The phenotype of Severe Early Childhood Onset Retinal Dystrophy (SECORD) from mutation of RPE65 and differentiation from Leber congenital amaurosis.

PURPOSE: To describe in detail the characteristic clinical phenotype and electrophysiological features of Severe Early Childhood Onset Retinal Dystrophy (SECORD) caused by mutation of RPE65. METHODS: Ophthalmological examination, color fundus photography, visual field testing, detailed electrophysiological assessment, and screening of RPE65 were undertaken in five subjects. Selected patients also had spectral domain optical coherence tomography. RESULTS: All five patients had life-long, extremely poor night vision. Variable degrees of nystagmus were present; three cases lacked nystagmus at the time of assessment. Bilateral disc drusen were evident in three subjects. While case 1 had an undetectable electroretinogram and features supporting a diagnosis of Leber congential amaurosis (LCA) as an infant, her level of acuity and function into the second decade of life was more consistent with SECORD. In two cases, both vision and electrophysiological responses were seen to improve into the second decade of life. The objective demonstration of improved retinal function over time, with electrophysiological testing, has not been previously reported. Cases 4 and 5 had evidence of fine white retinal dots. The authors propose that these represent abnormal accumulations of retinyl esters, as has been demonstrated in animal models, and has also been observed as lipid droplets within the retinal pigment epithelium (RPE). These white dots were seen to fade with time in the patients and were replaced by RPE changes. CONCLUSIONS: The identification of patients with mutations in RPE65 has attained greater significance now that gene replacement trials have begun. The features presented in this article assist in the recognition of this form of LCA/SECORD.

Choroideremia: analysis of the retina from a female symptomatic carrier.

PURPOSE: To define the retinal pathology in a 91 year-old affected matriarch of a three-generation choroideremia family with multiple manifesting carriers. METHODS: Tissue from three different retinal areas was processed for immunohistochemistry. The macular area was processed for transmission electron microscopy. Cryosections were studied by indirect immunofluorescence, using well-characterized antibodies to cone cytoplasm, rhodopsin and cone opsins. The affected donor eyes were compared to a postmortem matched normal eye. RESULTS: The retina displayed areas of severe degeneration, with no photoreceptor outer segments, photoreceptor nuclear atrophy, and atrophy of the inner retina. Other retinal areas were near to normal. The RPE was severely degenerated, with thinning, pigment clumping and sub-epithelial debris deposition in all the areas examined. The choroid displayed depigmentation. Labeling with cone opsin antibodies revealed that cones were drastically affected: blue opsin was almost completely absent, while red/green opsins were distributed along the entire plasma membrane of the cell. Rhodopsin was also distributed along the entire rod plasma membrane. Ultrastructural analysis of the affected macula revealed the absence of RPE apical microvilli and basal infoldings. Instead, RPE's basal surface and choroid displayed the presence of banded fibers composed of clumps of wide-spacing collagen. Bruch's membrane was filled with vesicular structures, some smooth and others with bristle-like projections. CONCLUSIONS: The histological data suggests that the clinical manifestation in this donor is related to degenerative changes in the retina, RPE, and choroid.

Combined retinal hamartomas leading to the diagnosis of neurofibromatosis type 2.

PURPOSE: To report two cases of neurofibromatosis type 2 (NF2) initially presenting with isolated bilateral combined hamartomas of the retina and retinal pigment epithelium (RPE). METHODS: Retrospective observational case reports. RESULTS: Two unrelated children presented to ophthalmology with isolated combined hamartomas of the retina and RPE. Patient one presented to ophthalmology at the age of 2 years; by 4 years, he developed what was thought to be a plexiform neurofibroma and, with more than 6 cafe au lait spots, was diagnosed with neurofibromatosis type 1 (NF1). By the age of 5, he had developed bilateral vestibular schwannomas, and was diagnosed with NF2. Subsequent molecular testing revealed a truncating mutation in exon 13 (c.1396C > T; p.R466X) of the NF2 gene. Patient two presented to ophthalmology at the age of 7 months; by age 6 she had developed two subcutaneous masses on her forehead, a mass in her left lower abdomen, and in her gumline. Despite lack of pathological evidence of neurofibroma upon biopsy, molecular testing was initiated at age 6 and revealed a truncating mutation in exon 8 (c.734delA) of the NF2 gene in the blood. CONCLUSIONS: Bilateral combined hamartomas of the retina and retinal pigment epithelium (RPE) in a young child should alert the clinician to the possibility of neurofibromatosis type 2. The recognition of this rare finding as a presenting feature of NF2 can lead to earlier diagnosis, which is vital to appropriate surveillance and possible surgical intervention.

