Chorioretinal Dystrophy Research Articles

Visual impairment and REP-1 gene mutations in Japanese choroideremia patients

Choroideremia (CHM), an X-linked recessive hereditary disease, is an intractable chorioretinal dystrophy. The rate of disease progression of CHM reportedly shows considerable variability. A number of mutations involving the gene that codes for Rab escort protein-1 (REP-1) have been detected in CHM patients. We have analyzed REP-1 gene mutations of Japanese CHM patients. The present study was designed to investigate the clinical variability and the genotype to phenotype relationship in 15 Japanese CHM patients referred to the Department of Ophthalmology of Juntendo University Hospital. The clinical investigation of visual acuity, visual field, color vision and refraction revealed inter-individual variability. Mutation analyses of the REP-1 gene revealed 10 types of mutations in 13 patients from 11 families, including an insertion, small deletions, nonsense mutations and an A to CC mutation. In 13 CHM patients with detectable REP-1 gene mutations, no relationship of genotype to phenotype was detected. At present, we consider the REP-1 genotype to be an unreliable prognostic factor for counseling of CHM patients. In two patients from one family, no mutations were detected in coding regions of the REP-1 gene. These patients may have intron mutations of the REP-1 gene, not detectable by the techniques employed in this study, or other causative genes. Both were observed to have somewhat slower disease progression than the other 13 patients. More advanced analyses are necessary to answer questions regarding the genotype-phenotype relationship in CHM patients.

Congenital-onset central chorioretinal dystrophy associated with high myopia.

We describe six siblings of a 12-member sibship affected with a macular dystrophy that is congenital in onset and is associated with progressive myopia. The age of these siblings ranged from 7 months to 19 years. The presenting feature was visual impairment and the best corrected visual acuity ranged between 1/60 and 6/36. Myopia ranged from -3.00 dioptres in the youngest to -10.50 dioptres in the second-eldest member. The macular lesions in our patients are characterised by a well-defined area of atrophy of choriocapillaris and retinal pigment epithelium. These lesions progressed with age in both size and depth. The extent of choroidal involvement in the lesions varied from only loss of superficial vasculature to sparing of large choroidal vessels as confirmed by fundus fluorescein angiography. One patient also exhibited bilateral Duane's syndrome (type III) and right unilateral ptosis. To the best of our knowledge such a fully established macular lesion presenting at the age of 6 months and associated with progressive myopia has never been described in literature.

Two sibs with chorioretinal dystrophy, hypogonadotrophic hypogonadism, and cerebellar ataxia: Boucher-Neuhäuser syndrome.

We describe two sibs with chorioretinal dystrophy, hypogonadotrophic hypogonadism, and cerebellar ataxia, Boucher-Neuhäuser syndrome, a rare but distinct pleiotropic single gene disorder with an autosomal recessive pattern of inheritance. The...

Granulocytopenia in Cohen syndrome.

Cohen syndrome is an autosomal recessive disorder characterized by mental retardation, microcephalia and typical craniofacial features, myopia and chorioretinal dystrophy. As some patients were reported to have leucopenia, we collected the haematological data of 26 Finnish Cohen patients. They all had experienced periods of isolated granulocytopenia from an early age. Granulocytopenia was mild to moderate, non-cyclic and never fatal. Most patients suffered from prolonged or repeated gingival or skin infections. We restudied 16 patients. Bone marrow examination revealed in all patients a normo- or hypercellular marrow, with a left-shifted granulopoiesis in 8/16 patients. The response to adrenaline stimulation was subnormal in 12/14 and to hydrocortisone in 8/16 patients, but administration of rhG-CSF caused granulocytosis in the three patients studied. No bone marrow malignancies were seen.

Sporadic heteroplasmic single 5.5 Kb mitochondrial DNA deletion associated with cerebellar ataxia, hypogonadotropic hypogonadism, choroidal dystrophy, and mitochondrial respiratory chain complex I deficiency

This report describes a patient with cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy, associated with mitochondrial respiratory chain complex I deficiency and a 5.5 kb mtDNA single deletion in skeletal muscle. Hum Mutat 10:212–216, 1997. © 1997 Wiley-Liss, Inc.

