Neurogenetics Research | Overview
Our research combines clinical, genetic, and molecular biological approaches to the study of strabismus and ocular motor neuron and axon development. Our work has focused primarily on a set of disorders we now refer to as the congenital cranial dysinnervation disorders. These are incomitant forms of strabismus in which primary gaze may be aberrant and one or both eyes are unable to move into one or multiple fields of gaze. These disorders can cause significant visual impairment and can be cosmetically disfiguring.
Through clinical and genetic studies of inherited forms of CCDDs, we have defined the following syndromes and their genetic etiologies:
We divide the CCDDs into disorders that primarily affect vertically acting extraocular muscles and those that primarily affect horizontally acting extraocular muscles. The various forms of congenital fibrosis of the extraocular muscles (CFEOM), congenital ptosis, and Marcus-Gunn primarily affect vertically acting muscles, and we propose that these disorders result primarily from aberrant development of the oculomotor and/or trochlear nuclei. The various forms of Duane syndrome, horizontal gaze palsy, and Moebius syndrome all fall within the second group, and we propose that these CCDD syndromes result primarily from aberrant development of the abducens nucleus.
Many of the forms of CCDD are inherited, and the laboratory's approach to understanding these syndromes begins with the identification and clinical classification of affected families and individuals. This ongoing process has led to the description of several new strabismus syndromes and to collaborations with clinicians worldwide. We use genetic linkage analysis to define and refine the chromosomal localization of the different CCDD syndromes, and positional cloning techniques to identify the mutated genes. The genetic work is complemented by neuropathologic and high-resolution orbital MRI investigations, conducted in collaboration with Dr. Joseph Demer at UCLA, to uncover anatomic defects and to guide the choice of candidate genes for future study.
Using this approach, our laboratory has identified the genetic etiologies of three forms of CFEOM (FEOM1-3) and four forms of Duane syndrome/horizontal gaze palsy (DURS2, DRRS, HGPPS, HOXA1 syndromes). As indicated in the figure above, four of these disorders result from errors in axon growth and guidance, while three result from mutations in transcription factors that result in early errors in cranial motor neuron development.
In addition, we have mapped a dominant locus for congenital ptosis and others have identified chromosomal breakpoints and rearrangements that result in syndromic Duane syndrome but in each case the underlying gene defect is not yet known.
Please use the links on the left to view information on the eye disorders we study and for detail on the muscles of the eye.