retinal pigment epitheliopathy

Best Macular Dystrophy

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 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.

Some have attempted to classify late-onset Best disease as a unique disorder (AVMD).  However, at the moment this seems to be a heterogenous group as at least some individuals have mutations in the RDS (PRPH2) gene (608161). Mutations in IMPG1 have also been reported in families with both autosomal dominant and autosomal recessive Best disease.  Likewise, mutations in IMPG2 have been implicated in macular disease resembling Best lesions (as well as in retinitis pigmentosa 56) but it is preferred practice to consider only retinal disease with mutations in BEST1 as Best macular dystrophy.

Autosomal dominant vitreoretinochoroidopathy (193220) is an allelic disorder.

Treatment Options

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

References

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

Manes G, Meunier I, Avila-Fernández 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, Sénéchal A, Hebrard M, Bocquet B, García 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

Piñeiro-Gallego T, Alvarez M, Pereiro I, Campos S, Sharon D, Schatz P, Valverde D. Clinical evaluation of two consanguineous families with homozygous mutations in BEST1. Mol Vis. 2011;17:1607-17.

PubMed ID: 
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Wittström E, Ponjavic V, Bondeson ML, Andréasson S. Anterior Segment Abnormalities and Angle-Closure Glaucoma in a Family with a Mutation in the BEST1 Gene and Best Vitelliform Macular Dystrophy. Ophthalmic Genet. 2011 Apr 7. [Epub ahead of print]

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Kinnick TR, Mullins RF, Dev S, Leys M, Mackey DA, Kay CN, Lam BL, Fishman GA, Traboulsi E, Iezzi R, Stone EM. Autosomal recessive vitelliform macular dystrophy in a large cohort of vitelliform macular dystrophy patients. Retina. 2011 Mar;31(3):581-95.

PubMed ID: 
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Marmorstein AD, Cross HE, Peachey NS. Functional roles of bestrophins in ocular epithelia. Prog Retin Eye Res. 2009 May;28(3):206-26. Review.

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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

Bakall B, Marknell T, Ingvast S, Koisti MJ, Sandgren O, Li W, Bergen AA, Andreasson S, Rosenberg T, Petrukhin K, Wadelius C. The mutation spectrum of the bestrophin protein--functional implications. Hum Genet. 1999 May;104(5):383-9.

PubMed ID: 
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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