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Personalized ophthalmology.

Porter LF, Black GC - Clin. Genet. (2014)

Bottom Line: It also promises to alter prediction, diagnosis and management of the complex disease age-related macular degeneration.Two important areas of focus are required for adoption of personalized approaches: disease stratification and individualization.Indeed, whilst many difficulties remain, personalized ophthalmology truly has the potential to revolutionize the specialty.

View Article: PubMed Central - PubMed

Affiliation: Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, UK; Manchester Royal Eye Hospital, Department of Ophthalmology, Manchester, UK.

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Monogenic macular dystrophies. A heterogenous group of disorders, each caused by mutations in a single gene. Incomplete penetrance and variability in disease expression complicate diagnosis. (a) Stargardt disease (STGD1) is the most prevalent juvenile retinal dystrophy. With an autosomal recessive (AR) pattern of inheritance, STGD1 is associated with rapid central vision loss. Mutations in ABCA4 give rise to STGD1. Defective ABCA4 protein leads to the accumulation of A2E lipofuscin in retinal pigment epithelium (RPE) cells, which is toxic in high concentrations. The accumulation of lipofuscin can be seen in and around the macula as yellowish white flecks (S91). (b) Doyne honeycomb retinal degeneration (Malattia Leventinese) is a dominant macular dystrophy caused by mutations in EFEMP1.Affected individuals present with drusen in the macula and around the edge of the optic nerve head (S92). (c) Sorsby fundus dystrophy results from mutations in TIMP3 and resembles neovascular age-related macular degeneration (AMD) with an age of onset in early adulthood (S93). (d) Best vitelliform macular dystrophy (BVMD) is one of the ‘bestrophinopathies’ caused by AD mutations in BEST1, encoding bestrophin-1, a calcium-activated chloride channel. Accumulation of subretinal fluid and vitelliform material originating from the outer photoreceptors is thought to cause RPE overload, leading to photoreceptor and RPE dysfunction (S94).
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fig04: Monogenic macular dystrophies. A heterogenous group of disorders, each caused by mutations in a single gene. Incomplete penetrance and variability in disease expression complicate diagnosis. (a) Stargardt disease (STGD1) is the most prevalent juvenile retinal dystrophy. With an autosomal recessive (AR) pattern of inheritance, STGD1 is associated with rapid central vision loss. Mutations in ABCA4 give rise to STGD1. Defective ABCA4 protein leads to the accumulation of A2E lipofuscin in retinal pigment epithelium (RPE) cells, which is toxic in high concentrations. The accumulation of lipofuscin can be seen in and around the macula as yellowish white flecks (S91). (b) Doyne honeycomb retinal degeneration (Malattia Leventinese) is a dominant macular dystrophy caused by mutations in EFEMP1.Affected individuals present with drusen in the macula and around the edge of the optic nerve head (S92). (c) Sorsby fundus dystrophy results from mutations in TIMP3 and resembles neovascular age-related macular degeneration (AMD) with an age of onset in early adulthood (S93). (d) Best vitelliform macular dystrophy (BVMD) is one of the ‘bestrophinopathies’ caused by AD mutations in BEST1, encoding bestrophin-1, a calcium-activated chloride channel. Accumulation of subretinal fluid and vitelliform material originating from the outer photoreceptors is thought to cause RPE overload, leading to photoreceptor and RPE dysfunction (S94).

Mentions: IRDs are a genetically and phenotypically heterogeneous group of conditions characterized by rod and cone photoreceptor degeneration (S24). Patients with IRD pose a compelling case for personalized ophthalmology and show the need for widespread genetic testing (9, S25–S26), particularly because of the advent of gene-based clinical trials 7. The nature of phenotypic and genetic heterogeneity amongst IRD is shown in Figs 3 and 4. Because conventional sequencing strategies are impractical in such contexts, NGS-based protocols are required to identify disease-causing mutations. In the clinical setting this is being achieved using custom-based target enrichment panels or whole exome sequencing approaches with a targeted bioinformatics analysis focusing upon genes causing IRD (5, S18). O'Sullivan et al. for example analyzed 105 genes in 50 patients with IRD, successfully identifying a disease-causing mutations in 50–55% of patients 5.


Personalized ophthalmology.

