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Bestrophinopathies: for professionals


Overview

Incidence
  • 1:10,000
Inheritance
  • Autosomal dominant (most common)
  • Autosomal recessive
Genes involved (OMIM No.)
Clinical phenotype (OMIM phenotype no.)
  • Macular dystrophy, vitelliform 2 (#153700)
  • Bestrophinopathy, autosomal recessive (#611809)
  • Retinitis pigmentosa 50 (#613194)
  • Vitreoretinoschoroidopathy (#193220)
Symptoms
  • Central vision disturbance/loss
  • Metamorphopsia
  • Photophobia
  • Nyctalopia
  • Age of symptom onset and severity of symptoms are highly variable
SignsBest vitelliform macular dystrophy
  • Range of macular appearance (normal, subtle RPE changes, elevated vitelliform lesion, macular atrophy)
  • Choroidal neovascularisation (CNV) may occur
Autosomal recessive bestrophinopathy (ARB)
  • Diffuse RPE abnormalities (most apparent on FAF)
  • Yellow-white punctate subretinal deposits scattered at the posterior pole or mid-periphery
  • Macular oedema (subretinal fluid and intraretinal cysts on OCT)
  • Macular atrophy may be present
  • Hypermetropia is common
  • Predisposition to developing acute angle closure glaucoma
Systemic features
  • No extraocular features reported
Key investigations
  • Electrophysiology: Severely reduced or absent EOG light rise (Arden ration <1.5) is characteristic
  • FAF: vitelliform lesion appears as an area of intense hyper-AF centrally
  • OCT: vitelliform lesion appears as a hyper-reflective dome between the RPE and ellipsoid zone; subretinal fluid and cystoid macular oedema are typical of ARB
  • Tonometry and gonioscopy in patients with ARB
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Management
  • Supportive ocular management
  • Regular monitoring of visual development in children to prevent amblyopia
  • Prophylactic laser peripheral iridotomies if angles are occludable on gonioscopy in ARB
  • Glaucoma monitoring for ARB patients
  • Intravitreal anti-VEGF injections can be considered for treating CNV
Therapies under research
  • Gene therapy
  • Stem cells

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Clinical phenotype

Pathogenic mutations in the BEST1 gene give rise to four clinical phenotypes, which are collectively known as bestrophinopathies. These four phenotypes are:

  • Best vitelliform macular dystrophy (BVMD)/ Best disease
  • Autosomal dominant vitreoretinochoroidopathy (ADVIRC)
  • Autosomal dominant retinitis pigmentosa 50
  • Autosomal recessive bestrophinopathy (ARB)

1) Best vitelliform macular dystrophy (BVMD)

BVMD is by far the most common bestrophinopathy affecting 1:10,000 people.[1] Patients typically present with central visual loss/disturbance, metamorphopsia, photophobia or even nyctalopia. Some may be asymptomatic and are only detected incidentally during a routine eye test.[2] The age of onset is highly variable, ranging from childhood up to the sixth decade of life.[3-7] The severity of visual dysfunction and the rate of disease progression also vary considerably among patients, but those with later-onset disease seem to have better preserved visual function and slower rate of visual decline.[8-10]

Fundoscopically, it is characterised by the presence of an elevated vitelliform lesion in the macula, which appears as an area of intense hyper-autofluorescence on fundus autofluorescence (FAF) imaging and a homogenous dome-shaped hyper-reflective deposit between the ellipsoid zone (EZ) and the retinal pigment epithelium (RPE) on optical coherence tomography (OCT). This may be accompanied by the presence of subretinal fluid when the vitelliform material is partially reabsorbed.[11]

However, the fundal appearance of BVMD is highly variable and some may display subtle RPE changes in the macula, inferiorly displaced vitelliform material (pseudohypopyon appearance) or macular atrophy instead. Some may even have a normal fundal appearance with only a reduced Arden ratio (<1.5) on EOG, which is characteristic of bestrophinopathies.[6,7,9,12,13] Full-field electroretinogram (ERG) responses are usually preserved. Occasionally, choroidal neovascularisation (CNV) may develop which may cause macular scarring and acute visual decline.

An egg-yolk like yellowish lesion is on the centre of the macula. A scan through the lesion shows it is deposited in the inner layers of the retina.
A typical vitelliform lesion is seen on the left retina (A). The lesion is hyper-autofluorescent on FAF imaging, with a “pseudohypopyon” appearance. OCT scan through the lesion shows a homogeneous deposit between the ellipsoid zone and the RPE.

