CMT AND NEUROGENIC DISEASE: P.337Giant axonal neuropathy presenting as CMT2: results from the NIH natural history study

Abstract

Giant axonal neuropathy (GAN) is a rare childhood onset neurodegenerative disorder of the peripheral and central nervous system caused by recessive mutations in the GAN gene resulting in loss of function of gigaxonin, a cytoskeletal regulatory protein. The true incidence of GAN is unknown but it has been reported in approximately 100 patients worldwide since the identification of the causative gene in 2000. In its classical form GAN displays a consistent phenotype with 'kinky' hair, early gait abnormality from sensory ataxia followed by a progressive length dependent decline in strength with uniform sensory more than motor axonal polyneuropathy on electrophysiology. Patients later develop progressive cerebellar dysfunction, optic neuropathy, respiratory insufficiency and seizures. Death from respiratory complications usually ensues by the 3rd decade. With the advent of whole exome sequencing patients with milder disease, often initially clinically diagnosed with hereditary axonal sensory motor polyneuropathy (CMT2), have been recognized. Here we conduct a careful clinical and genetic characterization of 6 individuals age 8-21 years with genetically confirmed GAN with a milder phenotype who participated in the single site NIH GAN natural history study evaluating 35 patients age 5-21 years. In addition to comparatively better motor function they displayed curly rather than kinky hair, minimal to no brain imaging abnormalities, normal intellect and pulmonary function and no optic neuropathy. No definitive genotype-phenotype correlations emerged. Overall GAN of milder clinical severity can present with a CMT2-like phenotype. Accurate and early diagnosis can be achieved by the inclusion of GAN on CMT NGS panels to facilitate timely initiation of disease modifying therapy, to improve understanding of the natural history of this disorder, and to further elucidate the pathogenic mechanism underlying a milder disease course.