Effects of failure of development of crossing brainstem pathways on ocular motor control.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, inherited disorder characterized by a congenital absence of conjugate horizontal eye movement with progressive scoliosis developing in childhood in patients who are otherwise neurologically intact. Detailed structural neuroimaging studies demonstrated abducens nerves and the absence of fibrosis in the extraocular muscles, and a remarkably dysmorphic hindbrain, with hypoplasia and flattened, butterfly-like medulla with deep midline cleft. Diffusion tensor imaging further demonstrated a widespread lack of crossing fibres in the brainstem, supported by evoked potential studies showing uncrossed descending motor and ascending sensory pathways in HGPPS patients. In these patients, we identified homozygous or compound heterozygous mutations in a gene we named ROBO3, which shares homology with evolutionarily conserved roundabout genes that are important in neural and vascular wiring. Removal of Robo3 in mice led to the absence of commissural crossing throughout the spinal cord and hindbrain (and death soon after birth). Therefore, ROBO3 is required for hindbrain axon midline crossing and morphogenesis in both human and mouse. We continue to investigate how ROBO3 mutations lead to massive miswiring in the hindbrain and disruption of conjugate horizontal gaze. Elucidation of the full extent of the anatomical abnormalities in HGPPS awaits improved neuroimaging techniques and detailed pathological studies.