Giant Axonal Neuropathy (GAN) is a recessively inherited condition that results in progressive nerve death. GAN is a loss of function disorder, meaning an intracellular protein needed for long-term nerve survival either isn’t being made or is being immediately degraded before it can perform its job. Every gene in the body has a function. Some genes encode or make secreted enzymes. Some genes make intracellular proteins. The protein that isn’t functioning in GAN is called gigaxonin. It is believed that the role of gigaxonin is to degrade its binding partners when they are done doing their job on the axon portion of the nerve. In the absence of functional gigaxonin, these other proteins are toxically communicating, causing densely packed, swollen giant axons, which interfere with the signaling between the peripheral nervous system (arms, legs, etc) and the central nervous system (brain and spinal cord). It’s easiest to think of a clogged vacuum hose.
Giant axonal neuropathy generally appears in early childhood. It progresses slowly as neuronal injury becomes more severe. Signs of giant axonal neuropathy first appear in the peripheral nervous system. These symptoms most often include clumsiness, lack of coordination (impaired proprioception), low muscle tone and impaired fine motor skills are caused by nerve damage in the central, autonomic and peripheral nervous systems. The motor neurons and sensory neurons are impacted by GAN and these nerves govern movement and sensation in the arms, legs, and other parts of the body. The autonomic nervous system controls involuntary processes like heart rate, body temperature, and communication with organs such as the lungs for involuntary breathing. Most individuals with this disorder first have problems with walking. Later they may lose sensation, coordination, strength, and reflexes in their limbs. Hearing and visual problems typically occur. Extremely kinky hair (as compared to others in the family) is characteristic of giant axonal neuropathy, but not all confirmed GAN cases have kinky hair.
As the disorder progresses, patients become quadriplegic, dependent on a feeding tube and ventilator before dying typically in the second or third decade.
Giant axonal neuropathy is a very rare disorder; the incidence is unknown. We now have a few milder progressing, confirmed GAN cases, as well as a few confirmed cases without kinky hair. MDs working with HHF now feel that some CMT Type 2 patients who have not yet had their causal gene identified may actually have GAN. If you have been clinically diagnosed with CMT and told you have nystagmus (involuntary eye movements when looking sideways) and/or optic motor atrophy and wish to have your GAN gene sequenced for free, please contact HHF to arrange for sequencing.