is postulated that they communicate with axons in the optic nerve. In addition, the outer epithelial layer of the eye cup, which normally becomes pigmented, forms retinal tissue in the homozygous mouse and this is also true of the dorsal part of the eyestalk near the eye.
Animals↗
Congenital malformations in a common marmoset (Callithrix jacchus) similar to human 13-trisomy syndrome.
This paper describes the finding of a number of malformations in a live-born common marmoset. The malformations included microphthalmia, ocular hypertelorism, cleft lip and palate and polydactyly. The findings are consistent with and strongly suggest chromosome trisomy similar to that which has been seen in man.
Abnormalities, Multiple↗
Internal hydrocephalus, optic nerve aplasia, and microphthalmia in CPB-WE (Wezob) and Cpb:WU (Wistar) rats.
Wistar rats of the inbred CPB-WE and the random bred Cpb:WU strains have been used in neuroanatomical studies. In both groups of rats a high incidence of hydrocephalus was observed. In the CPB-WE rats the ventricular dilatation was accompanied by optic tract lesions and microphthalmia. The present report describes the gross and microscopic findings in these rats and discusses the possible aetiology.
Animals↗
Oculodento-digital dysplasia: a rare syndrome.
A rare syndrome that can be diagnosed radiographically has been reviewed. A characteristic physiognomy, variable ophthalmologic anomalies and relatively specific dental and digital defects provide the diagnostic features. No hereditary component was identified and the chromosomal pattern was normal. The history, appearance and characteristic radiographic changes may, as in this case, allow the radiologist to provide a diagnosis not previously appreciated.
Adult↗