Horizontal gaze palsy with progressive scoliosis | Overview
Horizontal gaze palsy with progressive scoliois (HGPPS) is a rare recessive Congenital Cranial Dysinnervation Disorder that has been reported in several dozen consanguineous families (related by blood) of Greek1-4, Japanese5,6, Chinese7,8, Israeli9, North American10-12, Dutch13, Italian14,15, German16-18, Asian19, Saudi Arabian20, and Indian20 descent.
Horizontal Gaze Palsy is rarely reported in isolation and may be diagnosed as Duane Syndrome Type III. Horizontal gaze palsy together with facial weakness is classified as Moebius syndrome. The only consistently inherited form of congenital Horizontal gaze palsy is when it is co-inherited with progressive scoliosis.
An individual with HGPPS demonstrating absent horizontal eye movement on attempted gaze to right or left but normal vertical gaze upward and downward.
Individuals with HGPPS are born with no horizontal eye movements and develop scoliosis (curvature of the spine) as infants or children. Vertical eye movements are typically normal.
An individual with scoliosis as demonstrated by a coronal scout MR imaging of the thoracic and lumbar spine.
The progressive thoracic scoliosis found in individuals with HGPPS can be detected as early as the first months of life and is typically diagnosed by mid-childhood. No underlying pathology of muscle, spinal cord, or spine has been detected and the defect seems to most closely mimic idiopathic scoliosis.
In 2002 Jen et al20 reported identification of two HGPPS pedigrees residing in Saudi Arabia, one of Saudi and one of Indian descent. Homozygosity mapping using a 10 cM genome-wide scan revealed a 30 cM homozygous region in all six affected individuals on chromosome 11q23-q25.
In collaboration with Joanna Jen and researchers at UCLA we identified 8 additional HGPPS families located in Saudi Arabia, Turkey, Greece, Pakistan and Italian that mapped or reduced to homozygosity in the HGPPS critical region. We then went on to identify missense, nonsense, frameshift, and splicing mutations in the axon guidance molecule gene, ROBO3, in all ten HGPPS families21. Results of neuroimaging and neurophysiology studies undertaken on HGPPS participants found that the axons that make up the major motor and sensory pathways for communication between the brain and the body fail to cross the midline in the hindbrain of these individuals.
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, last updated 6/23/2004 (entry number #607313). Home page: http://www3.ncbi.nlm.nih.gov/Omim/.
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- Pieh, C., Lengyel, D., Neff, A., Fretz, C. & Gottlob, I. Brainstem hypoplasia in familial horizontal gaze palsy and scoliosis. Neurology 59, 462-3 (2002).
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- Stavrou, P. & Willshaw, H.E. Familial congenital horizontal gaze palsy. J Pediatr Ophthalmol Strabismus 36, 47-9. (1999).
- Jen, J. et al. Familial horizontal gaze palsy with progressive scoliosis maps to chromosome 11q23-25. Neurology 59, 432-5 (2002).
- Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rub U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004 Jun 4;304(5676):1509-13. Epub 2004 Apr 22.
Learn about ROBO3
This year in collaboration with Dr. Joanna Jen's laboratory at UCLA, we identified ROBO3 to be the gene mutated in Horizontal gaze palsy with progressive scoliosis (HGPPS).1
10 conserved homozygous mutations identified in ROBO3 in participants with Horizontal gaze palsy with progressive scoliosis
ROBO3 is a developmental gene that functions to guide axons across the midline of the developing brainstem and spinal cord. During fetal development, axons, the tails of neurons, must travel long distances to connect precisely with their target - another neuron or muscle. Some axons must cross the midline during their travels, and others must not. Therefore our studies of HGPPS provided insight into a very basic and poorly understood aspect of human brain development.
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, creation date 11/12/2003 (entry number *608630). Home page: http://www3.ncbi.nlm.nih.gov/Omim/.
- Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rub U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004 Jun 4;304(5676):1509-13. Epub 2004 Apr 22