Giant Axonal Neuropathy (GAN) is an ultra-rare autosomal recessive early childhood onset neurodegenerative disorder manifesting with progressive sensorimotor peripheral and optic neuropathy, central nervous system (CNS) involvement (including cerebellar findings and leukoencephalopathy), and respiratory failure typically resulting in death in the second to third decade of life in the classic disease form. A milder form with later onset, longer maintenance of independent ambulation, and longer survival has been identified, termed the ‘axonal CMT-plus’ form. In addition, an intermediate phenotypic group exists, with early onset and electrophysiologic decline but without overt CNS clinical or neuroimaging findings. All GAN phenotypes are caused by biallelic variants in GAN, the gene which encodes for gigaxonin, a protein responsible for the regulation of intermediate filament turnover, and which leads to intermediate filament accumulation driving progressive degeneration and disease in the central and peripheral nervous system. The aim of this natural history study for GAN is to characterize the longitudinal progression in motor function, electrophysiologic nerve conduction response, and pulmonary function across these phenotypic groups. 105 total visits across 54 patients were conducted in a natural history study (NCT:01568658) including 41 classic, 7 intermediate, and 6 mild phenotypic group participants, spanning ages 1.5 years to 23.4 years old. Assessments included motor function measure (MFM), timed graded functional testing, Friedreich’s Ataxia Rating Scale (FARS), nerve conduction study, neuroimaging, and pulmonary function testing. Longitudinal data analysis demonstrates differences in annualized slope of the MFM total percent score and FARS total score and time to loss of sensory responses between the phenotypic groups. The classical versus axonal CMT-plus GAN phenotypes are distinct, and interestingly the differences in ambulatory status between the intermediate versus classic GAN groups may be driven by the CNS contribution to disease in the classic GAN cohort, given that the peripheral electrophysiologic declines are comparable between these two subgroups. Understanding the impact of phenotypic group and defining the longitudinal motor, functional, electrophysiologic and pulmonary progression in GAN is imperative for clinical anticipatory guidance, trial design and understanding the clinical impact or efficacy of therapeutic interventions.