Horizontal gaze palsy with progressive scoliosis (HGPPS) is a disorder that affects vision and also causes an abnormal curvature of the spine (scoliosis). People with this condition are unable to move their eyes side-to-side (horizontally). As a result, affected individuals must turn their head instead of moving their eyes to track moving objects. Up-and-down (vertical) eye movements are typically normal.

In people with HGPPS, an abnormal side-to-side curvature of the spine develops in infancy or childhood. It tends to be moderate to severe and worsens over time. Because the abnormal spine position can be painful and interfere with movement, it is often treated with surgery early in life.

HGPPS is caused by mutations in the ROBO3 gene. This gene provides instructions for making a protein that is important for the normal development of certain nerve pathways in the brain. These include motor nerve pathways, which transmit information about voluntary muscle movement, and sensory nerve pathways, which transmit information about sensory input (such as touch, pain, and temperature). For the brain and the body to communicate effectively, these nerve pathways must cross from one side of the body to the other in the brainstem, a region that connects the upper parts of the brain with the spinal cord.

The ROBO3 protein plays a critical role in ensuring that motor and sensory nerve pathways cross over in the brainstem. In people with HGPPS, these pathways do not cross over, but stay on the same side of the body. Researchers believe that this miswiring in the brainstem is the underlying cause of the eye movement abnormalities associated with the disorder. The cause of progressive scoliosis in HGPPS is unclear. Researchers are working to determine why the effects of ROBO3 mutations appear to be limited to horizontal eye movement and scoliosis.

Normal Function

The ROBO3 gene provides instructions for making a protein that is critical for the normal development of the nervous system. The protein is active in the developing spinal cord and in the brainstem, a region that connects the upper parts of the brain with the spinal cord. In the brainstem, the ROBO3 protein helps direct nerve cells (neurons) to their proper positions in a process called neuronal migration. The protein also helps guide the growth of axons, which are specialized extensions of neurons that transmit nerve impulses throughout the nervous system. Some axons are very long, connecting neurons in the brain with those in the spinal cord and elsewhere in the body.

For the brain and body to communicate effectively, certain bundles of axons must cross from one side of the body to the other in the brainstem. These include axons of motor neurons, which transmit information about voluntary muscle movement, and axons of sensory neurons, which transmit information about sensory input (such as touch, pain, and temperature). The ROBO3 protein plays a critical role in ensuring that this crossing over occurs during brain development.

Health Conditions Related to Genetic Changes

Horizontal gaze palsy with progressive scoliosis

At least 19 different mutations in the ROBO3 gene have been identified in people with horizontal gaze palsy with progressive scoliosis (HGPPS). These mutations change the structure of the ROBO3 protein in different ways; however, all of the mutations appear to result in a nonfunctional protein. A lack of functional ROBO3 protein disrupts normal brainstem development.

In people with HGPPS, the axons of motor and sensory neurons do not cross over in the brainstem, but stay on the same side of the body. Researchers believe that this miswiring is the underlying cause of the eye movement abnormalities associated with the disorder. The cause of progressive scoliosis in HGPPS is unclear. Researchers are working to determine why the effects of ROBO3 mutations appear to be limited to horizontal eye movement and scoliosis.

Other Names for This Gene

• FLJ21044
• HGPS
• RBIG1
• retinoblastoma inhibiting gene 1
• RIG1
• ROBO3_HUMAN
• Roundabout homolog 3
• roundabout, axon guidance receptor, homolog 3
• roundabout, axon guidance receptor, homolog 3 (Drosophila)
• Roundabout-like protein 3

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

HGPPS has been reported in several dozen families worldwide.