2) Autosomal recessive bestrophinopathy (ARB)

ARB is a rare phenotype caused by homozygous or compound heterozygous BEST1 mutations. The age of symptom onset is again highly variable, ranging from childhood up to the fifth decade.[14-16] Patients typically present with a slowly progressive central visual loss, where the presenting VA ranges from 6/6 to 6/60.[17] Hypermetropia is common and approximately half of the ARB patients are at risk of developing angle closure glaucoma.[14-16]

Fundal examination usually reveals diffuse RPE abnormalities, macular oedema and yellow-white punctate subretinal deposits scattered at the posterior pole and mid-periphery.[14-16] The RPE abnormalities are best visualised on FAF, manifesting as diffuse patches of increased and decreased AF signals accompanied by hyperautofluorescent punctate deposits. On macular OCT, the presence of subretinal fluid and intraretinal cysts are typical features. However, some patients may display macular atrophy instead.[15,16]In addition to a reduced EOG light rise, patients often have reduced amplitudes in rod and cone responses on full-field electroretinogram (ERG), indicating generalised retinal dysfunction.

The initial visual loss experienced by patients are mostly due to cystoid macular oedema (CMO), which may be amenable to carbonic anhydrase inhibitors but treatment response varies.[18] Overall, ARB is a slowly progressive condition where visual function can remain relatively stable for a protracted period.[15,16,19]

The right retina of another patient with autosomal recessive bestrophinopathy showing multiple yellow-white dots around the macula. There is an area of degeneration in the centre of the macula.
Wide field colour fundus photography (A) showing multiple yellow-white punctate subretinal lesions distributed around the posterior pole. Corresponding wide field FAF (B) and 55 degree FAF (C) imaging show patches of increased and decreased autofluorescence with some hyper-autofluorescent deposits. Macular atrophy is seen on (A) and OCT (D). Green line indicates direction of the OCT scan.
Photographs of the right retina of a patient with autosomal recessive bestrophinopathy showing multiple small yellow dots along the bottom blood vessel. A scan through the macula shows fluid accumulation.
Wide field colour photography (A) of an ARB patient with yellow punctate sub retinal deposits in the inferior temporal arcade. The wide field FAF imaging (B) demonstrating patches of increased and decreased autofluorescence. OCT scan of the macula (C) showing showing subretinal fluid and cystoid macular oedema. The photoreceptor outer segments appear thickened and elongated, which is typical of bestrophinopathies.

3) Autosomal dominant vitreoretinochoroidopathy (ADVIRC)

ADVIRC is a very rare progressive BEST1 phenotype characterised by a sharply delineated peripheral annular retinal hyperpigmentation between the equator and ora serrata along with vitreous degeneration.[20] Other associated fundal features include retinal neovascularisation, vessel attenuation, chorioretinal atrophy, CMO, optic nerve dysplasia and disc pallor.[20-24] In addition, it is also associated with ocular developmental anomalies such as microcornea, nanophthalmos, shallow anterior chamber depth, iris dysgenesis and pre-senile cataracts.[20-23,25] Therefore, patients are at increased risk of developing angle closure glaucoma.

Visual deterioration in ADVIRC is typically thought to be milder compared to other progressive retinal dystrophies as the peripheral retina is predominantly affected.[23] However, advancement of hyperpigmentation towards the posterior pole and macular atrophy development have been reported in long-term follow-up studies.[24,26,27]

A seemingly distinct phenotype, Microcornea, Rod-cone dystrophy, Cataract and posterior Staphyloma (MRCS) (OMIM #193220) was first described by Reddy et al. The fundal features of the reported patients were similar to ADVIRC, and they also had additional features such as posterior staphyloma, nanophthalmia and microcornea. It is believed that ADVIRC and MRCS belong to the same phenotypic spectrum due to overlapping features.[19]

More information on bestrophinopathies can be found on OMIM.

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Genetics

The BEST1 gene encodes for bestrophin-1 protein, which acts as a regulator of intracellular calcium signalling and a chloride ion channel to maintain the homeostasis of the RPE-photoreceptor interface.[28-30] There are no clear genotype-phenotype relationships established yet, but studies have suggested that variants causing BVMD exert a dominant negative effect on the normal allele, leading to reduced degradation of shed photoreceptor outer segments and subsequent accumulation of autofluorescent material.[28,31] ARB is thought to represent the BEST1 null phenotype as a consequence of very little or absent expression of functional bestrophin-1 due to recessive mutations.[14] ADVIRC is postulated to be caused by protein mislocalisation, with a greater effect on the peripheral retina due to higher levels of bestrophin-1 expression there during early ocular development.[32]

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Key investigations

1) Multimodal imaging

A combination of FAF and OCT imaging is key to identify features of bestrophinopathies, especially in BVMD cases where fundoscopic features may be subtle or minimal. Imaging is especially helpful to exclude macular/retinal dystrophies in children who are referred with blurry vision not fully corrected by glasses.  

