We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific β-tubulin isotype III, result in a spectrum of human nervous system disorders 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 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 normal TUBB3 is required for axon guidance and maintenance in mammals.

The mechanisms controlling axon guidance are of fundamental importance in understanding brain development. Growing corticospinal and somatosensory axons cross the midline in the medulla to reach their targets and thus form the basis of contralateral motor control and sensory input. The motor and sensory projections appeared uncrossed in patients with horizontal gaze palsy with progressive scoliosis (HGPPS). In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila , zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain axon midline crossing.

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.

PurposeThe optic nerve (ON) sheath's role in limiting duction has been previously unappreciated. This study employed magnetic resonance imaging (MRI) to demonstrate this constraint on adduction.MethodsHigh-resolution, surface coil axial MRI was obtained in 11 normal adults, 14 subjects with esotropia (ET) having normal axial length (AL) < 25.8 mm, 13 myopic subjects with ET and mean AL 29.3 ± 3.3 (SD) mm, and 7 subjects with exotropia (XT). Gaze angles and ON lengths were measured for scans employing eccentric lateral fixation in which an ON became completely straightened.ResultsIn all groups, ON straightening occurred only in the adducting, not abducting, eye. Adduction at ON straightening was 26.0 ± 8.8° in normal subjects, not significantly different from XT at 22.2 ± 11.8°. However, there was significant increase in comparable adduction in ET to 36.3 ± 9.3°, and in myopic ET to 33.6 ± 10.7° (P < 0.04). Optic nerve length at straightening was 27.6 ± 2.7 mm in normals, not significantly different from 28.2 ± 2.8 mm in ET and 27.8 ± 2.7 mm in XT. In myopic ET, ON length at straightening was significantly reduced to 24.0 ± 2.9 mm (P < 0.002) and was associated with globe retraction in adduction, suggesting ON tethering.ConclusionsLarge adduction may exhaust length redundancy in the normally sinuous ON and sheath, so that additional adduction must stretch the sheath and retract or deform the globe. These mechanical effects are most significant in ET with axial myopia, but may also exert traction on the posterior sclera absent strabismus or myopia. Tethering by the ON sheath in adduction is an important, novel mechanical load on the globe.

The vestibulo-ocular reflex (VOR) generates compensatory eye movements in response to angular and linear acceleration sensed by semicircular canals and otoliths respectively. Gaze stabilization demands that responses to linear acceleration be adjusted for viewing distance. This study in humans determined the transient dynamics of VOR initiation during angular and linear acceleration, modification of the VOR by viewing distance, and the effect of unilateral deafferentation. Combinations of unpredictable transient angular and linear head rotation were created by whole body yaw rotation about eccentric axes: 10 cm anterior to eyes, centered between eyes, centered between otoliths, and 20 cm posterior to eyes. Subjects viewed a target 500, 30, or 15 cm away that was extinguished immediately before rotation. There were four stimulus intensities up to a maximum peak acceleration of 2,800 degrees/s2. The normal initial VOR response began 7-10 ms after onset of head rotation. Response gain (eye velocity/head velocity) for near as compared with distant targets was increased as early as 1-11 ms after onset of eye movement; this initial effect was independent of linear acceleration. An otolith mediated effect modified VOR gain depending on both linear acceleration and target distance beginning 25-90 ms after onset of head rotation. For rotational axes anterior to the otoliths, VOR gain for the nearest target was initially higher but later became less than that for the far target. There was no gain correction for the physical separation between the eyes and otoliths. With lower acceleration, there was a nonlinear reduction in the early gain increase with close targets although later otolith-mediated effects were not affected. In subjects with unilateral vestibular deafferentation, the initial VOR was quantitatively normal for rotation toward the intact side. When rotating toward the deafferented side, VOR gain remained less than half of normal for at least the initial 55 ms when head acceleration was highest and was not modulated by target distance. After this initial high acceleration period, gain increased to a degree depending on target distance and axis eccentricity. This behavior suggests that the commissural VOR pathways are not modulated by target distance. These results suggest that the VOR is initially driven by short latency ipsilateral target distance dependent and bilateral target-distance independent canal pathways. After 25 ms, otolith inputs contribute to the target distance dependent pathway. The otolith input later grows to eventually dominate the target distance mediated effect. When otolith input is unavailable the target distance mediated canal component persists. Modulation of canal mediated responses by target distance is a nonlinear effect, most evident for high head accelerations.

