Jade S. East

Autosomal recessive retinitis pigmentosa due to ABCA4 mutations: clinical, pathologic, and molecular characterization.

PURPOSE Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous condition characterized by progressive loss of retinal photoreceptor cells. In order to gain new insights into the pathogenesis of ARRP, we evaluated the morphological, biochemical, and gene expression changes in eyes from a human donor with ARRP due to mutations in the ABCA4 gene. METHODS Eyes were obtained postmortem from a donor with end-stage retinitis pigmentosa. The coding sequences of the RDS, RHO, and ABCA4 genes were screened for disease-causing mutations. Morphological changes in different regions of the retina were examined histologically, and levels of lipofuscin-associated bisretinoids were measured. Gene expression was examined in retinal/choroidal tissue using microarray analysis, and all parameters were compared to those in unaffected control donors. RESULTS Genetic analysis of the donors DNA identified two mutations in the ABCA4 gene, IVS14+1G > C and Phe1440del1 cT, each on a separate allele. Morphological evaluation revealed complete loss of the outer nuclear layer, remodeling of the inner retina, loss of retinal vasculature, and regional neovascularization. The retinal pigment epithelium and choriocapillaris exhibited regional preservation. Microarray analysis revealed loss of photoreceptor cell-associated transcripts, with preservation of multiple genes expressed specifically in inner retinal neurons. CONCLUSIONS The persistence of transcripts expressed by inner retinal neurons suggests that despite significant plasticity that occurs during retinal degeneration, bipolar cells and ganglion cells remain at least partially differentiated. Findings from this study suggest that some forms of therapy currently under investigation may have benefit even in advanced retinal degeneration.

Different inner retinal pathways mediate rod-cone input in irradiance detection for the pupillary light reflex and regulation of behavioral state in mice.

PURPOSE Detection of light in the eye contributes both to spatial awareness (form vision) and to responses that acclimate an animal to gross changes in light (irradiance detection). This dual role means that eye disease that disrupts form vision can also adversely affect physiology and behavioral state. The purpose of this study was to investigate how inner retinal circuitry mediating rod-cone photoreceptor input contributes to functionally distinct irradiance responses and whether that might account for phenotypic diversity in retinal disease. METHODS The sensitivity of the pupillary light reflex and negative masking (activity suppression by light) was measured in wild-type mice with intact inner retinal circuitry, Nob4 mice that lack ON-bipolar cell function, and rd1 mice that lack rods and cones and, therefore, have no input to ON or OFF bipolar cells. RESULTS An expected increase in sensitivity to negative masking with loss of photoreceptor input in rd1 was duplicated in Nob4 mice. In contrast, sensitivity of the pupillary light reflex was more severely reduced in rd1 than in Nob4 mice. CONCLUSIONS Absence of ON-bipolar cell-mediated rod-cone input can fully explain the phenotype of outer retina degeneration for negative masking but not for the pupillary light reflex. Therefore, inner retinal pathways mediating rod-cone input are different for negative masking and the pupillary light reflex.

Mitochondrial Variant G4132A is Associated with Familial Non-Arteritic Anterior Ischemic Optic Neuropathy in One Large Pedigree

Objective: To identify the genetic factors associated with familial non-arteritic anterior ischemic optic neuropathy (NA-AION) in a large pedigree. Methods: Eleven family members of a single pedigree, including six affected with NA-AION, underwent detailed clinical examinations. The mitochondrial DNA of the proband was sequenced in its entirety in search of disease-causing mutations associated with NA-AION in the pedigree. A control panel comprising 1488 patients suspected of having Leber hereditary optic neuropathy (LHON) and 97 general-population control subjects was screened for the mitochondrial sequence variant identified in the family. Results: Affected family members were all male and exhibited classic features of NA-AION. Their mean age was 50.2 ± 5.0 years. A total of 23 sequence variations were detected in the mitochondrial genome of the proband, including one novel sequence variation (G4132A, Ala276Thr) in the NADH dehydrogenase subunit 1 gene (ND1). The G4132A mitochondrial variant was detected in six members of a single pedigree with NA-AION. The G4132A variation was not observed in any of the 1585 subjects in the control panel. Moreover, this variant was not identified in over 2469 ethnically diverse individuals previously evaluated through the Human Mitochondrial Genome Database. None of the three major mutations associated with LHON (G3460A, G11778A, T14484C) were identified in the family. Conclusion: The G4132A mitochondrial variation is associated with familial NA-AION in our pedigree.

Phenotypic Variation in a Family With Pseudodominant Stargardt Disease

Importance Stargardt disease is a phenotypically diverse macular dystrophy caused by the autosomal recessive inheritance of mutations in ABCA4. Pseudodominant transmission occurs more often than might be expected because of the relatively high carrier frequency of pathogenic ABCA4 variants. Genetic characterization of affected individuals permits a more precise understanding of these genotype-phenotype associations. Observations In this case series, we explore the clinical courses and genotypes of a woman and her 2 daughters with pseudodominant transmission of Stargardt disease. The mother had choroidal neovascularization that was treated with bevacizumab. Both daughters exhibited worse vision than their mother, despite lacking choroidal neovascularization, because of the extent of photoreceptor and retinal pigment epithelium atrophy in the macula. Genetic testing confirmed pseudodominant inheritance and the presence of 3 ABCA4 alleles within the family. Conclusions and Relevance These cases emphasize the clinical relevance of recognizing pseudodominant transmission and the resultant phenotypic variability. Differing degrees of visual impairment in these patients emphasize the need to continue refining our understanding of how individual ABCA4 mutations contribute to phenotype.

Genetic variants within chromosome 4q28.3 are not reproducibly associated with Age-related Macular Degeneration (AMD)

nique that allows observing retinal pathology directly at a cellular level and provides a measure of photoreceptor loss in retinal diseases. In our patient with type 2 IMT, AO showed an overall rarefaction and disruption of the continuity of the photoreceptor mosaic within 5 to the fixation point. Similar findings have been recently reported (Povazay et al. 2009) using AO OCT. In our case, AO displayed also disappearance of macular cones in correspondence to an area showing on SD OCT presence of intraretinal cysts and disruption of IS ⁄OS junction. However, we cannot exclude that the apparent disappearance of macular cones could be attributed to alterations in the mosaic, which change the ability of the cones to wave-guide light. In conclusion, AO ophthalmoscopy and SD-OCT in tandem create a more powerful imaging approach than either alone which may help establishing an early diagnosis of type 2 IMT and may improve therapeutic approach to the disease.