Molecular genetics of central retinal dystrophies.

A range of chorioretinal dystrophies that principally affect the central retina have recently been associated with either specific genetic mutations or mapped to refined genomic loci. Mutations of two genes, peripherin/RDS (chromosome 6p) and TIMP3 (chromosome 22q) have been shown to be of particular importance to this group of disorders. Other conditions such as Stargardt's disease, Best's disease, pattern dystrophy, cone dystrophy and cone-rod dystrophy have been mapped to different regions of the genome, however the underlying genetic mutations await identification. Molecular genetic diagnostic techniques are now available for a number of central choroidoretinal dystrophies allowing for earlier, accurate diagnosis and laying the groundwork for future studies of potential therapeutic protocols.

Clinical Features of Progressive Bifocal Chonoretinal Atrophy: A Retinal Dystrophy Linked to Chromosome 6q

Purpose: The gene for progressive bifocal chorioretinal atrophy (PBCRA) has been linked to chromosome 6% near the genomic assignment for North Carolina macular dystrophy. A study was undertaken to define the clinical features of a large PBCRA pedigree and to determine whether PBCRA and North Carolina macular dystrophy are phenotypically distinct entities.Methods: Fifteen affected individuals from 1 large family were examined clinically, which included angiography and electrophysiologic studies.Results: The PBCRA is an autosomal dominant chorioretinal dystrophy of early onset characterized by large atrophic macular and nasal retinal lesions, nystagmus, myopia, poor vision, and slow progression. A large atrophic macular lesion and nasal subretinal deposits are evident soon after birth. An atrophic area nasal to the optic nerve head appears in the second decade, which enlarges progressively. Electro-oculographic and electroretinographic studies indicated marked, diffuse abnormalities of rod and cone function. Fluorescein and indocyanine green angiography showed a large circumscribed area of macular choroidal atrophy with staining of deposits in the peripheral retina. In addition to previously documented features, nasal retinal abnormalities from a few weeks of age, marked photopsia in a number of patients, and retinal detachments in three eyes are reported as new features of the disease.Conclusions: An extended description of PBCRA is presented highlighting that the phenotype is distinct from North Carolina macular dystrophy, although some phenotypic similarities exist between the two conditions. These disorders may be the result of different mutations on the same gene or nearby genes.

Macrophage Subpopulations and RPE Elimination in the Pathogenesis of Experimental Autoimmune Pigment Epithelial Protein-Induced Uveitis (EAPU)

Experimental autoimmune pigment epithelial protein-induced uveitis (EAPU) is a new type of disease that destroys the retinal pigment epithelium (RPE), and exhibits a hitherto unknown form of progressive chorioretinal dystrophy in which neuroretinal inflammatory foci are absent. The present study was aimed at studying the expression of adhesion molecules, and the kinetics of the appearance of the main types of macrophages and other intraocular immunocompetent cell populations in the various stages of this disease. EAPU was evoked in Lewis rats by immunization with the membrane protein from bovine RPE cells containing PEP-65 as main constituent. In the uvea, increased expression of intercellular adhesion molecule-1, of class II major histocompatibility complex antigen, and of ED2 macrophage reactivity were observed closely before the onset of EAPU. Expression of these reactivities was also slightly elevated by injections of the applied adjuvants alone. The onset of EAPU was mainly characterized by initial uveal infiltrations of ED1+macrophages and a minor population of CD4 T cells, and an increase in ED3, ED7 and perivascular ED2 reactive macrophages. This was followed by the development of focal accumulations of ED1+ cells at both sides of the Bruch's membrane–RPE layer (Dálen–Fuchs nodules) which was permeated and disintegrated at these sites. The outer choroidal layer, the anterior iridal surface, and the base of the ciliary body more frequently contained active inflammatory cells than the other uveal areas. Lymphoid cells were found scattered through the uvea, aqueous and vitreous. The sites of increased activity of ED2+ and ED3+ cells in the uvea were rather similar to those of ED1 macrophages in the various stages of EAPU. Starting from multiple foci, the process of the formation of plaque-shaped cell accumulations in severe EAPU progressed along the RPE and exhibited a chronic character. The results of this study show that ED1+, ED2+, ED3+ and ED7+ subpopulations of macrophages are actively involved in an immunopathological process in which the RPE is the target. The thickening of the plaque-shaped cell accumulations stops if the integrity of all RPE cells at that site has been affected. We postulate that this is the result of antigen elimination while additional influence of the abrogation of RPE cytokine production is presumed.

