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Objective: To report findings in asymptomatic family members of patients with macular telangiectasia type 2., Design: Prospective, observational, cross-sectional case series., Participants: Four patients with symptomatic macular telangiectasia type 2 (index patients) and 5 relatives, including 2 sets of monozygotic twins., Methods: Screening of family members of participants in a non-interventional natural history study of macular telangiectasia type 2. Ophthalmologic examination included best-corrected visual acuity testing, fundus biomicroscopy, fluorescein angiography (FA), optical coherence tomography (OCT), and fundus autofluorescence (FAF) imaging., Main Outcome Measures: Evidence for macular telangiectasia type 2 in any of the imaging methods used and visual function of the family members studied., Results: In the first family, 2 of 3 daughters of a severely affected 68-year-old woman had features of macular telangiectasia type 2. Although one of the daughters was diagnosed by biomicroscopic examination, the second daughter was diagnosed only by subtle changes on OCT and FAF imaging. Both affected daughters were asymptomatic and were unaware that they had the condition. In the second family, clinical examination showed that the 60-year-old brother of the 75-year-old index patient obviously was affected, despite a lack of any subjective visual dysfunction. The 65-year-old monozygotic twin of the third index patient showed a slight retinal thinning within a small area temporal to the foveola in both eyes as well as minor staining on FA and a subtle monocular loss of macular pigment. The 56-year-old asymptomatic monozygotic twin of the last proband had opacification of the retina with leakage on FA in the right eye. The fellow eye was unremarkable except for an abnormal FAF signal that was present in both eyes., Conclusions: Macular telangiectasia type 2 may be more common than previously assumed, but patients may not seek ophthalmic care if their visual function is normal. The study of these early, asymptomatic cases may yield valuable insights into the pathogenesis of the condition. Further research is warranted to determine whether there is an underlying, dominantly inherited genetic abnormality in macular telangiectasia type 2 of variable penetrance and expressivity.

Purpose: Pseudoxanthoma elasticum (PXE) is an inherited multisystem disorder of the elastic tissue. Typical ocular manifestations include angioid streaks, peau d'orange, salmon spots, and choroidal neovascularization (CNV). Changes in Bruch membrane lead to progressive atrophy of the retinal pigment epithelium (RPE), secondary CNVs, and visual loss. The RPE-photoreceptor complex was studied in vivo using fundus autofluorescence (FAF) imaging., Methods: Forty-six patients (92 eyes) with PXE were investigated using digital fundus photography, fluorescein angiography (FA), and FAF imaging. The diagnosis was confirmed by multisystem clinical examination, mutation analysis of the ABCC6 gene, and skin biopsy., Results: The mean age of the patient cohort was 50 years (range, 13-74 years), and mean visual acuity was 20/125. Fundus changes typical for PXE were observed in all eyes. Angioid streaks were detected in all but six eyes. Peau d'orange was hardly detectable on FAF, whereas comet tail lesions were apparent. Retinal pigment epithelium atrophy typically was widespread and heterogeneous, located mostly adjacent to angioid streaks or CNVs. Pattern dystrophy-like changes were only found in patients with previous CNV formation in the same or the contralateral eye., Conclusion: Abnormalities of the RPE-photoreceptor complex detected by FAF imaging were more diverse and widespread than expected from conventional fundus imaging. The exhibition of pattern dystrophy-like changes may be a transitional state toward a neovascular event in a subgroup of patients. The extensive alteration of the RPE suggests an important role of pathologic RPE changes in the evolution of visual loss in PXE.

