Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.

Effect of surgical correction of congenital ptosis on amblyopia.

PURPOSE: To determine if amblyopia improves following surgical correction of congenital ptosis. METHODS: Clinical records from 130 congenital ptosis patients presenting to the Childrens Hospital Los Angeles Department of Ophthalmology between January 1999 and April 2006 were retrospectively reviewed. Patient ages ranged from 2 months to 17 years old. Amblyopia was defined as best-corrected visual acuity of less than 20/40 and greater than 2 Snellen lines of difference between the 2 eyes. In younger patients, amblyopia was defined by a lack of fixation in the ptotic eye compared with the nonptotic one. All patients diagnosed with amblyopia were treated with occlusion therapy. RESULTS: Of the 130 patients, amblyopia was found in 21.5% (28/130), associated strabismus was found in 16.2% (21/130), and associated anisometropia was found in 14.6% (19/130). There were 50 congenital ptosis patients treated surgically. Of these patients, using an upper age limit of 8 years, 15 patients were diagnosed with preoperative amblyopia (37.5%) reducing to 2 patients (5%, p < 0.005) postoperatively (average follow-up 19.8 months). There were 40 congenital ptosis patients without associated anisometropia or strabismus treated surgically. In this group, using an upper age limit of 8 years, 9 (27%) were diagnosed with preoperative amblyopia reducing to 1 (3%, p < 0.0196) postoperatively (average follow-up 18.1 months). No new cases of amblyopia were diagnosed postoperatively. Comparatively, in the nonsurgical group, amblyopia was present on initial examination in 8.7% (2/23), and was present in 17% (4/23) of these patients at follow-up (mean, 17.2 months). CONCLUSION: Surgical correction of congenital ptosis may aid in the treatment of amblyopia.

Efficacy and complications of the transconjunctival entropion repair for lower eyelid involutional entropion.

PURPOSE: To evaluate the efficacy of the transconjunctival entropion repair (TCER) for lower eyelid involutional entropion. DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: One hundred fifty-one eyelids in 120 patients who underwent TCER for involutional entropion over a 12-year period from February 1991 through January 2003. METHODS: Surgical technique addressed all 3 anatomic factors underlying the entropion and was performed through a transconjunctival incision. Lateral tarsal strip procedure addressed horizontal eyelid laxity, lower eyelid retractor reinsertion addressed retractor disinsertion, and excision of a strip of the preseptal orbicularis oculi addressed preseptal orbicularis override. MAIN OUTCOME MEASURES: Entropion resolution, entropion recurrence, postoperative eyelid retraction, and complication rate. RESULTS: Transconjunctival entropion repair resulted in resolution of entropion, with a success rate of 96.7% (146 of 151 eyelids); entropion recurrence rate was 3.3% (5 of 151 eyelids). No patient had postoperative eyelid retraction or scleral show, and there were no overcorrections or secondary ectropions in any of the 151 eyelids. Postoperative complications occurred in 6 of 151 eyelids (4.0%) of 6 of 120 patients (5.0%) and included stitch abscess (1 eyelid, 0.7%), lateral tarsal strip dehiscence (2 eyelids, 1.3%), lateral canthal dystopia (2 eyelids, 1.3%), and conjunctivochalasis (1 eyelid, 0.7%). CONCLUSIONS: The transconjunctival lower eyelid entropion repair is effective and safe with low recurrence and complication rates. The TCER circumvents the risk of lower eyelid retraction and overcorrections that may occur with the transcutaneous approach.

Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).

PURPOSE: Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS: All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS: Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS: The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.

Full-thickness eyelid penetration during cosmetic blepharopigmentation causing eye injury.

PURPOSE: This paper aims to present a case of iatrogenic injury to the globe during cosmetic eyelid blepharopigmentation (tattooing). DESIGN/METHODS: Observational case report. RESULTS: A 46-year-old Asian female presented with chemosis and injection of the conjunctiva one day following cosmetic blepharopigmentation. The tattoo needle had penetrated full-thickness through the lid margin, resulting in a line of pigment along the superior bulbar conjunctiva with an associated inflammatory reaction. The conjunctivitis resolved with treatment, but the pigment remained. CONCLUSION: Physicians should be aware of the potential complications of cosmetic tattooing. Some measures for the prevention of iatrogenic injury are suggested.

Orbitotemporal neurofibromatosis: classification and treatment.

PURPOSE: To review the clinical findings in orbitotemporal neurofibromatosis and discuss treatment options. Clinical features, histopathologic characteristics, and treatment options are reviewed. METHODS: A Medline literature search from 1966 to 2004 was performed, using the key words: orbitotemporal neurofibromatosis, orbitopalpebral neurofibromatosis, orbitofacial neurofibromatosis, cranio-orbital neurofibromatosis, and cranio-orbital-temporal neurofibromatosis, and the pertinent literature was reviewed. Additionally, our experience with two patients is reported. The surgical procedures are discussed. CONCLUSION: The management of orbitotemporal neurofibromatosis is challenging. The planned surgical approach and extent of resection depend on the severity of the orbital soft tissue and bony involvement and on the visual potential. Ultimately, orbital exenteration may be needed for rehabilitation and cosmesis.