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Albert O. Edwards - One of the best experts on this subject based on the ideXlab platform.
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Snowflake Vitreoretinal Degeneration (SVD) mutation R162W provides new insights into Kir7.1 ion channel structure and function.
PloS one, 2013Co-Authors: Bikash R. Pattnaik, Albert O. Edwards, Anil K. Sharma, Sara Tokarz, Matti P. Asuma, Tyler Schroeder, Julie C. Mitchell, De-ann M. PillersAbstract:Snowflake Vitreoretinal Degeneration (SVD) is associated with the R162W mutation of the Kir7.1 inwardly-rectifying potassium channel. Kir7.1 is found at the apical membrane of Retinal Pigment Epithelial (RPE) cells, adjacent to the photoreceptor neurons. The SVD phenotype ranges from RPE Degeneration to an abnormal b-wave to a liquid vitreous. We sought to determine how this mutation alters the structure and function of the human Kir7.1 channel. In this study, we expressed a Kir7.1 construct with the R162W mutation in CHO cells to evaluate function of the ion channel. Compared to the wild-type protein, the mutant protein exhibited a non-functional Kir channel that resulted in depolarization of the resting membrane potential. Upon co-expression with wild-type Kir7.1, R162W mutant showed a reduction of IKir7.1 and positive shift in ‘0’ current potential. Homology modeling based on the structure of a bacterial Kir channel protein suggested that the effect of R162W mutation is a result of loss of hydrogen bonding by the regulatory lipid binding domain of the cytoplasmic structure.
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Mutations in KCNJ13 Cause Autosomal-Dominant Snowflake Vitreoretinal Degeneration
American journal of human genetics, 2008Co-Authors: J. Fielding Hejtmancik, Xiaodong Jiao, Yuri V. Sergeev, Xiaoyan Ding, Anil K. Sharma, Chi-chao Chan, Igor Medina, Albert O. EdwardsAbstract:Snowflake Vitreoretinal Degeneration (SVD, MIM 193230) is a developmental and progressive hereditary eye disorder that affects multiple tissues within the eye. Diagnostic features of SVD include fibrillar Degeneration of the vitreous humor, early-onset cataract, minute crystalline deposits in the neurosensory retina, and retinal detachment. A genome-wide scan previously localized the genetic locus for SVD to a 20 Mb region flanked by D2S2158 and D2S2202. This region contains 59 genes, of which 20 were sequenced, disclosing a heterozygous mutation (484C > T, R162W) in KCNJ13, member 13 of subfamily J of the potassium inwardly rectifying channel family in all affected individuals. The mutation in KCNJ13, the gene encoding Kir7.1, was not present in unaffected family members and 210 control individuals. Kir7.1 localized to human retina and retinal pigment epithelium and was especially prevalent in the internal limiting membrane adjacent to the vitreous body. Molecular modeling of this mutation predicted disruption of the structure of the potassium channel in the closed state located immediately adjacent to the cell-membrane inner boundary. Functionally, unlike wild-type Kir7.1 whose overexpression in CHO-K1 cells line produces highly selective potassium current, overexpression of R162W mutant Kir7.1 produces a nonselective cation current that depolarizes transfected cells and increases their fragility. These results indicate that the KCNJ13 R162W mutation can cause SVD and further show that Vitreoretinal Degeneration can arise through mutations in genes whose products are not structural components of the vitreous.