Purpose: To assess metamorphopsia in patients with macular telangiectasia (MacTel) type 2., Methods: In a prospective observational cohort study, 40 eyes of 20 patients with MacTel type 2 were investigated by funduscopy, fluorescein angiography, optical coherence tomography and microperimetry. Metamorphopsia was assessed using Amsler grids following a standard protocol and standardized questionnaire., Results: Metamorphopsia was present in 30 (83%) out of 36 nonproliferative eyes and in all four eyes with neovascular membranes. In the 30 nonproliferative eyes with distortions, metamorphopsia was always present in the nasal quadrant of the central visual field. Distortions were most pronounced in the nasal and lower quadrant in 70 and 30%, respectively. Three nonproliferative eyes with a very early and three eyes with a late disease stage did not perceive metamorphopsia. The degree of distortions was often but not necessarily correlated with the degree of leakage. Metamorphopsia was present in five out of eight eyes with normal sensitivity in microperimetry testing. Detection of scotoma by Amsler grid testing was poor., Conclusion: Metamorphopsia is a frequent clinical symptom in MacTel type 2 even in the absence of neovascularization. Since macular thickness was within normal limits in such eyes, extensive swelling or distortion of the neurosensory retina would not account for metamorphopsia in contrast to other macular diseases such as age-related macular degeneration or idiopathic epiretinal membranes.

A 44-year-old male patient first noticed a pain-free light red swelling of the right eye in 1983. Based on the results of the early indocyanine green angiography, MRI and sonography, a racemose hemangioma of the conjunctiva was diagnosed. Although a racemose hemangioma already exists at birth, it remains clinically silent for a long time and symptoms often first appear in early adulthood. In this patient external surgical excision was terminated due to substantial bleeding. A symptomatic treatment in the sense of surface care is considered to be the best option.

Purpose: To investigate morphologic alterations in geographic atrophy caused by age-related macular degeneration (AMD) in the presence of foveal sparing using high-resolution in vivo imaging., Methods: Simultaneous spectral domain optical coherence tomography (SD-OCT, 870 nm, 40,000 A-scans/s) and confocal scanning laser ophthalmoscopy (cSLO; fundus autofluorescence; excitation, 488 nm; emission, 500-700 nm) were performed in 18 eyes with geographic atrophy and foveal sparing using a combined instrument. Anatomic layers were evaluated, and retinal thickness in the fovea and the peripheral macula were measured and compared with those in controls of similar age., Results: Fundus autofluorescence imaging showed an inhomogeneously reduced signal at the residual foveal island. SD-OCT scans disclosed mitigation of the foveal pit in the absence of extracellular fluid accumulation and an increased mean central retinal thickness of 248 +/- 28 microm compared with 225 +/- 12 microm in control eyes (P = 0.005). No difference in retinal thickness in the peripheral macula was observed (245 +/- 16 vs. 253 +/- 11 microm; P = 0.6). Subanalysis revealed marked appearance of swelling and widening of visible structures at the central outer nuclear layer (153 +/- 22 microm vs. 127 +/- 12 microm; P = 0.003). Below the external limiting membrane, a broad band of irregular high reflectivity was detected instead of the normal three separate reflective bands., Conclusions: Thickening at the foveal site may reflect a pre-apoptotic stage of neuronal cellular elements indicating imminent atrophy. Limited structure-function correlation found in our study suggests that future therapeutic intervention may be beneficial in only a subset of AMD patients with foveal sparing.

Aim: To characterise the ocular phenotype of a family segregating the splice site mutation c.2189+1G>T in the tyrosine kinase receptor gene MERTK., Methods: Five affected children of a consanguineous Moroccan family were investigated by ophthalmic examinations, including fundus photography, autofluorescence (FAF) imaging, optical coherence tomography (OCT), psychophysical and electrophysiological methods., Results: Affected children were between 5 and 19 years of age, allowing an estimation of disease progression. Electroretinography demonstrated loss of scotopic and photopic function in the first decade of life. Younger siblings showed drusen-like deposits with focal relatively increased FAF in the macular area. With increasing age, a yellowish lesion with relatively increased FAF and subsequent macular atrophy developed. Visual acuity deteriorated with age and ranged between 20/50 in the best eye of the youngest affected and 20/400 in the worst eye of the oldest affected sibling. Spectral-domain OCT revealed debris-like material in the subneurosensory space., Conclusion: The splice site mutation c.2189+1G>T in MERTK causes rod-cone dystrophy with a distinct macular phenotype. The debris in the subneurosensory space resembles that in the Royal College of Surgeons (RCS) rat being the mertk animal model. Patients might therefore benefit from advances in gene therapy that were previously achieved in the RCS rat.

