Giant axonal neuropathy.

Giant axonal neuropathy (GAN) is a rare hereditary autosomal recessive neurodegenerative disease affecting both the peripheral and the central nervous system. Clinically it is characterized by an age of onset during the first decade, progressive and severe motor sensory neuropathy followed, in some patients, by the occurrence of various central nervous system signs such as cerebellar syndrome, upper motor neuron signs, or epilepsy. Although kinky hairs are reported in the majority of patients, it is not a constant finding. The prognosis is usually severe with death occurring during the second or third decade; nevertheless a less severe course is reported in some patients. The presence of a variable number of giant axons filled with neurofilaments in the nerve biopsy represents the pathological feature of the disease and it is usually associated to a variable degree with axonal loss and demyelization. Giant axons are also found in the central nervous system associated with Rosenthal fibers and a variable degree of involvement of white matter and neuronal loss. The disease is caused by mutation in the GAN gene encoding for gigaxonin, a member of BTB-Kelch. Up to now 37 mutations in the GAN gene have been reported. These mutations are scattered over the 11 exons of the gene without a clear genotype-phenotype correlation. These mutations resulting in gigaxonin deficiency lead to a slow down in ubiquitin-mediated protein degradation and possibly of other unidentified proteins. GAN represents a good model of a neurodegenerative disorder in which there is a primary defect of the ubiquitin proteasome system and its network with neurofilaments. The clarification of molecular mechanisms involved in GAN can help in understanding other frequent neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson disease.