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Genetic Linkage of Snowflake Vitreoretinal Degeneration to Chromosome 2q36
Investigative ophthalmology & visual science, 2004Co-Authors: Xiaodong Jiao, Robert Ritter, J. Fielding Hejtmancik, Albert O. EdwardsAbstract:PURPOSE. To identify the chromosomal location of the gene causing snowflake Vitreoretinal Degeneration (SVD), an autosomal dominant retinal Degeneration characterized by small yellow-white dots in the retina, fibrillar anomaly of the vitreous humor, and retinal detachment. METHODS. Clinical data were collected on 31 family members by history and examination. Thirteen family members underwent prospective examination. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two‐point and multipoint linkage analysis was performed (FASTLINK version of the MLINK program and the VITESSE algorithm, both available at http://linkage. rockefeller.edu/soft/list.html). Direct DNA sequencing of amplified genomic DNA and mRNA was performed for candidate gene analysis. RESULTS. The SVD locus was linked to markers in a region of chromosome 2q36 defined by D2S2158 and D2S2202, based on meiotic breakpoint mapping of affected individuals. A maximum two-point lod score of 5.5 was obtained with marker D2S172 at 0 within this region. Direct DNA sequencing of all 52 exons of the COL4A3 gene revealed no potentially pathogenic coding sequence variation or evidence for deletion. CONCLUSIONS. The genetic locus for SVD lies i na9M bregion flanked by D2S2158 and D2S2202. Localization of SVD to a genomic region distinct from both Wagner disease and the Stickler syndromes indicates that SVD is a distinct genetic entity. The absence of coding sequence variation in the only collagen gene within the disease-region, suggests a novel pathogenesis for Vitreoretinal Degeneration. Snowflake Vitreoretinal Degeneration should be considered in the differential diagnosis of families with fibrillar anomaly of the vitreous. (Invest Ophthalmol Vis Sci. 2004;45:4498‐4503) DOI:
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Snowflake Vitreoretinal Degeneration: follow-up of the original family
Ophthalmology, 2003Co-Authors: Mike M Lee, Robert Ritter, Tatsuo Hirose, Albert O. EdwardsAbstract:Abstract Purpose The ocular findings, systemic features, and genetic loci distinguishing known genetic causes of Vitreoretinal Degenerations were studied in the original Snowflake family. Design Prospective, comparative study and molecular genetic investigation. Participants Members of the original snowflake Vitreoretinal Degeneration family. Methods Clinical data were collected on 26 family members by history and examination. Thirteen of the 26 total family members underwent prospective examination. Linkage to known Vitreoretinal Degeneration loci ( COL2A1 , COL11A1 , and the Wagner disease locus) was evaluated with short tandem repeat markers. Main outcome measures Ocular and systemic features of known Vitreoretinal Degenerations. Results Six of the 13 prospectively examined subjects had snowflake Vitreoretinal Degeneration. Corneal guttae (4/5; 80%), early onset cataract (5/6; 83%), fibrillar vitreous Degeneration (6/6; 100%), and peripheral retinal abnormalities (5/6; 83%), including minute crystallinelike deposits called snowflakes (4/6; 67%), were common. Retinal detachment was seen in 1 of 6 of these prospectively examined subjects (17%). A total of 14 affected subjects were identified within the family, and in 3 (21%), retinal detachment developed. Orofacial features, early-onset hearing loss, and arthritis typical of Stickler syndrome were absent. Linkage to known Vitreoretinal Degeneration loci was excluded. Conclusions The absence of vitreous gel in the retrolental space and presence of fibrillar vitreous Degeneration were consistent with the vitreous structure reported for collagen 11A1 ( COL11A1 ) but not collagen 2A1 ( COL2A1 ) mutations. The absence of systemic features was characteristic of the vitreoretinopathies linked to chromosome 5q13 (Wagner disease and erosive vitreoretinopathy) and mutations in exon 2 of the COL2A1 gene. Snowflakes in the peripheral retina and the absence of nyctalopia, posterior chorioretinal atrophy, and tractional retinal detachment were inconsistent with the chromosome 5q13 vitreoretinopathies. The association of Fuchs' corneal endothelial dystrophy found in this family has not been reported previously in other Vitreoretinal Degenerations. These findings and the exclusion of known genetic loci suggest snowflake is a distinct Vitreoretinal Degeneration.
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Clinical variability of Stickler syndrome: role of exon 2 of the collagen COL2A1 gene.