Recently, a unique distribution, namely a reduction of macular pigment optical density (MPOD) within the central retina with a surrounding ring-like structure of preserved MPOD at about 6 degrees eccentricity was suggested to be a common finding in macular telangiectasia (MacTel) type 2. In order to quantify this reduced MPOD, 28 eyes of 14 patients with MacTel type 2 were investigated by fundus reflectometry and two wavelengths fundus autofluorescence (FAF; at 488 nm and 514 nm). Fundus reflectometry showed a reduced MPOD within the central 4 degrees eccentricity that was most absent temporal to the foveola. At 6 degrees, MP density was not different from normative values. Two wavelengths FAF was in accordance with these findings. Fundus reflectometry also allowed separate determination of lutein and zeaxanthin. The patients with MacTel type 2 showed a disproportionally high zeaxanthin reduction. The study suggests that in MacTel type 2, there might be an inability to accumulate MP in the central retina. This disease might serve as a model to further study abnormalities of MP distribution in retinal disorders and to elucidate the mechanisms of MP deposition in the retina.

Purpose: To describe the occurrence of discrete arcs of increased fundus autofluorescence (FAF) associated with various retinal dystrophies and to assess their functional significance by fundus-controlled microperimetry., Methods: Seven patients, three with pigmented paravenous retinochoroidal atrophy (PPRCA), one with sector retinitis pigmentosa (RP), one with typical RP, and two with macular dystrophy were assessed by retinal imaging including FAF imaging. Serial images were obtained within a review period of 6 and 10 years in a patient with PPRCA and macular dystrophy, respectively. Fundus-controlled microperimetry was performed in eight eyes of five patients to determine light increment sensitivity., Results: A discrete arched line of increased FAF was observed without obvious correlate on fundus biomicroscopy. The orientation of this line differed from ring shape in RP and macular dystrophy, a semi-circle structure in sector RP to crescent shape with tiplike extensions towards branching retinal veins in PPRCA. Longitudinal investigation revealed slight migration of the arc in PPRCA and peripheral extension of the ring diameter in macular dystrophy. Microperimetry revealed that the arc of increased FAF sharply delineated areas of severely impaired retinal sensitivity., Conclusions: The findings indicate that arcs of increased FAF in PPRCA and other retinal dystrophies demarcate areas of impaired retinal function and may migrate over time. FAF imaging may therefore reveal the exact extent of neurosensory dysfunction that may exceed the dimensions anticipated by conventional examinations.

Pseudoxanthoma elasticum (PXE) is an inherited disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Bruch's membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye including peau d'orange, angioid streaks, and choroidal neovascularisations, of the skin including soft, ivory-colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces, and of the cardiovascular system with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings. There is yet no definitive therapy. Recent studies suggest that PXE is inherited almost exclusively as an autosomal recessive trait. Its prevalence has been estimated to be 1:25,000-100,000. Very recently, the ABCC6 gene on chromosome 16p13.1 was found to be associated with the disease. Mutations within ABCC6 cause reduced or absent transmembraneous transport that leads to accumulation of extracellular material. Presumably, this mechanism causes calcification of elastic fibers. Despite the characteristic clinical features, the variability in phenotypic expressions, and the low prevalence may be responsible for the disease being underdiagnosed. This review compiles and summarizes current knowledge of PXE pathogenesis and clinical findings. Furthermore, different therapeutic strategies to treat retinal manifestations are discussed, including thermal laser coagulation, photodynamic therapy, and intravitreal injections of drugs inhibiting vascular endothelial growth factor.

