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Abstract Background Occult Macular Dystrophy (OMD), primarily caused by retinitis pigmentosa 1-like 1 (RP1L1) variants, is a complex retinal disease characterised by progressive vision loss and a normal fundus appearance. This study aims to investigate the diverse phenotypic expressions and genotypic correlations of OMD in Chinese patients, including a rare case of Vitelliform Macular Dystrophy (VMD) associated with RP1L1. Methods We analysed seven OMD patients and one VMD patient, all with heterozygous pathogenic RP1L1 variants. Clinical assessments included Best Corrected Visual Acuity (BCVA), visual field testing, Spectral Domain Optical Coherence Tomography (SD-OCT), multifocal Electroretinograms (mfERGs), and microperimetry. Next-generation sequencing was utilised for genetic analysis. Results The OMD patients displayed a range of phenotypic variability. Most (5 out of 7) had the RP1L1 variant c.133 C > T; p.R45W, associated with central vision loss and specific patterns in SD-OCT and mfERG. Two patients exhibited different RP1L1 variants (c.3599G > T; p.G1200V and c.2880G > C; p.W960C), presenting milder phenotypes. SD-OCT revealed photoreceptor layer changes, with most patients showing decreased mfERG responses in the central rings. Interestingly, a unique case of VMD linked to the RP1L1 variant was observed, distinct from traditional OMD presentations. Conclusions This study highlights the phenotypic diversity within OMD and the broader spectrum of RP1L1-associated macular dystrophies, including a novel association with VMD. The findings emphasise the complexity of RP1L1 variants in determining clinical manifestations, underscoring the need for comprehensive genetic and clinical evaluations in macular dystrophies.

Background: Occult Macular Dystrophy (OMD), primarily caused by retinitis pigmentosa 1-like 1 (RP1L1) variants, is a complex retinal disease characterised by progressive vision loss and a normal fundus appearance. This study aims to investigate the diverse phenotypic expressions and genotypic correlations of OMD in Chinese patients, including a rare case of Vitelliform Macular Dystrophy (VMD) associated with RP1L1. Methods: We analysed seven OMD patients and one VMD patient, all with heterozygous pathogenic RP1L1 variants. Clinical assessments included Best Corrected Visual Acuity (BCVA), visual field testing, Spectral Domain Optical Coherence Tomography (SD-OCT), multifocal Electroretinograms (mfERGs), and microperimetry. Next-generation sequencing was utilised for genetic analysis. Results: The OMD patients displayed a range of phenotypic variability. Most (5 out of 7) had the RP1L1 variant c.133 C > T; p.R45W, associated with central vision loss and specific patterns in SD-OCT and mfERG. Two patients exhibited different RP1L1 variants (c.3599G > T; p.G1200V and c.2880G > C; p.W960C), presenting milder phenotypes. SD-OCT revealed photoreceptor layer changes, with most patients showing decreased mfERG responses in the central rings. Interestingly, a unique case of VMD linked to the RP1L1 variant was observed, distinct from traditional OMD presentations. Conclusions: This study highlights the phenotypic diversity within OMD and the broader spectrum of RP1L1-associated macular dystrophies, including a novel association with VMD. The findings emphasise the complexity of RP1L1 variants in determining clinical manifestations, underscoring the need for comprehensive genetic and clinical evaluations in macular dystrophies. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to estimate the number of patients in Japan who had visited an ophthalmologist for macular dystrophy of various types, including Best vitelliform macular dystrophy (BVMD), Stargardt disease, occult macular dystrophy (OMD), cone (-rod) dystrophy, X-linked retinoschisis (XLRS), and central areolar choroid dystrophy (CACD). Study design: Nationwide epidemiologic survey Methods: Questionnaires were distributed to 965 major facilities, including all the university hospitals in Japan. The aim of the questionnaire was to determine the number of patients with each type of macular dystrophy who had visited an outpatient clinic during the past 5 years (January 2015 to December 2019). Results: Over 70% of the patients were diagnosed and followed up at university hospitals. The estimated annual number of newly diagnosed cases was as follows: 55.3 for BVMD, 36.7 for Stargardt disease, 35.8 for OMD, 160.6 for cone (-rod) dystrophy, 31.0 for XLRS, 29.8 for CACD, and 174.1 for other types of macular dystrophy. The total number of patients with macular dystrophy diagnosed and followed at major institutions was estimated to be 6651. Conclusion: This was the first nationwide survey of macular dystrophy in Japan and provided an approximate number of affected patients. The diagnosis of macular dystrophy is primarily carried out at facilities with affiliated specialists, such as university hospitals. By examining the incidence of multiple diseases simultaneously, we were able to compare the incidence of each type of macular dystrophy. [ABSTRACT FROM AUTHOR]

Macular dystrophies (MDs) constitute a collection of hereditary retina disorders leading to notable visual impairment, primarily due to progressive macular atrophy. These conditions are distinguished by bilateral and relatively symmetrical abnormalities in the macula that significantly impair central visual function. Recent strides in fundus imaging, especially optical coherence tomography (OCT), have enhanced our comprehension and diagnostic capabilities for MD. OCT enables the identification of neurosensory retinal disorganization patterns and the extent of damage to retinal pigment epithelium (RPE) and photoreceptor cells in the dystrophies before visible macular pathology appears on fundus examinations. It not only helps us in diagnostic retinal and choroidal pathologies but also guides us in monitoring the progression of, staging of, and response to treatment. In this review, we summarize the key findings on OCT in some of the most common MD. [ABSTRACT FROM AUTHOR]