Survey of ophthalmology, 2003Co-Authors: Larry A Donoso, Tamara R Vrabec, Jerry Rogers, Robert Ritter, Albert O. Edwards, Arcilee Frost, N. Nina Ahmad, David Meyer, Scott ParmaAbstract:Abstract Stickler syndrome (progressive arthro-ophthalmopathy) is a genetically heterogeneous disorder resulting from mutations in at least three collagen genes. The most common disease-causing gene is COL2A1, a 54-exon–containing gene coding for type II collagen. At least 17 different mutations causing Stickler syndrome have been reported in this gene. Phenotypically, it is also a variably expressed disorder in which most patients present with a wide range of eye and extraocular manifestations including auditory, skeletal, and orofacial manifestations. Some patients, however, present without clinically apparent systemic findings. This observation has led to difficulty distinguishing this Stickler phenotype from other hereditary Vitreoretinal Degenerations, such as Wagner syndrome and Snowflake Vitreoretinal Degeneration. In this regard, review of the literature indicates type II collagen exists in two forms resulting from alternative splicing of exon 2 of the COL2A1 gene. One form, designated as type IIB (short form), is preferentially expressed in adult cartilage tissue. The other form, designated as type IIA (long form), is preferentially expressed in the vitreous body of the eye. Because of this selective tissue expression, mutations in exon 2 of the COL2A1 gene have been hypothesized to produce this Stickler syndrome phenotype with minimal or absent extraocular findings. We review the evidence for families with exon 2 mutations of the collagen COL2A1 gene presenting in a distinct manner from families with mutations in the remaining 53 exons, as well as other hereditary Vitreoretinal Degenerations without significant systemic manifestations.
Noriyuki Azuma - One of the best experts on this subject based on the ideXlab platform.
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Analysis of the vitreous membrane in a case of type 1 Stickler syndrome
Graefe's Archive for Clinical and Experimental Ophthalmology, 2009Co-Authors: Tadashi Yokoi, Ryouhei Koide, Kentaro Matsuoka, Atsuko Nakagawa, Noriyuki AzumaAbstract:Background Stickler syndrome causes ocular abnormalities, including retinal detachment and Vitreoretinal Degeneration, and systemic anomalies such as arthritis and deafness. Although retinal detachment is characteristic of this syndrome, the pathogenesis is unknown. Case report A 10-year-old boy reported decreased vision and presented 5 days after visual loss. Results Ophthalmoscopy showed a retinal detachment with a giant tear in the right eye, and a nonpigmented epithelial detachment with pars plicata breaks in the left eye. Bilateral findings included an empty vitreous and a vitreous membrane at the equator. The systemic abnormalities included short stature and joint hypermobility. The diagnosis was type 1 Stickler syndrome, and the eyes were treated surgically. Immunohistochemistry showed that the vitreous membrane resected intraoperatively was comprised primarily of Müller cells. Electron microscopy showed dense collagen fibers around the cells in the membrane that were identical to the vitreous collagen inserted into the basement membrane of the cells, which was similar to the ultrastructure of the vitreous base. Conclusion Müller cells might be primary components of the vitreous membrane in type 1 Stickler syndrome. The Vitreoretinal interface, which resembled the ectopic vitreous base, in the vitreous membrane may be related to the pathogenesis of the retinal detachment.
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Analysis of the vitreous membrane in a case of type 1 Stickler syndrome.
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 2008Co-Authors: Tadashi Yokoi, Ryouhei Koide, Kentaro Matsuoka, Atsuko Nakagawa, Noriyuki AzumaAbstract:Background Stickler syndrome causes ocular abnormalities, including retinal detachment and Vitreoretinal Degeneration, and systemic anomalies such as arthritis and deafness. Although retinal detachment is characteristic of this syndrome, the pathogenesis is unknown.
Vinit B. Mahajan - One of the best experts on this subject based on the ideXlab platform.
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early onset neovascular inflammatory vitreoretinopathy due to a de novo capn5 mutation report of a case
Ocular Immunology and Inflammation, 2019Co-Authors: Ghazala Okeefe, Vinit B. Mahajan, Adam M Hanif, Nieraj JainAbstract:Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a rare autoimmune condition that typically presents as progressive uveitis and Vitreoretinal Degeneration between the second and third decades of life. Though traditionally attributed to inherited mutations of the CAPN5 gene, few reports of de novo variants exist. This report of vision and hearing loss in a 3 year-old girl describes the youngest documented case of ADNIV due to a de novo pathogenic c.865C>T (p.Arg289Trp) CAPN5 variant, illustrating the early stages of this enigmatic disease process.
