Located between vessels of the choriocapillaris and light-sensitive outer segments of the photoreceptors, the retinal pigment epithelium (RPE) closely interacts with photoreceptors in the maintenance of visual function. Increasing knowledge of the multiple functions performed by the RPE improved the understanding of many diseases leading to blindness. This review summarizes the current knowledge of RPE functions and describes how failure of these functions causes loss of visual function. Mutations in genes that are expressed in the RPE can lead to photoreceptor degeneration. On the other hand, mutations in genes expressed in photoreceptors can lead to degenerations of the RPE. Thus both tissues can be regarded as a functional unit where both interacting partners depend on each other.

The Retinal Pigment Epithelium in Visual Function

Mutations in RPE65 cause Leber's congenital amaurosis

Crx, an Otx-like homeobox gene, is expressed specifically in the photoreceptors of the retina and the pinealocytes of the pineal gland. Crx has been proposed to have a role in the regulation of photoreceptor-specific genes in the eye and of pineal-specific genes in the pineal gland. Mutations in human CRX are associated with the retinal diseases, cone-rod dystrophy-2 (adCRD2; refs 3, 4, 5), retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), which all lead to loss of vision. We generated mice carrying a targeted disruption of Crx. Crx-/- mice do not elaborate photoreceptor outer segments and lacked rod and cone activity as assayed by electroretinogram (ERG). Expression of several photoreceptor- and pineal-specific genes was reduced in Crx mutants. Circadian entrainment was also affected in Crx-/- mice.

Retinopathy and attenuated circadian entrainment in Crx-deficient mice.

Leber's congenital amaurosis (LCA, MIM 2040001), the earliest and most severe form of inherited retinopathy, accounts for at least 5% of all inherited retinal dystrophies2,3. This autosomal recessive condition is usually recognized at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus and extinguished electroretinogram (ERG4). Nystagmus (pendular type) and characteristic eye poking are frequently observed in the first months of life (digitoocular sign of Franceschetti5). Hypermetropia and keratoconus frequently develop in the course of the disease6,7. The observation by Waardenburg8 of normal children born to affected parents supports the genetic heterogeneity of LCA. Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photore-ceptors or extremely early degeneration of cells that have developed normally9. We have recently mapped a gene for LCA to chromosome 17p13.1 (LCA1) by homozygosity mapping in consanguineous families of North African origin and provided evidence of genetic heterogeneity in our sample, as LCA1 accounted for 8/15 LCA families in our series10,11. Here, we report two missense mutations (F589S) and two frameshift mutations (nt 460 del C, nt 693 del C) of the retinal guanylate cyclase (RETGC, GDB symbol GUC2D) gene in four unrelated LCA1 probands of North African ancestry and ascribe LCA1 to an impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels.

Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis.

Mutations in the crumbs homologue 1 (CRB1) gene cause a specific form of retinitis pigmentosa (RP) that is designated "RP12" and is characterized by a preserved para-arteriolar retinal pigment epithelium (PPRPE) and by severe loss of vision at age <20 years. Because of the early onset of disease in patients who have RP with PPRPE, we considered CRB1 to be a good candidate gene for Leber congenital amaurosis (LCA). Mutations were detected in 7 (13%) of 52 patients with LCA from the Netherlands, Germany, and the United States. In addition, CRB1 mutations were detected in five of nine patients who had RP with Coats-like exudative vasculopathy, a relatively rare complication of RP that may progress to partial or total retinal detachment. Given that four of five patients had developed the complication in one eye and that not all siblings with RP have the complication, CRB1 mutations should be considered an important risk factor for the Coats-like reaction, although its development may require additional genetic or environmental factors. Although no clear-cut genotype-phenotype correlation could be established, patients with LCA, which is the most severe retinal dystrophy, carry null alleles more frequently than do patients with RP. Our findings suggest that CRB1 mutations are a frequent cause of LCA and are strongly associated with the development of Coats-like exudative vasculopathy in patients with RP.

https://www.cell.com/ajhg/pdf/S0002-9297(07)61458-X.pdf

Leber Congenital Amaurosis and Retinitis Pigmentosa with Coats-like Exudative Vasculopathy Are Associated with Mutations in the Crumbs Homologue 1 (CRB1) Gene

• We retrospectively studied 36 patients with congenital (Leber's amaurosis) and early onset retinitis pigmentosa (RP) to develop a new schematic classification system based on the age at onset of symptoms, severity of visual loss, and associated nonocular abnormalities. Our four groups were designated as complicated and uncomplicated Leber's congenital amaurosis and juvenile and early onset RP. Criteria for patient selection included an extinguished or barely recordable electroretinogram, well-documented age of onset, and comprehensive ocular and medical examinations before the age of 10 years. Among the congenitally blind, the distinguishing features were the degree of hyperopia and the presence or absence of neurologic abnormalities. Among patients with infantile or juvenile onset of retinal degeneration, the distinguishing features were the severity of visual loss and the age at onset of symptoms. The presence of nystagmus and hyperopia and the severity of central visual loss differentiated congenital from early onset RP.

