Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Mervyn G Thomas,Frank A Proudlock,Brenda Barry,Rebecca J Mclean,Wai-Man Chan,Helen J Kuht,Bashir Al-Diri,Gail D E Maconachie,Michael Hisaund,Irene Gottlob,Elizabeth C Engle,Zhanhan Tu,Viral Sheth

doi:10.3390/ijms22052575

Abstract

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Highlights

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder characterized by non-progressive ophthalmoplegia with or without blepharoptosis [1]
CFEOM1 is inherited in an autosomal dominant manner and can arise from mutations of KIF21A (CFEOM1A) [4] or TUBB3 (CFEOM1B) [5]
We identify that patients with CFEOM have smaller optic nerves with deeper optic cups and significantly thinner neuro-retinal rims

Summary

Introduction

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder characterized by non-progressive ophthalmoplegia with or without blepharoptosis [1]. CFEOM1 is the most common subtype and typically presents with bilateral congenital non-progressive restrictive ophthalmoplegia with the eyes partially or fully fixed in depression, limited upgaze, and blepharoptosis [3]. CFEOM1 is inherited in an autosomal dominant manner and can arise from mutations of KIF21A (CFEOM1A) [4] or TUBB3 (CFEOM1B) [5]. CFEOM2 is characterized by congenital non-progressive bilateral exotropic ophthalmoplegia and blepharoptosis. CFEOM3 has variable clinical features, which can include varying degrees of congenital non-progressive external ophthalmoplegia and blepharoptosis. CFEOM3 is inherited in an autosomal dominant manner and arises from TUBB3 or TUBB2B mutations [5]. We have reported that congenital monocular elevation deficiency, or double elevator palsy, can be part of CFEOM3 and arise from TUBB3 mutations [8]

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