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Background/aim To evaluate relationships between subretinal fluid (SRF), macular atrophy (MA) and visual outcomes in ranibizumab-treated neovascular age-related macular degeneration (nAMD). Methods This post hoc HARBOR trial (NCT00891735) analysis included ranibizumab-treated (0.5 or 2.0 mg, monthly or as-needed, all treatment arms pooled) eyes with nAMD and baseline (screening, baseline and week 1) SRF. SRF presence, SRF thickness (0, >0-50, >50-100 and >100 µm) and subretinal fluid volume (SRFV) were determined by spectral domain optical coherence tomography (SD-OCT). Best-corrected visual acuity (BCVA) was assessed. MA was identified using fluorescein angiograms and colour fundus photographs, as well as SD-OCT. Results Seven hundred eighty-five of 1097 eyes met analysis criteria. In eyes without baseline MA, residual versus no SRF at month (M) 3 was associated with lower MA rates at M12 (5.1% vs 22.1%) and M24 (13.3% vs 31.2%) (both p<0.0001); MA percentages at M12/M24 were similar among patients with residual SRF at M6. Higher baseline SRFV was associated with a lower MA rate. Greater mean BCVA was observed with residual SRF of any thickness (>0-50 µm, 71.2 letters; >50-100 µm, 71.3 letters; >100 µm, 69.2 letters) versus no SRF (63.6 letters), but the change in BCVA from baseline to M12 or M24 was the same for eyes with or without treatment-resistant subretinal fluid (TR-SRF) at M3 or M6. Conclusion TR-SRF was not detrimental to vision outcomes over 2 years, regardless of thickness. MA rates were significantly higher without TR-SRF. [ABSTRACT FROM AUTHOR]

Background/Aim To provide a comprehensive multimodal retinal imaging characterisation of patients with North Carolina macular dystrophy (NCMD). Methods Clinical evaluation and retinal imaging in six families. Results Twenty-one subjects showed phenotypic characteristics of NCMD. Small drusen-like deposits were found in all affected individuals, either tightly grouped in the macula, or surrounding atrophic or fibrotic macular alterations. These small subretinal lesions showed an increased fundus autofluorescence and were associated with only mild irregularities on optical coherence tomography imaging. Similar drusen-like deposits were regularly seen in the peripheral fundus, predominantly temporally and often with a radial distribution. Two patients showed a bilateral chorioretinal atrophy and two had a macular neovascularisation (MNV). Findings from follow-up examinations were available from 11 patients. The retinal phenotype remained overall stable, except for two patients: one patient with atrophy showed a distinct growth of the atrophic lesions on longitudinal AF imaging over a review period of 14 years. One patient with MNV showed a unilateral decline of best-corrected visual acuity. Genetic testing identified the single nucleotide variant chr6:100040987G>C upstream of the PRDM13 gene in all family members with NCMD phenotype. Conclusion Patients with NCMD show a characteristic retinal phenotype and distribution of drusen that differ from drusen in patients with age-related macular degeneration. Although the prognosis of this developmental condition is overall better than for other macular diseases with drusen, patients may be at risk of developing MNV or enlargement of pre-existing atrophy. [ABSTRACT FROM AUTHOR]

In pemphigus vulgaris, a life-threatening autoimmune skin disease, epidermal blisters are caused by autoantibodies primarily targeting desmosomal cadherins desmoglein 3 (DSG3) and DSG1, leading to loss of keratinocyte cohesion. Due to limited insights into disease pathogenesis, current therapy relies primarily on nonspecific long-term immunosuppression. Both direct inhibition of DSG transinteraction and altered intracellular signaling by p38 MAPK likely contribute to the loss of cell adhesion. Here, we applied a tandem peptide (TP) consisting of 2 connected peptide sequences targeting the DSG adhesive interface that was capable of blocking autoantibody-mediated direct interference of DSG3 transinteraction, as revealed by atomic force microscopy and optical trapping. Importantly, TP abrogated autoantibody-mediated skin blistering in mice and was effective when applied topically. Mechanistically, TP inhibited both autoantibody-induced p38 MAPK activation and its association with DSG3, abrogated p38 MAPK-induced keratin filament retraction, and promoted desmosomal DSG3 oligomerization. These data indicate that p38 MAPK links autoantibody-mediated inhibition of DSG3 binding to skin blistering. By limiting loss of DSG3 transinteraction, p38 MAPK activation, and keratin filament retraction, which are hallmarks of pemphigus pathogenesis, TP may serve as a promising treatment option., Introduction Pemphigus vulgaris (PV) is a life-threatening blistering disease histopathologically characterized by acantholysis, i.e., cleft formation within the epidermis or mucous membranes (1). The disease is caused by autoantibodies predominantly [...]

In the human autoimmune blistering skin disease pemphigus vulgaris autoantibodies (PV-IgG), which are mainly directed against keratinocyte cell adhesion molecules desmoglein (Dsg) 3 and Dsg1, cause keratinocyte cell dissociation (acantholysis). Recent studies reported that loss of keratinocyte cell adhesion was accompanied by profound alterations of the actin cytoskeleton. Nevertheless, the relevance of actin reorganization in this process is unclear at present. In this study, we provide evidence for an important role of actin reorganization in pemphigus pathogenesis. In parallel to loss of cell adhesion and fragmentation of Dsg3 staining along cell borders, PV-IgG treatment resulted in striking changes in actin cytoskeleton organization. Moreover, in experiments using fluorescence recovery after photobleaching (FRAP), PV-IgG were detected to interfere with actin dynamics. Therefore, we investigated whether pharmacological manipulation of actin polymerization modulates pathogenic effects of PV-IgG. Pharmacological stabilization of actin filaments via jasplakinolide significantly blocked cell dissociation and Dsg3 fragmentation, whereas cytochalasin D-induced actin depolymerization strongly enhanced pathogenic effects of PV-IgG. To substantiate these findings, we studied whether the protective effects of Rho GTPases, which are potent regulators of the actin cytoskeleton and were shown to be involved in pemphigus pathogenesis, were dependent on modulation of actin dynamics. Cytotoxic necrotizing factor-1 (CNF-1)-mediated activation of Rho-GTPases enhanced the cortical junction-associated actin belt and blunted PV-IgG-induced cell dissociation. However, when actin polymerization was blocked under these conditions via addition of latrunculin B, the protective effects of CNF-1 were abrogated. Taken together, these experiments indicate that reorganization of cortical actin filaments is a critical step in PV-IgG-induced keratinocyte dissociation. cytoskeleton; Rho-GTPase; cytotoxic necrotizing factor-1; desmoglein doi: 10.1152/ajpcell.00075.2010.