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vcan canonical splice site mutation is associated with Vitreoretinal Degeneration and disrupts an mmp proteolytic site
Investigative Ophthalmology & Visual Science, 2019Co-Authors: Peter H Tang, Gabriel Velez, Stephen H Tsang, Alexander G Bassuk, Vinit B. MahajanAbstract:Purpose: To gain insight into the pathophysiology of Vitreoretinal Degeneration, the clinical course of three family members with Versican Vitreoretinopathy (VVR) is described, and a canonical splice site mutation in the gene encoding for versican (VCAN) protein was biochemically analyzed. Methods: A retrospective chart review, human eye histopathology, Sanger DNA sequencing, protein structural modeling, and in vitro proteolysis assays were performed. Results: The proband (II:1), mother (I:2), and younger sibling (II:2) suffered retinal Degeneration with foveal sparing and retinal detachments with proliferative vitreoretinopathy, features that were confirmed on histopathologic analysis. All affected members carried a heterozygous adenine to guanine variant (c.4004-2A>G) predicted to result in exon 8 skipping or the deletion of 13 amino acids at the beginning of the GAGβ chain (VCAN p.1335-1347). This deleted region corresponded to a putative MMP cleavage site, validated using fluorescence resonance energy transfer (FRET)-based proteolysis assays. Proteomic network analysis identified 10 interacting partners in the human vitreous and retina linked to retinal detachment and Degeneration. Conclusions: VVR causes significant ocular disease, including retinal detachment and retinal dystrophy. The intronic VCAN mutation removes an MMP cleavage site, which alters versican structure and results in abnormal vitreous modeling. Disruption of a versican protein network may underlie clinicopathologic disease features and point to targeted therapies.
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Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia.
American journal of medical genetics. Part A, 2010Co-Authors: Vinit B. Mahajan, Ann Haskins Olney, Penny Garrett, Ajit Chary, Ecaterina Dragan, Gary Lerner, Jeffrey Murray, Alexander G BassukAbstract:Knobloch syndrome (KNO) is caused by mutations in the collagen XVIII gene (COL18A1) and patients develop encephalocele and Vitreoretinal Degeneration. Here, we report an El Salvadorian family where two sisters showed features of KNO. One of the siblings also developed acute lymphoblastic leukemia. DNA sequencing of COL18A1 revealed a homozygous, 2-bp deletion (c3514-3515delCT) in exon 41, which leads to abnormal collagen XVIII and deficiency of its proteolytic cleavage product endostatin. KNO patients with mutations in COL18A1 may be at risk for endostatin-related conditions including malignancy.
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Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia.
American Journal of Medical Genetics Part A, 2010Co-Authors: Vinit B. Mahajan, Ann Haskins Olney, Penny Garrett, Ajit Chary, Ecaterina Dragan, Gary Lerner, Jeffrey C. Murray, Alexander G BassukAbstract:Knobloch syndrome (KNO) is caused by mutations in the collagen XVIII gene (COL18A1) and patients develop encephalocele and Vitreoretinal Degeneration. Here, we report an El Salvadorian family where two sisters showed features of KNO. One of the siblings also developed acute lymphoblastic leukemia. DNA sequencing of COL18A1 revealed a homozygous, 2-bp deletion (c3514-3515delCT) in exon 41, which leads to abnormal collagen XVIII and deficiency of its proteolytic cleavage product endostatin. KNO patients with mutations in COL18A1 may be at risk for endostatin-related conditions including malignancy. © 2010 Wiley-Liss, Inc.
Robert Ritter - One of the best experts on this subject based on the ideXlab platform.