Purpose: Occult macular dystrophy (OMD) is a cause of visual loss in young adults with a grossly normal fundus appearance. It is considered an autosomal dominant disorder, related to heterozygous pathogenic variants in the gene RP1L1. The purpose of this study is to report a biallelic form of the disease. Results: A 29-year-old female had undergone neurological workup and ophthalmic examinations for transient visual loss in her left eye over the past two years but there was no definitive diagnosis. The best-corrected visual acuity was 20/30, 20/20. Indirect ophthalmoscopy with a 78D lens revealed subtle central retinal pigment epithelium mottling and optical coherence tomography confirmed subtle central thickening of the ellipsoid zone. Full-field electroretinography was normal, but pattern electroretinography showed decreased p50 responses. OMD was suspected. Retinal gene panel testing was significant only for a homozygous variant in RP1L1 (NM_178857.6: c.3571 G>T; p.Glu1191*). The parents and older brother were unavailable for segregation analysis. By history they did not have visual complaints other than a need for glasses. Conclusions: This report presents the clinical and genetic findings of a biallelic form of OMD associated with a novel pathogenic variant in RP1L1. It would be of interest to carefully assess macular function in heterozygotes with this variant. [ABSTRACT FROM AUTHOR]

A 29-year-old female with no family history presented with bilateral progressive blurred vision. Her symptoms appeared at 12-years-old and her visual acuity had since deteriorated from 0.6 to 0.2 bilaterally with decreased critical flicker frequency and bilateral central scotomas. She did not have a relative afferent pupillary defect. Fundoscopy revealed no distinct disc hyperaemia, atrophy, or peripapillary telangiectatic vessels. The retinal nerve fibre layer appeared normal on optical coherence tomography in each eye; however, loss of the interdigitation zone and the disruption of the ellipsoid zone at the fovea were observed in both eyes. Multifocal electroretinography revealed decreased amplitudes at both macula regions. Mitochondrial deoxyribonucleic acid analysis identified an m.14502T>C mutation, one of the primary mutations causing Leber's hereditary optic neuropathy (LHON). Despite the presence of a marked LHON mutation, however, she was clinically diagnosed as having an occult macular dystrophy. There have only been five previous case reports, all of which were sporadic, which detail the clinical characteristics of the m.14502T>C mutation. The m.14502T>C phenotype is somewhat consistent with that of the other major mutations, including young onset, bilateral progressive visual impairment, and a typical LHON fundus. Nevertheless, m.14502T>C alone has an extremely low penetrance and its phenotype may be minimal or subclinical, as seen in our case. Since little is known about the clinical course of the m.14502T>C mutation it may be possible that the LHON phenotype may appear in later stages of life. Moreover, m.14502T>C may function as a modifier gene, which alters the phenotype of other coexisting major LHON mutations, including penetrance and the severity of the disease, through synergistic effects. [ABSTRACT FROM AUTHOR]

Occult macular dystrophy (OMD) is the most prevalent form of macular dystrophy in East Asia. Beyond RP1L1, causative genes and mechanisms remain largely uncharacterised. This study aimed to delineate the clinical and genetic characteristics of OMD syndrome (OMDS). Patients clinically diagnosed with OMDS in Japan, South Korea, and China were enrolled. The inclusion criteria were as follows: (1) macular dysfunction and (2) normal fundus appearance. Comprehensive clinical evaluation and genetic assessment were performed to identify the disease-causing variants. Clinical parameters were compared among the genotype groups. Seventy-two patients with OMDS from fifty families were included. The causative genes were RP1L1 in forty-seven patients from thirty families (30/50, 60.0%), CRX in two patients from one family (1/50, 2.0%), GUCY2D in two patients from two families (2/50, 4.0%), and no genes were identified in twenty-one patients from seventeen families (17/50, 34.0%). Different severities were observed in terms of disease onset and the prognosis of visual acuity reduction. This multicentre large cohort study furthers our understanding of the phenotypic and genotypic spectra of patients with macular dystrophy and normal fundus. Evidently, OMDS encompasses multiple Mendelian retinal disorders, each representing unique pathologies that dictate their respective severity and prognostic patterns. [ABSTRACT FROM AUTHOR]

• Focal photoreceptor defects are alterations in foveal architecture due to loss or rarefaction of outer retinal layers (usually external limiting membrane, ellipsoid or interdigitation zone). • Etiologies include vitreomacular interface disorders, photic retinopathy, retinal dystrophies, drug toxicity, blunt trauma and acute retinal pigment epitheliopathy. • Optical coherence tomography imaging provides in-depth analysis of foveal photoreceptor defects, helpful in prognostication and understanding the course of this condition. Fovea centralis, located at the center of the macula, is packed with cone photoreceptors and is responsible for central visual acuity. Isolated foveal photoreceptor disruption may occur in a variety of hereditary, degenerative, traumatic, and toxic chorioretinal diseases. These have been known previously by multiple synonyms including macular microhole, foveal spot, and outer foveal microdefects. A common clinical feature underlying these conditions is the presence of apparently normal fovea or subtle hypopigmented lesion at the foveal or juxtafoveal area. A detailed history along with high-resolution optical coherence tomography is often helpful to derive a conclusive diagnosis in majority of these cases. Focal photoreceptor disruption usually involves loss or rarefaction of ellipsoid/interdigitation zone, either in isolation or associated with external limiting membrane or retinal pigment epithelium disruption in the fovea. Vitreomacular interface (VMI) disorders including vitreomacular traction, posterior vitreous detachment, epiretinal membrane, and impending macular hole possibly remain the most common cause. Retinal dystrophies such as cone dystrophy, occult macular dystrophy, and achromatopsia may present with diminution of vision and normal appearing fundus in a younger age group. Other causes include photic retinopathy (e.g., from a history of sun gazing or laser pointer exposure), blunt trauma, drug exposure (e.g., poppers maculopathy or tamoxifen retinopathy), and acute retinal pigment epitheliopathy (ARPE). Visual prognosis depends on the underlying etiology with complete recovery common in the subset of patients with VMI, and ARPE, whereas persistent outer retinal defects are the rule in other conditions. We discuss the differential diagnoses that lead to isolated foveal photoreceptor defects. Identifying and understanding the underlying disease processes that cause foveal photoreceptor disruption may help predict visual prognosis. [ABSTRACT FROM AUTHOR]

