Giant axonal neuropathy (GAN): Year of the Zebra 2026

Giant axonal neuropathy is a rare inherited neurodegenerative disorder that damages axons, the long extensions of nerve cells that carry electrical signals to other nerve cells, glands, and muscles throughout the body.

Some axons are pretty unique because they are extraordinarily long, with some stretching from the spinal cord all the way to the tip of the fingers or toes. To function, they depend on constant flow of nutrients and proteins being shipped from one end to the other along a very intricate system called the cytoskeleton.

In giant axonal neuropathy, a person inherits disease-causing variants in both copies of the GAN gene, resulting in too little of a functional protein called gigaxonin. Normally, gigaxonin acts like a cellular recycling manager, clearing out old, worn-out structural filaments for breakdown. Without enough functional gigaxonin, these neurofilaments accumulate and become disorganized. This disrupts axonal function, causing it to balloon in size, producing the “giant” appearance seen under the microscope.

Now, as these filaments accumulate, axonal structure and transport become disrupted. This particularly affects the long spinal nerves first, which is why individuals develop problems like muscle weakness, decreased reflexes, sensory abnormalities, and difficulty walking and coordinating their movements.

These signs usually show up in early childhood, often before age 5. For example, a parent or caregiver may first notice frequent falls, difficulty running, an unsteady gait, or loss of previously acquired motor skills. Loss of muscle tone and muscle sensation also often results in difficulty for the child to keep their spine straight, leading to scoliosis, which is an abnormal curvature of the spine.

As time goes on, involvement of the central nervous system may become apparent, with symptoms such as worsening balance and coordination, speech or swallowing difficulties, muscle stiffness, seizures, and developmental or cognitive changes.