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Genetic Linkage of Snowflake Vitreoretinal Degeneration to Chromosome 2q36
Investigative ophthalmology & visual science, 2004Co-Authors: Xiaodong Jiao, Robert Ritter, J. Fielding Hejtmancik, Albert O. EdwardsAbstract:PURPOSE. To identify the chromosomal location of the gene causing snowflake Vitreoretinal Degeneration (SVD), an autosomal dominant retinal Degeneration characterized by small yellow-white dots in the retina, fibrillar anomaly of the vitreous humor, and retinal detachment. METHODS. Clinical data were collected on 31 family members by history and examination. Thirteen family members underwent prospective examination. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two‐point and multipoint linkage analysis was performed (FASTLINK version of the MLINK program and the VITESSE algorithm, both available at http://linkage. rockefeller.edu/soft/list.html). Direct DNA sequencing of amplified genomic DNA and mRNA was performed for candidate gene analysis. RESULTS. The SVD locus was linked to markers in a region of chromosome 2q36 defined by D2S2158 and D2S2202, based on meiotic breakpoint mapping of affected individuals. A maximum two-point lod score of 5.5 was obtained with marker D2S172 at 0 within this region. Direct DNA sequencing of all 52 exons of the COL4A3 gene revealed no potentially pathogenic coding sequence variation or evidence for deletion. CONCLUSIONS. The genetic locus for SVD lies i na9M bregion flanked by D2S2158 and D2S2202. Localization of SVD to a genomic region distinct from both Wagner disease and the Stickler syndromes indicates that SVD is a distinct genetic entity. The absence of coding sequence variation in the only collagen gene within the disease-region, suggests a novel pathogenesis for Vitreoretinal Degeneration. Snowflake Vitreoretinal Degeneration should be considered in the differential diagnosis of families with fibrillar anomaly of the vitreous. (Invest Ophthalmol Vis Sci. 2004;45:4498‐4503) DOI:
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Snowflake Vitreoretinal Degeneration: follow-up of the original family
Ophthalmology, 2003Co-Authors: Mike M Lee, Robert Ritter, Tatsuo Hirose, Albert O. EdwardsAbstract:Abstract Purpose The ocular findings, systemic features, and genetic loci distinguishing known genetic causes of Vitreoretinal Degenerations were studied in the original Snowflake family. Design Prospective, comparative study and molecular genetic investigation. Participants Members of the original snowflake Vitreoretinal Degeneration family. Methods Clinical data were collected on 26 family members by history and examination. Thirteen of the 26 total family members underwent prospective examination. Linkage to known Vitreoretinal Degeneration loci ( COL2A1 , COL11A1 , and the Wagner disease locus) was evaluated with short tandem repeat markers. Main outcome measures Ocular and systemic features of known Vitreoretinal Degenerations. Results Six of the 13 prospectively examined subjects had snowflake Vitreoretinal Degeneration. Corneal guttae (4/5; 80%), early onset cataract (5/6; 83%), fibrillar vitreous Degeneration (6/6; 100%), and peripheral retinal abnormalities (5/6; 83%), including minute crystallinelike deposits called snowflakes (4/6; 67%), were common. Retinal detachment was seen in 1 of 6 of these prospectively examined subjects (17%). A total of 14 affected subjects were identified within the family, and in 3 (21%), retinal detachment developed. Orofacial features, early-onset hearing loss, and arthritis typical of Stickler syndrome were absent. Linkage to known Vitreoretinal Degeneration loci was excluded. Conclusions The absence of vitreous gel in the retrolental space and presence of fibrillar vitreous Degeneration were consistent with the vitreous structure reported for collagen 11A1 ( COL11A1 ) but not collagen 2A1 ( COL2A1 ) mutations. The absence of systemic features was characteristic of the vitreoretinopathies linked to chromosome 5q13 (Wagner disease and erosive vitreoretinopathy) and mutations in exon 2 of the COL2A1 gene. Snowflakes in the peripheral retina and the absence of nyctalopia, posterior chorioretinal atrophy, and tractional retinal detachment were inconsistent with the chromosome 5q13 vitreoretinopathies. The association of Fuchs' corneal endothelial dystrophy found in this family has not been reported previously in other Vitreoretinal Degenerations. These findings and the exclusion of known genetic loci suggest snowflake is a distinct Vitreoretinal Degeneration.