Ophthalmologic Findings in a Patient With Cerebellar Ataxia, Hypogonadotropic Hypogonadism, and Chorioretinal Dystrophy

To determine the ophthalmologic findings in a 39-year-old woman with the Boucher-Neuhäuser syndrome, which is a disorder of autosomal recessive inheritance characterized by the triad of spinocerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism. The patient underwent clinical and electrophysiologic examinations and fluorescein angiography. The main clinical findings were extensive areas of retinal pigment epithelial and choriocapillaris atrophy affecting the posterior pole and midperiphery of both eyes. Results of electroretinographic examination showed subnormal photopic and scotopic responses. The Boucher-Neuhäuser syndrome should be included in the differential diagnosis of patients with chorioretinal degeneration, particularly if there are neurologic or endocrinologic manifestations.

Practical Atlas of Retinal Diseases and Therapy

Practical Atlas of Retinal Diseases and Therapy , edited by William R. Freeman, MD, is a multiauthor effort to present current information in the field of vitreoretinal diseases. Each chapter is written by an internationally renowned authority in the field. The first part of the book deals with the hereditary chorioretinal dystrophies and new devices for retinal function testing. This is followed by inflammatory diseases of the retina and choroid, including uveitis, multifocal chorioretinopathies, and opportunistic retinitis. The last section of the first part discusses the diagnosis and treatment of posterior uveal tumors. The next part of the book covers most of the common retinopathies that involve the retina and choroid, such as vascular occlusions, diabetic retinopathy, macular degeneration, complications of cataract surgery, and peripheral retinal lesions. The last chapters discuss surgical aspects of vitreoretinal disease, including scleral buckling, pneumatic retinopexy, vitreoretinal surgery, proliferative retinopathy and retinopathy of prematurity, and management

Localization of the gene for progressive bifocal chorioretinal atrophy (PBCRA) to chromosome 6q.

Progressive bifocal chorioretinal atrophy (PBCRA) is a rare, autosomal dominant congenital chorioretinal dystrophy. We have performed genetic linkage analysis on a five-generation British pedigree. Two-point linkage analysis showed significant linkage with nine microsatellite marker loci mapping to chromosome 6q. Multipoint analysis gave a maximum lod score of 11.8 (theta = 0.05) between D6S249 and D6S283. This region overlaps with that to which the gene for North Carolina macular dystrophy (MCDR1) has been assigned. However, given the range of differences in phenotype between these two retinal disorders, it is likely that different mutation mechanisms are responsible for each disease.

Ocular manifestations of metabolic disorders

Articles published between October 1991 and September 1992 on the ocular manifestations of metabolic diseases are reviewed. Articles of special interest include a study that shows that compliance to a low-arginine diet in affected siblings with gyrate atrophy of the choroid and retina dramatically slows the progression of the chorioretinal dystrophy. The efficacy of cysteamine topical eye drops in the treatment of corneal crystals in patients with nephropathic cystinosis was described in a case report from Germany confirming the previous report of a clinical trial. The ophthalmic findings in 33 patients with classic galactosemia were reviewed. Sequential electroretinograms in two siblings with Batten's disease are described and help confirm that the primary lesion is in the inner retinal layers. And finally, clinical and histopathological studies of two families with lattice corneal dystrophy and type IV amyloidotic polyneuropathy (Meretoja syndrome) are presented. Current Opinion in Ophthalmology 1993, 4;VI:83-88

Retinitis pigmentosa and allied disorders in Denmark

We analyzed the composition of a retinitis pigmentosa (RP) sample with respect to clinical appearance. The material included 1301 affected persons derived from a national Danish survey with a high degree of completeness. The cases were grouped according to ocular signs and symptoms into typical RP, atypical RP, vitreoretinal RP, chorioretinal dystrophy, and unclassified. The relative frequency with which these groups were nosologically allocated to systemic and non-systemic retinitis pigmentosa is presented. Among 837 cases of non-systemic RP 60% had ophthalmoscopic abnormalities and visual symptoms in accordance with typical RP, 29% were characterized as atypical and 6% presented with chorioretinal dystrophy. The results of earlier epidemiological studies, sex distribution, and new diagnostic concepts based on DNA analysis are discussed.