Purpose: The aim of the study was to quantify choriocapillaris (CC) flow alterations in early Sorsby fundus dystrophy (SFD) and to investigate the relationship of the CC flow deficits with the choroidal and outer retinal microstructure. Methods: In this prospective case-control study, 18 eyes of 11 patients with early SFD and 31 eyes of 31 controls without ocular pathology underwent multimodal imaging, including spectral-domain optical coherence tomography (OCT), followed by deep-learning-based layer segmentation. OCT angiography (OCTA) was performed to quantify CC flow signal deficits (FDs). Differences in CC FD density between SFD patients and controls were determined, and the relationships with choroidal thickness, retinal pigment epithelium-drusen complex (RPEDC) thickness and outer retinal layer thicknesses were analyzed using mixed-model analysis. Results: SFD patients exhibited a significantly greater CC FD density than controls (estimate [95% CI]: +20.0%FD [13.3; 26.7], p < 0.001 for SFD patients), even when adjusted for age. Square-root transformed choroidal thickness was a structural OCT surrogate of the CC FD density (−2.1%FD per √µm, p < 0.001), whereas RPEDC thickness was not informative regarding CC FD (p = 0.061). The CC FD density was associated with an altered microstructure of the overlying photoreceptors (outer segments, inner segments, and outer nuclear layer thinning of −0.19 μm, −0.08 μm and −0.30 μm per %FD, respectively, all p < 0.001). Conclusions: Patients with early SFD exhibit pronounced abnormalities of CC flow signal on OCTA, which are not limited to areas of sub-RPE deposits seen on OCT imaging. Thus, analysis of the CC flow may enable clinical trials at earlier disease stages in SFD. [ABSTRACT FROM AUTHOR]

Aim Biallelic ABCC6 mutations cause pseudoxanthoma elasticum, a systemic disease characterised by calcification of elastic tissue and a specific retinal phenotype. In this study, we investigated if monoallelic ABCC6 mutations are also associated with retinal alterations. Methods In this prospective, cross-sectional, monocentre case–control study, carriers of monoallelic ABCC6 mutations were investigated and compared with age-matched controls. The retinal phenotype was characterised using fundus photography, fundus autofluorescence, confocal near-infrared reflectance imaging, spectral domain optical coherence tomography and in selected cases late-phase indocyanine green angiography. Results Thirty-eight subjects carrying monoallelic ABCC6 mutations (mean age 70.2 years, range 50–90, 26 female) were examined and compared with 77 agematched controls (mean age 69.9 years, range 50–93, 43 female). Retinal alterations were more frequently found in carriers of monoallelic ABCC6 mutations compared with controls (50% vs 33.8%, p=0.107) with increasing prevalence at older age. Typical findings were peripapillary atrophy (37% vs 23%, p=0.184), pattern dystrophy-like changes (24% vs 12%, p=0.109), reticular pseudodrusen (21% vs 5%, p=0.019), small angioid streaks (8% vs 1%, p=0.105), choroidal neovascularisations and atrophic lesions (both 8% vs 0%, p=0.034). Late-phase indocyanine green angiography showed a reduced cyanescence centred to the posterior pole in 11 of 14 examined subjects with monoallelic ABCC6 mutations. Conclusion The findings of this study indicate a possible ocular ABCC6 haploinsufficiency phenotype. Due to its late-onset and phenotypic similarities, misinterpretation as age-related macular degeneration is possible. [ABSTRACT FROM AUTHOR]

Importance: Uncommon characteristics in genetically unsolved retinitis pigmentosa (RP) patients may indicate an incorrect clinical diagnosis or as yet unknown genetic causes resulting in specific retinal phenotypes. The diagnostic yield of targeted next‐generation sequencing may be increased by a reasonable preselection of RP‐patients. Background: To systematically evaluate and compare features of genetically solved and unsolved RP‐patients. Design Retrospective, observational study. Participants: One‐hundred and twelve consecutive RP‐patients who underwent extensive molecular genetic analysis. Methods: Characterization of patients based on multimodal imaging and medical history. Main Outcome Measures: Differences between genetically solved and unsolved RP‐patients. Results: Compared to genetically solved patients (n = 77), genetically unsolved patients (n = 35) more frequently had an age of disease‐onset above 30 years (60% vs 8%; P < 0.0001), showed atypical fundus features (49% vs 8%; P < 0. 0001) and indicators for phenocopies (eg, autoimmune diseases) (17% vs 0%; P < 0. 001). Evidence for a particular inheritance pattern was less common (20% vs 49%; P < 0. 01). The diagnostic yield was 84% (71/85) in patients with first symptoms below 30 years‐of‐age, compared to 69% (77/112) in the overall cohort. The other selection criteria alone or in combination resulted in limited further increase of the diagnostic yield (up to 89%) while excluding considerably more patients (up to 56%) from genetic testing. Conclusions and Relevance: The medical history and retinal phenotype differ between genetically solved and a subgroup of unsolved RP‐patients, which may reflect undetected genotypes or retinal conditions mimicking RP. Patient stratification may inform on the individual likelihood of identifying disease‐causing mutations and may impact patient counselling. [ABSTRACT FROM AUTHOR]