Macular dystrophies are a heterogeneous group of genetic disorders that often severely threatens the bilateral central vision of the affected patient. While advances in molecular genetics have been instrumental in the understanding and diagnosis of these disorders, there remains significant phenotypical variation among patients within any particular subset of macular dystrophies. Electrophysiological testing remains a vital tool not only to characterize vision loss for differential diagnosis but also to understand the pathophysiology of these disorders and to monitor the treatment effect, potentially leading to therapeutic advances. This review summarizes the application of electrophysiological testing in macular dystrophies, including Stargardt disease, bestrophinopathies, X-linked retinoschisis, Sorsby fundus dystrophy, Doyne honeycomb retina dystrophy, autosomal dominant drusen, occult macular dystrophy, North Carolina macular dystrophy, pattern dystrophy, and central areolar choroidal dystrophy. [ABSTRACT FROM AUTHOR]

Occult Macular Dystrophy (OMD), a rare autosomal dominant disorder caused by mutations in the retinitis pigmentosa 1-like protein 1 gene (RP1L1), is characterized by loss of central visual acuity in the absence of fundoscopic abnormalities. In patients suspected of having OMD based on unexplained central vision loss and/or photophobia, changes may be detected with spectral-domain optical coherence tomography. Subsequently, the diagnosis can be confirmed with genetic analysis. We report a case of an 18-year-old White male whose suspected diagnosis of OMD was confirmed by molecular testing. We conducted an extensive review of the literature of previously reported patients with OMD to date. A PubMed search of "RP1L1 and Occult Macular Dystrophy" revealed 34 papers. There were 225 individuals with genetically confirmed, symptomatic OMD; an additional 15 had a confirmed mutation but were asymptomatic and discovered incidentally. Our patient presented with a 10-year history of unexplained loss of central visual acuity and photophobia. Genetic analysis confirmed the presence of a p.R45W substitution on the RP1L1 gene, the most common pathologic mutation in OMD. Due to the lack of appreciable fundoscopic changes, correct identification of the disease can be difficult. Incomplete penetrance has been associated with the condition, and the age of onset is highly variable. Much of the research discussing OMD has come from Eastern Asia, but whether this is due to a heightened awareness and screening protocols, or increased incidence is unclear. Additional research and increased awareness globally will help with more timely and accurate diagnoses. [ABSTRACT FROM AUTHOR]

To report the ophthalmological findings of a new phenotypical variant of RP1L1 maculopathy in an Indian patient with a homozygous variant in the RP1L1 gene A 39-year-old male presented with complaints of disturbance in the central field of vision in both eyes (BE) for a duration of 6 months. He underwent ophthalmic examinations and diagnostic imaging. A complete retinal degeneration panel consisting of 228 genes was evaluated for pathologic variations using next-generation sequencing (NGS), which showed a variant in the RP1L1 gene. On fundus examination, he was found to have ill-defined foveal mottling in BE. Spectral domain optical coherence tomography (SD-OCT) showed sub-foveal hyper-reflective deposits and outer retinal layer disruption. A provisional diagnosis of the atypical variant of adult-onset foveomacular vitelliform dystrophy (AOFVD) was made on the basis of clinical, OCT, Fundus autofluorescence (FAF) and electrophysiological features. Genetic assessment of the proband revealed the presence of a homozygous base pair deletion in exon 4 of RP1L1 gene (chr8:g.10468194_10468195del), which results in frameshift and premature truncation of the protein 24 amino acids downstream to codon 1138 (p.Lys1138SerfsTer24). This variant was confirmed in the proband's parents by Sanger sequencing. The diagnosis was revised to RP1L1 maculopathy, as the RP1L1 gene variant is most commonly associated with this entity. This report presents the multimodal imaging of a previously unreported phenotype of RP1L1 maculopathy associated with a genetic variant of RP1L1 gene, thereby expanding the spectrum associated with RP1L1 maculopathy. [ABSTRACT FROM AUTHOR]