2) Electrophysiology

EOG is crucial in diagnosing bestrophinopathies. Patients typically have a reduced EOG light rise (Arden ratio <1.5). Full-field and pattern ERG should be performed in conjunction with EOG to assess overall retinal and macular function respectively.

3) Gonioscopy

Patients with ARB tend to be hypermetropic and about half of these patients can develop angle closure glaucoma. Performing a gonioscopy assessment is recommended in these patients to identify those that may benefit from prophylactic laser peripheral iridotomies (PI).

4) Automated/kinetic perimetry

To establish baseline visual field.

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Diagnosis

Bestrophinopathies can be diagnosed clinically based on characteristic fundal and electrophysical features. However, given the phenotypic variability of BVMD, genetic testing should be undertaken to confirm the diagnosis. A molecular diagnosis can help facilitate genetic counselling, provide accurate advice on prognosis and future family planning, and aid in clinical trial participation.

This can be achieved through a variety of next generation sequencing (NGS) methods:

  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing

Related links

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Management

Ocular

1) Supportive management

  • Correcting any refractive errors
  • Regular monitoring of visual development in children and commence treatment for amblyopia promptly if detected
  • Glaucoma monitoring for ARB patients; laser PI should be performed for those with occludable angles
  • CNV usually resolves spontaneously but intravitreal anti-VEGF treatment can be considered (usually only require small number of injections)[33,34]
  • Referral to low vision services
  • Directing patients to supporting organisations 
  • Encourage the use of assistive technology that may improve quality of life 
  • Blue light screen protectors on mobile devices or computer screens*

*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.

Systemic

Visual impairment from an early age can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as Developmental Paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.

The Developmental Journal for babies and young children with visual impairment (DJVI) is a structured early intervention programme designed to track developmental and vision progress from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents.

Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.

Family management and counselling

Bestrophinopathies are mostly inherited in an autosomal dominant manner, except for ARB which has an autosomal recessive mode. Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist service

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research in bestrophinopathies

1) Gene therapy

Gene therapy works by introducing a normal gene (transgene) into the appropriate cells to compensate for the mutated gene that is not producing enough functional protein. The transgene is carried by a viral vector, usually adeno-associated virus (AAV) and delivered to the target cells through sub-retinal/intravitreal injections.

Sub-retinal BEST1 gene therapy has been shown to be safe and efficacious in reversing the ARB phenotype in canine models. The treatment effect was seen as early as 4 weeks after injection and lasted up to 245 weeks after injection. The promising results from this study has subsequently led to the planning of a human clinical trial in the near future.

2) Stem cells

Human induced pluripotent stem cells (hIPSCs) derived from patients affected by bestrophinopathies will help researchers to better understand the molecular pathogenesis of each phenotype and to efficiently screen for potential pharmaceutical therapies such as valproic acid.[35] There are currently two trials underway aiming to establish hiPSC-RPE cell lines derived from somatic cells (skin and hair) of patients with bestrophinopathies (NCT 02162953 and NCT 01432847).

Related links

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Further information and support

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References

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  2.  Renner AB, Tillack H, Kraus H, et al. Morphology and functional characteristics in adult vitelliform macular dystrophy. Retina. Dec 2004;24(6):929-39. doi:10.1097/00006982-200412000-00014
  3.  Boon CJ, Klevering BJ, Leroy BP, Hoyng CB, Keunen JE, den Hollander AI. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog Retin Eye Res. May 2009;28(3):187-205. doi:10.1016/j.preteyeres.2009.04.002
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  5.  Clemett R. Vitelliform dystrophy: long-term observations on New Zealand pedigrees. Aust N Z J Ophthalmol. Aug 1991;19(3):221-7. doi:10.1111/j.1442-9071.1991.tb00665.x
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  33.  Khan KN, Mahroo OA, Islam F, Webster AR, Moore AT, Michaelides M. FUNCTIONAL AND ANATOMICAL OUTCOMES OF CHOROIDAL NEOVASCULARIZATION COMPLICATING BEST1-RELATED RETINOPATHY. Retina. Jul 2017;37(7):1360-1370. doi:10.1097/iae.0000000000001357
  34.  Querques G, Angulo Bocco MC, Soubrane G, Souied EH. Intravitreal ranibizumab (Lucentis) for choroidal neovascularization associated with vitelliform macular dystrophy. Acta Ophthalmologica. 2008;86(6):694-695. doi:10.1111/j.1600-0420.2007.01132.x
  35.  Singh R, Kuai D, Guziewicz KE, et al. Pharmacological Modulation of Photoreceptor Outer Segment Degradation in a Human iPS Cell Model of Inherited Macular Degeneration. Mol Ther. Nov 2015;23(11):1700-1711. doi:10.1038/mt.2015.141

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Updated on December 3, 2020

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