Importance The diagnostic accuracy of different retinal imaging modalities to detect active choroidal neovascularization (CNV) in pseudoxanthoma elasticum (PXE) is essential to enable a correct diagnosis but is currently poorly understood. Background: Optical coherence tomography (OCT), fluorescein angiography (FA) and OCT angiography (OCT‐A) are employed in daily practice, but a systematic comparison of these imaging techniques is lacking. Design Retrospective, observational study. Participants: Twenty patients (31 eyes) with PXE. Methods: OCT, FA and OCT‐A imaging was performed in each eye and graded separately by independent readers. Main Outcome Measures: Diagnostic accuracy, sensitivity and specificity to detect CNV‐activity of each modality and longitudinal change of CNV size measured by OCT‐A. Results: OCT showed the highest diagnostic accuracy (kappa = 0.57) in comparison to OCT‐A or FA (kappa = 0.39 and 0.37, respectively). OCT‐A, OCT and FA showed a diagnostic sensitivity of 0.9, 0.85 and 0.6, and a diagnostic specificity of 0.45, 0.72 and 0.82, respectively. Evaluation of longitudinal OCT recordings (24 eyes) resulted in optimal sensitivity and specificity (kappa = 1.0). Although median CNV size assessed using OCT‐A remained stable on longitudinal measures of seven eyes, two eyes showed a distinct increase over time despite anti‐vascular endothelial growth factor treatment. Conclusions and Relevance: The systematic use of OCT, FA and OCT‐A imaging can facilitate the diagnostic accuracy for detection and follow‐up of CNV activity in PXE. While structural OCT is of high value, especially when longitudinal follow‐up images are available, FA and OCT‐A data might contribute to diagnostic accuracy in more complex cases. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is an inherited degenerative disease causing severe retinal dystrophy and visual impairment mainly with onset in infancy or adolescence. Targeted next-generation sequencing (NGS) has become an efficient tool to encounter the enormous genetic heterogeneity of diverse retinal dystrophies, including RP. To identify disease-causing mutations in unselected, consecutive RP patients, we conducted Sanger sequencing of genes commonly involved in the suspected genetic RP subtype, followed by targeted large-panel NGS if no mutation was identified, or NGS as primary analysis. A high (70%) detection rate of disease-causing mutations was achieved in a large cohort of 116 unrelated patients. About half (48%) of the solved RP cases were explained by mutations in four genes: RPGR, EYS, PRPF31 and USH2A. Overall, 110 different mutations distributed across 30 different genes were detected, and 46 of these mutations were novel. A molecular diagnosis was achieved in the majority (82–100%) of patients if the family history was suggestive for a particular mode of inheritance, but only in 60% in cases of sporadic RP. The diagnostic potential of extensive molecular analysis in a routine setting is also illustrated by the identification of unexpected genotype-phenotype correlations for RP patients with mutations in CRX, CEP290, RPGRIP1, MFSD8. Furthermore, we identified numerous mutations in autosomal dominant (PRPF31, PRPH2, CRX) and X-linked (RPGR) RP genes in patients with sporadic RP. Variants in RP2 and RPGR were also found in female RP patients with apparently sporadic or dominant disease. In summary, this study demonstrates that massively parallel sequencing of all known retinal dystrophy genes is a valuable diagnostic approach for RP patients. [ABSTRACT FROM AUTHOR]

Background: Pseudoxanthoma elasticum (PXE) is an autosomal-recessive mineralisation disorder caused by loss of function mutations in the ABCC6 Gen. Histological findings and data of an autopsy of a PXE-patient suggest a possible pulmonal calcification. So far, there exists no clinical data whether PXE patients actually are at high risk of developing pulmonary disorder. Methods: In a cross-sectional study, 35 PXE patients and 15 healthy controls underwent a pulmonary function testing, including spirometry, body plethysmography and carbon monoxide diffusing test. Additionally, PXE patients completed a COPD–Assessment-Test (CAT). Results: We observed in PXE patients normal values for predicted vital capacity (VC%; 96.0±13.0%), predicted total lung capacity (TLC%; 98.2±12.0%) and predicted forced expiration volume (FEV1%; 102.5±15.6%), whereas compared to healthy controls the PXE group showed significant diminished values for carbon monoxide diffusing capacity (DLCO, 7.2 ±1.4mmol/min/kPa vs. 8.6 ±1.5 mmol/min/kPa; p = 0.008) and predicted carbon monoxide diffusing capacity (DLCO%; 79.7±11.5% vs. 87.2±6.6%; p = 0.008). 11/35 (31.4%) PXE patients showed pathological DLCO% values under 75% (68.5%±5.4%). Conclusion: PXE patients demonstrated a regular lung function testing, but nevertheless they had impaired CO diffusing parameters, which might be associated with a preclinical state of an interstitial lung disease and a risk for restrictive ventilation disorders. [ABSTRACT FROM AUTHOR]

Purpose To investigate the association of reticular pseudodrusen (RPD) with Sorsby fundus dystrophy (SFD). Design Prospective, monocenter, cross-sectional case series. Subjects Sixteen patients of 4 unrelated families with SFD caused by mutations in TIMP3 . Methods All subjects underwent multimodal imaging including near-infrared (NIR) reflectance and fundus autofluorescence with a confocal scanning laser ophthalmoscope and spectral-domain optical coherence tomography (SD OCT). Main Outcome Measures Prevalence, topographic distribution, and phenotype of RPD. Results Mean age of the investigated patients was 56.8 years (range, 23–78 years). Reticular pseudodrusen were identified frequently in SFD patients in the sixth decade of life (5 of 7 [71%]) and were absent in younger (n = 3) or older (n = 6) patients. They were most abundant in the superior quadrant and spared the foveal region. Reticular pseudodrusen appeared as yellowish round to oval (dot subtype; n = 5) or confluent, wriggled (ribbon subtype; n = 3) lesions, sometimes forming irregular networks. Reticular pseudodrusen were hyporeflective on NIR reflectance and hypofluorescent on fundus autofluorescence imaging. They appeared as subretinal deposits on SD OCT imaging. Other lesions, such as peripheral pseudodrusen and soft drusen, were present less frequently. Conclusions Reticular pseudodrusen are a frequent finding in patients with SFD. Although SFD patients with RPD are younger, distribution and phenotype of RPD are similar to those observed in patients with age-related macular degeneration. The association of RPD with SFD implicates a role of Bruch's membrane, the Bruch's membrane–retinal pigment epithelium interface, or both in the pathogenesis of RPD. [ABSTRACT FROM AUTHOR]