Purpose: Macular telangiectasia (MacTel) type 2 typically exhibits sharply demarcated parafoveal scotomas. In an investigation of their significance for reading performance, reading acuity and speed were measured and correlated with parafoveal sensitivity and fixation stability., Methods: In this prospective controlled cross-sectional observational study, 49 eyes of 26 patients with MacTel type 2 were investigated. Twenty-four eyes of 14 age-matched normal subjects served as the control. Reading acuity and reading speed (in words per minute [wpm]) were assessed by Radner charts. Retinal sensitivity was measured using fundus controlled microperimetry (MP1; Nidek Technologies). Fixation stability was quantified by the bivariate contour ellipse area (BCEA). Multiple logistic regression analysis was used to delineate outcome predictors of reading acuity and speed., Results: Mean reading speed was considerably reduced in patients (to 141 wpm; control speed, 190 wpm; P < 0.001) as was reading acuity (patients, 20/63; control subjects, 20/32; P < 0.001). Mean best corrected visual acuity (BCVA) was reduced in most eyes (patients, 20/50; control subjects, 20/20; P < 0.001). Mean BCEA was not reduced compared with that in the control subjects. BCVA reduction predicted reading acuity loss (P = 0.02) and a decrease in maximum reading speed (P < 0.001). Parafoveal sensitivity loss resulted in decreased reading acuity (P = 0.03) and reading speed reduction (P < 0.001)., Conclusions: These findings indicate that parafoveal sensitivity loss in MacTel type 2 is associated with loss of reading performance despite stable central fixation. Reading performance appears to be a sensitive variable of functional impairment in MacTel type 2 and should therefore be considered an outcome measure in future interventional trials.

A 68-year-old man with solar retinopathy had a lamellar foveal lesion on ophthalmoscopy and optical coherence tomography in one eye while the fellow eye appeared unremarkable. However, macular imaging by means of confocal scanning laser ophthalmoscopy (reflectance imaging and autofluorescence) revealed alterations in both eyes. Visual deterioration due to solar retinopathy may be a diagnostic challenge and the patient's history may be incomplete. The authors recommend including noninvasive confocal scanning laser ophthalmoscopy imaging in the work-up of unexplained visual disturbances because it may add important information beyond ophthalmoscopy and other imaging techniques.

Purpose: To describe morphologic variations in outer retinal layers in eyes with atrophic age-related macular degeneration (AMD) using high-resolution, spectral-domain optical coherence tomography (SD-OCT)., Methods: SD-OCT scans were obtained with a combined confocal scanning laser ophthalmoscope (cSLO) and SD-OCT for simultaneous tomographic and topographic in vivo imaging. A total of 81 eyes of 56 patients (mean age, 77.8 +/- 7.4 years) with geographic atrophy (GA) were examined. Morphologic alterations were analyzed and classified in the perilesional zone, at the junction between GA and nonatrophic retina, and in the atrophic area itself., Results: In the perilesional zone, distinct morphologic alterations included elevations of the outer retinal layers, thickening, and spikes of the outer hyperreflective band as well as clumps at different neurosensory retinal levels. At the junction, highly variable transitions of the outer retinal layers were present with different degrees of loss of the normal hyperreflective bands. Within the actual GA, hyperreflective clumps at different retinal levels, segmented plaques of the outer band and elevations with variable reflectivity were visualized., Conclusions: SD-OCT imaging in eyes with GA revealed a wide spectrum of morphologic alterations, both in the surrounding retinal tissue and in the atrophic area. These alterations may reflect different disease stages or, alternatively, heterogeneity on a cellular and molecular level. Longitudinal studies using in vivo SD-OCT imaging may allow evaluation of the relevance of these phenotypic changes as potential predictive markers for the progression of disease (i.e., enlargement rates of GA over time) and may be used for monitoring of future therapeutic interventions.

Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.

Background: Malignant melanoma of the conjunctiva is a rare tumour. Early disease stages may be difficult to distinguish from benign lesions such as pigmented nevi or primary acquired melanosis. We describe the therapeutic procedure and histological findings in two patients and review the epidemiology and pathogenesis of malignant conjunctival melanoma. Two female patients (84 and 85 years old, respectively) presented with a pigmented tumor close to the limbus with surrounding conjunctival pigmentation and involvement of the cornea., Results: Following complete excision of the tumour, conjunctival malignant melanoma arising from primary acquired melanosis was diagnosed histologically. Subsequent treatment with mitomycin C eye drops was initiated. There was no recurrence of the tumor within the follow-up period (24 and 6 months)., Discussion: Patients with primary acquired melanosis need to be reviewed on a regular basis to detect malignant transformation at an early stage.

