Long-Term Follow-Up of Normal Tension Glaucoma Patients With TBK1 Gene Mutations in One Large Pedigree

Abstract

Purpose: To characterize features of glaucoma associated with a TANK binding kinase 1 (TBK1) gene duplication, which is among the most common molecularly defined causes of normal tension glaucoma (NTG).

Design: Retrospective observational case series.

Methods: We conducted a retrospective case series, by reviewing medical records of 7 members of a pedigree with NTG caused by TBK1 gene duplications. Clinical features of these patients at diagnosis, throughout management, and at latest follow-up were identified, including age, intraocular pressure (IOP), central corneal thickness (CCT), optic nerve head appearance, and mean deviation (MD) assessed with Humphrey visual field (HVF) testing protocols.

Results: At initial diagnosis, the mean age was 35 ± 7 years, IOP was 16 ± 2.1 mm Hg, cup-to-disc (C/D) ratio was 0.9 ± 0.08, and MD assessed via HVF 30-2 and/or 24-2 testing protocols was -9.0 ± 8.9 (range: -1.8 to -27) dB in the 14 study eyes. At initial diagnosis, 4 of 14 eyes (28%) had no visual field defect, 4 (28%) had early visual field defects, and 6 (43%) had severe visual field defects. Patients had a mean follow-up of 21.5 ± 9.0 years and experienced an average reduction of IOP by 28%. Four of 12 eyes (33%) had stable visual fields throughout follow-up, while 8 eyes (67%) had slow-to-moderate progression. The 30-2 and/or 24-2 HVF tests had an average change in MD of -0.53 ± 0.26 dB/year. No eyes had rapid progression with an MD >1.0 dB/year. At final follow-up, the mean IOP was 11.5 ± 2.9, and C/D ratio was 0.94 ± 0.4. At final follow-up, 3 of 14 eyes (21%) had early visual field defects, 4 (29%) had moderate visual field defects, and 7 (50%) had severe visual field defects. Six of 14 eyes (43%) met criteria for legal blindness.

Conclusions: We provide the first report of the clinical features and long-term clinical course in a family of NTG patients with TBK1 gene duplications. TBK1-associated glaucoma exhibits classic features of NTG. Patients present with severe disease at a relatively early age and most (67%) have slow-to-moderate progression of their visual field defects. The rate of visual field change appears correlated with the magnitude of IOP, suggesting that it may be advantageous to set extremely low IOP targets for some patients with TBK1-associated glaucoma.

Figure 1.. A three generation African American pedigree with NTG caused by a TBK1 gene duplication.

Family members diagnosed with NTG are indicated by shaded symbols. All ten living family members with NTG carry a TBK1 gene duplication. This family has been described in a previous report.

Figure 2.. First and last available disc photos and Humphrey visual field tests.

Long term clinical follow-up data were available from seven family members with NTG caused by a TBK1 gene duplication. First and last available disc photos demonstrate progressive optic disc cupping. First and last available Humphrey visual field tests (30-2, 24-2, and/or 10-2 protocols) demonstrate progressive glaucomatous visual field loss. Visual field tests that were obtained at the same time as optic disc photos are also presented. Patients are indicated by their pedigree symbol identification number from Figure 1. Only one set of disc photos was available from patient III-6.

Figure 3.. Longitudinal measures of IOP and Humphrey visual field tests.

Panels A-H show longitudinal plots of IOP and mean deviation (MD) from HVF tests for 8 eyes of patients with NTG caused by a TBK1 gene duplication. Linear fits Panel A and B show plots for Patient III-7 OD and OS that have stable HVF tests throughout follow-up. Panel C – E show plots for Patient III-2 OD and Patient II-2 OD and OS that have HVF tests with slow progression with a change in MD < 0.5 dB / year. Panel F – H show plots for Patient III-5 OD and OS and Patient III-1 OS that have HVF tests with moderate progression with a change in MD of 0.5 – 1.0 dB / year. The time at which a trabeculectomy surgery was performed is indicated by a vertical line in these patients.