Myopia-26, the female-limited form of early-onset high myopia is associated with retinal ganglion cell dysfunction and primary open angle glaucoma

Abstract Background: Female-limited early-onset high myopia, also called Myopia-26 is a rare monogenic disorder characterized by severe short sightedness starting in early childhood and progressing to blindness potentially by the middle ages. Despite the X-linked locus of the mutated ARR3 gene, the disease paradoxically affects females only, with males being asymptomatic carriers. Previously, this disease has only been observed in Asian families and has not gone through detailed investigation concerning collateral symptoms or pathogenesis Results: We found a large Hungarian family displaying female-limited early-onset high myopia. Whole exome sequencing of two individuals identified a novel nonsense mutation (c.214C>T, p.Arg72*) in the ARR3 gene. We carried out basic ophthalmological testing for 18 family members, as well as detailed ophthalmological examination (intraocular pressure, axial length, fundus appearance, optical coherence tomography, visual field- and colour vision testing) and electrophysiology tests (standard and multifocal electroretinography, pattern electroretinography and visual evoked potentials) for eight individuals. We found variously impaired visual fields in four affected myopic females and a carrier male. Abnormal pattern electroretinography responses were detected in both symptomatic and carrier patients. Conclusions: This is the first description of a Caucasian family displaying Myopia-26. Pattern electroretinography implies retinal ganglion cell dysfunction present in both sexes. In conjunction with the visual field loss, this suggests the development of age-related open angle glaucoma in addition to high myopia, both attributable to the rare genetic variant of ARR3. We present two hypotheses that could potentially explain the pathomechanism of this disease.