PURPOSE: To investigate the impact of Bruch membrane pathology on the choroid in pseudoxanthoma elasticum (PXE). DESIGN: Monocenter cross-sectional prospective case series. METHODS: The study included 61 eyes of 51 patients with PXE and 54 eyes of 54 normal subjects. The diagnosis of PXE was based on skin biopsy, genetic analysis or both. Eyes with PXE were subdivided into 3 groups: eyes without choroidal neovascularization (CNV) or chorioretinal atrophy (Group 1); eyes with active or fibrotic CNV (Group 2); and eyes with chorioretinal atrophy only (Group 3). Choroidal thickness was measured using enhanced-depth imaging optical coherence tomography (EDI-OCT). RESULTS: Compared to controls (331 mm ± 24; mean ± 95% CI), mean subfoveal choroidal thickness in eyes of patients with PXE was significantly reduced within all 3 groups (Group 1: 243 mm ± 29; Group 2: 184 mm ± 28; Group 3: 104mm± 28;P<0.001).Associated structural changes included apparent loss of small choroidal vessels. The difference of PXE compared to control eyes was largest close to the optic disc and approximated the level of controls toward the periphery. Within the PXE subgroups, eyes without CNV or chorioretinal atrophy (Group 1) showed the least reduction of choroidal thickness, while it was most pronounced in Group 3. CONCLUSIONS: The results indicate that changes of Bruch membrane can be associated with choroidal alterations, which are most pronounced in the presence of advanced disease. A role of Bruch membrane in choroidal homeostasis may reflect a possible contribution of Bruch membrane alterations to CNV and geographic atrophy development in age-related macular degeneration. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover “hidden mutations” such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 5′ exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e.g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5′-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even truncating mutations may be misleading. [ABSTRACT FROM AUTHOR]

Inherited retinal dystrophies (IRDs) are characterized by high clinical and genetic heterogeneity. A precise characterization is desirable for diagnosis and has impact on prognosis, patient counseling, and potential therapeutic options. Here, we demonstrate the effectiveness of the combination of in-depth retinal phenotyping and molecular genetic testing in complex pedigrees with different IRDs. Four affected Caucasians and two unaffected relatives were characterized including multimodal retinal imaging, functional testing, and targeted next-generation sequencing. A considerable intrafamilial phenotypic and genotypic heterogeneity was identified. While the parents of the index family presented with rod-cone dystrophy and ABCA4-related retinopathy, their two sons revealed characteristics in the spectrum of incomplete congenital stationary night blindness and ocular albinism, respectively. Molecular testing revealed previously described variants in RHO, ABCA4, and MITF as well as a novel variant in CACNA1F. Identified variants were verified by intrafamilial co-segregation, bioinformatic annotations, and in silico analysis. The coexistence of four independent IRDs caused by distinct mutations and inheritance modes in one pedigree is demonstrated. These findings highlight the complexity of IRDs and underscore the need for the combination of extensive molecular genetic testing and clinical characterization. In addition, a novel variant in the CACNA1F gene is reported associated with incomplete congenital stationary night blindness. [ABSTRACT FROM AUTHOR]