PURPOSE-In axial high myopes with "heavy eye" syndrome, orbital magnetic resonance imaging (MRI) demonstrates degeneration of the lateral rectus-superior rectus (LR-SR) band, so that the lateral rectus muscle slips inferiorly to produce esotropia and hypotropia. We asked if this degeneration might also cause strabismus in nonmyopic elderly patients. METHODS-Three strabismic elderly patients, three strabismic high myopes, and 12 orthotropic elderly subjects underwent ophthalmic examinations and orbital MRI. Lateral rectus position was determined relative to globe center from quasicoronal images and correlated with LR-SR band structure. MRI was compared to histology of four cadaveric orbits ranging in age from 17 months to 93 years. RESULTS-Two strabismic patients exhibited hypotropia and one exhibited esotropia. Their mean axial length was 24.1 ± 0.8 mm (mean ± SD), compared to 31.6 ± 1.4 mm for myopes. The lateral rectus muscle position of elderly strabismic subjects averaged 4.6 ± 1.7 mm inferior to globe center, which was significantly lower than that of orthotropic elderly subjects (2.1 ± 1.9 mm; P = 0.01) and similar to that of high myopes (5.1 ± 3.2 mm). By MRI, 100% of strabismic elderly orbits, 67% of strabismic myopic orbits, and 12.5% of control elderly orbits showed LR-SR band thinning, discontinuity, or displacement. LR-SR band degeneration was present histologically only in older cadavers. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. CONCLUSION-Age-related LR-SR band degeneration permits the lateral rectus muscle to slip inferiorly in elderly non-myopes, a mechanism of strabismus similar to myopic "heavy eye" syndrome. Imaging may assist in diagnosing this mechanical cause of age-related strabismus. NIH Public Access

Magnetic resonance imaging (MRI) now enables precise visualization of the mechanical state of the living human orbit. Resulting insights have motivated histological re-examination of human and simian orbits, providing abundant consistent evidence for the active pulley hypothesis, a re-formulation of ocular motor physiology. Each extraocular muscle (EOM) consists of a global layer (GL) contiguous with the tendon and inserting on the eyeball, and a similar-sized orbital layer (OL) inserting on a connective tissue ring forming the EOM pulley. The pulley controls the EOM path and serves as the EOM's functional origin. Activity of the OL positions the pulley along each rectus EOM to assure that its pulling direction shifts by half the change in ocular orientation, the half-angle behavior characteristic of a linear ocular motor plant. Half-angle behavior is equivalent to Listing's law of ocular torsion, and makes 3-D ocular rotations effectively commutative. Pulleys are configured to maintain oblique EOM paths orthogonal to half-angle behavior, and violate Listing's law during the vestibulo-ocular reflex. Rectus pulley positions shift during convergence, facilitating stereopsis. Innervations, fiber types, and metabolism of the OL and GL differ, consistent with the elastic loading of the former, and viscous loading of the latter. Disorders of the location and stability of rectus pulleys are associated with predictable patterns of incomitant strabismus that may mimic cranial nerve palsies. Surgical interventions improve defective pulley function. Understanding of ocular motor control requires characterization of the behavior of the EOM pulleys as well as knowledge of angular eye orientation.

Overview. Neurologists are frequently called upon to evaluate patients with vertigo and dizziness and, in some cases, to make sense of abnormal vestibular tests. Consequently, it is useful to have some familiarity with the methods used to test vestibular function.The vestibulo-ocular reflex (VOR) is a reflex that acts at short latency to generate eye movements that compensate for head rotations in order to preserve clear vision during locomotion. The VOR is the most accessible gauge of vestibular function. Evaluating the VOR requires application of a vestibular stimulus and measurement of the resulting eye movements.This report reviews the advantages and limitations of the methods of stimulating the vestibular system: caloric irrigation, rotational chair testing, and auto-rotational testing. Vestibular testing in children is given additional consideration because of the paucity of recent reviews on the topic. This report will not address eye movement recording techniques, the neurophysiology of the VOR, which is reviewed elsewhere, 1,2 or interpretation of nystagmus.Literature review. This evidence-based assessment was developed from a review of published articles obtained through the MEDLINE database of the National Library of Medicine. Relevant publications were rated by the strength of evidence according to a scheme approved by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (see Appendix 2).