Assessment of the Phenotypic Range Seen in Doyne Honeycomb Retinal Dystrophy

Evans, K; Gregory, Cheryl Y.; Wijesuriya, Sujeewa D.; Kermani, Sana; Jay, Marcelle; Plant, Catherine; Bird, Alan C.

doi:10.1001/archopht.1997.01100160074012

Cited by 58 publications

(32 citation statements)

References 25 publications

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“…44 Alterations in physiology of extracellular matrix caused by mutations in TIMP3 and EFEMP1 have been associated with choroidal neovascular disease in Sorsby fundus dystrophy and Malattia Leventinese. 6,7,45 The presence on fluorescin angiography of a dark choroid in several of the family members in the current study supports the possibility of accumulation of an abnormal metabolite in the pigment epithelium and underlying Bruch's membrane.…”

Section: Discussionsupporting

confidence: 76%

Late-Onset Autosomal Dominant Macular Dystrophy with Choroidal Neovascularization and Nonexudative Maculopathy Associated with Mutation in theRDSGene

Khani

Karoukis

Young

et al. 2003

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To examine the molecular genetic basis and phenotypic characteristics of an unusual late-onset autosomal dominant macular dystrophy with features of age-related macular degeneration (AMD) in a large family (SUNY901), by using linkage and mutation analyses. METHODS. Blood samples were collected from 17 affected members, 17 clinically unaffected members, and 5 unrelated spouses. Clinical analyses included a review of medical history and standard ophthalmic examination with fundus photography, fluorescein angiography, and electroretinography. Linkage and haplotype analyses were performed with microsatellite markers. Mutation analysis was performed by amplification of exons followed by sequencing. RESULTS. A wide spectrum of clinical phenotypes including exudative and nonexudative maculopathy was observed, with onset in the late fifth decade. Linkage analysis excluded most of the previously known maculopathy loci. Markers D6S1604 (Z max of 3.18 at ϭ 0), and D6S282 (Z max of 3.18 at ϭ 0) gave significant positive LOD scores and haplotype analysis localized the disease gene to a 9-centimorgan (cM) interval between markers D6S1616 and D6S459. Mutation analysis excluded the GUCA1A and GUCA1B genes and revealed a missense mutation in the RDS/peripherin gene leading to a Tyr141Cys substitution. A phenotype and haplotype comparison between this and a separate family with the Tyr141Cys mutation suggested the presence of a common ancestral haplotype. CONCLUSIONS.The RDS mutation in codon 141 is associated with an unusual AMD-like late-onset maculopathy. An apparent selective bias was noted favoring the transmission of the mutant allele. These observations broaden the spectrum of phenotypes associated with RDS gene mutations. (Invest Ophthalmol Vis Sci.

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Section: Discussionsupporting

confidence: 76%

Late-Onset Autosomal Dominant Macular Dystrophy with Choroidal Neovascularization and Nonexudative Maculopathy Associated with Mutation in theRDSGene

Khani

Karoukis

Young

et al. 2003

Invest. Ophthalmol. Vis. Sci.

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“…21 Subsequent to the investigations described in this report, these patients were found to show the EFEMP1 mutation associated with both ML and DHRD. 24 All patients underwent a complete ophthalmologic evaluation, fundus photography, and fluorescein angiography.…”

Section: Methodsmentioning

confidence: 70%

“…The marked functional deficits in patients with DHRD and ML reported in this study represent the more severe end of the spectrum for this disorder. 21 This is likely to be due to the presence of the confluent macular deposits in the subgroup studied. The basis of diminished retinal function over areas of confluent deposits are compatible with one or more of the following explanations: decreased outer retinal photopigment content, 66 photoreceptor misalignment, 4,6,49,55 retinal pigment epithelial dysfunction, 56 and delayed metabolic exchange across a thickened Bruch's membrane.…”