Purpose: Occult Macular Dystrophy (OMD) is an autosomal dominant inherited retinal dystrophy caused by mutations in the retinitis pigmentosa 1-like 1 (RP1L1) gene. The present study describes a novel RP1L1 variant, identified for the first time in two Italian sisters diagnosed with OMD, along with multimodal imaging features, including Optical Coherence Tomography (OCT) Angiography. Methods: We performed multimodal imaging including spectral-domain OCT, blue light autofluorescence (BAF), infrared autofluorescence (IRAF), swept-source OCT Angiography (OCTA), full-field and multifocal electroretinography. Genetic analysis was performed using Next-Generation Sequencing. Pathogenic potential of nonsynonymous novel variants was scored with two in silico algorithms. Results: Proband 1 (P1) and proband 2 (P2) were two Italian sisters of 61 and 56 years old. Both reported a history of progressive visual loss without fundoscopic alterations. P1 reported a 4-year history of rapid visual function worsening, and her best-corrected visual acuity (BCVA) was counting fingers in both eyes. P2 reported a 20-year history of mild but progressive visual acuity loss, and her BCVA was 1/10 and 2/10 respectively in her right and left eye. Structural OCT displayed disorganization of outer retinal bands at the macula and foveal cavitation; loss of foveal photoreceptors was remarkably evident on en-face OCT slabs. OCTA quantitative analysis found that vessel density was reduced both at SCP and DCP while choriocapillaris blood flow was relatively spared. Genetic analysis found the same rare dominant c.2873G > C, p.Arg958Pro variant in the RP1L1 gene. The substitution was regarded as moderately radical according to Grantham score while PolyPhen2 classified the amino acidic substitution as probably damaging. Conclusions and importance: Our study expands the mutational spectrum of RP1L1 gene: the rare c.2873G > C, p.Arg958Pro missense variant may be considered a new pathogenic variant for OMD, the first to be identified exclusively in an Italian family. Moreover, our quantitative OCTA data suggest that OMD is characterized by a rarefaction of superficial and deep capillary plexus.

Purpose: To analyze the microstructures of the photoreceptor layer in detail in eyes with occult macular dystrophy (OMD, Miyake's disease) by ultrahigh-resolution spectral-domain optical coherence tomography (UHR-SD-OCT). Observations: Twenty-eight normal subjects and 5 patients with OMD of different severities were studied. Cross-sectional images through the fovea were recorded with a UHR-SD-OCT system with a depth resolution of

Purpose: We report a first case of bilateral occult macular dystrophy (OMD) with a c.133C>T (p.Arg45Trp) pathogenic variant in the retinitis pigmentosa 1-like 1 (RP1L1) gene in a patient of Caucasian Swiss decent. Observations: A 34-year-old man presented with decreased visual acuity known since childhood. Fundus examination of both eyes revealed no pathology other than mildly increased granularity of the foveal retinal pigment epithelium. The full-field electroretinogram (ffERG) presented with normal findings while the multifocal electroretinogram (mfERG) showed severely reduced amplitudes of the foveal response. Optical coherence tomography (OCT) showed foveal outer retinal atrophy. Fundus autofluorescence (FAF) imaging demonstrated near-normal findings with minimal mottling at the posterior pole. The genetic analysis revealed a heterozygous pathogenic variant (c.133C>T, p.Arg45Trp) in the RP1L1 gene. Conclusion and importance: Our present case suggests that OMD shows a wide range of clinical presentations with a variety of ophthalmological findings, age of disease onset, visual acuity, and genetic diversity.

Background Occult macular dystrophy (OMD) is a rare hereditary macular dystrophy characterized by severe bilateral progressive loss of central vision with normal fundus appearance and normal fundus fluorescein angiography. Aim The aim of this study was to assess the correlation between multifocal electroretinogram (mf-ERG) parameters and best-corrected visual acuity (BCVA) in patients with OMD. Patients and methods In all, 20 eyes of 10 patients with OMD and 20 eyes of 10 age-matched and sex-matched normal individuals were included in this study. Full ophthalmic examination, fundus fluorescein angiography, optical coherence tomography, full-field ERG and mf-ERG were performed for all participants. The average amplitude density of P1 wave, amplitude, and implicit time of P1 and N1 waves were recorded in the five concentric hexagonal rings. Correlation between these mf-ERG parameters and BCVA (LogMAR) was analyzed. Results There were no statistically significant differences in age, sex, and refraction between the studied groups (P=0.54, 1.0, and 0.82, respectively). Mf-ERG parameters in OMD patients showed significant central depression with less affection of peripheral rings. The average amplitude density of P1 wave and the amplitude of P1 and N1 waves were significantly reduced in the central rings (rings 1, 2, and 3), with less impairment in paracentral areas (rings 4 and 5). The implicit time of P1 and N1 waves were significantly delayed across the central rings in OMD patients. The BCVA (LogMAR) was significantly negatively correlated with the amplitude of P1 and N1 waves (P≤0.001). The BCVA (LogMAR) was significantly positively correlated with the implicit time of P1 and N1 waves (P≤0.001). Multiple regression analysis demonstrated that the amplitude and latency of P1 and N1 waves in the central rings (1 and 2) were the most important determinants for BCVA. Conclusion Mf-ERG has a key role in the detection of OMD and can be considered as a valuable objective test for the detection of central/macular dysfunction. The amplitude and latency of P1 and N1 waves in rings 1 and 2 may be used as biomarkers for the prediction of visual prognosis in these patients.