Purpose: To determine the distribution of macular pigment in type 2 idiopathic macular telangiectasia (IMT)., Methods: Twenty-two eyes of 12 patients with type 2 IMT were examined by means of best-corrected visual acuity testing, fundus biomicroscopy, fundus photography, fluorescein angiography, and optical coherence tomography. Macular pigment optical density (MPOD) was assessed using a modified confocal scanning laser ophthalmoscope whereby MPOD was calculated from fundus autofluorescence images acquired at two different excitation wavelengths (488 and 514 nm). The results were verified with a method that provides density maps after digital subtraction of log fundus reflectance maps (four patients) and by means of heterochromatic flicker photometry (four patients)., Results: MOPD distribution showed an abnormal pattern for all patients with type 2 IMT. In correspondence to the late-phase hyperfluorescent areas shown by fluorescein angiography, MPOD was reduced in the macular area, while there was preserved MPOD at 5 degrees to 7 degrees eccentricity., Conclusions: The central depletion of macular pigment represents a novel phenotypic characteristic of type 2 IMT. Recording of macular pigment distribution may prove useful in the diagnosis of type 2 IMT and implicates an impaired trafficking or storage of lutein and zeaxanthin in the disease process.

Purpose: To report the characteristics of confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia (type 2 IMT)., Methods: In a prospective observational cross-sectional study, both eyes of 33 patients with type 2 IMT were examined by means of fundus biomicroscopy, fundus photography, fluorescein angiography, and optical coherence tomography (OCT). Confocal blue reflectance (CBR) imaging was performed using a confocal scanning laser ophthalmoscope (HRA2; Heidelberg Engineering, Heidelberg, Germany). To compare the results derived from different imaging modalities, an analysis was performed using image analysis software (Heidelberg Eye Explorer; Heidelberg Engineering)., Results: CBR imaging revealed a parafoveal area of increased reflectance that was slightly larger than the area of hyperfluorescence in late-phase fluorescein angiography. The area usually encompassed an oval parafoveal area, but sectors could be spared. A parafoveal area of increased CBR was detected in 98% of eyes that showed angiographic evidence for type 2 IMT., Conclusions: CBR imaging is a new, noninvasive, and sensitive method that may contribute to differentiate type 2 IMT from other diseases. Abnormalities of macular pigment distribution and Müller cell pathology may contribute to the phenomenon of increased CBR and thus the pathophysiology of type 2 IMT.

Purpose: To correlate macular thickness determined by optical coherence tomography (OCT) with light increment sensitivity and visual acuity in patients with type 2 idiopathic macular telangiectasia (IMT)., Design: Prospective, cross-sectional study., Methods: Fifty-one eyes of 30 patients with type 2 IMT were investigated. Functional assessment included best-corrected visual acuity and fundus-related microperimetry (MP1; Nidek Technologies, Padova, Italy). Retinal thickness was analyzed quantitatively by OCT3 (Carl Zeiss Meditec, Jena, Germany). The main outcome measure was the correlation of light sensitivity and visual acuity with retinal thickness., Results: Mean central retinal thickness was reduced compared with that of normal eyes. There was no significant correlation between central foveal thickness and foveal light sensitivity or visual acuity, respectively. Also, there was no significant correlation between mean retinal thickness temporal to the fovea and the lowest light sensitivity within that area. However, central light sensitivity in eyes with normal central foveal thickness was lower than in eyes with subnormal central foveal thickness (P = .032); this was also true for the lowest light sensitivity found temporal to the fovea (P = .025). Mean visual acuity was 20/40 and did not show significant differences in the two thickness groups., Conclusions: A subnormal foveal thickness in type 2 IMT may be associated with better macular function as assessed by microperimetry. It is hypothesized that in type 2 IMT, both a primary neurosensory thinning and a low-grade macular edema can be involved. The coincidence may result in normal retinal thickness but decreased retinal function.