Classification of congenital and early onset retinitis pigmentosa.

Objectives To estimate the prevalence of 4 categories of infantile cataract in subjects surviving the neonatal period in a US cohort, and to investigate risk factors for isolated infantile cataract. Design Prospective study of 55 908 pregnancies enrolled in the Collaborative Perinatal Project from 1959 to 1965 at 12 university medical centers. Methods We gathered data on demographic, lifestyle, and prenatal and perinatal obstetrical and postnatal factors using a standardized protocol. Pediatricians and neurologists examined infants at birth, 4 months, 1 year, and 7 years. We used exact logistic regression methods to compare putative risk factors in infants with isolated cataract with those in infants with no history of cataract. Outcome Measures Infantile cataract as diagnosed using a standardized dilated ophthalmic examination. Results Infantile cataract occurred in 13.6 per 10 000 infants (95% confidence interval [CI], 10.7-17.1). Isolated infantile cataract occurred 3.8 times as often among infants born at weights at or below 2500 g than among those born at or above 2500 g (95% CI, 1.5-8.6; P Conclusions Infantile cataract is a rare disorder occurring during childhood. Prevalence estimates reported here are within the limits of those from large-cohort studies in economically developed nations. Infants born at weights at or below 2500 g have a 3- to 4-fold increased odds of developing infantile cataract.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/272683/eeb20000.pdf

Infantile Cataract in the Collaborative Perinatal Project: Prevalence and Risk Factors

Growth of the Human Optic Disk and Nerve During Gestation, Childhood, and Early Adulthood

Summary: A 3½-year-old male is described with the rare triad of ACTH insensitivity, achalasia, and alacrima. Adrenal insufficiency presented with hypoglycemia and hyperpigmentation at age 2½ years. Achalasia was diagnosed at age 3½ years and alacrima, retrospectively, had been present since birth. Evaluation of adrenal function revealed complete resistance of the glucocorticoid-producing zonas fasciculata and reticularis to both endogenous and exogenous ACTH. No chemical evidence was found for the presence of either an abnormal ACTH molecule or a circulating antibody to ACTH. Additionally, adrenal miner-alocorticoid function was clearly responsive to both exogenous ACTH and to perturbations of the renin-angiotensin system. Only glucocorticoid deficiency due to selective ACTH resistance was documented. Shortly after diagnosis, glucocorticoid production could be stimulated by intravenous theophylline administration. Presumably, this agent, whose intracellular actions may be mediated by either enhancement of cyclic AMP action or alterations in calcium transport, circumvented the usual interaction of ACTH with its receptor and thereby stimulated steroidogenesis. The responsiveness to theophylline was lost 1 year later, perhaps as a result of final atrophy of the zonas fasciculata and reticularis secondary to lack of effective ACTH stimulation; thus, our patient appears to have a unique syndrome characterized by ACTH insensitivity and a multifocal defect of the autonomie, specifically parasympathetic, nervous system, resulting in achalasia and alacrima. A putative pathogenic defect linking hormone-receptor cyclic AMP-mediated processes with abnormalities in parasympathetic neuronal innervation or receptor-mediated transmitter function, as may occur in achalasia and alacrima, remains to be demonstrated.

/pdf/selective-acth-insensitivity-achalasia-and-alacrima-a-2gbrs07x19.pdf

J. Bronwyn Bateman

Papers

Classification of congenital and early onset retinitis pigmentosa.

Infantile Cataract in the Collaborative Perinatal Project: Prevalence and Risk Factors

Growth of the Human Optic Disk and Nerve During Gestation, Childhood, and Early Adulthood

Selective ACTH insensitivity, achalasia, and alacrima: a multisystem disorder presenting in childhood.

Cycloplegic refraction in esotropic children. Cyclopentolate versus atropine.