ABSTRACT
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.
Subject(s)
Tubulin/metabolism , Amino Acid Sequence , Animals , Axons/metabolism , Brain/embryology , Brain/metabolism , Cell Survival , Child , Developmental Disabilities , Female , Humans , Kinesins/metabolism , Male , Mice , Mice, Inbred C57BL , Microtubules/metabolism , Models, Molecular , Molecular Sequence Data , Mutation, Missense , Protein Transport , Tubulin/chemistry , Tubulin/geneticsABSTRACT
Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.
Subject(s)
Cytoskeletal Proteins/genetics , Genes, X-Linked , Membrane Proteins/genetics , Nystagmus, Congenital/genetics , Brain/embryology , Brain/metabolism , Chromosome Mapping , Chromosomes, Human, X , Cytoskeletal Proteins/physiology , Eye Movements/genetics , Eye Movements/physiology , Female , Gene Expression Regulation, Developmental , Genetic Linkage , Humans , Male , Membrane Proteins/physiology , Mutation/physiology , Pedigree , Retina/metabolismABSTRACT
PURPOSE: To investigate the development of smooth pursuit in infants and to assess the influence of different stimulus characteristics. METHODS: A total of 131 eye movement recordings were obtained from 71 infants between 1 and 18 months of age using infrared photo-oculography. Smooth pursuit eye movements (SPEM) were stimulated using targets of different sizes (1.2° and 4.7° of visual angle) and velocities (7.5°/s, 15°/s and 30°/s). RESULTS: Smooth pursuit maturation peaked between 2 and 6 months of age with smooth pursuit gain showing a steep rise for all stimulus velocities and target sizes within this age range (p<0.0001). Higher stimulus velocities were associated with shorter durations of the longest smooth pursuit (p<0.0001) and higher saccadic frequencies (p<0.0001). A larger stimulus size led to an increased saccadic frequency (p=0.035). Tracking time was highest when the larger stimulus of 4.7° of visual angle was applied (p=0.022) and when it moved at a medium stimulus velocity of 15°/s (p=0.0002). The choice between a schematic face and a scrambled face did not influence the quality of the infants' smooth pursuit. CONCLUSION: SPEM show an intensive maturation between 2 and 6 months of life. By 6 months of age SPEM have already reached an almost adult-like gain of 0.8 or higher. Further maturation is slow and still incomplete by the age of 18 months. Stimulus velocity and size have an important impact on the smooth pursuit quality, which should be considered in smooth pursuit testing in infants.
Subject(s)
Child Development/physiology , Eye/growth & development , Photic Stimulation/methods , Pursuit, Smooth/physiology , Vision, Ocular/physiology , Female , Humans , Infant , Infant, Newborn , Infrared Rays , Male , Photography , Saccades/physiologyABSTRACT
PURPOSE. To prospectively study plasma levels of soluble E-selectin (sE-selectin) in premature infants and to identify their relationship to retinopathy of prematurity (ROP) on the background of known clinical risk factors. METHODS. Eighty-five sE-selectin plasma samples from 42 preterm infants born at 23 to 32 weeks of gestational age (GA) were analyzed. Twenty-two of the infants did not have ROP, eight had stage I, seven stage II, and five stage III. Infants having no ROP or stage I were designated as the no-ROP group, and infants with stage II or III formed the ROP group. RESULTS. In ROP infants, sE-selectin levels were significantly increased, with a median plasma level of 74.7 ng/mL (range, 28.5-222.0) compared with that in the no-ROP infants, with a median sE-selectin plasma level of 39.7 ng/mL (range, 11.9-130.0, P = 0.005). Children with ROP were born with lower birth weight and at lower GA. They were ventilated and needed surfactant therapy more often. However, multivariate analysis identified only sE-selectin level and GA as independent predictors. An increase of 10 ng/mL in sE-selectin increased the risk of ROP 1.6-fold. Receiver operating characteristic curve analysis confirmed the clinical usefulness of sE-selectin plasma levels in the prediction of ROP. CONCLUSIONS. Elevated sE-selectin plasma levels are associated with the development of ROP and are an independent risk predictor in addition to other known risk factors. A score based on the infant's GA and sE-selectin plasma concentrations would improve ROP prediction. Plasma concentrations in premature infants should be assessed 2 to 3 weeks after birth.
Subject(s)
Biomarkers/blood , E-Selectin/blood , Infant, Premature/blood , Retinopathy of Prematurity/blood , Birth Weight , Enzyme-Linked Immunosorbent Assay , Gestational Age , Humans , Infant, Newborn , Prospective Studies , ROC Curve , Risk FactorsABSTRACT
BACKGROUND: A relative afferent pupillary defect (RAPD) is usually a sign of visual dysfunction. Here, an unusual case of an RAPD combined with vertical strabismus but normal vision is described. Implications for pupillary pathway anatomy are discussed. METHODS: A 12-year-old girl with chronic headache was shown to have a midbrain tumour. She presented to us with intermittent diplopia. Examination included visual acuity, visual fields, pupillary function, anterior and posterior segments, and strabismus evaluation with the tangent screen. RESULTS: There was a right-sided pathologic RAPD but no afferent visual impairment. Isocoria was present in light and darkness. There was a right-sided strabismus sursoadductorius. CONCLUSIONS: A pathologic RAPD with normal vision can be caused by tumour compression of the contralateral pretectal nucleus or its afferent or efferent fibres. As an implication for pupillary pathway anatomy, our case suggests that there is equal distribution between crossing and non-crossing intercalated neurons. An associated strabismus can show a non-paralytic pattern.