Purpose: To report the short-term effects of intravitreal bevacizumab in patients with type 2 idiopathic macular telangiectasia (IMT)., Design: Noncomparative, interventional, retrospective case series., Participants: Seven eyes of 6 patients with type 2 IMT were studied., Methods: Patients received 2 doses of intravitreal bevacizumab (1.5 mg) at 4-week intervals. Serial examinations included standardized Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity (VA), fluorescein angiography, and optical coherence tomography (OCT)., Main Outcome Measures: Assessments of OCT retinal thickness, angiographic characteristics, and VA were performed at baseline and at 4 and 8 weeks after the initial treatment., Results: A mean increase in VA of 8 ETDRS letters at 8 weeks was found (P<0.05). Visual acuity improved by more than 15 letters in 1 patient and by 10 to 15 letters in 2 patients and remained stable (-1 to +10 letters) in another 4 patients compared with baseline. All patients showed a reduction in extension and intensity of late-stage parafoveal hyperfluorescence on fluorescein angiography. In OCT imaging, mean retinal thickness showed a reduction in the foveal and in the parafoveal zones (P<0.01). The most pronounced effect (mean decrease, 22 microm) was in the parafoveal temporal zone. No significant ocular or systemic side effects were observed., Conclusions: Short-term results indicate that inhibition of vascular endothelial growth factor by intravitreal bevacizumab is associated with a decrease in retinal thickness and a reduction in angiographic leakage in type 2 IMT. Furthermore, intravitreal bevacizumab may improve VA in affected patients.

Purpose: To assess changes of the light increment sensitivity (LIS) of the macular area in patients with type 2 idiopathic macular telangiectasia (IMT)., Methods: Fifty-eight eyes of 30 patients were examined in a cross-sectional study. All eyes were assigned to group A (early disease stages) or group B (late disease stages with retinal pigment clumping or vascular membranes). Investigation of visual function included visual acuity and fundus-related microperimetry., Results: Thirty-seven and 16 eyes were assigned to group A and group B, respectively. Temporal to the fovea, each eye of group B had an absolute scotoma. Topographically, the areas with reduced LIS correlated well with the angiographically hyperfluorescent areas or retinal pigmentations and showed a sharp demarcation from areas with normal LIS. However, within areas with angiographic alterations, at least some test locations exhibited preserved LIS in group B eyes; in 51% of group A eyes, none of those test locations showed abnormal LIS. Group A eyes that showed marked LIS reduction revealed common abnormalities: either hyporeflective spaces between the neurosensory retina and the retinal pigment epithelium in OCT imaging or atrophic areas, both topographically related to the scotoma. Visual acuity was correlated with foveal LIS but not with the LIS temporal to the fovea., Conclusions: Long-standing morphologic macular alterations from type 2 IMT are associated with topographically related functional impairment. Eyes with profound parafoveal scotomas can exhibit relatively preserved visual acuity. Therefore, testing for retinal light sensitivity should be included as an additional outcome measure for future interventional studies.

We have identified a consanguineous family from Morocco segregating autosomal recessive congenital progressive hearing loss (ARNSHL) and retinal degeneration. Detailed clinical investigation of the six siblings revealed combined severe cone-rod dystrophy (CORD) and severe/profound hearing impairment in two of them, while there is isolated CORD in three and nonsyndromic profound hearing loss in one. We therefore assumed a partial overlap of two nonsyndromic autosomal recessive conditions instead of a monogenic syndrome and performed genomewide linkage analysis. The disease loci were mapped to chromosome 2q31.1-2q32.1 for ARNSHL and to 2q13-2q14.1 for CORD, respectively. The retinal phenotype was shown to be due to homozygosity for a novel splice site mutation, c.2189+1G>T, in the retinitis pigmentosa gene MERTK. The ARNSHL interval comprised the DFNB59 locus. The DFNB59 gene has been identified recently, and two missense mutations (p.R183W and p.T54I) have been shown to cause auditory neuropathy in both humans and transgenic mice. Mutation screening in the DFNB59 gene in our family revealed homozygosity for a 1-bp insertion in exon 2 (c.113&#95;114insT), predicting a truncated protein of 47 amino acids, in all three hearing impaired subjects. This is the first description of biallelic putative loss-of-function of the DFNB59 gene. Detailed audiological investigation clearly indicated hair cell dysfunction and, in contrast to cases reported previously, excluded auditory neuropathy. We show that besides otoferlin (OTOF), DFNB59 is the second known gene in which mutations can result in these two distinct forms of hearing impairment. Moreover, all patients in our family with homozygosity for the DFNB59 mutation display central vestibular dysfunction., ((c) 2007 Wiley-Liss, Inc.)

