What is GAN?
Giant Axonal Neuropathy (GAN) is a recessively inherited condition that results in progressive nerve death. GAN is believed to be 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 interferes 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, but these symptoms are caused by nerve damage in the central nervous system. 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. 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 quadriplegics, dependent on a feeding tube and ventilator before dying typically in the second or third decade.
How common is giant axonal neuropathy?
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 wish to have your GAN gene sequenced for free, please contact Lori Sames@Yahoo.com to arrange for sequencing
Mutations in a single gene called the GAN gene.
Giant axonal neuropathy is caused by mutations in the GAN gene, which provides instructions for making a protein called gigaxonin. Some GAN mutations change the shape of the protein, affecting how it binds to other proteins to form a functional complex. Other mutations prevent cells from producing any gigaxonin protein.
Gigaxonin is involved in a cellular function that destroys and gets rid of excess or damaged proteins using a mechanism called the ubiquitin-proteasome system. Neurons without functional gigaxonin accumulate excess neurofilaments in the axon, causing the axons to become distended. These giant axons do not transmit signals properly and eventually deteriorate, resulting in problems with movement and other nervous system dysfunction.
- giant axonal
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