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Clinical variability of Stickler syndrome: role of exon 2 of the collagen COL2A1 gene.
Survey of ophthalmology, 2003Co-Authors: Larry A Donoso, Tamara R Vrabec, Jerry Rogers, Robert Ritter, Albert O. Edwards, Arcilee Frost, N. Nina Ahmad, David Meyer, Scott ParmaAbstract:Abstract Stickler syndrome (progressive arthro-ophthalmopathy) is a genetically heterogeneous disorder resulting from mutations in at least three collagen genes. The most common disease-causing gene is COL2A1, a 54-exon–containing gene coding for type II collagen. At least 17 different mutations causing Stickler syndrome have been reported in this gene. Phenotypically, it is also a variably expressed disorder in which most patients present with a wide range of eye and extraocular manifestations including auditory, skeletal, and orofacial manifestations. Some patients, however, present without clinically apparent systemic findings. This observation has led to difficulty distinguishing this Stickler phenotype from other hereditary Vitreoretinal Degenerations, such as Wagner syndrome and Snowflake Vitreoretinal Degeneration. In this regard, review of the literature indicates type II collagen exists in two forms resulting from alternative splicing of exon 2 of the COL2A1 gene. One form, designated as type IIB (short form), is preferentially expressed in adult cartilage tissue. The other form, designated as type IIA (long form), is preferentially expressed in the vitreous body of the eye. Because of this selective tissue expression, mutations in exon 2 of the COL2A1 gene have been hypothesized to produce this Stickler syndrome phenotype with minimal or absent extraocular findings. We review the evidence for families with exon 2 mutations of the collagen COL2A1 gene presenting in a distinct manner from families with mutations in the remaining 53 exons, as well as other hereditary Vitreoretinal Degenerations without significant systemic manifestations.
Tadashi Yokoi - One of the best experts on this subject based on the ideXlab platform.
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Analysis of the vitreous membrane in a case of type 1 Stickler syndrome
Graefe's Archive for Clinical and Experimental Ophthalmology, 2009Co-Authors: Tadashi Yokoi, Ryouhei Koide, Kentaro Matsuoka, Atsuko Nakagawa, Noriyuki AzumaAbstract:Background Stickler syndrome causes ocular abnormalities, including retinal detachment and Vitreoretinal Degeneration, and systemic anomalies such as arthritis and deafness. Although retinal detachment is characteristic of this syndrome, the pathogenesis is unknown. Case report A 10-year-old boy reported decreased vision and presented 5 days after visual loss. Results Ophthalmoscopy showed a retinal detachment with a giant tear in the right eye, and a nonpigmented epithelial detachment with pars plicata breaks in the left eye. Bilateral findings included an empty vitreous and a vitreous membrane at the equator. The systemic abnormalities included short stature and joint hypermobility. The diagnosis was type 1 Stickler syndrome, and the eyes were treated surgically. Immunohistochemistry showed that the vitreous membrane resected intraoperatively was comprised primarily of Müller cells. Electron microscopy showed dense collagen fibers around the cells in the membrane that were identical to the vitreous collagen inserted into the basement membrane of the cells, which was similar to the ultrastructure of the vitreous base. Conclusion Müller cells might be primary components of the vitreous membrane in type 1 Stickler syndrome. The Vitreoretinal interface, which resembled the ectopic vitreous base, in the vitreous membrane may be related to the pathogenesis of the retinal detachment.
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Analysis of the vitreous membrane in a case of type 1 Stickler syndrome.
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 2008Co-Authors: Tadashi Yokoi, Ryouhei Koide, Kentaro Matsuoka, Atsuko Nakagawa, Noriyuki AzumaAbstract:Background Stickler syndrome causes ocular abnormalities, including retinal detachment and Vitreoretinal Degeneration, and systemic anomalies such as arthritis and deafness. Although retinal detachment is characteristic of this syndrome, the pathogenesis is unknown.