Usher syndrome is an autosomal recessive condition characterized by sensorineural hearing loss, variable vestibular dysfunction, and visual impairment due to retinitis pigmentosa (RP). The seven proteins that have been identified for Usher syndrome type 1 (USH1) and type 2 (USH2) may interact in a large protein complex. In order to identify novel USH genes, we followed a candidate strategy, assuming that mutations in proteins interacting with this "USH network" may cause Usher syndrome as well. The DFNB31 gene encodes whirlin, a PDZ scaffold protein with expression in both hair cell stereocilia and retinal photoreceptor cells. Whirlin represents an excellent candidate for USH2 because it binds to Usherin (USH2A) and VLGR1b (USH2C). Genotyping of microsatellite markers specific for the DFNB31 gene locus on chromosome 9q32 was performed in a German USH2 family that had been excluded for all known USH loci. Patients showed common haplotypes. Sequence analysis of DFNB31 revealed compound heterozygosity for a nonsense mutation, p.Q103X, in exon 1, and a mutation in the splice donor site of exon 2, c.837+1G>A. DFNB31 mutations appear to be a rare cause of Usher syndrome, since no mutations were identified in an additional 96 USH2 patients. While mutations in the C-terminal half of whirlin have previously been reported in non-syndromic deafness (DFNB31), both alterations identified in our USH2 family affect the long protein isoform. We propose that mutations causing Usher syndrome are probably restricted to exons 1-6 that are specific for the long isoform and probably crucial for retinal function. We describe a novel genetic subtype for Usher syndrome, which we named USH2D and which is caused by mutations in whirlin. Moreover, this is the first case of USH2 that is allelic to non-syndromic deafness.

Age-related macular degeneration (AMD) is a genetically complex disorder of the photoreceptor-RPE-Bruch's membrane-choriocapillaris complex. Family and twin studies have shown that the susceptibility for this disease is genetically influenced. The heritability has been estimated to be up to 71%. Linkage and association studies have identified several chromosomal regions that are likely to contain susceptibility loci with strongest evidence found on chromosome 1q31 and 10q26. Variants in the complement factor H (CFH) gene have been shown by several independent studies to be associated with an increased risk for AMD in Caucasian populations. These findings imply that the innate immune system may play a significant role in AMD pathogenesis. The LOC387715/HTRA1 locus within 10q26 has been identified as a second major locus contributing to AMD pathogenesis. The two late forms of AMD, choroidal neovascularization and geographic atrophy, have not been found to be different in risk allele distribution. Variants within CFH and LOC387715/HTRA1 may contribute to the increased risk of late AMD largely through their impact on precursors, such as drusen and/or other RPE/Bruch's membrane changes. Considering variants at CFH, LOC387715/HTRA1 and complement component 2-complement factor B (C2-FB), high-risk homozygotes at all three loci may have a 250-fold increased risk compared to baseline. However, the identification of genetic factors has not resulted in therapeutic strategies to modify the disease so far and additional genetic and environmental factors are yet to be discovered in order to influence the onset and the progression of AMD.

