TY - CHAP
T1 - Effects of failure of development of crossing brainstem pathways on ocular motor control
AU - Jen, Joanna C.
N1 - Funding Information:
This work was supported by the National Institutes of Health R01 EY15311.
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - ROBO3 mutations
KW - brainstem maldevelopment
KW - disrupted midline crossing
KW - horizontal gaze palsy
KW - roundabout
KW - scoliosis
UR - http://www.scopus.com/inward/record.url?scp=49449104453&partnerID=8YFLogxK
U2 - 10.1016/S0079-6123(08)00618-3
DO - 10.1016/S0079-6123(08)00618-3
M3 - Chapter
C2 - 18718292
AN - SCOPUS:49449104453
SN - 9780444531636
T3 - Progress in Brain Research
SP - 137
EP - 141
BT - Using Eye Movements as an Experimental Probe of Brain function A Symposium in Honor of Jean Buttner-Ennever
PB - Elsevier
ER -