Purpose: To elucidate morphological determinants of rod and cone dysfunction in Sorsby fundus dystrophy (SFD), and to systematically compare visual function tests for interventional trials., Design: Prospective cross-sectional study., Methods: Patients with SFD (n = 16) and controls (n = 20) underwent visual function testing (best-corrected visual acuity [BCVA] and low luminance visual acuity [LLVA], contrast sensitivity, mesopic and dark-adapted (DA) fundus-controlled perimetry [FCP], rod-mediated dark adaptation [RMDA]), and multimodal imaging. Vision-related quality of life was evaluated. FCP and RMDA thresholds were analyzed using mixed models and structure-function correlation using machine learning (ML). Longitudinal data of 1 patient with high-dose vitamin A supplementation were available., Results: Although photopic BCVA was normative in SFD, LLVA was impaired (0.30 LogMAR [0.20; 0.45] vs 0.20 LogMAR [0.03; 0.28], P < .05). Scotopic visual function exhibited a delayed rod-intercept time (21 minutes [12.15; 21] vs 4.05 minutes [3.22; 5.36], P < .001), and marked DA cyan mean sensitivity loss (-11.80 dB [-3.47; -19.85]), paralleled by a reduced vision-related quality of life. ML-based structure-function correlation allowed prediction of mesopic, DA cyan, and red sensitivity with high accuracy (cross-validated mean absolute error: 4.36, 7.77, and 5.31 dB, respectively), whereas RMDA could be slowed even in the absence of fundus alterations on multimodal imaging. After high-dose vitamin A supplementation, RMDA and DA thresholds improved markedly., Conclusions: Patients with SFD exhibit severely impaired scotopic visual function even in the absence of funduscopic alterations on multimodal imaging. In contrast to BCVA, scotopic visual function tests are suitable to quantify dysfunction in the early stages. Improvement of scotopic dysfunction after (off-label) high-dose vitamin A intake, as observed in one patient in our study, is compatible with the hypothesized local deficiency of vitamin A secondary to Bruch's membrane alterations., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To report the retinal phenotype and the associated genetic and systemic findings in patients with mitochondrial disease., Design: Retrospective case series., Participants: Twenty-three patients with retinopathy and mitochondrial disease, including chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes and deafness (MIDD), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Kearns-Sayre syndrome, neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, and other systemic manifestations., Methods: Review of case notes, retinal imaging, electrophysiologic assessment, molecular genetic testing including protein modeling, and histologic analysis of muscle biopsy., Main Outcome Measures: Phenotypic characteristics of mitochondrial retinopathy., Results: Genetic testing identified sporadic large-scale mitochondrial DNA deletions and variants in MT-TL1, MT-ATP6, MT-TK, MT-RNR1, or RRM2B. Based on retinal imaging, 3 phenotypes could be differentiated: type 1 with mild, focal pigmentary abnormalities; type 2 characterized by multifocal white-yellowish subretinal deposits and pigment changes limited to the posterior pole; and type 3 with widespread granular pigment alterations. Advanced type 2 and 3 retinopathy presented with chorioretinal atrophy that typically started in the peripapillary and paracentral areas with foveal sparing. Two patients exhibited a different phenotype: 1 revealed an occult retinopathy, and the patient with RRM2B-associated retinopathy showed no foveal sparing, no severe peripapillary involvement, and substantial photoreceptor atrophy before loss of the retinal pigment epithelium. Two patients with type 1 disease showed additional characteristics of mild macular telangiectasia type 2. Patients with type 1 and mild type 2 or 3 disease demonstrated good visual acuity and no symptoms associated with the retinopathy. In contrast, patients with advanced type 2 or 3 disease often reported vision problems in dim light conditions, reduced visual acuity, or both. Short-wavelength autofluorescence usually revealed a distinct pattern, and near-infrared autofluorescence may be severely reduced in type 3 disease. The retinal phenotype was key to suspecting mitochondrial disease in 11 patients, whereas 12 patients were diagnosed before retinal examination., Conclusions: Different types of mitochondrial retinopathy show characteristic features. Even in absence of visual symptoms, their recognition may facilitate the often challenging and delayed diagnosis of mitochondrial disease, in particular in patients with mild or nebulous multisystem disease., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the role of fundus autofluorescence (FAF) imaging in the diagnosis of macular telangiectasia type 2 (MacTel) and to describe disease-associated FAF patterns and their origin., Design: Cross-sectional multicenter study METHODS: FAF images were collected from the multicenter MacTel Natural History Observation and Registry Study. In a first qualitative approach, common FAF phenotypes were defined and correlated with multimodal imaging. We then evaluated how many eyes showed FAF changes, and temporal vs nasal asymmetry of FAF changes was graded. Finally, 100 eyes of MacTel patients and 100 control eyes (50 normal eyes and 50 eyes with other macular diseases) were combined and 2 masked graders assessed the presence of MacTel based on FAF images alone., Results: The study included 807 eyes of 420 patients (33 eyes were excluded owing to poor image quality). Loss of macular pigment, cystoid spaces, pigment plaques, neovascular membranes, and ectatic vascular changes commonly caused characteristic changes on FAF images. All MacTel patients had macular FAF changes in at least 1 eye. In 95% of eyes, these changes were more pronounced temporally than nasally. Common FAF patterns were increased (60%) and mixed/decreased FAF (38%) and/or visibility of vascular changes such as blunted vessels or ectatic capillaries (79%). Based on those features, high diagnostic performance was achieved for detection of the disease based on FAF alone (Youden index up to 0.91)., Conclusions: The study demonstrates that MacTel is consistently associated with disease-specific changes on FAF imaging. Those changes are typically more pronounced in the temporal parafovea., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To investigate lipofuscin-related quantitative autofluorescence measures and their association with demographic characteristics, retinal structure, retinal function and genotype in ABCA4-related retinopathy (Stargardt disease 1)., Design: Cross-sectional study with age-matched healthy control subjects., Methods: A total of 77 patients with ABCA4-related retinopathy and 110 control subjects underwent quantitative fundus autofluorescence (qAF) imaging using a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to measure qAF as surrogate for lipofuscin accumulation. Measures of qAF were correlated with demographic characteristics, structural alterations on optical coherence tomography and fundus autofluorescence imaging, retinal function assessed by full-field electroretinography (ERG) and fundus-controlled perimetry, and genotype., Results: Most patients (76.6%) had qAF levels >95% prediction interval of the age-related control group, with best discrimination between cases and control subjects in younger patients. Reduced discrimination based on qAF measures was associated with mild disease, more advanced disease with dark flecks, or older age because of the physiological age-related increase in qAF and a ceiling effect in patients. Nullizygous patients presented with high qAF levels earlier in life compared with those with at least 1 milder ABCA4 variant. Within the sectors of qAF measurements, at approximately 7-9° eccentricity, increased qAF without flecks or with only bright flecks was associated with topographically related preserved retinal thickness and fundus-controlled perimetry results, and with normal full-field ERG recordings. All 3 parameters were increasingly abnormal with the development of dark flecks and decreasing qAF., Conclusions: The accumulation of lipofuscin depends on the severity of ABCA4 variants, precedes other structural changes, and may remain without clinically relevant effect on retinal function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To investigate quantitatively lipofuscin-associated fundus autofluorescence in patients with macular and cone/cone-rod dystrophies (MD/CCRDs)., Design: Prospective, single-center, case-control study., Participants: Two hundred thirty patients with MD/CCRDs who had undergone genetic testing and 110 control participants without any eye disease., Methods: Participants were examined using quantitative fundus autofluorescence (qAF) imaging with a modified confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference (modified Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany). Mean qAF values were obtained by averaging measurements from an 8-segment ring centered on the fovea (qAF 8 ) and compared with controls., Main Outcome Measures: The qAF 8 levels., Results: Elevated qAF 8 values were a frequent finding (n = 105 [45%]) and associated with ABCA4 (n = 73 [70%]), PRPH2 (n = 9 [9%]), CERKL (n = 3 [3%]), PROM1 (n = 2 [2%]), CRX (n = 1 [1%]), and CDHR1 (n = 1 [1%]) mutations. Reduced qAF 8 values were rare (n = 15 [7%]) and found predominantly among patients with MERTK (n = 3 [20%]) and RDH5 (n = 2 [13%]) mutations. Patients with normal qAF 8 values (n = 110 [48%]) showed high genotypic heterogeneity. For various genes including ABCA4, PRPH2, CDHR1, and PROM1, higher qAF 8 measures were associated with specific phenotypes and genotypes. For instance, qAF 8 values were normal in PRPH2-related central areolar chorioretinal dystrophy but increased in PRPH2-related Stargardt-like retinopathy. Accordingly, high qAF 8 levels were associated with specific genetic causes and mutation detection rates in characteristic but genetically heterogenous clinical phenotypes, such as a Stargardt-like flecked fundus, bull's eye maculopathy, or pattern dystrophy. In genetically unsolved cases (16 with elevated, 35 with normal, 7 with reduced qAF values), qAF 8 was used to support or reject ambiguous results of genetic testing, to suggest underlying pathogenic pathways, and to predict disease in otherwise healthy participants., Conclusions: Quantitative fundus autofluorescence imaging revealed characteristic qAF levels in association with certain gene mutations and in participants without detected mutations. These findings indicate that qAF may facilitate differential diagnostics of MD/CCRDs and may offer novel pathogenetic insights that may be of particular value for the assessment of future treatment approaches., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To demonstrate that peripapillary sparing on autofluorescence images is a characteristic feature of autosomal recessive bestrophinopathy (ARB)., Design: Retrospective, cross-sectional case series and review of previous published cases., Participants: Twelve patients with ARB., Methods: Ophthalmic assessment included best-corrected visual acuity testing, electrophysiologic examinations, and multimodal retinal imaging. Retinal imaging included OCT, blue-light autofluorescence imaging, fundus photography, and widefield pseudocolor and autofluorescence fundus imaging., Main Outcome Measures: Presence of peripapillary sparing on fundus autofluorescence images., Results: Relatively normal-appearing peripapillary autofluorescence was identified in all patients, independent of the disease stage or presence of widespread changes on autofluorescence widefield images. OCT images of the peripapillary region revealed mild structural abnormalities, including a thinned outer nuclear layer and intraretinal or subretinal fluid. A review of previously published cases confirmed peripapillary sparing as consistent feature on fundus autofluorescence images. Genetic analysis revealed 10 previously reported mutations, 1 novel missense (c.83T>A; p.Ile28Asn) and 2 novel truncating (c.658C>T; p.Gln220* and c.1370C>G; p.Ser457*) variants in BEST1., Conclusions: In ARB patients, peripapillary sparing is a consistent feature on fundus autofluorescence images, whereas the same region is less preserved on OCT images., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the functional relevance and structural correlates of autofluorescence (AF) alterations under short-wavelength (SW) and near-infrared (NIR) excitation light in ABCA4 -related retinopathy., Methods: In this prospective, cross-sectional case series, 88 eyes of 44 patients with ABCA4 -related retinopathy (mean age, 37.6 years; range, 9-77 years) underwent SW-AF and NIR-AF imaging. The AF images were graded for disease characteristic patterns by two independent readers and correlated with alterations in optical coherence tomography (OCT) and impairment of retinal sensitivity along a foveo-papillary line assessed by fundus-controlled microperimetry., Results: A centrifugal sequence of AF patterns from atrophic lesions to homogeneous background was found for both AF modalities. The eccentricity of each AF pattern in NIR-AF was larger compared to those in SW-AF ( P < 0.001). Increasing eccentricity of each pattern correlated with increasing retinal sensitivity. The distant border of the zone of hyperfluorescent flecks in SW-AF and hypoautofluorescent flecks in NIR-AF correlated with the margins of the ellipsoid zone loss in OCT ( r = 0.979 and r = 0.971, P < 0.001). The expansion of hypofluorescent flecks in SW-AF was associated with the boundaries of external limiting membrane loss ( r = 0.933, P < 0.001)., Conclusions: SW-AF and NIR-AF revealed a characteristic sequence of AF patterns that correlated with functional and structural alterations, suggesting different stages in disease progression., Translational Relevance: Alterations in NIR-AF exceeded those in SW-AF images, substantiating the hypothesis of different AF origins and suggesting NIR-AF as surrogate marker for early disease-related changes., (Copyright 2019 The Authors.)

