Best vitelliform macular dystrophy

Best vitelliform macular dystrophy is a slowly progressive disorder of the central retina with marked variability in clinical presentation and course. Manifestations commonly develop during childhood or adolescence, although the diagnosis may be made considerably later. The characteristic vitelliform macular lesion is usually bilateral but may be asymmetric; its number and location can vary. The retinal changes may evolve through vitelliform, pseudohypopyon and vitelliruptive stages, followed in some individuals by macular atrophy or fibrosis. Central visual acuity may remain relatively well preserved for many years but can deteriorate with advanced macular changes or the development of choroidal neovascularisation. Amblyopia may contribute to visual impairment in a minority of affected individuals.

Best vitelliform macular dystrophy is rare, with population-based prevalence estimates ranging from approximately 1 in 20,000 to 1 in 100,000 individuals.

Best vitelliform macular dystrophy is caused by heterozygous germline pathogenic variants in BEST1, located at chromosome 11q12.3. BEST1 encodes bestrophin-1, a calcium-activated anion channel expressed at the basolateral membrane of the retinal pigment epithelium. Impaired bestrophin-1 function disrupts retinal pigment epithelial homeostasis and the interaction between the retinal pigment epithelium and photoreceptors, contributing to the accumulation of vitelliform material in the subretinal space. The clinical presentation and severity vary considerably, and genotype-phenotype correlations are not established for most variants.

The classical form of Best vitelliform macular dystrophy is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the familial pathogenic variant. Biallelic BEST1 variants cause a separate autosomal recessive bestrophinopathy.

Biallelic pathogenic variants in BEST1 cause autosomal recessive bestrophinopathy, a distinct clinical condition characterised by more widespread bilateral retinal involvement, often with multiple vitelliform deposits, subretinal fluid and cystoid intraretinal changes.

No consensus diagnostic criteria have been established. The diagnosis rests on suggestive clinical findings together with a heterozygous BEST1 pathogenic or likely pathogenic variant. The electro-oculogram is usually abnormal in symptomatic individuals, with an Arden ratio below 1.5, whereas the full-field electroretinogram remains normal. Optical coherence tomography documents subretinal fluid and lesion morphology, and hyperautofluorescence at the posterior pole is the most frequent autofluorescence pattern, seen in about a third of eyes.

Main differential diagnoses include:

• Adult-onset foveomacular vitelliform dystrophy: typically later onset, with smaller vitelliform lesions that may progress to macular atrophy; associated with PRPH2, IMPG1 or IMPG2 in some cases, although many cases remain genetically unexplained
• Acquired vitelliform lesions and age-related macular degeneration: non-hereditary macular changes that may resemble vitelliform, atrophic or neovascular stages of Best disease
• Autosomal recessive bestrophinopathy: a distinct BEST1-associated disorder characterised by more widespread bilateral retinal involvement, often with multiple subretinal deposits and intraretinal or subretinal fluid

• Establishing the diagnosis: identifying the underlying pathogenic variant confirms the clinical diagnosis and separates Best vitelliform macular dystrophy from clinically overlapping vitelliform presentations and enables predictive testing of at-risk family members.
• The identified entity supports condition-specific monitoring and management decisions; therapeutic options are evaluated individually by the treating physicians.

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