Section: Discussionmentioning

confidence: 93%

“…[18][19][20] Subsequent descriptions show that they may occur in a small number of members of the Doyne family, but are not prominent. 21 Despite these discrepancies, genes from ML and DHRD families colocalise 22,23 and a single EFEMP1 (EGF containing fibrillin-like extracellular matrix protein 1) mutation is associated with both disorders. 24 We wish to report six patients with EFEMP1 retinal dystrophy (ML/DHRD) who presented with subjective visual loss in association with diffuse peripapillary and macular drusen and associated radially-orientated peripheral drusen.…”

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confidence: 99%

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Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy)

Haimovici

Wroblewski

Piguet

et al. 2002

Eye

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“…Specifically, these maculopathies lead to the bilateral loss of central vision due to choroidal neovascularization and/or RPE atrophy (6,53,54). Pathologically these diseases are characterized by common alterations, including drusen formation and thickening of Bruch's membrane (1-5).…”

Section: Discussionmentioning

confidence: 99%

Drusen in patient-derived hiPSC-RPE models of macular dystrophies

Galloway

Dalvi

Hung

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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122

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Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are a major cause of vision loss. However, the mechanisms underlying their progression remain ill-defined. This is partly due to the lack of disease models recapitulating the human pathology. Furthermore, in vivo studies have yielded limited understanding of the role of specific cell types in the eye vs. systemic influences (e.g., serum) on the disease pathology. Here, we use human induced pluripotent stem cell-retinal pigment epithelium (hiPSC-RPE) derived from patients with three dominant MDs, Sorsby's fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy/malattia Leventinese (DHRD), and autosomal dominant radial drusen (ADRD), and demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases. Consistent with clinical studies, sub-RPE basal deposits were present beneath both control (unaffected) and patient hiPSC-RPE cells. Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid-and protein-rich "drusen-like" composition. Furthermore, increased accumulation of COL4 was observed in ECM isolated from control vs. patient hiPSC-RPE cultures. Interestingly, RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD). Finally, although serum exposure was not necessary for drusen formation, COL4 accumulation in ECM, and complement pathway gene alteration, it impacted the composition of drusen-like deposits in patient hiPSC-RPE cultures. Together, the drusen model(s) of MDs described here provide fundamental insights into the unique biology of maculopathies affecting the RPE-ECM interface.human induced pluripotent stem cells | retinal pigment epithelium | macular dystrophies | drusen | sub-RPE deposits M aculopathies are a major cause of blindness, with agerelated macular degeneration (AMD) being the leading cause of irreversible vision loss in adults in the United States. Histopathological and clinical studies have shown that AMD and a subset of inherited macular dystrophies (MDs) share extensive phenotypic and clinical similarities (1-4). Specifically, AMD and related MDs have a cumulative etiology with adult onset of signs and symptoms and similar disease presentation including drusen formation, extracellular matrix (ECM) protein accumulation, thickening of Bruch's membrane, development of choroidal neovascularization, retinal pigment epithelium (RPE) atrophy, and ultimately the loss of vision (1-5). Although, the major pathological manifestations in these maculopathies are localized to the RPE-ECM interface in the retina, the multifactorial nature of these diseases, including the involvement of multiple retinal cell layers (photoreceptors, RPE, and choriocapillaris) (3, 6-9) and environmental risk factors (e.g., cigarette smoke) (10), has complicated the pursuit of t...

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Assessment of the Phenotypic Range Seen in Doyne Honeycomb Retinal Dystrophy

Cited by 58 publications

References 25 publications

Late-Onset Autosomal Dominant Macular Dystrophy with Choroidal Neovascularization and Nonexudative Maculopathy Associated with Mutation in theRDSGene

Late-Onset Autosomal Dominant Macular Dystrophy with Choroidal Neovascularization and Nonexudative Maculopathy Associated with Mutation in theRDSGene

Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy)

Drusen in patient-derived hiPSC-RPE models of macular dystrophies

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