B.J. Klevering

Clinical characteristics of rod and cone photoreceptor dystrophies in patients with mutations in the C8orf37 gene

PURPOSE To provide the clinical features in patients with retinal disease caused by C8orf37 gene mutations. METHODS Eight patients--four diagnosed with retinitis pigmentosa (RP) and four with cone-rod dystrophy (CRD), carrying causal C8orf37 mutations--were clinically evaluated, including extensive medical history taking, slit-lamp biomicroscopy, ophthalmoscopy, kinetic perimetry, electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), autofluorescence (AF) imaging, and fundus photography. RESULTS In families A and D, respectively, one and three patients showed a classic RP phenotype with night blindness followed by concentric loss of visual field. Severe visual loss to light perception occurred early in the course of the disease. The symptoms initiated during infancy (family A) or adolescence (family D). Ophthalmoscopy revealed macular atrophy, bone spicules, attenuated vessels, and waxy pale optic discs. SD-OCT showed profound photoreceptor degeneration and AF demonstrated atrophy of the retinal pigment epithelium (RPE). ERG responses were nonrecordable in these patients. In families B and C, the patients were diagnosed with CRD. Initial symptoms were photophobia or loss of visual acuity and occurred during infancy (family B) or adolescence (family C). Ophthalmoscopy and AF revealed profound macular RPE atrophy and SD-OCT demonstrated macular photoreceptor degeneration. ERG responses were severely reduced in a cone-rod pattern or were nonrecordable. Interestingly, both patients in family B demonstrated polydactyly. CONCLUSIONS Mutations in C8orf37 give rise to an early or adolescent-onset autosomal recessive CRD or RP phenotype with early macular atrophy. The occurrence of postaxial polydactyly in one family suggests a syndromic phenotype, which may indicate C8orf37 has a ciliary function.

Genetic, behavioral, and sociodemographic risk factors for second eye progression in age-related macular degeneration.

PURPOSE This study was conducted to investigate the correlation of genetic, sociodemographic, and behavioral risk factors with second eye progression to end-stage AMD. METHODS One hundred and eight patients with end-stage AMD in one or both eyes were included in a retrospective time-to-event analysis of the onset of end-stage AMD in the second eye. Multivariate Cox regression survival analysis was performed for sex, age, smoking, body mass index (BMI), education, and 16 single nucleotide polymorphisms (SNPs) associated with AMD. RESULTS Except for education, all sociodemographic and behavioral risk factors analyzed were significantly associated with a more rapid progression toward second eye involvement. Hazard ratios (HRs) were 2.6 (95% confidence interval [CI], 1.4-5.0) for female sex; 5.0 (95% CI, 2.0-12.5) for age >80; 2.2 (95% CI, 1.1-4.1) for BMI >30; and 4.4 (95% CI, 1.4-14.3) for >40 pack years, compared with the referent groups. Carriers of the lipoprotein lipase (LPL; rs12678919) risk alleles were at risk for more rapid progression to end-stage AMD in the second eye compared with the referent wild-type genotype (HR 2.0; 95% CI, 1.0-3.6). For complement factor I (CFI; rs10033900), homozygous carriers of the risk allele progressed faster than wild-type individuals (HR 2.2; 95% CI, 1.1-4.3). CONCLUSIONS Sociodemographic, behavioral, and genetic risk factors are associated with the rate of second eye progression toward end-stage AMD. The findings of this study underline the importance of lifestyle factors and the complement pathway in AMD progression and suggest a role of the high-density-lipoprotein metabolism in second eye progression.

[Fundus autofluorescence in patients with inherited retinal diseases : patterns of fluorescence at two different wavelengths].

BACKGROUND Fundus autofluorescence (FAF) may be excited and measured at different wavelengths. In the present study we compared short wavelength and near-infrared FAF patterns of retinal dystrophies. METHODS We analysed both eyes of 108 patients with diverse retinal dystrophies. Besides colour fundus photographs, FAF images were obtained with the Heidelberg Retina Angiograph (HRA 2). Excitation wavelengths of 488 nm (blue; filter at 500 nm) and 787 nm (near-infrared; filter at 810 nm) were applied. For improvement of the signal-to-noise ratio a total of nine images were averaged, and the mean images (original grey values, not normalized) were analysed. RESULTS Useful FAF images of both excitation wavelengths were achieved in all patients. We observed characteristic FAF patterns, which differed between excitation wavelengths depending on the disease. With time, FAF pattern changes and progression could be observed. CONCLUSION FAF of both wavelengths provided additional information for phenotype description in retinal dystrophies. Other than short wavelength FAF, near-infrared FAF showed different pathological changes, which may be related to changes in RPE melanin. However, any conclusions may be limited by the still incomplete knowledge about the prognostic value of FAF in the diseases studied here.