Purpose: To assess whether near infrared autofluorescence (NIR-AF) imaging is a useful imaging modality in the diagnosis of handheld laser retinal injuries., Design: Retrospective observational case series., Methods: Twelve patients identified to have handheld laser retinal injuries were included at 2 academic centers. Patients underwent ophthalmic assessment and retinal imaging including fundus photography, optical coherence tomography (OCT), conventional blue autofluorescence (B-AF), and NIR-AF imaging., Results: In all cases, lesions consistent with retinal laser injury were detected by NIR-AF imaging. The lesions showed a characteristic appearance with central hyperfluorescence and surrounding hypofluorescence, although the number and extent of lesions varied between patients. Findings using other imaging modalities were variable: on color fundus photography these included localized pigmentary changes and on OCT imaging an ellipsoid zone interruption or outer nuclear layer changes. Only subtle changes were evident on B-AF imaging. Other macular conditions, such as poppers retinopathy or solar maculopathy, which may have similar findings on OCT imaging as laser damage, can be differentiated using NIR-AF imaging., Conclusion: An increased incidence of retinal injuries secondary to handheld lasers has been reported in recent years. We show that the diagnosis and full extent of retinal laser injuries is best demonstrated by NIR-AF, as other modalities give variable results. We propose that NIR-AF should be included when investigating patients suspected of macular injury secondary to exposure to handheld lasers., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To investigate ophthalmic features in a large group of patients with primary hyperoxaluria type 1 (PH1) and to determine the relation between ocular involvement and systemic disease severity., Design: Retrospective, cross-sectional, multicenter study of the OxalEurope Registry Network., Methods: Sixty-eight patients with PH1 were included. Infantile PH1 was diagnosed in 12 patients, and non-infantile PH1 was diagnosed in 56 patients (17 with end-stage renal disease). Ophthalmic examination included best corrected visual acuity (BCVA) testing and multimodal retinal imaging, including fundus photography and optical coherence tomography (OCT). In selected cases, fundus autofluorescence imaging was performed., Results: All eyes (n = 24) of infantile PH1 patients revealed severe retinal alterations and oxalate deposits, including macular crystals and hyperpigmentations (n = 9, 38%), and subretinal fibrosis (n = 15, 63%) with (n = 7, 47%) or without (n = 8; 53%) associated chronic retinal edema. In 9 eyes (38%, all with subretinal fibrosis), BCVA was significantly reduced (<20/50 Snellen equivalent). In contrast, all eyes (n = 112) of patients with non-infantile PH1 had a BCVA in the normal range (median, 20/20). Only 6 patients with non-infantile disease (11%, all with end-stage renal disease) showed mild, likely PH1-related retinal features. These deposits appeared as focal hyperreflective subretinal lesions on OCT imaging and were hyperautofluorescent on autofluorescence images., Conclusions: Severe ocular alterations occur in infantile cases, whereas mild or no ocular alterations are typical in non-infantile PH1 patients. The natural history of (sub)retinal oxalate deposits, the pathogenesis of subretinal fibrosis, and exact factors influencing the overall severity of ocular disease manifestation remain to be determined., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To report the clinical and molecular findings in patients with retinal dystrophy associated with the c.783G>A variant in CDHR1., Methods: The retinal phenotype of 10 patients with CDHR1-related retinopathy was characterized by multimodal imaging including color fundus photography, optical coherence tomography (OCT), and blue- and near-infrared fundus autofluorescence imaging. Functional testing included electroretinography, visual acuity, and visual field testing., Results: Six patients homozygous for the c.783G>A variant in CDHR1 showed a retinal phenotype resembling central areolar choroidal dystrophy (CACD) on multimodal imaging. Retinal function outside an area of slowly progressive macular atrophy remained relatively preserved. In contrast, biallelic severe/truncating CDHR1 mutations result in retina-wide retinal degeneration in addition to macular atrophy, with overall severely reduced retinal function. Patients compound heterozygous for the c.783G>A mutation and a truncating mutation in CDHR1 showed an intermediate phenotype. All patients except one with biallelic severe CDHR1 mutations were asymptomatic in the first four decades of life, irrespective of their individual CDHR1 mutations. Analysis of blood RNA from patients with the c.783G>A variant revealed in-frame skipping of exon 8 in vivo, predicting a partial deletion of CDHR1 ectodomains 2 and 3., Conclusions: Patients with biallelic c.783G>A CDHR1 mutations demonstrate a retinal phenotype consistent with autosomal recessive CACD. The apparently silent dbSNP-annotated c.783G>A CDHR1 variant (rs147346345) has a relatively high minor allele frequency (0.31%), with homozygous individuals annotated in the general population, and it may therefore have been disregarded in many next-generation sequencing (NGS)-based studies. The differential diagnosis includes PRPH2-associated CACD and age-related macular degeneration.

