OMIM ID:
Macular Dystrophy, Vitelliform 2
Alternate Names
Defective Genes
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
Inheritance
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 dominant disorders require only one mutation for the disease to be expressed. Since an affected parent has two chromosomes, only one of which has the mutant gene, parents can expect that half (50%) of their children will receive that one and inherit the disease. It is common for individuals that inherit the mutation, however, to not have evidence of the disease (nonpenetrance).
Autosomal dominant inheritance leads to a vertical pattern of transmission
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.