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The responsible genetic variants for occult macular dystrophy (OMD) were found at the predicted intrinsically disordered region (IDR) of the RP1L1 gene. We examined the phenotypes and genotypes of family members from OMD. In addition, the genetic characteristics of the RP1L1 gene in OMD were investigated. Whole-exome sequencing was applied on two affected family members, and Sanger sequencing was performed on three members. The structural property of RP1L1 and pathogenic variants was analyzed using predictor of natural disordered regions (PONDR). Two affected members showed moderate visual impairment and relative central scotoma. The spectral domain optical coherence tomography (SD-OCT) images showed an absence of the interdigitation zone (IZ) and ellipsoid zone (EZ) in one case, and an obscure EZ line in the other case. A RP1L1 variant (c.3593 C > T, p.Ser1198Phe) was identified in two affected members but not in the unaffected member. The PONDR analysis showed that the region from p.1189 to p.1248 could be predicted to be an IDR in the RP1L1 molecule. And the p. Ser1198Phe variant showed significant reduction of PONDR score. Although, the major pathogenic variant of OMD is p.Arg45Trp, multiple reports indicate that the region between p.1194 and p.1201 is another hot spot of OMD. The PONDR analysis predicted that the RP1L1 molecule is one of the intrinsically disordered proteins. It is speculated that the region around p.1200 is essential for the normal function of the RP1L1 molecule, and the missense variants of that area cause the development of OMD. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa 1–like 1 (RP1L1) is a component of the photoreceptor cilium. Pathogenic variants in RP1L1 lead to photoreceptor disease, suggesting an important role for RP1L1 in photoreceptor biology, though its exact function is unknown. To date, RP1L1 variants have been associated with occult macular dystrophy (a cone degeneration) and retinitis pigmentosa (a rod disease). Here, we summarize reported RP1L1 -associated photoreceptor conditions and disease-causing RP1L1 variants. We also discuss novel associations between RP1L1 and additional photoreceptor conditions—besides occult macular dystrophy and retinitis pigmentosa—and fit RP1L1 into the broader scope of photoreceptor disease. RP1L1 appears to have a complex relationship with other photoreceptor proteins and may modify disease phenotype. Ultimately, further exploration of the relationship between RP1L1 , other cilium components, and their impact on photoreceptor health is needed. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia Type 7 (SCA7) is an autosomal dominant, progressive neurodegenerative disorder, primarily characterized by cerebellar ataxia. The disease is caused by the expansion of a CAG trinucleotide repeat within the ataxin-7 gene when its CAG repeat sequences are extended beyond 38. The degree of retinopathy can vary from pigment change in the fovea to foveal atrophy and is correlated with the number of CAG repeats. The present study describes a case of SCA7 with a retinal presentation similar to occult macular dystrophy (OMD) which is an inherited macular dystrophy characterized by presenting with a normal fundus and fluorescein angiography but with progressive central visual loss. Materials and Methods: Report of a case. Results: In this case, no specific abnormality was found on fundus examination, fluorescein angiography, full-field electroretinography and infrared autofluorescence. Spectral-domain optical coherence tomography showed foveal thinning, focal disruption of the ellipsoid zone, and central loss of the outer segment–retinal pigment epithelium interdigitation zone that were well matched with the multifocal electroretinography finding. Thirty-nine CAG repeats in ataxin-7 gene were identified through genetic testing. Conclusions: SCA7 can present with a very mild form of retinal degeneration similar to the classic phenotype of RP1L1-negative OMD in case of the lower number of CAG repeats. [ABSTRACT FROM AUTHOR]

Purpose: To investigate appropriate diagnostic testing for occult macular dystrophy (OMD) in a patient with unexplained progressive visual loss. Methods: Observational case report. Results: Occult macular dystrophy is an uncommon autosomal dominant macular disease, but sporadic occurrences have been noted. We report a patient with progressive visual decline, but with normal findings in fundus photography, visual field, fluorescein angiography, and full-field standard electroretinography. Direct sequencing of the RP1L1 gene showed a c. 133C.T mutation, which confirmed the diagnosis of OMD genetically. The only two ocular examinations that can show abnormal findings in such cases are spectral domain optical coherence tomography and multifocal electroretinography. Therefore, spectral domain optical coherence tomography and multifocal electroretinography are very important in making a diagnosis of OMD before applying expansive techniques such as brain computed tomography or magnetic resonance imaging. Conclusion: Spectral domain optical coherence tomography and multifocal electroretinography can serve as diagnostic testings for patients with OMD. [ABSTRACT FROM AUTHOR]

Occult macular dystrophy is an inherited macular dystrophy characterized by a progressive decline of bilateral visual acuity with normal fundus appearance, fluorescein angiogram and full-field electroretinogram. This case report presents a 20-year-old female patient with bilateral progressive decline of visual acuity for six years. Her visual acuity was 3-4/10 in both eyes. Anterior segment and fundus examination, fluorescein angiogram and full-field electroretinogram were normal. She could read all Ishihara pseudoisochromatic plates. Fundus autofluorescence imaging was normal. There was a mild central hyporeflectance on fundus infrared reflectance imaging in both eyes. Reduced foveal thickness and alterations of the photoreceptor inner and outer segment junction were observed by optical coherence tomography in both eyes. Central scotoma was also found by microperimetry and reduced central response was revealed by multifocal electroretinogram in both eyes. These findings are consistent with the clinical characteristics of occult macular dystrophy

Photoreceptor disease results in irreparable vision loss and blindness, which has a dramatic impact on quality of life. Pathogenic mutations in RP1L1 lead to photoreceptor degenerations such as occult macular dystrophy and retinitis pigmentosa. RP1L1 is a component of the photoreceptor axoneme, the backbone structure of the photoreceptor’s light-sensing outer segment. We generated an rp1l1 zebrafish mutant using CRISPR/Cas9 genome editing. Mutant animals had progressive photoreceptor functional defects as determined by electrophysiological assessment. Optical coherence tomography showed gaps in the photoreceptor layer, disrupted photoreceptor mosaics, and thinner retinas. Mutant retinas had disorganized photoreceptor outer segments and lipid-rich subretinal drusenoid deposits between the photoreceptors and retinal pigment epithelium. Our mutant is a novel model of RP1L1-associated photoreceptor disease and the first zebrafish model of photoreceptor degeneration with reported subretinal drusenoid deposits, a feature of age-related macular degeneration.

