Congenital monocular elevation deficiency associated with a novel TUBB3 gene variant

Abstract

Background: The genetic basis of monocular elevation deficiency (MED) is unclear. It has previously been considered to arise due to a supranuclear abnormality.

Methods: Two brothers with MED were referred to Leicester Royal Infirmary, UK from the local opticians. Their father had bilateral ptosis and was unable to elevate both eyes, consistent with the diagnosis of congenital fibrosis of extraocular muscles (CFEOM). Candidate sequencing was performed in all family members.

Results: Both affected siblings (aged 7 and 12 years) were unable to elevate the right eye. Their father had bilateral ptosis, left esotropia and bilateral limitation of elevation. Chin up head posture was present in the older sibling and the father. Bell's phenomenon and vertical rotational vestibulo-ocular reflex were absent in the right eye for both children. Mild bilateral facial nerve palsy was present in the older sibling and the father. Both siblings had slight difficulty with tandem gait. MRI revealed hypoplastic oculomotor nerve. Left anterior insular focal cortical dysplasia was seen in the older sibling. Sequencing of TUBB3 revealed a novel heterozygous variant (c.1263G>C, p.E421D) segregating with the phenotype. This residue is in the C-terminal H12 α-helix of β-tubulin and is one of three putative kinesin binding sites.

Conclusion: We show that familial MED can arise from a TUBB3 variant and could be considered a limited form of CFEOM. Neurological features such as mild facial palsy and cortical malformations can be present in patients with MED. Thus, in individuals with congenital MED, consideration may be made for TUBB3 mutation screening.

Keywords: CFEOM; TUBB3; congenital fibrosis of extraocular muscles; double elevator palsy; monocular elevation deficiency.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

(A) Pedigree of family with TUBB3 mutation. (B and C) MRI from F1:II-1 showing the left anterior insular cortical malformation. (B) Axial T1-weighted image showing thickening of the anterior insular cortex (arrows) with indistinct grey–white matter interface, and (C) corresponding T2 hyperintensity (arrows) on the T2-weighted fluid-attenuated inversion recovery image. (D) Axial T2-weighted image showing thread-like oculomotor nerves (arrows) in F1:I-1. (E) Coronal T1-weighted image showing small medial recti (arrows) in F1:I-1

Figure 2

Nine positions of gaze showing monocular elevation deficiency of the right eye in F1:II-1.

Figure 3

Nine positions of gaze showing monocular elevation deficiency of the right eye in F1:II-2.

Figure 4

(A) Rotational vestibulo-ocular reflex during pitch rotations in F1:II-1 shows lack of upward movement of the right eye. (B) Abduction of the left eye is noted on downgaze which could be a pathological synkinetic movement or due to a tight inferior rectus in F1:II-1 (upper panel=upgaze; middle panel=primary position; lower panel=downgaze). (C) Eye movement recordings in F1:II-1 showing poor elevation of the right eye from primary position. Deflection upwards represents movement of the eyes upwards, while deflection downwards represents movement of the eyes downwards. X-axis=time (in seconds); Y-axis=eye rotation (in degrees). (D) Plot of the peak saccadic velocity in relation to the saccadic amplitude, showing reduced saccadic velocity of the right eye compared with the left for upgaze.

Figure 5

(A) Electropherogram from F1:II-2, showing G>C nucleotide substitution in TUBB3. This results in the amino acid substituition glutamic acid (E) to aspartic acid (D) at amino acid position 421. (B) The location of the E421 residue (cyan) mapped on the solved protein structure of TUBB3 (PDB ID: 5IJ0). This is adjacent to previously reported mutations at residues 417 and 410 associated with congenital fibrosis of extraocular muscles (orange). All three mutations are located on the H12 α-helix and predicted to be direct binding sites required for kinesin binding to the microtubule polymer.