Emin Cumhur Sener

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.

Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development

We identified homozygous truncating mutations in HOXA1 in three genetically isolated human populations. The resulting phenotype includes horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder. This is the first report to our knowledge of viable homozygous truncating mutations in any human HOX gene and of a mendelian disorder resulting from mutations in a human HOX gene critical for development of the central nervous system.

Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.

Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2.

Isolated strabismus affects 1–5% of the general population. Most forms of strabismus are multifactorial in origin; although there is probably an inherited component, the genetics of these disorders remain unclear. The congenital fibrosis syndromes (CFS) represent a subset of monogenic isolated strabismic disorders that are characterized by restrictive ophthalmoplegia, and include congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DURS). Neuropathologic studies indicate that these disorders may result from the maldevelopment of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei. To date, five CFS loci have been mapped (FEOM1, FEOM2, FEOM3, DURS1 and DURS2), but no genes have been identified. Here, we report three mutations in ARIX (also known as PHOX2A) in four CFEOM2 pedigrees. ARIX encodes a homeodomain transcription factor protein previously shown to be required for nIII/nIV development in mouse and zebrafish. Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain. These findings confirm the hypothesis that CFEOM2 results from the abnormal development of nIII/nIV (ref. 7) and emphasize a critical role for ARIX in the development of these midbrain motor nuclei.

Magnetic resonance imaging in evaluation of congenital and acquired superior oblique palsy

BACKGROUND According to the recently popularized classification of superior oblique (SO) palsy based on congenital variations of the tendon, the primary pathology is the abnormality of the SO tendon rather than an innervational problem in congenital cases. If this hypothesis is true, denervation atrophy of SO muscle should not occur in patients with congenital SO palsy. METHODS Eight patients with traumatic and nine patients with definite congenital SO palsy underwent magnetic resonance imaging (MRI) of the orbit. SO muscle width and cross-sectional area measurements were taken from coronal images and compared with the clinically uninvolved superior oblique muscles. RESULTS Atrophy of varying degrees was observed in the SO muscle both in congenital and acquired cases. No significant difference was found in the appearance of the SO muscle between acquired and congenital SO palsy groups. CONCLUSION We have been unable to demonstrate abnormalities of the SO tendon in both groups. The MRI appearance of the SO muscle suggested that in congenital SO palsy, the pathology is not limited to the tendon; there also is an abnormality of the muscle itself.

Factors influencing the successful outcome and response in strabismus surgery

In this retrospective study based on 140 esotropic and 51 exotropic patients, the factors influencing successful outcome and response to strabismus surgery were investigated. Thirteen independent variables were chosen. The pre-operative deviation was found to be the only discriminant factor for early and late successful surgical outcomes in esotropic patients. For exotropic patients the visual acuity of the left eye was the discriminant factor for early successful surgical outcome. In esotropic patients the response to surgery increased with increasing amounts of pre-operative deviation. It was lower for patients with older age of onset and larger amounts of medial rectus recession. For exotropic patients the response to surgery was higher for larger pre-operative deviations. Eliminating possible sources of error when determining the pre-operative deviation will improve the predictability of the response to surgery and surgical outcome.

A comparative study on the effects of apraclonidine and timolol on the ophthalmic blood flow velocity waveforms

Purpose: To evaluate the effects of topical timolol and apraclonidine on retrobulbar blood flow velocity waveforms in a group of healthy volunteers.Methods: Apraclonidine 1% and timolol maleate 0.5% single dose administrations were crossed over double masked in 12 healthy volunteers. The intraocular pressure measurements were followed by Doppler examination of the ophthalmic artery and the central retinal artery.Results: Intraocular pressure was reduced significantly on both treated and fellow eyes after timolol (p = 0.003, p = 0.04 respectively) and after apraclonidine (p = 0.002, p = 0.01 respectively). After apraclonidine administration end diastolic velocity, mean velocity decreased and pulsatility index increased in the ophthalmic artery of both treated and fellow eyes. Resistivity index increased and peak systolic velocity decreased only in the ophthalmic artery of treated eyes. All Doppler indices remained nonsignificant for central retinal artery of both eyes.After timolol administration there were no significant changes of the Doppler indices in the ophthalmic artery and central retinal artery of the treated and fellow eyes.Conclusion: Topical timolol and apraclonidine significantly reduced the intraocular pressure. Single dose administration of apraclonidine 1% increased the vascular impedance distal to the ophthalmic artery. On the other hand, timolol 0.5% had no effect on vascular impedance.