Two siblings aged 9 and 15 years with unexplained visual loss had normal pupillary reactions, unremarkable anterior and posterior segment, normal fluorescein angiography, visual evoked potential, and flash electroretinogram (ERG). Spectral domain optical coherence tomography (OCT) showed loss of normal inner segment-outer segment (IS-OS) junction line bump at fovea in one and absent IS-OS junction line at fovea in the other. Characteristic hypovoltaged responses from central macula in multifocal ERG (mfERG) confirmed the diagnosis of occult macular dystrophy (OMD) in both siblings. Marked difference in OCT findings despite same visual acuity indicate that structural changes in OCT might not always correlate with the extent of functional loss. Obvious mfERG changes and very subtle OCT defect in the younger one suggests that functional changes probably appear much earlier than the structural changes. OMD is often underdiagnosed because of lack of high index of suspicion and detailed work up. The patients presented here represent first OMD report from India, one of them being the second youngest reported so far (medline search).

Purpose: To show early, rapid and accurate molecular diagnosis of occult macular dystrophy (OMD) in a four-generation Chinese family with inherited macular dystrophy.Methods: In the current study, we comprehensively screened 130 genes involved in common inherited non-syndromic eye diseases with next-generation sequencing-based target capture sequencing of the proband of a four-generation Chinese family that has suffered from maculopathy without a definitive diagnosis for over 10 years. Variants were filtered and analyzed to identify possible disease-causing variants before validation by Sanger sequencing.Results: Two heterozygous mutations—RP1L1 c.133 C > T (p.Arg45Trp), which is a hot spot for OMD, and ABCA4 c.6119 G > A (p.Arg2040Gln), which was identified in Stargardt’s disease were found in three patients, but neither of the mutations was found in the unaffected individuals in the same family, who are phenotypically normal or in the normal control volunteers.Conclusion: These results cannot only confirm the diagnosis of OMD in the proband, but also provide presymptomatic diagnosis of the proband’s children before the onset of visual acuity impairment and guidance regarding the prognosis and management of these patients. Heterozygous mutations of RP1L1 c.133 C > T (p.Arg45Trp) and ABCA4 c.6119 G > A (p.Arg2040Gln) are likely responsible for OMD. Our results further extend our current understanding of the genetic basis of OMD, and emphasize the importance of molecular diagnosis and genetic counseling for OMD.

Occult macular dystrophy is an inherited macular dystrophy characterized by a progressive decline of bilateral visual acuity with normal fundus appearance, fluorescein angiogram and full-field electroretinogram. This case report presents a 20-year-old female patient with bilateral progressive decline of visual acuity for six years. Her visual acuity was 3-4/10 in both eyes. Anterior segment and fundus examination, fluorescein angiogram and full-field electroretinogram were normal. She could read all Ishihara pseudoisochromatic plates. Fundus autofluorescence imaging was normal. There was a mild central hyporeflectance on fundus infrared reflectance imaging in both eyes. Reduced foveal thickness and alterations of the photoreceptor inner and outer segment junction were observed by optical coherence tomography in both eyes. Central scotoma was also found by microperimetry and reduced central response was revealed by multifocal electroretinogram in both eyes. These findings are consistent with the clinical characteristics of occult macular dystrophy. [ABSTRACT FROM AUTHOR]

Two siblings aged 9 and 15 years with unexplained visual loss had normal pupillary reactions, unremarkable anterior and posterior segment, normal fluorescein angiography, visual evoked potential, and flash electroretinogram (ERG). Spectral domain optical coherence tomography (OCT) showed loss of normal inner segment-outer segment (IS-OS) junction line bump at fovea in one and absent IS-OS junction line at fovea in the other. Characteristic hypovoltaged responses from central macula in multifocal ERG (mfERG) confirmed the diagnosis of occult macular dystrophy (OMD) in both siblings. Marked difference in OCT findings despite same visual acuity indicate that structural changes in OCT might not always correlate with the extent of functional loss. Obvious mfERG changes and very subtle OCT defect in the younger one suggests that functional changes probably appear much earlier than the structural changes. OMD is often underdiagnosed because of lack of high index of suspicion and detailed work up. The patients presented here represent first OMD report from India, one of them being the second youngest reported so far (medline search). [ABSTRACT FROM AUTHOR]

