retinal pigment epitheliopathy

Macular Dystrophy, Patterned 3

Clinical Characteristics
Ocular Features: 

This condition has been found in an extended pedigree among peoples originating in the West Indies.  Vision loss is noted after the age of 50 years but clinical evidence can be seen in the fourth or fifth decades. The findings are primarily in the retinal pigment epithelium but Bruch's membrane is also involved.  Choroidal neovascularization and macular scarring may be present. The fundus pigmentary pattern has been described as resembling "dried-out soil" or crocodile skin.  In late stages the fundus picture resembles retinitis pigmentosa with loss of the RPE and photoreceptors.  The loss of photoreceptors continues throughout life. An 85 year old woman with light perception only has been described. 

In early stages the full-field ERG can be nomal but later rod and cone responses are severely reduced.  The OCT may show scalloped elevation at the borders of the scalloped patches corresponding to the irregular thickness of the RPE and Bruch membrance.

Knockout mice have both thickened and thinned areas of the Bruch membrane.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This autosomal dominant condition results from heterozygous mutations in MAPKAPK3 (3p21.3), a mitogene-activated kinase of the p38 signaling pathway.  It is highly expressed in the RPE.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Martinique Crinkled Retinal Pigment Epitheliopathy: Clinical Stages and Pathophysiologic Insights

Jean-Charles A, Merle H, Audo I, Desoudin C, Bocquet B, Baudoin C, Sidibe M, Mauget-Faysse M, Wolff B, Fichard A, Lenaers G, Sahel JA, Gaudric A, Cohen SY, Hamel CP, Meunier I. Martinique Crinkled Retinal Pigment Epitheliopathy: Clinical Stages and Pathophysiologic Insights. Ophthalmology. 2016 Jul 26. pii: S0161-6420(16)30496-1. doi: 10.1016/j.ophtha.2016.06.028. [Epub ahead of print].

PubMed ID: 
27474146

A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium

Meunier I, Lenaers G, Bocquet B, Baudoin C, Piro-Megy C, Cubizolle A, Quiles M, Jean-Charles A, Cohen SY, Merle H, Gaudric A, Labesse G, Manes G, Pequignot M, Cazevieille C, Dhaenens CM, Fichard A, Ronkina N, Arthur SJ, Gaestel M, Hamel CP. A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium. Hum Mol Genet. 2016 Jan 6. pii: ddv624. [Epub ahead of print].

PubMed ID: 
26744326

Macular Dystrophy, Vitelliform 2

Clinical Characteristics
Ocular Features: 

Best disease primarily affects the macular and paramacular areas.  The classical lesion resembles an egg yolk centered on the fovea.  Most patients, however, never exhibit the typical vitelliform lesion and may instead have normal maculae, or irregular yellowish deposits that may even be extrafoveal.  Histologically the RPE contains increased amounts of lipofuscin.  The ‘egg yolk’ is located beneath the neurosensory retina and the overlying retinal circulation often remains intact.  It can evolve into a ‘scrambled egg’ appearance and an apparent fluid level may be evident.  Some patients exhibit only RPE changes including hyper-  or hypopigmentation throughout the macula.  Choroidal neovasculariztion with hemorrhage leading to scarring and gliosis are uncommon but present a serious risk to vision.  The common end point for symptomatic patients is some degree of photoreceptor damage.

Until recently, most reports of Best macular dystrophy did not include genotypic data.  It is therefore difficult to classify families with variants of the disease, such as adult-onset or atypical vitelliform dystrophy but these at least suggest that this may be a heterogeneous disorder.  At the present time, the diagnosis should be reserved for those with an abnormal light-to-dark (Arden) ratio on electro-oculography and a mutation in the BEST1 gene. 

Visual function varies widely and has considerable fluctuation.   As many as 7-9 percent of patients are asymptomatic throughout life and few have vision loss to 20/200.  Many individuals maintain vision of 20/40 or better throughout life.  Some experience episodic acute vision loss to 20/80 or worse but often recover to at least 20/30.  It has been reported that as many as 76 per cent under the age of 40 retain 20/40 and 30 per cent retain this level of vision into the 5th and 6th decade of life.