Purpose: To investigate near-infrared fundus autofluorescence (NIR-AF) characteristics in patients with choroideremia and to correlate these with anatomic and functional parameters., Design: Retrospective, observational case series., Methods: In this multicenter study, 43 consecutive choroideremia patients (79 eyes) underwent multimodal retinal imaging, including near-infrared fundus autofluorescence (NIR-AF), blue autofluorescence (B-AF), optical coherence tomography (OCT), fundus photography, and functional testing including fundus-controlled microperimetry., Results: All eyes could be categorized into 3 groups based on patterns of NIR-AF over the island of surviving retinal pigment epithelium: Group 1 (preserved NIR-AF centrally), Group 2 (only disrupted NIR-AF), or Group 3 (absence of NIR-AF). Group 1 eyes showed areas of NIR-AF that matched the areas of B-AF islands (R 2  = 0.94, slope 0.84 ± 0.04) while Group 2 eyes showed significantly smaller areas of NIR-AF compared with B-AF (R 2  = 0.08; slope 0.02 ± 0.01). The 3 groups differed significantly in terms of residual B-AF island size (P < .0001), length of foveal ellipsoid zone (P = .03), foveal thickness (P = .04), and foveal sensitivity (P = .01). Visual acuity (P = .07) and central retinal thickness (P = .06) did not differ statistically. The length of the ellipsoid zone line was similar to the horizontal diameter of NIR-AF in Group 1 (R 2  = 0.97, slope 0.96 ± 0.04), while Group 2 eyes showed broader ellipsoid zone than NIR-AF (R 2  = 0.60, slope 0.19 ± 0.03)., Conclusions: Choroideremia patients can be stratified into 3 groups based on NIR-AF imaging, which showed morphologic and functional changes correlating with different stages of retinal pigment epithelium degeneration. NIR-AF could be a marker for disease staging in choroideremia, and could be used for patient selection or as an outcome parameter in interventional trials., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To investigate the interreader and intermodality agreement for grading of retinal pigment epithelium (RPE) atrophy lesion size in ABCA4 -related retinopathy using green (GAF) and blue fundus autofluorescence (BAF) imaging., Methods: In this cross-sectional case series, 97 eyes of 49 patients with RPE atrophy secondary to ABCA4 -related retinopathy underwent GAF- (518 nm excitation light) and BAF- (488 nm excitation light) imaging using confocal scanning laser ophthalmoscopy (Spectralis HRA, Heidelberg Engineering, Heidelberg, Germany). Lesions with definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) in GAF and BAF imaging were analyzed separately by five independent readers using semiautomated software (RegionFinder, Heidelberg Engineering). Intermodality and interreader agreements were assessed for the square-root lesion size, lesion perimeter, and circularity., Results: GAF- and BAF-based measurements of DDAF and QDAF showed high intermodality and interreader agreement concerning square-root lesion size, as well as shape descriptive parameters (perimeter and circularity). Interreader agreement of square-root lesion size was slightly, hence not significantly higher for GAF-based grading ([95% coefficients of repeatability, intraclass correlation coefficient] DDAF: 0.215 mm, 0.997; QDAF: 0.712 mm, 0.981) compared to BAF-based grading (DDAF: 0.232 mm, 0.997; QDAF: 0.764 mm, 0.978). However, DDAF-measurements revealed distinctly more reproducible results than QDAF-measurements. Foveal sparing did not interfere with intermodality agreement., Conclusions: Both GAF- and BAF-based quantification of RPE atrophy showed very reliable results with possible superiority of GAF in the context of less energetic excitation light., Translational Relevance: The high interreader agreement qualifies the use of DDAF progression in GAF and BAF imaging as potential morphologic outcome measure for interventional clinical trials and disease monitoring.

