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Jessica K. Rankin, Wai-Man Chan, Caroline Andrews, David G. Hunter, Darren Oystreck, Sarah Mackinnon, Elizabeth C. Engle; TUBB3 Missense Mutations Cause Atypical Moebius Syndrome Phenotypically Identical to CFEOM3. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6346.
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We screened patients diagnosed with Moebius syndrome for mutations in the TUBB3 gene, which encodes the neuron-specific β-tubulin isotype and is mutated in CFEOM3 (Tischfield et al, Cell, 2010).
Twenty-four probands diagnosed with Moebius Syndrome and who attended the 2008 or 2010 Moebius Syndrome Foundation Family Meeting underwent orthoptic examination, answered detailed questionnaires, and submitted blood or saliva samples. TUBB3 exons and flanking introns were sequenced. Medical records were examined for 4 of the probands.
Sequence analysis revealed TUBB3 mutations in 4 of the 24 probands and each of these was de novo. Two harbored1228G>A (E410K) and one harbored 785G>A (R262H), both previously reported mutations. A novel TUBB3 mutation 1229A > T (E410V) was identified in the fourth. On examination, all four mutation-positive probands had bilateral facial palsy and infraducted eyes that did not get to midline on attempted elevation. All had prior surgery to correct exotropia and three had undergone surgeries to correct ptosis. Two had significant residual exotropia on examination. Brain MRI were reviewed for three and revealed thinning of the corpus collosum. These findings were similar to those described in CFEOM3. None of the 20 mutation-negative probands had ptosis or infraduction on examination. Seventeen of the mutation-negative probands had full vertical movements and were either orthotropic or esotropic. Two were exotropic, but had full vertical movements. One had limitation in vertical movements and was esotropic. Seven of the mutation-negative probands had prior surgeries to correct esotropia. None of the mutation-negative probands had surgery to correct ptosis.
A subset of children diagnosed with Moebius syndrome harbor de novo heterozgyous missense mutations in TUBB3 resulting in an atypical Moebius syndrome phenotype characterized by exotropia, infraduction in primary gaze with limitation in up-gaze, and bilateral ptosis. Most affected individuals also have thinning of the corpus callosum by MR imaging. Thus, Moebius patients with this distinctive phenotype, which appears to overlap with CFEOM3, should be screened for mutations in the TUBB3 gene.
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