Porter LF, Black GC - Clin. Genet. (2014)

Monogenic macular dystrophies. A heterogenous group of disorders, each caused by mutations in a single gene. Incomplete penetrance and variability in disease expression complicate diagnosis. (a) Stargardt disease (STGD1) is the most prevalent juvenile retinal dystrophy. With an autosomal recessive (AR) pattern of inheritance, STGD1 is associated with rapid central vision loss. Mutations in ABCA4 give rise to STGD1. Defective ABCA4 protein leads to the accumulation of A2E lipofuscin in retinal pigment epithelium (RPE) cells, which is toxic in high concentrations. The accumulation of lipofuscin can be seen in and around the macula as yellowish white flecks (S91). (b) Doyne honeycomb retinal degeneration (Malattia Leventinese) is a dominant macular dystrophy caused by mutations in EFEMP1.Affected individuals present with drusen in the macula and around the edge of the optic nerve head (S92). (c) Sorsby fundus dystrophy results from mutations in TIMP3 and resembles neovascular age-related macular degeneration (AMD) with an age of onset in early adulthood (S93). (d) Best vitelliform macular dystrophy (BVMD) is one of the ‘bestrophinopathies’ caused by AD mutations in BEST1, encoding bestrophin-1, a calcium-activated chloride channel. Accumulation of subretinal fluid and vitelliform material originating from the outer photoreceptors is thought to cause RPE overload, leading to photoreceptor and RPE dysfunction (S94).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig04: Monogenic macular dystrophies. A heterogenous group of disorders, each caused by mutations in a single gene. Incomplete penetrance and variability in disease expression complicate diagnosis. (a) Stargardt disease (STGD1) is the most prevalent juvenile retinal dystrophy. With an autosomal recessive (AR) pattern of inheritance, STGD1 is associated with rapid central vision loss. Mutations in ABCA4 give rise to STGD1. Defective ABCA4 protein leads to the accumulation of A2E lipofuscin in retinal pigment epithelium (RPE) cells, which is toxic in high concentrations. The accumulation of lipofuscin can be seen in and around the macula as yellowish white flecks (S91). (b) Doyne honeycomb retinal degeneration (Malattia Leventinese) is a dominant macular dystrophy caused by mutations in EFEMP1.Affected individuals present with drusen in the macula and around the edge of the optic nerve head (S92). (c) Sorsby fundus dystrophy results from mutations in TIMP3 and resembles neovascular age-related macular degeneration (AMD) with an age of onset in early adulthood (S93). (d) Best vitelliform macular dystrophy (BVMD) is one of the ‘bestrophinopathies’ caused by AD mutations in BEST1, encoding bestrophin-1, a calcium-activated chloride channel. Accumulation of subretinal fluid and vitelliform material originating from the outer photoreceptors is thought to cause RPE overload, leading to photoreceptor and RPE dysfunction (S94).
Mentions: IRDs are a genetically and phenotypically heterogeneous group of conditions characterized by rod and cone photoreceptor degeneration (S24). Patients with IRD pose a compelling case for personalized ophthalmology and show the need for widespread genetic testing (9, S25–S26), particularly because of the advent of gene-based clinical trials 7. The nature of phenotypic and genetic heterogeneity amongst IRD is shown in Figs 3 and 4. Because conventional sequencing strategies are impractical in such contexts, NGS-based protocols are required to identify disease-causing mutations. In the clinical setting this is being achieved using custom-based target enrichment panels or whole exome sequencing approaches with a targeted bioinformatics analysis focusing upon genes causing IRD (5, S18). O'Sullivan et al. for example analyzed 105 genes in 50 patients with IRD, successfully identifying a disease-causing mutations in 50–55% of patients 5.

Bottom Line: It also promises to alter prediction, diagnosis and management of the complex disease age-related macular degeneration.Two important areas of focus are required for adoption of personalized approaches: disease stratification and individualization.Indeed, whilst many difficulties remain, personalized ophthalmology truly has the potential to revolutionize the specialty.

View Article: PubMed Central - PubMed

Affiliation: Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, UK; Manchester Royal Eye Hospital, Department of Ophthalmology, Manchester, UK.

Show MeSH
Related in: MedlinePlus