Evidence of an Asymmetrical Endophenotype in Congenital Fibrosis of Extraocular Muscles Type 3 Resulting from TUBB3 Mutations
ABSTRACT 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.
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.
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.
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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Article: Evidence of an Asymmetrical Endophenotype in Congenital Fibrosis of Extraocular Muscles Type 3 Resulting from TUBB3 Mutations
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ABSTRACT: BACKGROUND Connective tissue pulleys determine extraocular muscle force directions and pulley heterotopy can induce strabismus. The etiology and type of pulley abnormalities vary with patient age, resulting in different but predictable types presentations of strabismus. METHODS Magnetic resonance imaging (MRI) was obtained in 95 patients with pulley heterotopy, of whom 56 had childhood-onset pattern strabismus, and was compared with published data on 28 patients aged 69 +/- 12 years who had sagging eye syndrome. Control data were from age-matched normal controls with no strabismus. RESULTS Patients with childhood-onset strabismus had intact lateral rectus superior rectus band ligaments and straight extraocular muscle paths but exhibited pulley array A pattern associated incyclorotation or V pattern associated excyclorotation. Rectus transposition surgery collapsed patterns. Patients with sagging eye syndrome exhibited blepharoptosis, superior sulcus defect, and inferolateral displacement of rectus pulleys with elongation of extraocular muscles that followed curved paths. Symmetrical lateral rectus pulley sag was associated with divergence paralysis esotropia; asymmetrical sag > 1 mm, with cyclovertical strabismus. Both lateral rectus resection and medial rectus recession treated divergence paralysis esotropia. Partial vertical rectus tenotomy treated cyclovertical strabismus. CONCLUSIONS Childhood onset pulley abnormalities are associated with A or V pattern strabismus and external anatomical features suggest that these pulley defects are probably congenital. Adult onset pulley defects commonly result from age-related tissue involution and external features such as adnexal laxity are also helpful in recognizing involution as a possible etiology of strabismus.Journal of American Association for Pediatric Ophthalmology and Strabismus 08/2014; 18(4):309-315. DOI:10.1016/j.jaapos.2014.01.019 · 1.14 Impact Factor
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ABSTRACT: A girl with a clinical presentation suggestive of unilateral congenital fibrosis of the extraocular muscles type 3 at 2 years of age years later developed progressive ophthalmoplegia and an afferent pupillary defect. Reimaging revealed a lesion diagnosed as a sclerosing cavernous sinus hemangioma with focal calcification. Cavernous sinus hemangioma is a rare, benign vascular malformation whose growth causes cranial nerve compression. Although frequently missed on routine neuroimaging, characteristic radiologic findings distinguish it from lesions such as meningioma.Journal of AAPOS: the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus 04/2014; 18(3). DOI:10.1016/j.jaapos.2014.02.006 · 1.14 Impact Factor
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ABSTRACT: In this article, an update is presented of the correlation of imaging and genetic findings in congenital malformations of the central nervous system (CMCNS). A nonsystematic search of the PubMed/Medline database was performed. The congenital disorders were classified in 3 groups of malformation: ventral induction disorders, cortical malformations, and congenital malformations of the posterior fossa. The highlights of genotype-imaging phenotype correlation of some congenital malformations are provided. It is hoped that developments in genotype-MR phenotype in CMCNS will foster further prognostic and pathogenic breakthroughs for the frequently associated neurologic dysfunction in children affected by these common diseases. Copyright © 2015 Elsevier Inc. All rights reserved.Neuroimaging Clinics of North America 02/2015; 25(1):53-67. DOI:10.1016/j.nic.2014.09.003 · 1.29 Impact Factor