Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of ATRIP-Seckel syndrome.

Seckel syndrome is a type of microcephalic primordial dwarfism (MPD) that is characterized by growth retardation and neurodevelopmental defects, including reports of retinopathy. Mutations in key mediators of the replication stress response, the mutually dependent partners ATR and ATRIP, are among the known causes of Seckel syndrome. However, it remains unclear how their deficiency disrupts the development and function of the central nervous system (CNS). Here, we investigated the cellular and molecular consequences of ATRIP deficiency in different cell populations of the developing murine neural retina. We discovered that conditional inactivation of Atrip in photoreceptor neurons did not affect their survival or function. In contrast, Atrip deficiency in retinal progenitor cells (RPCs) led to severe lamination defects followed by secondary photoreceptor degeneration and loss of vision. Furthermore, we showed that RPCs lacking functional ATRIP exhibited higher levels of replicative stress and accumulated endogenous DNA damage that was accompanied by stabilization of TRP53. Notably, inactivation of Trp53 prevented apoptosis of Atrip-deficient progenitor cells and was sufficient to rescue retinal dysplasia, neurodegeneration and loss of vision. Together, these results reveal an essential role of ATRIP-mediated replication stress response in CNS development and suggest that the TRP53-mediated apoptosis of progenitor cells might contribute to retinal malformations in Seckel syndrome and other MPD disorders.This article has an associated First Person interview with the first author of the paper.

Nystagmus associated with macular dysplasia.

Purpose: To describe Optical Coherence Tomography (OCT) findings of the macula in patients with nystagmus, mainly the relationship between spectral-domain OCT (SD-OCT) images and nystagmus in macular dysplasia.Methods: In this study, 17 cases (29 eyes) with congenital macular abnormalities in patients with albinism, macular heterotopias, congenital aniridia, foveal hypoplasia, congenital macular coloboma, and congenital retinoschisis were retrospectively analyzed. Patients underwent multimodal retinal imaging examinations including ultra-widefield fundus imaging, SD-OCT, autofluorescence, and visual field. When the pit was not clearly presented, SD-OCT imaging was centered at the expected foveal center.Results: In cases of oculocutaneous albinism SD-OCT showed the absence of the foveal pit and increased foveal thickness, with nystagmus. Their fundus revealed a lack of pigment in retinal pigment epithelium with visible large choroidal vessels. SD-OCT in congenital aniridia showed a planar fovea in the macula with the lack of a foveal pit and nystagmus. SD-OCT showed the absence of a foveal pit in foveal hypoplasia with nystagmus. In cases of monocular macular heterotopia, no nystagmus was found; the fellow eye had good vision and the macular morphology was usually normal. Nystagmus was not found in patients with congenital macular coloboma and congenital retinoschisis in this study.Conclusion: SD-OCT plays an important role in the diagnosis and prognosis of macular dysplasia in patients with nystagmus. Absence of a normal foveal pit is an OCT-imaging characteristic of macular dysplasia associated with nystagmus.

Acute Blindness.

Sudden loss of vision is an ophthalmic emergency with numerous possible causes. Abnormalities may occur at any point within the complex vision pathway, from retina to optic nerve to the visual center in the occipital lobe. This article reviews specific prechiasm (retina and optic nerve) and cerebral cortical diseases that lead to acute blindness. Information regarding specific etiologies, pathophysiology, diagnosis, treatment, and prognosis for vision is discussed.

[MRI in congenital nystagmus]. / Apport de l'IRM dans les nystagmus congénitaux.

INTRODUCTION: Congenital nystagmus (CN) that is present by the age of 3 months is the most common form of nystagmus in childhood. We present a prospective study (2001-2008) in which we report imaging findings in 48 children with CN. MATERIALS AND METHODS: Twenty-six boys and 22 girls with CN underwent a complete ophthalmologic assessment and a cerebral MRI (mean age of examination under general anesthesia: 11 months). Three CN groups were formed: neurologic (n=27), sensory visual disturbance (n=14), and isolated (n=7). Cerebral MRI was interpreted by the same pediatric neuroradiologist (NG). Of the children studied, 98 % were born at term. The MRI abnormalities were classified as morphologic abnormalities (malformative or nonmalformative) and as signal abnormalities. The location of brain abnormalities was within the posterior fossa, (brain stem, cerebellum, dental nuclei, cisterna magna) and the cerebral hemisphere (white matter, perivascular spaces, midline commissures, basal ganglia). RESULTS: Pendular nystagmus was prevalent in sensory and neurologic nystagmus. On fundus examination, optic disc abnormalities were present in 70 % (19) of neurologic CN and associated with white matter abnormalities of the optic radiations in 40 % of cases. On MRI, malformative morphologic abnormalities were present in 27 cases, nonmalformative abnormalities were found in 67, and signal abnormalities in 68. Within the brain stem, signal abnormalities were found as a cockade appearance of the posterior pons in the reticular regions (neurologic n=14, sensory n=6, isolated n=3). Other bright (most frequent) signal abnormalities were found within the dentate nuclei of the posterior fossa (neurologic n=10, sensory n=3, isolated n=3) and the cerebral white matter (neurologic n=17, sensory n=7, isolated n=5) of which 24 (neurologic n=15, sensory n=5, isolated n=4) involved the optic radiations. Most of these abnormalities were related and were seen most frequently in neurologic nystagmus. The most frequent association was signal abnormalities of the white matter, ventricular dilatation, and dilatation of the perivascular spaces (60.4 %) (neurologic n=13, sensory n=6). CONCLUSION: This study showed the fundamental contribution of the cerebral MRI in CN. Cerebral abnormalities were found at the pathways for ocular motility, particularly at the saccadic pathways.

