Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3-21 years with genetically confirmed GAN to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with GAN of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross-correlational analysis of measures of strength, motor function and electrophysiological markers of disease severity, we identified the Motor Function Measure 32 to have the strongest correlation across measures and age in individuals with GAN. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a subcohort of individuals with a milder form of GAN and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of GAN, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in GAN as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed GAN is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of GAN in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with GAN.