Occult macular dystrophy (OMD) was first reported in 1989 as a hereditary macular disease without visible fundus abnormalities. Patients with OMD are characterized by a progressive decrease of visual acuity but have normal fundus and fluorescein angiograms with both the rod and cone components of the full-field electroretinograms (ERGs) essentially normal. However, the focal macular ERGs and multifocal ERGs are severely attenuated. These findings indicate that the retinal dysfunction is confined to the macula. Optical coherence tomography (OCT) has shown structural changes in the outer nuclear and/or photoreceptor layers. Genetic analyses of OMD pedigrees have identified dominant mutations in the RP1L1 gene. However, the same mutations were not detected in sporadic cases, suggesting that several independent mutations can lead to the OMD phenotype. The purpose of this paper is to review the history of OMD, the visual functions determined psychophysically, ERG findings, OCT characteristics and genetic findings in patients with OMD. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate if high resolution adaptive optics confocal scanning laser ophthalmoscopy (AO-SLO) can be used as an adjunct complementary diagnostic tool to spectral domain optical coherent tomography (SD-OCT) in characterizing three macular diseases: rod-cone dystrophy, acute retinal pigment epitheliitis (Krill’s disease), and occult macular dystrophy. Methods: As part of a complete clinical examination, each patient was subjected to color fundus pictures, multimodal imaging scans with Heidelberg SpectralisTM and high resolution retinal images with a custom built adaptive optics scanning laser ophthalmolscope (AO-SLO). The registered AO-SLO images were averaged to improve the signal to noise ratio and used to generate larger photoreceptor mosaics. Results: AO-SLO mosaics for all three conditions showed distinct, characteristic disruptions of the photoreceptors in areas that corresponded to the abnormalities observed on fundus photography and SD-OCT scans. Conclusions: AO-SLO defined fine structural changes associated with retinal pathology at the photoreceptor level that could not be achieved using standard diagnostic methods. A combination of adaptive optics scanning laser ophthalmoscopy (AO-SLO) and SD-OCT provided views of the retina with enhanced lateral and axial resolution. High-resolution, ultra-structural details of the retina may provide additional insights into the disease etiology, progression and management of patients with vision threatening macular diseases.

Purpose: The purpose of this study was to present an atypical case of occult macular dystrophy (OMD) with bilateral chronic subfoveal serous retinal detachment (SRD). Methods: A 53-year-old man was ophthalmologically evaluated because of decreased visual acuity in both eyes. Genomic DNA was extracted from venous blood samples. Mutational analysis of the retinitis pigmentosa 1- like 1 ( RP1L1) gene was performed by Sanger sequencing. Results: Best-corrected visual acuity (BCVA) was 0.1 logMAR in both eyes until the age of 53, after which it gradually declined. Full-field electroretinography (ERG) was unremarkable, while multifocal ERG revealed a reduced central response in both eyes. Optical coherence tomography showed subfoveal SRD in both eyes, and fundus fluorescein angiography yielded unremarkable results. His brother and cousin had similar subjective symptoms. At age 58, his logMAR BCVA was 0.532 (OD) and 0.347 (OS). He was given 23 administrations of intravitreal bevacizumab (IVB; 1.25 mg) in both eyes alternately over a 2-year period and also underwent reduced-fluence photodynamic therapy in both eyes. Two years after the first administration of IVB, a reduction in SRD was obtained, and IVB was therefore discontinued. Three years after the first administration, logMAR BCVA was 0.155 (OD) and 0.523 (OS). Mutational analysis revealed a novel heterozygous missense mutation (p.S1199P). Conclusions: We describe in detail a case of bilateral chronic subfoveal SRD in an atypical OMD patient carrying a novel heterozygous RP1L1 mutation (p.S1199P). Our results further extend the phenotypic spectrum of RP1L1-associated OMD. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of pseudo-unilateral occult macular dystrophy (OMD) with an Arg45Trp mutation in the RP1L1 gene and had unilateral functional changes for about 9 years. Case report: A 64-year-old woman with a decimal visual acuity of 1.0 in both eyes complained about difficulties with visual tasks because of presbyopia. At the age of 65 years, her visual acuity in the left eye decreased to 0.2, while that in the right eye was 0.7. The fundus of both eyes was normal except for drusen. After 10 years and at the age of 75 years, her visual acuity in the right eye decreased to 0.3. Focal macular electroretinograms (ERGs) at this time were severely attenuated in both eyes, while the full-field ERGs were within normal limits. Ophthalmoscopy showed that the fundus of both eyes was still normal. Genetic analysis revealed a heterozygous mutation, Arg45Trp, in the RP1L1 gene. Conclusions: These findings indicate that the phenotype in some cases of OMD with an Arg45Trp mutation in the RP1L1 gene can be unilateral for a considerable period. [ABSTRACT FROM AUTHOR]

Background: We report our findings in two siblings with late-onset cone-rod dystrophy (CRD) with no visible macular degeneration. Cases and methods: Case 1 was an 82-year-old man who first noticed a decrease in vision and color blindness in his early seventies. His mother and younger sister also had visual disturbances. His decimal visual acuity was 0.3 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed normal fundi, and fluorescein angiography was also normal in both eyes. The photopic single flash and flicker eletroretinograms (ERGs) were severely attenuated and the scotopic ERGs were slightly reduced in both eyes. Case 2 was the 80-year-old younger sister of Case 1. She first noticed a decline in vision and photophobia in both eyes in her early seventies. Her decimal visual acuity was 0.4 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed mottling of the retinal pigment epithelium in the midperiphery with no visible macular degeneration. The photopic single flash and flicker ERGs were severely attenuated, and the scotopic ERGs were slightly reduced in both eyes. Conclusion: These siblings are the oldest reported cases of CRD with no visible macular degeneration. Thus, CRD should be considered in patients with reduced visual acuity, color blindness, and photophobia even if they are older than 70 years. [ABSTRACT FROM AUTHOR]

