Abnormal retinal development associated with FRMD7 mutations

Mervyn G Thomas,Susan Lindsay,Bart P Leroy,Shery Thomas,Irene Gottlob,Rebecca J Mclean,Gail Maconachie,Viral Sheth,Anthony T Moore,Moira Crosier,Masasuke Araki,Anil Kumar

doi:10.1093/hmg/ddu122

Abstract

Idiopathic infantile nystagmus (IIN) is a genetically heterogeneous disorder, often associated with FRMD7 mutations. As the appearance of the retina is reported to be normal based on conventional fundus photography, IIN is postulated to arise from abnormal cortical development. To determine whether the afferent visual system is involved in FRMD7 mutations, we performed in situ hybridization studies in human embryonic and fetal stages (35 days post-ovulation to 9 weeks post-conception). We show a dynamic retinal expression pattern of FRMD7 during development. We observe expression within the outer neuroblastic layer, then in the inner neuroblastic layer and at 9 weeks post-conception a bilaminar expression pattern. Expression was also noted within the developing optic stalk and optic disk. We identified a large cohort of IIN patients (n = 100), and performed sequence analysis which revealed 45 patients with FRMD7 mutations. Patients with FRMD7 mutations underwent detailed retinal imaging studies using ultrahigh-resolution optical coherence tomography. The tomograms were compared with a control cohort (n = 60). The foveal pit was significantly shallower in FRMD7 patients (P < 0.0001). The optic nerve head morphology was abnormal with significantly decreased optic disk area, retinal nerve fiber layer thickness, cup area and cup depth in FRMD7 patients (P < 0.0001). This study shows for the first time that abnormal afferent system development is associated with FRMD7 mutations and could be an important etiological factor in the development of nystagmus.

Highlights

Infantile nystagmus is characterized by involuntary to and fro movements of the eyes, which is present at birth or manifesting within the first few months of life
We show a dynamic expression pattern of FRMD7 mRNA in the developing neural retina between Carnegie stages CS15 –CS23 and 9 weeks postconception
This study shows for the first time that patients with infantile nystagmus (IIN) have retinal and optic nerve changes

Summary

Introduction

Infantile nystagmus is characterized by involuntary to and fro movements of the eyes, which is present at birth or manifesting within the first few months of life. Nystagmus has an estimated prevalence of 2.4 in 1000 [1] and is associated with significant negative social stigma and poor visual function scores [2,3]. The pathophysiology of this disorder is unclear, numerous hypotheses have been put forward. Previous animal models for infantile nystagmus have suggested that axonal misrouting at the level of the chiasm could be a common mechanism [4]. In patients with albinism and achiasma, both associated with infantile nystagmus, misrouting of retinal ganglion cell axons within the retinofugal pathway at the level of the chiasm is observed. In many other forms of infantile nystagmus [e.g. aniridia, achromatopsia, idiopathic infantile nystagmus (IIN)] visually evoked potentials show interhemispherical symmetry, suggestive of normal decussation of retinal ganglion

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