Giant axonal neuropathy

Giant axonal neuropathy is a rare, autosomal recessive neurodegenerative disease of both the peripheral nervous system (PNS) and the central nervous system (CNS). It is one of the inherited leukodystrophies. 

Epidemiology

Approximately 50 affected families have been reported in the literature; the prevalence is unknown. Of note, giant axonal neuropathy is often reported in the context of parental consanguinity ^1-3. 

Clinical presentation

Children typically presents in infancy (often age 3 years) with motor sensory neuropathy in the absence of prodromal signs or symptoms. The CNS is affected later in disease progression, which is demonstrated by cerebellar ataxia, cognitive dysfunction, epilepsy and pyramidal insufficiency ^4-6. Of note, kinky hair is often reported. 

Pathology

Etiology

Mutations in both alleles of the giaxonin gene on chromosome 16 cause large accumulations of neurofilaments, axonal distention ("giant" axons), and degeneration of the myelin sheath ⁷. The exact mechanism of pathogenesis is unclear; however, giaxonin is thought to have a role in neurofilament degradation as part of an E3 ubiquitin ligase complex ⁷.

Radiographic features

MRI

A leukodystropy pattern is often observed on MRI. Specifically, T2/FLAIR-weighted images will show periventricular white matter hyperintensity. In addition, T2/FLAIR-weighted images show hyperintensities diffusely within the cerebellum and cerebrum. Of the latter, the deep brain structure, particularly the basal ganglia, are often abnormal ^8,9.

Treatment and prognosis

Treatment focuses on symptom control. The severe and rapidly progressive nature of giant axonal neuropathy unfortunately contributes to death in young adulthood - often by the 30th decade - in the majority of affected individuals ⁴. 

History and etymology

Interestingly, "neuropathy" classically refers to a disease of the PNS only. As GAN also affects the CNS, "giant axonal neurodegeneration" has been proposed as a more appropriate name ⁴.