Subject(s)
Astrocytoma/complications , Brain Neoplasms/complications , Nerve Compression Syndromes/etiology , Optic Nerve Diseases/etiology , Pupil Disorders/etiology , Strabismus/etiology , Visual Pathways/pathology , Astrocytoma/diagnosis , Brain Neoplasms/diagnosis , Child , Female , Humans , Magnetic Resonance Imaging , Pupil Disorders/physiopathology , Strabismus/physiopathology , Visual Acuity/physiology , Visual Fields/physiologyABSTRACT
BACKGROUND: In order to assess the influence of optical factors on the multifocal visual evoked potential (mfVEP), we obtained mfVEPs with optimal refraction and compared them to recordings with various degrees of dioptrical defocus. METHODS: Monocular mfVEPs were recorded from the right eye in eight normal subjects. Dartboard stimuli with 60 sectors arranged in six concentric annuli spanning 60 degrees were generated with a VERIS system and presented on a computer monitor. Two pairs of electrodes were placed 3 cm above and below and 3 cm to the right and left of the inion. Two sets of mfVEP records per subject were obtained, one with best-corrected visual acuity and another when the stimulus was defocused by +1.0, +2.0 or +3.0 D. A signal-to-noise ratio (SNR) measure was calculated for every response from the two channels. RESULTS: The effect of defocus depended on eccentricity: when defocus was at +2.0 D and higher, reducing visual acuity to <0.3, the central mfVEP responses were reduced to approximately 60%, while defocus had no marked effect at eccentricities >7 degrees. CONCLUSIONS: The results suggest that, in contrast to the mfERG, the mfVEP requires optimal refraction to correctly assess the cortical responses.
Subject(s)
Evoked Potentials, Visual/physiology , Refraction, Ocular/physiology , Refractive Errors/physiopathology , Vision Disorders/physiopathology , Visual Acuity/physiology , Adult , Electroretinography , HumansABSTRACT
BACKGROUND: Congenital fibrosis of extraocular muscles (CFEOM) is a complex strabismus syndrome that typically occurs in isolation and results from dysfunction of all or part of cranial nerves III (CNIII) and IV (CNIV) and/or the muscles that these nerves innervate. Only a few patients with CFEOM and additional central nervous system malformations have been reported. We describe four additional patients with CFEOM associated with central nervous system (CNS) abnormalities. METHODS: Four patients who presented with congenital restriction of eye movements in association with neurological abnormalities underwent complete ophthalmological examination including electroretinography (ERG) and eye movement recordings. Neurological examinations, neuroradiological studies, muscle histology, chromosomal and genetic linkage analysis were performed. RESULTS: Clinical examination and forced duction testing confirmed that all four patients met criteria for CFEOM; all had congenital restrictive ophthalmoplegia primarily affecting extraocular muscles innervated by the oculomotor nerve. Two brothers had CFEOM and Marcus Gunn jaw winking. In each of the four cases, CFEOM occurred in association with one or several neuroradiological findings, including agenesis of the corpus callosum, colpocephaly, hypoplasia of the cerebellar vermis, expansion of the ventricular system, pachygyria, encephalocele and/or hydrancephaly. CONCLUSIONS: We present four cases of CFEOM in association with CNS malformations that confirm that CFEOM can be part of a more complex neurological dysfunction and provide further support to a neurogenic aetiology for this disorder. We also describe for the first time the coexistence of CFEOM and Marcus Gunn jaw winking in two siblings. This suggests a genetic mechanism. Aberrant innervation supports primary developmental abnormality of cranial nerves in CFEOM.
Subject(s)
Blepharoptosis/congenital , Blepharoptosis/complications , Central Nervous System/abnormalities , Oculomotor Muscles/pathology , Ophthalmoplegia/congenital , Ophthalmoplegia/complications , Blepharoptosis/diagnosis , Blepharoptosis/physiopathology , Child , Electrooculography , Electroretinography , Eye Movements , Fibrosis , Humans , Infant , Infant, Newborn , Magnetic Resonance Imaging , Male , Nervous System Malformations/complications , Ophthalmoplegia/diagnosis , Ophthalmoplegia/physiopathology , SyndromeABSTRACT
A patient with chronic inflammatory demyelinating polyneuropathy (CIDP) presented with an isolated unilateral adduction deficit and ptosis. Investigations were negative until the onset of limb weakness and fatigue 2 years later. At that time, electroneuromyography, cerebrospinal fluid examination, and magnetic resonance imaging confirmed the diagnosis of CIDP. Thus, ophthalmic signs can precede extremity and bulbar signs with a long latency in CIDP.
Subject(s)
Blepharoptosis/diagnosis , Diplopia/diagnosis , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Adult , Blepharoptosis/drug therapy , Brain/pathology , Diplopia/drug therapy , Glucocorticoids/therapeutic use , Humans , Immunoglobulins, Intravenous/therapeutic use , Magnetic Resonance Imaging , Male , Methylprednisolone/therapeutic use , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/drug therapyABSTRACT
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.