The discovery of the complement factor H (CFH) polymorphism in age-related macular degeneration (AMD) strongly suggests a causative role of the complement system in the pathogenesis of this disease. The complement system is part of the innate immune system and is closely associated with the cellular response and the adaptive immune system. This article provides an overview of the complement system and, taking the new data into account, of possible immunopathogenetic processes in AMD.

Small-diameter sensory neurones found in the rat dorsal root ganglia (DRG) include cells sensitive to glial cell line-derived neurotrophic factor (GDNF), which express the inhibitory peptide somatostatin (SOM). Here we addressed the functional relationship between GDNF and sensory neurone-derived SOM. Topical application of GDNF through the rat isolated dorsal horn of the spinal cord promoted activity-induced release of SOM from central terminals of sensory neurones. Once released by sensory neurones, SOM is known to act, at least in part, by opposing the action of Substance P (SP) in neurogenic inflammation. Therefore, we evaluated GDNF ability to modulate two well-documented effects of peripherally and centrally administered SP. Local application of GDNF in the mouse air pouch reduced SP-induced leukocyte migration. This effect of GDNF was mimicked by the SOM analog octreotide (OCT) and required intact SOM neuronal pools. Intrathecal injection of GDNF activated rat lumbar dorsal horn neurones and inhibited intrathecal SP-induced thermal hypersensitivity. This effect of GDNF was reversed by the SOM antagonist c-SOM and mimicked by OCT. In conclusion we propose GDNF regulation of neuronal SOM release as a novel mechanism that, if explored, may lead to new therapeutic strategies based on local release of somatostatin.

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor with an established role in sensory neuron development. More recently it has also been shown to support adult sensory neuron survival and exert a neuroprotective effect on damaged sensory neurons. Some adult small-sized dorsal root ganglion (DRG) cells that are GDNF-sensitive sensory neurons express the inhibitory peptide somatostatin (SOM). Thus, we tested the hypothesis that prolonged GDNF administration would regulate SOM expression in sensory neuron cell bodies in the dorsal root ganglia (DRG) and activity-induced release of SOM from axon terminals in the dorsal horn. Continuous intrathecal delivery of GDNF for 11-13 days significantly increased the number of small DRG cells that expressed SOM. Furthermore, GDNF treatment evoked SOM release in the isolated dorsal horn following electrical stimulation of the dorsal roots that was otherwise undetectable in control rats. Conversely capsaicin-induced release of SOM (EC(50) 50 nM) was not modified by GDNF treatment. These results show that GDNF can regulate central synaptic function in SOM-containing sensory neurons.

Calcitonin gene-related peptide is involved in the spinal processing of nociceptive input from the knee joint and in the generation and maintenance of joint inflammation-evoked hyperexcitability of spinal cord neurons. The present study examined whether this peptide influences the excitation of nociceptive spinal cord neurons by agonists at the N-methyl-D-aspartate and the non-N-methyl-D-aspartate [(R, S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate] receptors, both of which are essential for the excitation and hyperexcitability of spinal cord neurons. In anaesthetized rats extracellular recordings were made from dorsal horn neurons with knee input, and compounds were administered ionophoretically close to the neurons recorded. When calcitonin gene-related peptide was administered the responses of the neurons to the application of both N-methyl-D-aspartate and AMPA were increased. The coadministration of the antagonist calcitonin gene-related peptide 8-37 had no effect on the responses to N-methyl-D-aspartate, but it prevented the enhancement of the responses to N-methyl-D-aspartate by calcitonin gene-related peptide. By contrast, the administration of calcitonin gene-related peptide 8-37 enhanced the responses of the neurons to AMPA, and it did not antagonize but rather increased the effects of calcitonin gene-related peptide on these responses. The data suggest that the facilitatory role of calcitonin gene-related peptide on the development and maintenance of inflammation-evoked hyperexcitability is caused at least in part by the modulation of the activation of the dorsal horn neurons through their N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors. The different effects of calcitonin gene-related peptide 8-37 on the respones to N-methyl-D-aspartate and AMPA suggest that different intracellular pathways may facilitate the activation of N-methyl-D-aspartate and ionotropic non-N-methyl-D-aspartate receptors.