Other ocular manifestations include hyperopia, esotropia, and, rarely, shallow anterior chambers with angle closure glaucoma.

Systemic Features: 

None have been reported.

Genetics

A mutation in the bestrophin gene (BEST1) located on chromosome 11 (11q13) is responsible for the disease in most patients.  Best disease is usually transmitted in an autosomal dominant pattern from parent to offspring.  A large number of mutations have been found in the BEST1 gene but so far no correlation with severity of disease is possible.  In fact, there is a great deal of clinical variation within families having identical mutations resembling that of the variation found among different mutations.

Several families have also been reported with autosomal recessive inheritance.  Affected offspring had homozygous mutations in the bestrophin gene with reduced light/dark responses and vision loss.  Some have atypical vitelliform retinal and sometimes multifocal lesions.  They may develop angle closure glaucoma.  Their heterozygous parents  have either normal or abnormal EOGs and no visible fundus disease.  So far no families with presumed recessive inheritance of Best macular dystrophy have demonstrated parent-to-child transmission of typical vitelliform lesions.

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease described here we know of at least four more variants and specific mutations have been identified in three.  No mutation or locus has yet been identified in VMD1 (153840) but it is likely a unique condition since mutations in other genes known to cause vitelliform dystrophy have been ruled out.  Other forms are VMD3 (608161) due to mutations in the PRPH2 gene, VMD4 (616151) resulting from mutations in the IMPG1 gene, and VMD5 (616152) caused by mutations in the IMPG2 gene.

Autosomal dominant vitreoretinochoroidopathy (193220) is an allelic disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

None known for disease.  Subretinal neovascularization may benefit from ablation treatments.

References
Article Title: 

Frequency and Clinical Pattern of Vitelliform Macular Dystrophy Caused by Mutations of Interphotoreceptor Matrix IMPG1 and IMPG2 Genes

Meunier I, Manes G, Bocquet B, Marquette V, Baudoin C, Puech B, Defoort-Dhellemmes S, Audo I, Verdet R, Arndt C, Zanlonghi X, Le Meur G, Dhaenens CM, Hamel CP. Frequency and Clinical Pattern of Vitelliform Macular Dystrophy Caused by Mutations of Interphotoreceptor Matrix IMPG1 and IMPG2 Genes. Ophthalmology. 2014 Jul 29. [Epub ahead of print].

PubMed ID: 
25085631

Mutations in IMPG1 Cause Vitelliform Macular Dystrophies. Am

Manes G, Meunier I, Avila-Fern?degndez A, Banfi S, Le Meur G, Zanlonghi X, Corton M, Simonelli F, Brabet P, Labesse G, Audo I, Mohand-Said S, Zeitz C, Sahel JA, Weber M, Dollfus H, Dhaenens CM, Allorge D, De Baere E, Koenekoop RK, Kohl S, Cremers FP, Hollyfield JG, S?(c)n?(c)chal A, Hebrard M, Bocquet B, Garc??a CA, Hamel CP. Mutations in IMPG1 Cause Vitelliform Macular Dystrophies. Am J Hum Genet. 2013 Aug 29. [Epub ahead of print] PubMed PMID: 23993198.

PubMed ID: 
23993198

Biallelic mutation of BEST1 causes a distinct retinopathy in humans

Burgess R, Millar ID, Leroy BP, Urquhart JE, Fearon IM, De Baere E, Brown PD, Robson AG, Wright GA, Kestelyn P, Holder GE, Webster AR, Manson FD, Black GC. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am J Hum Genet. 2008 Jan;82(1):19-31. PubMed PMID: 18179881

PubMed ID: 
18179881

Identification of the gene responsible for Best macular dystrophy

Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, Vujic M, Bergen AA, McGarty-Dugan V, Figueroa D, Austin CP, Metzker ML, Caskey CT, Wadelius C. Identification of the gene responsible for Best macular dystrophy. Nat Genet. 1998 Jul;19(3):241-7.

PubMed ID: 
9662395
Subscribe to RSS - retinal pigment epitheliopathy