Proteomic profiling of the retinal dysplasia and degeneration chick retina.

PURPOSE: In our previous paper we undertook proteomic analysis of the normal developing chick retina to identify proteins that were differentially expressed during retinal development. In the present paper we use the same proteomic approach to analyze the development and onset of degeneration in the retinal dysplasia and degeneration (rdd) chick. The pathology displayed by the rdd chick resembles that observed in some of the more severe forms of human retinitis pigmentosa. METHODS: Two-dimensional gel electrophoresis (pH 4-7), gel image analysis, and mass spectrometry were used to profile the developing and degenerating retina of the rdd and wild-type (wt) chick retina. RESULTS: Several proteins were identified by mass spectrometry that displayed differential expression between normal and rdd retina between embryonic day 12 (E12) and post-hatch day 1 (P1). Secernin 1 displayed the most significant variation in expression between rdd and wt retina; this may be due to differential phosphorylation in the rdd retina. Secernin 1 has dipeptidase activity and has been demonstrated to play a role in exocytosis; it has been shown to be overexpressed in certain types of cancer and has also been suggested as a potential neurotoxicologically relevant target. Its role in the retina and in particular its differential expression in the degenerate rdd retina remains unknown and will require further investigation. Other proteins that were differentially expressed in the rdd retina included valosin-containing protein, beta-synuclein, stathmin 1, nucleoside diphosphate kinase, histidine triad nucleotide-binding protein, and 40S ribosomal protein S12. These proteins are reported to be involved in several cellular processes, including the ubiquitin proteasome pathway, neuroprotection, metastatic suppression, transcriptional and translational regulation, and regulation of microtubule dynamics. CONCLUSIONS: This proteomic study is the first such investigation of the rdd retina and represents a unique data set that has revealed several proteins that are differentially expressed during retinal degeneration in the rdd chick. Secernin 1 showed the most significant differences in expression during this degeneration period. Further investigation of the proteins identified may provide insight into the complex events underlying retinal degeneration in this animal model.

Microcephaly with chorioretinopathy in a brother-sister pair: evidence for germ line mosaicism and further delineation of the ocular phenotype.

Microcephaly with chorioretinopathy (OMIM 156590) is an autosomal dominant syndrome, characterized primarily by chorioretinal lesions and microcephaly. The phenotype is variable, and has been described in association with retinal dysplasia that can be stable or show progressive degeneration, retinal folds, lymphedema, and mental retardation. We describe two siblings with microcephaly, mental retardation, and variable retinal and choroidal abnormalities. Patient 1 has multiple atrophic and dysplastic-appearing lesions of the retina and choroid in each eye. An ERG at 5 months of age disclosed markedly subnormal scotopic and photopic responses with delayed flicker timing. Patient 2 has bilateral macular folds with vitreoretinopathy, serous retinal detachments, glaucoma, and cataracts OU. Both have mental retardation with hypotonia and severe microcephaly. Chorioretinopathy and retinal folds have been described independently in microcephaly with chorioretinopathy. The present sibs are the first in whom these features are observed while the parents are normal. Our findings support an expansion of the ocular phenotype and suggest the existence of germ line mosaicism.

A case of Fukuyama-type congenital muscular dystrophy with a very mild mental deficit.

A boy had the clinical features of congenital muscular dystrophy with a very mild mental deficit. A muscle biopsy at one year of age showed the typical findings of Fukuyama-type congenital muscular dystrophy, including selective loss of immunoreactions for alpha dystroglycan. Magnetic resonance imaging showed no findings suggestive of migration disorders. The diagnosis of Fukuyama-type congenital muscular dystrophy was confirmed by a molecular assay at 8 years of age, and his haplotype analysis was heterozygous. At 9 years of age, his FIQ on the Wechsler Scale for Children revealed 69, while his IQ on the Tanaka Binnet scale of intelligence was 97. In this report the relationship between mild clinical condition of the studied case and its genotype is discussed.

The ocular manifestations of Jacobsen syndrome: a report of four cases and a review of the literature.

