Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion.

Giant axonal neuropathy (GAN) is an autosomal recessive disease caused by mutations in the GAN gene encoding gigaxonin. Patients develop a progressive sensorimotor neuropathy affecting peripheral nervous system (PNS) and central nervous system (CNS). Methods: In this multicenter observational retrospective study, we recorded French patients with GAN mutations, and 10 patients were identified. Mean age of patients was 9.7 years (2-18), eight patients were female (80%), and all patients met infant developmental milestones and had a family history of consanguinity. Mean age at disease onset was 3.3 years (1-5), and progressive cerebellar ataxia and distal motor weakness were the initial symptoms in all cases. Proximal motor weakness and bulbar symptoms appeared at a mean age of 12 years (8-14), and patients used a wheelchair at a mean age of 16 years (14-18). One patient died at age 18 years from aspiration pneumonia. In all cases, nerve conduction studies showed a mixed demyelinating and axonal sensorimotor neuropathy and MRI showed brain and cerebellum white matter abnormalities. Polyneuropathy and encephalopathy both aggravated during the course of the disease. Patients also showed a variety of associated findings, including curly hair (100% of cases), pes cavus (80%), ophthalmic abnormalities (30%), and scoliosis (30%). Five new GAN mutations were found, including the first synonymous mutation and a large intragenic deletion. Our findings expand the genotypic spectrum of GAN mutations, with relevant implications for molecular analysis of this gene, and confirm that GAN is an age-related progressive neurodegenerative disease involving PNS and CNS.