Ophthalmic Desk Reference

Part 1 Synopsis of clinical ophthalmology: ocular trauma and emergency care orbital disease ocular motility neuro-ophthalmology external eye disease uveitis the glaucomas retinal and choroidal vascular disease hereditary chorioretinal dystrophies intraocular tumors systemic disease nonstrabismic pediatric ophthalmology clinical refraction contact lenses. Part 2 Surgical topics: ophthalmic anesthesia common ophthalmic plastic procedures orbital surgery corneal surgery management of cataracts surgical management of the glaucomas retinal and vitreous surgery ophthalmic laser surgery refractive surgery miscellaneous ophthalmic surgical procedures. Part 3 Differential diagnosis. Appendices: glossary of ophthalmic terminology, eponyms and syndromes therapeutics genetics, embryology and anatomic drawings ocular dimensions and basic optical data intraocular lenses, sutures and needles selected diagnostic modalities laboratory norms and conversion tables.

Gyrate Atrophy of the Choroid and Retina

Gyrate atrophy of the choroid and retina is an autosomal recessive, chorioretinal dystrophy that begins in childhood and leads to blindness in the fourth to seventh decade of life. The primary defect is deficiency of ornithine-delta-amino-transferase, which results in accumulation of ornithine. We examined six pairs of affected siblings to determine if intrafamilial variability in the phenotype was less than interfamilial, and to determine if long-term (5- to 7-year) reduction of ornithine with an arginine-restricted diet had an effect on the progression of the chorioretinal degeneration. All but one set of siblings underwent periodic ophthalmologic examinations. The clinical diagnosis was confirmed with the demonstration of hyperornithinemia and deficiency of ornithine-delta-aminotransferase. The molecular defects in their ornithine-delta-amino-transferase genes also were determined. The two younger pairs of siblings were given an arginine-restricted diet and followed up for 5 to 7 years. We found strikingly similar phenotypes in affected members of the same pair of siblings. In the young patients receiving the diet, there was substantial reduction of ornithine levels. These children had only modest progression of their ocular disease during this period. Furthermore, a comparison of the outcome of the younger with their older siblings at an equivalent age showed that the younger siblings, who started receiving the diet at an earlier age, had much less ocular disease. We conclude that intrafamilial phenotypic variation in gyrate atrophy is less than interfamilial and, therefore, that genetic heterogeneity plays a role in the phenotypic variability of gyrate atrophy. Furthermore, we conclude that chronic reduction of ornithine with an arginine-restricted diet dramatically slows the progression of the chorioretinal dystrophy.

A far advanced case of gyrate atrophy in a 12‐year‐old girl

Gyrate atrophy (GA; McKusick 25887) is a progressive chorioretinal dystrophy with an autosomal recessive mode of inheritance. In this disorder there is a deficiency of the mitochondrial matrix enzyme ornithine-f-aminotransferase (OAT). Ocular symptoms usually present late in the first decade of life. Ophthalmological findings include myopia, constricted visual fields, elevated dark adaptation thresholds (night blindness), very small or absent electroretinographic responses, and characteristic patchy chorioretinal atrophy distributed circumferentially around the peripheral fundus. Gradually the round patches of atrophy coalesce to form widespread chorioretinal atrophy extending to the posterior pole. Cataracts develop requiring surgical intervention, and eventually blindness occurs due to progressive loss of functional retina at the age of 40 to 50 (Valle and Simell, 1989). Plasma ornithine levels range from 400 to 1400/~mol/L, and 0.5 to 10mmol of ornithine is excreted daily. Glutamate, glutamine, lysine, creatine and creatinine concentrations in plasma are modestly reduced. The pathophysiological mechanism responsible for the chorioretinal dystrophy in GA is not known. Hyperornithinaemia or associated secondary metabolic abnormalities may play an important role, but until the pathophysiology is understood, there is no assurance that correction of biochemical abnormalities in plasma will actually be beneficial (Berson et al., 1981). Four general therapeutic approaches have been used: pharmacological doses of pyridoxine, reducing the intake of arginine and administration of creatine or proline. In this paper we described a 12-year-old patient with night blindness and myopia as the first symptoms of gyrate atrophy with ornithinaemia.

