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. 2010 Sep;51(9):4600-11.
doi: 10.1167/iovs.10-5438. Epub 2010 Apr 14.

Evidence of an asymmetrical endophenotype in congenital fibrosis of extraocular muscles type 3 resulting from TUBB3 mutations

Joseph L Demer  1 , Robert A Clark, Max A Tischfield, Elizabeth C Engle
Affiliations

Evidence of an asymmetrical endophenotype in congenital fibrosis of extraocular muscles type 3 resulting from TUBB3 mutations

Joseph L Demer et al. Invest Ophthalmol Vis Sci. 2010 Sep.

Abstract

Purpose: Orbital magnetic resonance imaging (MRI) was used to investigate the structural basis of motility abnormalities in congenital fibrosis of the extraocular muscles type 3 (CFEOM3), a disorder resulting from missense mutations in TUBB3, which encodes neuron-specific beta-tubulin isotype III.

Methods: Ophthalmic examinations in 13 volunteers from four CFEOM3 pedigrees and normal control subjects, were correlated with TUBB3 mutation and MRI findings that demonstrated extraocular muscle (EOM) size, location, contractility, and innervation.

Results: Volunteers included clinically affected and clinically unaffected carriers of R262C and D417N TUBB3 amino acid substitutions and one unaffected, mutation-negative family member. Subjects with CFEOM3 frequently had asymmetrical blepharoptosis, limited vertical duction, variable ophthalmoplegia, exotropia, and paradoxical abduction in infraduction. MRI demonstrated variable, asymmetrical levator palpebrae superioris and superior rectus EOM atrophy that correlated with blepharoptosis, deficient supraduction, and small orbital motor nerves. Additional EOMs exhibited variable hypoplasia that correlated with duction deficit, but the superior oblique muscle was spared. Ophthalmoplegia occurred only when the subarachnoid width of CN3 was <1.9 mm. A-pattern exotropia was frequent, correlating with apparent lateral rectus (LR) muscle misinnervation by CN3. Optic nerve (ON) cross sections were subnormal, but rectus pulley locations were normal.

Conclusions: CFEOM3 caused by TUBB3 R262C and D417N amino acid substitutions features abnormalities of EOM innervation and function that correlate with subarachnoid CN3 hypoplasia, occasional abducens nerve hypoplasia, and subclinical ON hypoplasia that can resemble CFEOM1. Clinical and MRI findings in CFEOM3 are more variable than those in CFEOM1 and are often asymmetrical. Apparent LR innervation by the inferior rectus motor nerve is an overlapping feature of Duane retraction syndrome and CFEOM1. These findings suggest that CFEOM3 is an asymmetrical, variably penetrant, congenital cranial dysinnervation disorder leading to secondary EOM atrophy.

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Figures

Figure 1.
Figure 1.
Subject 1 with the CFEOM3 phenotype, exhibiting left-side blepharoptosis, limited supraduction and adduction, and λ-pattern exotropia. Ductions were are normal for the right eye. The eyelids were manually elevated for photography in deorsumversion.
Figure 2.
Figure 2.
Subject 3 with the CFEOM3 phenotype limited to the right eye, which exhibited blepharoptosis and limitation of supraduction, infraduction, and adduction. The subject had A-pattern strabismus, with esotropia in supraversion, and exotropia in infraversion.
Figure 3.
Figure 3.
Subject 5 from pedigree AT with the CFEOM3 phenotype exhibiting left-side congenital blepharoptosis and limitation of abduction, supraduction, and infraduction, with synkinetic abduction in both infraversion and lid closure. Right eye motility was normal. Unable, version position could not be attained.
Figure 4.
Figure 4.
Subject 6 from pedigree BT with the CFEOM3 phenotype who had right blepharoptosis and right hypotropia, A-pattern strabismus, and paradoxical supraduction and abduction of the left eye on attempted deorsumversion. Both eyes had limited supraduction. Unable, version position could not be attained.
Figure 5.
Figure 5.
Quasicoronal T2 FSE MRI in subject 9 with a severe CFEOM3 phenotype. Image planes are 2 mm thick with a 4-mm gap between them, arranged from posterior at top to anterior at bottom. There was marked bilateral hypoplasia of the LPS, SR, and MR. The IR was mildly hypoplastic bilaterally. The SO muscle was preserved. An epithelial inclusion cyst present near the IR insertion was a probable effect of prior IR surgery. The globe cross section was bilaterally irregular and nonspherical. SOT, reflected SO tendon.
Figure 6.
Figure 6.
Quasi-sagittal T2 FSE MRI in subject 9 with a severe CFEOM3 phenotype, exhibiting severe bilateral hypoplasia of the LPS and SR muscles, as well as bilateral absence of the IO muscle. An epithelial inclusion cyst and artificial IOL were present in the surgically treated left orbit.
Figure 7.
Figure 7.
Quasicoronal T1 MRI in phenotypically less affected subject 1, with asymmetric hypoplasia of the left LPS and milder hypoplasia of the deep portion of the left MR and SR muscles. The inferior division of the left oculomotor nerve (CN3) was in contact with the inferior portion of the left LR muscle (top right). The motor nerve branch to the right but not left MR was visualized. CN6, abducens nerve; N to IO, motor nerve to inferior oblique muscle.
Figure 8.
Figure 8.
Quasisagittal T1 MRI in less affected subject 1, in whom only the left eye was phenotypically involved. The subject exhibited hypoplasia of the involved left LPS and SR muscles, as well as severe hypoplasia of the left IO muscle in this image plane. The left IR muscle had been surgically transected, displacing the IO nasally.
Figure 9.
Figure 9.
Coronal MRI of left orbit of subject 2 with CFEOM3, illustrating anomalous contractile thickening of LR with the fellow right eye fixating in infraduction. The subject had hypoplasia of the MR and superior rectus/levator (SR/LPS) muscles. SOV, superior ophthalmic vein.
Figure 10.
Figure 10.
Heavily T2-weighted MRI of the subarachnoid oculomotor nerve (CN3) in subject 1 with a unilateral left CFEOM3 phenotype. The right CN3 was normal at 2.0 mm wide, whereas the left CN3 was subnormal at 1.0 mm wide.
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