lipofuscin

Macular Dystrophy, Vitelliform 4

Clinical Characteristics
Ocular Features: 

This is a late onset form of vitelliform dystrophy in which symptoms are usually noted between the ages of 20 to 45 years.  The vitelliform lesions usually occur singly and are often small.  Some individuals have small drusen-like macular lesions adjacent to the vitelliform lesions, at the periphery of the macula, or even outside the macula.  The lesions contain lipofuscin which can be seen on autofluorescence photographs.  Visual acuity can remain near normal for many years.  The EOG ratio and ERG responses are usually normal or near normal.  Choroidal neovascularization has not been described. 

Systemic Features: 

There are no systemic manifestations.

Genetics

This form of vitelliform dystrophy (VMD4) is caused by heterozygous mutations in the IMPG1 gene (6q14.1).  However, rare families have been reported in which compound heterozygous or homozygous mutations have been found.  Some of the heterozygous parents of children with two mutations were found to have minor fundus changes such as tiny extramacular vitelliform spots in spite of being asymptomatic. This suggests that the transmission pattern of fundus changes may be both autosomal recessive and autosomal dominant. 

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease (VMD2, 153700) apparently first described by Friedreich Best in 1905 and now attributed to mutations in the Best1 gene, we know of at least 4 more 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 described here, and VMD5 (616152) caused by mutations in the IMPG2 gene.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the vitelliform disease but low vision devices can be helpful in some patients for selected tasks.

References
Article Title: 

Mutations in IMPG1 cause vitelliform macular dystrophies

Manes G, Meunier I, Avila-Fernandez 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, Senechal A, Hebrard M, Bocquet B, Ayuso Garcia C, Hamel CP. Mutations in IMPG1 cause vitelliform macular dystrophies. Am J Hum Genet. 2013 Sep 5;93(3):571-8.

PubMed ID: 
23993198

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: 

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
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