PURPOSE: We report ophthalmic manifestations in four Jacobsen syndrome cases, review the literature, and suggest phenotype-genotype correlations. METHODS: Chart review of Ocular Genetics Program patients at The Hospital for Sick Children, Toronto, Canada. RESULTS: Four del11qter cases are presented. Hypertelorism/telecanthus, abnormally slanted palpebral fissures, abnormal retinal findings, nasolacrimal duct obstruction, anomalous extraocular muscles, amblyopia, and microcornea were found. CONCLUSIONS: We report typical findings and novel ocular presentations. Visual prognosis is generally good. Retinal dysplasia and coloboma seem associated with del11q23. ABCG4, NCAM, and Mfrp are candidate genes in this region that theoretically may be disrupted.

Blindness due to retinal dysplasia in broiler chicks.

Thirty-three live 9-day-old broiler chicks were submitted for laboratory evaluation because of blindness. Blindness was observed in up to 1% of 25,000 birds from four different houses. All the chicks were from the same breeder source. Blindness was apparent when the chicks were 2-3 days old. Clinically, the blind chicks were smaller than their counterparts, were unable to find feed and water, and wandered aimlessly. Necropsy did not reveal any lesions. Two chicks examined clinically at 14 days of age lacked pupillary reflexes after light stimulation, and the anterior and posterior segments of the eye were normal. Microscopically, degeneration of photoreceptor cells characterized by vacuoles was evident at 9 days of age, and rosette formation of the retina, disorganization of retinal layers, synechia of the retina with mild inflammation in the choroid, and proliferation of the retinal pigment epithelial cells were evident by 15 days of age. Because the chicks came from the same breeder source and the incidence of blindness was low, a probable genetic etiology is suspected as the cause of blindness in this flock.

Staphyloma in a cat.

A unilateral scleral staphyloma in an 18-month-old, female spayed Domestic Short-haired cat was treated with excision, primary closure and fascial graft. Other ocular abnormalities noted on examination included iris coloboma, anterior cortical cataract, focal lens equator flattening and retinal dysplasia. The staphyloma was presumed to be congenital in origin.

Focal retinal pigment epithelial dysplasia associated with fundus flavimaculatus.

BACKGROUND: One or more focal dysplastic lesions of the retinal pigment epithelium (RPE) occurred in 15 eyes of 10 patients with fundus flavimaculatus. METHODS: Review of patient records including an attempt to obtain follow-up information concerning a history of previous ocular trauma. RESULTS: Mild antecedent ocular trauma occurred to the eye with a dysplastic lesion in two patients. Dysplastic lesions were most frequently solitary and located temporal to the macula. Subretinal neovascularization accompanied two of the dysplastic lesions. The lesions were multifocal and present bilaterally in two patients. CONCLUSIONS: In fundus flavimaculatus, progressive lipofuscin storage is responsible for engorgement and hypertrophy of the RPE. Dysplastic lesions of the RPE probably result from reactive hyperplasia and fibrous metaplasia of RPE cells in response to acute disruption of fragile, hypertrophied RPE cells that may be enormously enlarged in the area of yellow flecks. This disruption may occur in response to trauma, focal inflammation, or other localized stimuli. Patients with fundus flavimaculatus should be cautioned concerning the possible role of trauma in causing dysplastic changes in the RPE and visual loss.

Bilateral macular dysplasia in fragile X syndrome.

PURPOSE: Few studies have investigated the eye and vision dysfunctions of children with the fragile X syndrome. CASE REPORT: We report on a preschool boy with bilateral macular dysplasia and fragile X syndrome. His ocular features and phenotypic and genetic expressions are described. His mentally normal mother was identified as an expansion mutation carrier, and his older sister has learning disabilities, astigmatic refractive error, squint, and mild ptosis. Intrauterine infection has been excluded. CONCLUSION: To our knowledge, the association of macular dysplasia with fragile X syndrome has not been reported. The finding of macular dysplasia might be a coincidental developmental disorder and not a part of the syndrome. It could be considered a condition causing visual deficit with nystagmus in fragile X syndrome.

Chorioretinal dysplasia-microcephaly-mental retardation syndrome: another family with autosomal dominant inheritance.

We describe a boy and his father with the chorioretinal dysplasia-microcephaly-mental retardation syndrome (CDMMS). Our report extends the phenotypic spectrum of autosomal dominant CDMMS by describing microphthalmia for the first time in an autosomal dominant family. The boy was also severely mentally retarded in contrast to the usual mild mental retardation in AD-CDMMS. Furthermore he had hypertonia, dysmorphic features and low body weight, which are uncommon in AD-CDMMS. CDMMS is a rare disorder. We traced 18 reports on CDMMS including 10 families, 6 with horizontal transmission and 4 with vertical transmission. There are 8 reports and observations on isolated cases with CDMMS. This might imply genetic heterogeneity with autosomal recessive and autosomal dominant inheritance, with a more severe clinical picture in the former but with quite variable inter- and intrafamilial expression. A review of the literature is given. The existence of autosomal recessive inheritance in families with so-called horizontal transmission is discussed as variable expression, reduced penetrance and germline mosaicism may also explain this condition. Careful (particularly ophthalmologic) examination of first degree relatives is necessary before genetic counseling is given.