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Editors Selection IGR 24-3

Basic Science: Myocilin and NTG

Comment by Tin Aung & Eranga Vithana on:

80536 Myocilin Mutations in Patients With Normal-Tension Glaucoma, Alward WLM; van der Heide C; Khanna CL et al., JAMA ophthalmology, 2019; 137: 559-563

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Can molecular analysis bring more clarity to the clinical divide of normal-tension glaucoma (NTG) and high-pressure primary open-angle glaucoma (POAG)? This is the question that springs to mind when reading the recent paper by Alward et al. Stark lines of clinical classifications have been redrawn for other disease after extensive and systematic molecular characterizations; corneal dystrophies are one such example. This paper is one for blurring the lines however, and demonstrates the molecular complexity of glaucoma and questions this division in glaucoma based on arbitrary measurements of intraocular pressure (IOP).

This paper demonstrates the molecular complexity of glaucoma and questions this division in glaucoma based on arbitrary measurements of intraocular pressure (IOP). .

In this paper, the authors evaluated the role of the p.Gln368Ter MYOC mutation in patients with NTG and found that this mutation was found in patients with IOPs that were 21 mmHg or lower (deemed NTG), although at a frequency that is lower than previously detected in patients with higher IOP. This suggests that the p.Gln368Ter mutation may be associated with glaucoma in patients with normal IOPs as well as in patients with IOPs that are greater. Moreover, the data suggest that the MYOC gene is associated with glaucoma across a broader range of IOP than was previously recognized.

The authors found eleven p.Gln368Ter mutation carriers with a clinical diagnosis of NTG. Prior to this study only a single NTG patient with this mutation has been described.¹One would feel more confident if the NTG patients with the p. Gln368Ter mutation had better characterization of pre-treatment IOP profiles. The authors mention that some patients who received a diagnosis of NTG might have had higher unrecognized IOP because of diurnal variation or infrequent testing. Amongst the 11 patients, there are cases one would describe as classic NTG and the association of p.Gln368Ter MYOC mutation in this clinical entity is therefore not in question, but the frequency may be lower than that described in this study and highlights the importance of molecular investigations in well-characterized clinical samples. Nevertheless, one can now safely say MYOC is no longer only a gene associated with only high IOP.

One can now safely say MYOC is no longer only a gene associated with only high IOP

Shared genetic risk factors in clinically different entities indicate that a lot more is involved in the pathogenesis of a disease. Other genetic variants in the wider genome and non-genetic risk factors may be involved to bring about this clinical heterogeneity for POAG.

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