Variation in retinal changes and muscle pathology in mitochondriopathies.

A variety of retinal changes that have so far not been classified under mitochondriopathies can now be included in this group, since muscle biopsy has identified ragged-red fibers with pathological mitochondriae. The ophthalmological findings in our relatively large group of 12 patients with mitochondrial myopathies are compared with the spectrum of myopathic findings. No obvious correlation exists between the severity of the pathological retinal changes and the characteristic of the myopathic alterations. In addition to fine pigmentation and depigmentation, severe dystrophic changes of the retina, pigment epithelium, and the choroid were observed. In two patients with severe chorioretinal dystrophy the correlation with generalized mitochondriopathy was not suspected prior to muscle biopsy.

Central chorioretinal dystrophy with drusen and retinal crystals

4 patients out of 2 pedigrees present an association of dominant drusen, central chorioretinal dystrophy and retinal crystals. It seems to be transmitted in an autosomal dominant mode. Drusen have also been found in 4 patients (3rd generation) at the age of 40 years. Central chorioretinal dystrophy and retinal crystals have not been found prior to the age of 60 years. Visual acuity and central scotoma depend on the central chorioretinal dystrophy. Electro-oculograms and electroretinograms exhibited relatively little changes. 2 patients showed phenotype II and IV of Fredriksen.

Hyperosmolarity response of ocular standing potential as a clinical test for retinal pigment epithelium activity chorioretinal dystrophies.

The hyperosmolarity response of the standing potential was recorded in retinitis pigmentosa (20 eyes), central (pericentral) retinitis pigmentosa (4 eyes), pigmented paravenous retinochoroidal atrophy (2 eyes), fundus albipunctatus (8 eyes), and Stargardt's disease (or fundus flavimaculatus) (14 eyes). The light peak/dark trough ratio (the L/D ratio) and the Diamox response were also determined.The hyperosmolarity response was greatly suppressed (less than M-4SD; M and SD indicate respectively the mean and the standard deviation in normal control subjects) in all examined eyes with retinitis pigmentosa (20 eyes) including retinitis pigmentosa sine pigmento (8 eyes), central (pericentral) retinitis pigmentosa (4 eyes), and pigmented paravenous retinochoroidal atrophy (2 eyes). The L/D ratio was larger than 1.26 (M-2.5 SD) in the half of the eyes with the above-described diseases.The hyperosmolarity response was abnormal (less than M-2 SD) in 4 of 8 eyes with fundus albipunctatus. The L/D ratio was normal in all 8 eyes.The hyperosmolarity response was abnormal (less than M-2 SD) in all 14 eyes with Stargardt's disease or fundus flavimaculatus. The L/D ratio was abnormal in 5 of these 14 eyes.The hyperosmolarity response was more frequently abnormal than the L/D ratio in the chorioretinal dystrophies mentioned above, and hence is useful particularly for early diagnosis of these disorders.

Further delineation of the Cohen syndrome; report on chorioretinal dystrophy, leukopenia and consanguinity.

Six new patients with the Cohen syndrome are reported from Finland and 25 published cases from elsewhere are reviewed. New findings are consanguinity among two pairs of parents, granulocytopenia, and marked ophthalmological changes: decreased visual acuity, hemeralopia, constricted visual fields, chorioretinal dystrophy with bull's-eye-like maculae and pigmentary deposits, optic atrophy, and isoelectric electroretinogram. Previously known features of the Cohen syndrome (non-progressive mental retardation, short stature, microcephaly, peculiar facies, slender hands and feet, floppiness, delayed puberty) are confirmed or revised. The ophthalmological features merit attention in the previous and future suspected cases of the Cohen syndrome. Autosomal recessive inheritance can be taken for granted.