Clinical characteristics: Giant axonal neuropathy (GAN) is an early-onset fatal neurodegenerative disorder. GAN starts as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade.
Diagnosis/testing: The diagnosis of GAN is suggested by clinical findings and the results of nerve conduction velocity (NCV) studies and brain MRI. The diagnosis is established in individuals with biallelic pathogenic variants in GAN (encoding gigaxonin, a subunit of an E3 ubiquitin ligase) or decreased quantities of gigaxonin on immunodiagnostic testing. Nerve biopsy, the former diagnostic modality, is no longer routinely used.
Management: Treatment of manifestations: A multidisciplinary team including (pediatric) neurologists, orthopedic surgeons, physiotherapists, psychologists, and speech and occupational therapists is recommended; goals are to optimize intellectual and physical development through speech therapy to improve communication, occupational therapy to maximize independence in activities of daily living, physiotherapy to preserve mobility as long as possible, and early intervention and special education; orthopedic surgery as needed for foot deformities; ophthalmologic treatment as needed for diplopia. Prevention of secondary complications: For wheelchair-bound or bedridden individuals, prophylaxis and frequent examination for decubitus ulcers. Surveillance: At least yearly reassessment of intellectual abilities, peripheral neuropathy, ataxia, spasticity, and cranial nerve dysfunction.
Genetic counseling: GAN is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Individuals with GAN have not been known to reproduce, most likely because they die at a young age. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the GAN pathogenic variants in a family are known.
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