Purpose: To investigate changes in cone photoreceptors with adaptive optics (AO) fundus imaging and spectral domain optical coherence tomography (SD-OCT) in a case of occult macular dystrophy (OMD). Patient and methods: Both eyes of a 42-year-old woman diagnosed with OMD were examined. We used an AO fundus camera to obtain images of cone photoreceptors in the macula of the OMD subject and five healthy control subjects. Correlations between the AO images and the SD-OCT images were examined. Cone photoreceptors in eight areas in the macula of OMD and healthy control subjects were analyzed and compared. Results: SD-OCT showed a loss of the cone outer-segment tips line outside of the fovea in both eyes of the subject with OMD. The left eye with decreased visual acuity showed a discontinuous photoreceptor inner-segment and outer-segment line and cone outer-segment tips line at the fovea in SD-OCT and loss of cone mosaics as a dark spot in the AO image. In panoramic AO images and cone-density maps, less cone density was observed in a ring-like region outside the fovea than in the peripheral retina. In most of the areas examined, the cone densities were lower in the OMD eyes than in the healthy control eyes. Conclusions: Cone densities in the macula of the OMD patient were greatly decreased. AO images were found to be useful to evaluate morphologic changes in cone photoreceptors in patients with OMD. [ABSTRACT FROM AUTHOR]

ABSTRACT In one consanguineous family with retinitis pigmentosa ( RP), a condition characterized by progressive visual loss due to retinal degeneration, homozygosity mapping, and candidate gene sequencing suggested a novel locus. Exome sequencing identified a homozygous frameshifting mutation, c.601del G, p. Lys203 Argfs*28, in RP1L1 encoding RP 1-like1, a photoreceptor-specific protein. A screen of a further 285 unrelated individuals with autosomal recessive RP identified an additional proband, homozygous for a missense variant, c.1637 G> C, p. Ser546 Thr, in RP1L1. A distinct retinal disorder, occult macular dystrophy ( OCMD) solely affects the central retinal cone photoreceptors and has previously been reported to be associated with variants in the same gene. The association between mutations in RP1L1 and the disorder OCMD was explored by screening a cohort of 28 unrelated individuals with the condition; 10 were found to harbor rare (minor allele frequency ≤0.5% in the 1,000 genomes dataset) heterozygous RP1 L1 missense variants. Analysis of family members revealed many unaffected relatives harboring the same variant. Linkage analysis excluded the possibility of a recessive mode of inheritance, and sequencing of RP1, a photoreceptor protein that interacts with RP1 L1, excluded a digenic mechanism involving this gene. These findings imply an important and diverse role for RP1 L1 in human retinal physiology and disease. [ABSTRACT FROM AUTHOR]

Purpose: To describe findings of spectral domain optical coherence tomography (SD-OCT) in the diagnosis of occult macular dystrophy (OMD). Materials and Methods: Five visually disturbed patients who had shown normal findings in full field electroretinogram (ERG), fundus photography and fluorescein angiography but abnormal findings in multifocal ERG had undergone SD-OCT. The morphologic changes in retina and macular thickness were detected and imaged by SD-OCT. We analysed the results of SD-OCT including macular thickness, inner segment and outer segment (IS /OS) boundary and external limiting membrane (ELM). Results: Mean age was 41.6 (22-63) in three male and two female patients in this study. Mean central foveal thickness was 142.9 (76-161) lm. All patients had shown decreased bowing of IS /OS boundary, and five of nine eyes were noted with disrupted IS /OS boundary of the photoreceptors according to SDOCT. The interruption of external limiting membrane was noted in three of nine eyes. Conclusions: Spectral domain optical coherence tomography findings are useful in diagnosing OMD. Morphologic changes of the retina including deformity of the OS/ IS boundary of the photoreceptors, disruption of the ELM and decreased foveal thickness may be important characteristics to consider when determining the pathophysiology and diagnosing criteria of OMD. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of occult macular dystrophy associated with mutations in the RP1L1 and KCNV2 genes. Methods: Case report. Multimodal retinal imaging and the results of genetic testing are described. Results: A 27-year-old Chinese man presented with complaints of decreased central vision and normal retinal examination. Color fundus photography and fundus autofluorescence were unremarkable. Spectral-domain optical coherence tomography did reveal central ellipsoid loss in each eye. Genetic testing confirmed mutations in the RP1L1 and KCNV2 genes. Conclusion: The presence of central ellipsoid loss with spectral-domain optical coherence tomography should be evaluated for genetic disorders such as RP1L1 and KCNV2 mutations. [ABSTRACT FROM AUTHOR]

Photoreceptor disease results in irreparable vision loss and blindness, which has a dramatic impact on quality of life. Pathogenic mutations in RP1L1 lead to photoreceptor degenerations such as occult macular dystrophy and retinitis pigmentosa. RP1L1 is a component of the photoreceptor axoneme, the backbone structure of the photoreceptor's light-sensing outer segment. We generated an rp1l1 zebrafish mutant using CRISPR/Cas9 genome editing. Mutant animals had progressive photoreceptor functional defects as determined by electrophysiological assessment. Optical coherence tomography showed gaps in the photoreceptor layer, disrupted photoreceptor mosaics, and thinner retinas. Mutant retinas had disorganized photoreceptor outer segments and lipid-rich subretinal drusenoid deposits between the photoreceptors and retinal pigment epithelium. Our mutant is a novel model of RP1L1-associated photoreceptor disease and the first zebrafish model of photoreceptor degeneration with reported subretinal drusenoid deposits, a feature of age-related macular degeneration. [ABSTRACT FROM AUTHOR]