Macular and cone/cone-rod dystrophies (MD/CCRD) demonstrate a broad genetic and phenotypic heterogeneity, with retinal alterations solely or predominantly involving the central retina. Targeted next-generation sequencing (NGS) is an efficient diagnostic tool for identifying mutations in patient with retinitis pigmentosa, which shows similar genetic heterogeneity. To detect the genetic causes of disease in patients with MD/CCRD, we implemented a two-tier procedure consisting of Sanger sequencing and targeted NGS including genes associated with clinically overlapping conditions. Disease-causing mutations were identified in 74% of 251 consecutive MD/CCRD patients (33% of the variants were novel). Mutations in ABCA4, PRPH2 and BEST1 accounted for 57% of disease cases. Further mutations were identified in CDHR1, GUCY2D, PROM1, CRX, GUCA1A, CERKL, MT-TL1, KIF11, RP1L1, MERTK, RDH5, CDH3, C1QTNF5, CRB1, JAG1, DRAM2, POC1B, NPHP1 and RPGR. We provide detailed illustrations of rare phenotypes, including autofluorescence and optical coherence tomography imaging. Targeted NGS also identified six potential novel genotype-phenotype correlations for FAM161A, INPP5E, MERTK, FBLN5, SEMA4A and IMPDH1. Clinical reassessment of genetically unsolved patients revealed subgroups with similar retinal phenotype, indicating a common molecular disease cause in each subgroup.

Pseudoxanthoma Elasticum (PXE), caused by autosomal-recessive mutations in the ATP-binding cassette transporter (ABCC6) gene, is known for high prevalence of atherosclerosis. A novel method investigating elastic properties of arteries in atherosclerotic patients is vascular strain analysis. We compared 44 PXE patients with peripheral artery disease (PXE+PAD group) with 50 control patients, each 25 without (control group) and with PAD (PAD group). All participants underwent an angiological examination including ankle-brachial index (ABI) and were examined with speckle-tracking based vascular strain analysis of common carotid arteries, measuring radial displacement (r.Dis), radial velocity (r.Vel), radial strain (r.Str), circumferential strain (c.Str), radial strainrate (r.SR) and circumferential strainrate (c.SR). We found significant lower ABI in patients with PXE compared to all other groups (each p < 0.01). The vascular strain analysis resulted in significantly decreased values in the PAD group compared to PXE with PAD (each p ≤ 0.01) and controls without PAD (each p ≤ 0.05), whereas no significant difference could be found between PXE+PAD and controls without PAD. We found significant negative correlations between low strain values and a higher prevalence of PAD in non-PXE patients (r.Str r = -0.34; c.Str r = -0.35; r.SR: r = -0.51; c.SR: r = -0.53). In conclusion, PXE patients had similar values for arterial stiffness compared to controls without PAD in vascular strain analysis. In this group, arterial stiffness parameters were significantly higher compared to non-PXE PAD patients. It is worth to discuss whether PAD-like manifestations in PXE are a different kind of disease and might need another strategy in diagnostics and therapy.

Purpose: To quantify lipofuscin-associated fundus autofluorescence in patients with pseudoxanthoma elasticum (PXE), a model disease for Bruch's membrane pathology., Methods: In this prospective, monocenter, cross-sectional case-control study, 49 patients with PXE (mean age: 46 years, range 18-62) underwent quantitative fundus autofluorescence (qAF) imaging with a modified scanning laser ophthalmoscope containing an internal fluorescent reference for normalization of images. The mean qAF values of a circular ring centered on the fovea (qAF8) were measured and compared to 108 healthy controls (mean age 40 years, range 18-64)., Results: Overall, patients with PXE showed lower qAF8 values compared to controls (difference from controls -23%, 95% confidence interval [CI] -29% to -16%, P < 0.001). The reduction was most pronounced in patients older than 40 years (-30%, 95% CI -36% to -23%, P < 0.001) and was negatively correlated with the extent of Bruch's membrane calcification (r = -0.49, 95% CI: -0.67 to -0.22). The topographic distribution revealed a greater reduction of qAF values toward the optic disc than temporally compared to controls (P < 0.001). The phenotype of patients with reduced qAF values was characterized by pattern-dystrophy-like changes (71%; 10 of 14), reticular pseudodrusen (71%; 10 of 14) and limited areas of atrophy (29%, 4 of 14)., Conclusions: Reduced qAF8 values are a characteristic finding in patients with PXE, indicating that Bruch's membrane disease may result in a modification of the accumulation, distribution, or composition (or a combination thereof) of lipofuscin in retinal pigment epithelial cells.

Purpose: This study sought to characterize the ophthalmic and extraocular phenotype in patients with known and novel KIF11 mutations., Methods: Four patients (3, 5, 36, and 38 years of age, on father-daughter constellation) from three unrelated families were characterized by retinal examination including multimodal retinal imaging, investigation for syndromic disease manifestations, and targeted next-generation sequencing. The subcellular localization of Kif11 in the retina was analyzed by light and electron microcopy., Results: There was considerable interindividual and intrafamilial phenotypic heterogeneity of KIF11-related retinopathy. Two patients presented with a progressive retinal dystrophy, one with chorioretinal dysplasia and one with familial exudative vitreoretinopathy (FEVR) in one eye and thinning of the photoreceptor layer in the fellow eye. Obvious syndromic disease manifestations were present only in the youngest patient, but minor signs (e.g. reduced head circumference) were present in the three other individuals. Immunohistochemistry results demonstrated Kif11 localization in the inner segment and ciliary compartments of photoreceptor cells and in the retinal pigment epithelium., Conclusions: Progressive retinal degeneration in KIF11-related retinopathy indicates a role for KIF11 not only in ocular development but also in maintaining retinal morphology and function. The remarkable variability of the ocular phenotype suggests four different types of retinopathy which may overlap. KIF11 should be considered in the screening of patients with retinal dystrophies because other syndromic manifestations may be subtle. Evaluation of head circumference may be considered as a potential shortcut to the genetic diagnosis. The localization of Kif11 in photoreceptor cells indicates a retinal ciliopathy.