A new paradigm for delivering personalised care: integrating genetics with surgical interventions in BEST1 mutations

Abstract

Background: The availability and reduced cost of genotyping has improved gene susceptibility testing and our scientific understanding of disease pathophysiology. Whilst several personalised translational models exist within medical frameworks, genetic-based surgical therapy is a translational application not widely used in surgical specialties.

Method: We present a clinical series of five patients with genetically confirmed bestrophinopathy and malignant glaucoma (MG). Patients were followed up for 12 months or more after receiving surgical intervention to manage refractory intraocular pressure (IOP) resistant to medical treatment.

Findings: Patients with BEST1 gene mutations are at higher risk of MG after filtration surgery. A multi-disciplinary approach after four patients experienced poor outcomes concluded that traditional first-line glaucoma surgery was not sufficient to prevent visual loss. A fifth patient presenting with the identified at-risk phenotype underwent primary pars plana vitrectomy, with pars plana Baerveldt tube insertion, successfully preventing MG and had no glaucoma progression after 5 years.

Interpretation: We provide proof-of-principle that genetic analysis can be used to inform the selection of surgical therapy to improve outcomes. In this case, a refinement of current surgical methods to avoid MG. Although challenges remain, personalised surgery has the potential to improve clinical outcomes beyond the scope of current surgical practice.

Fig. 1

Anterior segment-OCT images of Case 2. First row: anterior segment-OCT images the day after tapering down g. atropine 1% from tds to od in both eyes. Second row: anterior segment-OCT images during the second aqueous misdirection episode in both eyes, during treatment with g. atropine 1% od. Third row: anterior segment-OCT images of anterior chamber angles, showing reduced angle opening distance 500 (AOD 500), and the marked shallowing of the anterior chamber during aqueous misdirection in both eyes. Fourth row: anterior segment-OCT images during initial resolution of aqueous misdirection in the left eye, 3 days after left CLCBA. Fifth row: anterior segment-OCT images 8 weeks after left CLCBA. Aqueous misdirection has now resolved in both eyes. Sixth and seventh row: colour photographs and fundus autofluorescence with bilateral advanced PACG, showing bilateral ARB, bilateral optic discs drusen and macular perifoveal lesions typical of ARB

Fig. 2

Colour photographs, visual fields and anterior segment imaging of patient 3. The right eye is shown in a–d, left eye in e–g. Significant iridotrabecular contact was seen in the right eye on AS-OCT (a), and upon instillation of g. pilocarpine 2% drops, the angle remained closed (b). One week after right clear lens extraction (c), the angles were still closed on gonioscopy and AS-10.1038/s41433-019-0553-5 OCT. The anterior chamber (AC) continued to shallow over 5 weeks, requiring g. atropine drops to deepen the AC, and treat any subclinical aqueous misdirection. d A good response to g. atropine, the IOP was lowered and more open AC angles were seen. The left eye underwent trabeculectomy before these images were taken (e, f). f A superior bleb is on the left side of this cross-sectional image, taken vertically. On high resolution AS-OCT, significant iridocorneal contact completely occluding the anterior chamber angle is seen in f. After clear lens extraction in the left eye, the AC shallowed initially, but deepened after cyclodiode ablation of the ciliary body (g). The IOP in the left eye remains high, despite deepening of the drainage angle and the patient subsequently had an anterior chamber Baerveldt tube inserted for IOP control

Fig. 3

The personalised surgical (surgico-genetic) model for managing angle-closure glaucoma secondary to BEST1 mutations. In sub-specialist clinics, the genetic aetiology of a condition may be recognised by a specialty group/physicians, while the surgical intervention is managed by a different specialty or surgical group. During joined-up care, careful recognition of any association between mutation status and adverse surgical outcomes provides a unique opportunity for further understanding of surgico-genetic interventions to personalise treatments. We provide an example here with BEST1 mutations. A known surgical intervention, primary pars plana vitrectomy and primary Baerveldt tube implantation in the posterior chamber, which addresses the vitreopathy, can become the treatment of choice when secondary angle-closure glaucoma is detected. This avoids the complications of malignant glaucoma that are highly frequent with treatments like lens extraction or trabeculectomy in the presence of BEST1 mutations. AR autosomal recessive, AD autosomal dominant