Factors influencing success and dose-effect relation of botulinum A treatment.

Botulinum toxin type A (BTA) treatment is an alternative to strabismus surgery. In this retrospective study the data on 45 esotropic and 49 exotropic patients with concomitant strabismus who were treated with BTA were analysed for dose-effect relationship, the effect of repeat doses and amblyopia on success of botulinum treatment. The esotropic patients were treated with a total of 80 and exotropic patients with 91 injections. The deviations were corrected within 5 degrees of straight in 33% of esotropic and 18% of exotropic patients. In esotropic patients the effect was dose dependent. This relation was not shown in exotropic patients. The repeat doses of BTA corrected the deviation to the same extent as the primary ones for both esotropic and exotropic patients.

An assessment of ocular morbidities of children born prematurely in early childhood.

PURPOSE To assess the ocular morbidities of premature children in early childhood. METHODS One hundred seventeen children with a history of gestational age of less than 37 weeks at birth underwent ophthalmic examination including visual acuity testing with Lea symbols, anterior and posterior segment examination, refraction, orthoptic examination for strabismus, and ocular biometry. They were subdivided into three groups according to gestational age (28 or less, 29 to 32, and 33 to 36 weeks). The prevalence of ocular morbidities and mean value of refractive errors were studied. RESULTS The mean age of the subjects at examination was 37.6 ± 1.1 months (range: 20 to 65 months). Only 62.4% of the eyes had visual acuity better than 20/32. The prevalence of high myopia (above -5.0 diopters [D]), myopia (below -5.0 D), and strabismus was 12.5%, 22.5% and 33.3% in the 28 weeks or less group and 3.6%, 18.9%, and 24.1% in the 29 to 32 weeks group, respectively, whereas 7.9% of the 33 to 36 weeks group had myopia and 13.2% had strabismus. Spherical equivalent in eyes that received cryotherapy and with macular heterotopia was -2.7 ± 3.9 and - 4.4 ± 3.4 D, respectively. Biometric measurements showed that high myopic eyes had statistically significantly thicker lenses compared to myopic and hyperopic eyes (P = .01). CONCLUSION This study confirms that children born prematurely are at increased risk of ocular morbidities such as defective visual acuity, myopia, and strabismus. High myopic eyes have thicker lenses compared to myopic and hyperopic eyes, and eyes with macular heterotropia and treated with cryotherapy are more prone to development of high myopia.

Inferior Oblique Muscle Weakening: Is It Possible to Quantify Its Effects on Horizontal Deviations?

Objective. To evaluate and quantify the effect of inferior oblique muscle weakening on horizontal deviations. Methods. The medical files of patients who had undergone an inferior oblique weakening as a single procedure were all reviewed. The main measures were the type of inferior oblique overaction (IOOA), pre- and postoperative amount of IOOA, and horizontal deviations in primary position. Results. The study was conducted with 66 patients (30 males, 36 females). The median age was 11 years (1–49). Of the 66 patients, 30 (45.5%) had primary and 36 (54.5%) had secondary IOOA. The most common procedure was inferior oblique anteriorization in 32 patients (48.5%). The mean postoperative horizontal and vertical deviations and the amount of IOOA were decreased postoperatively (p = 0.001 for all). The median amount of correction of horizontal near and distance deviations was 4Δ (0–20). The preoperative amount of IOOA, the presence of fourth nerve palsy, and the type of the weakening procedure had no significant effect on the amount of correction of horizontal deviations. Conclusion. The inferior oblique weakening procedures have secondary effects and warrant reduction of horizontal deviations in varying degrees. This should be borne in mind in planning a simultaneous horizontal muscle surgery and setting the surgical amount.