Myopia-26, the female-limited form of early-onset high myopia, occurring in a European family

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 pathogenesisResults: 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- testing) as well as colour vision- and electrophysiology tests (standard and multifocal electroretinography, pattern electroretinography and visual evoked potentials) for eight individuals. Ophthalmological examinations did not reveal any signs of cone dystrophy as opposed to animal models. Electrophysiology and colour vision tests similarly did not evidence a general cone system alteration, rather a central macular dysfunction affecting both the inner and outer (postreceptoral and receptoral) retinal structures in all patients with ARR3 mutation. Conclusions: This is the first description of a Caucasian family displaying Myopia-26. We present two hypotheses that could potentially explain the pathomechanism of this disease.

Early onset X‐linked female limited high myopia in three multigenerational families caused by novel mutations in the ARR3 gene

“…With this study-up, an ophthalmologist or clinical geneticist can identify a specific cause of myopia which may have implications for diagnosis, therapy and prognosis for the patient, but also for its relatives. In this report we describe three early onset high myopia Dutch families with a rare but unique and recognizable inheritance pattern caused by a pathogenic ARR3 variant and provide new insights in addition to previous reports on this type of high myopia (Széll et al, 2021;Xiao et al, 2016).…”

“…Although only four other families have been described before (Széll et al, 2021;Xiao et al, 2016), mutations in ARR3 might be a relative frequent cause of nonsyndromic early onset high myopia, because an ARR3 mutation has been found in 5% of our cohort of high myopia index patients. It can be missed in patients without taking a careful family history.…”

“…Our study lacked data on electrophysiological testing, although none of the patients exhibited color vision aberrations. In the Hungarian study, diffuse color discrimination defects without a specific axis, delayed visual evoked potential responses and a reduced amplitude of both multifocal electroretinogram (ERG) and pattern ERG was detected in both female carriers with high myopia and male carriers without myopia pointing toward a mechanism of central macular dysfunction but a normal functioning cone system, opposed to cone dysfunction in animal models Széll et al, 2021). Selective cone dysfunction, however, could not be tested.…”

“…In the Hungarian Study, four potential mechanisms were suggested to explain how pathogenic variants in ARR3 could cause myopia: a hyperopic defocus, a blue light, an ocular circadian rhythm and finally a systemic circadian rhythm mechanism (Széll et al, 2021). The hyperopic defocus hypothesis was based on the predominant expression of ARR3 in L/M cones leading to differences in sensitization of opsins to red/green stimuli potentially leading to a hyperopic defocus signal, which is a known potential trigger for myopization in animal studies (Smith & Hung, 1999; VAN MAZIJK ET AL.…”