Novel mutations in the KCNV2 gene in patients with cone dystrophy and a supernormal rod electroretinogram.

PURPOSE: To identify mutations in KCNV2 in patients with a form of cone dystrophy characterized by a supernormal rod electroretinogram (ERG). METHODS: The 2 exons and flanking intron DNA of KCNV2 from 8 unrelated patients were PCR amplified and sequenced. RESULTS: We found 1 frameshift, 2 nonsense, 1 non-stop, and 6 missense mutations. Every patient had one or two mutations identified. Of the missense mutations, 4 affected residues were in the amino terminal region of the protein, and two in the pore region. CONCLUSIONS: KCNV2 mutations account for most if not all cases of cone dystrophy with a supernormal rod ERG.

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.

Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies.

PURPOSE: Paraneoplastic and autoimmune retinopathies are immunologically mediated retinal degenerations that are associated with antibodies directed against any of several retinal proteins, including alpha-enolase. We report the clinical and electrophysiological features of antienolase retinopathy in contrast to the features of antirecoverin retinopathy. DESIGN: Retrospective, observational case series. METHODS: Patients were referred for evaluation of unexplained acquired visual symptoms, including photopsias, and loss of visual acuity or field considered of possible retinal origin. Full-field and multifocal electroretinograms (ERGs) were performed. Sera from patients were examined for antiretinal antibodies by Western blot analysis using proteins extracted from human retinas and by immunohistochemistry; antienolase was confirmed by incubating patient sera with purified alpha-enolase. RESULTS: Of 87 patients with unexplained retinal visual symptoms associated with abnormal ERGs, 37 (43%) demonstrated autoantibodies to retinal antigens, including 12 against alpha-enolase, of whom 4 had cancer. Initial visual loss was typically central and often asymmetric. The ERGs demonstrated mostly normal rod responses but central cone abnormalities (evident on multifocal ERG) and, for many, global cone abnormalities. Seven patients developed optic disk pallor. Corticosteroid and immunosuppressive therapy, when attempted, was clinically ineffective. CONCLUSIONS: Antienolase retinopathy is a protean autoimmune retinopathy that characteristically presents with cone dysfunction. The visual impairment and course vary from relative stability for years to slow progression with loss of central vision. With time, optic disk pallor can evolve, presumably from attrition of ganglion cells.

Electroretinographic and clinicopathologic correlations of retinal dysfunction in infantile neuronal ceroid lipofuscinosis (infantile Batten disease).

Infantile neuronal ceroid lipofuscinosis (INCL) is an autosomal recessive disease that results from deficiency of palmitoyl-protein thioesterase-1 (PPT1). INCL leads to retinal blindness, neurodegeneration, and early death. We studied the clinical features and electroretinogram (ERG) in three patients and histopathologic and immunofluorescence analyses of the retina in the third patient, who died at 3 years 2 months of age. The ERGs for the 2 youngest patients (ages 1.7 and 2.3 years) showed normal scotopic bright flash a-wave amplitudes with severe loss of b-wave (electronegative ERG), indicating dysfunction at or proximal to the photoreceptor inner segments. The third patient at 2.9 years of age showed subnormal a-wave amplitudes and even greater loss of b-wave amplitudes. Histopathology revealed reduced cell numbers in all retinal layers, including the inner nuclear layer (INL), and a central epiretinal membrane. Autofluorescent lipofuscin granules were present in all neuronal cell types in the retina. Cones and rods in the parafoveal area were labeled with a cone cytoplasmic marker, mAb 7G6, and anti-rhodopsin, respectively, and had extremely short outer segments. The periphery showed better preservation but photoreceptor outer segments were short. Immunofluorescence revealed degenerate rods and cones throughout the retina with better preservation in the periphery. Autofluorescent lipofuscin was found in all cell types, including cone inner segments, to a greater degree than seen in normal ageing. The ERG findings support the existence early in the disease of a relative pre- or post-synaptic block of effective neurotransmission from photoreceptor inner segments to the second order bipolar neurons.

Treatment of retinal and choroidal degenerations and dystrophies: current status and prospects for gene-based therapy.

Inherited retinal and choroidal degenerations account for a significant portion of blindness in children and young adults. This article reviews the current status and future prospects for the treatment of these disorders. Current treatment strategies include nutritional intervention for gyrate atrophy of the choroid and retina with hyperornithinemia, abetalipoproteinemia, and Refsum's disease, as well as vitamin A supplementation for retinitis pigmentosa. Future therapeutic prospects include gene therapy for both recessive and dominant disease, secondary gene-based therapies, such as pharmaceutic gene product replacement and treatment with survival factors, anti-apoptotic agents, and calcium blockers, and, finally, stem cell therapy.