Multimodal imaging of the macula in hereditary and acquired lack of macular pigment

Purpose:  Macular pigment (MP) deficit has been described in macular teleangiectasia type 2 (MTA; acquired MP loss) and in Sjögren–Larsson syndrome (SLS; hereditary MP deficiency). Central blue light‐induced fundus autofluorescence (FAF) and blue light fundus reflectance (BLR) are thought to reflect MP distribution. This study was performed to describe the macular morphology in SLS and MTA by multimodal imaging to further investigate the causes of FAF and BLR changes in these disorders.

Fundusautofluoreszenz bei erblichen Netzhauterkrankungen

BACKGROUND Fundus autofluorescence (FAF) may be excited and measured at different wavelengths. In the present study we compared short wavelength and near-infrared FAF patterns of retinal dystrophies. METHODS We analysed both eyes of 108 patients with diverse retinal dystrophies. Besides colour fundus photographs, FAF images were obtained with the Heidelberg Retina Angiograph (HRA 2). Excitation wavelengths of 488 nm (blue; filter at 500 nm) and 787 nm (near-infrared; filter at 810 nm) were applied. For improvement of the signal-to-noise ratio a total of nine images were averaged, and the mean images (original grey values, not normalized) were analysed. RESULTS Useful FAF images of both excitation wavelengths were achieved in all patients. We observed characteristic FAF patterns, which differed between excitation wavelengths depending on the disease. With time, FAF pattern changes and progression could be observed. CONCLUSION FAF of both wavelengths provided additional information for phenotype description in retinal dystrophies. Other than short wavelength FAF, near-infrared FAF showed different pathological changes, which may be related to changes in RPE melanin. However, any conclusions may be limited by the still incomplete knowledge about the prognostic value of FAF in the diseases studied here.

Antisense Oligonucleotide-Based Splicing Correction in Individuals with Leber Congenital Amaurosis due to Compound Heterozygosity for the c.2991+1655A>G Mutation in CEP290

Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with CEP290 (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing CEP290 mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of CEP290 transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in CEP290. We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat CEP290-associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant.

Fundusautofluoreszenz bei erblichen NetzhauterkrankungenFundus autofluorescence in patients with inherited retinal diseases

BACKGROUND Fundus autofluorescence (FAF) may be excited and measured at different wavelengths. In the present study we compared short wavelength and near-infrared FAF patterns of retinal dystrophies. METHODS We analysed both eyes of 108 patients with diverse retinal dystrophies. Besides colour fundus photographs, FAF images were obtained with the Heidelberg Retina Angiograph (HRA 2). Excitation wavelengths of 488 nm (blue; filter at 500 nm) and 787 nm (near-infrared; filter at 810 nm) were applied. For improvement of the signal-to-noise ratio a total of nine images were averaged, and the mean images (original grey values, not normalized) were analysed. RESULTS Useful FAF images of both excitation wavelengths were achieved in all patients. We observed characteristic FAF patterns, which differed between excitation wavelengths depending on the disease. With time, FAF pattern changes and progression could be observed. CONCLUSION FAF of both wavelengths provided additional information for phenotype description in retinal dystrophies. Other than short wavelength FAF, near-infrared FAF showed different pathological changes, which may be related to changes in RPE melanin. However, any conclusions may be limited by the still incomplete knowledge about the prognostic value of FAF in the diseases studied here.

Fundusautofluoreszenz bei erblichen Netzhauterkrankungen@@@Fundus autofluorescence in patients with inherited retinal diseases: Fluoreszenzmuster in zwei verschiedenen Wellenlängenbereichen@@@Patterns of fluorescence at two different wavelengths

BACKGROUND Fundus autofluorescence (FAF) may be excited and measured at different wavelengths. In the present study we compared short wavelength and near-infrared FAF patterns of retinal dystrophies. METHODS We analysed both eyes of 108 patients with diverse retinal dystrophies. Besides colour fundus photographs, FAF images were obtained with the Heidelberg Retina Angiograph (HRA 2). Excitation wavelengths of 488 nm (blue; filter at 500 nm) and 787 nm (near-infrared; filter at 810 nm) were applied. For improvement of the signal-to-noise ratio a total of nine images were averaged, and the mean images (original grey values, not normalized) were analysed. RESULTS Useful FAF images of both excitation wavelengths were achieved in all patients. We observed characteristic FAF patterns, which differed between excitation wavelengths depending on the disease. With time, FAF pattern changes and progression could be observed. CONCLUSION FAF of both wavelengths provided additional information for phenotype description in retinal dystrophies. Other than short wavelength FAF, near-infrared FAF showed different pathological changes, which may be related to changes in RPE melanin. However, any conclusions may be limited by the still incomplete knowledge about the prognostic value of FAF in the diseases studied here.