Autophagy Induction in C12orf65 Mutation-related Autosomal Recessive Hereditary Spastic Paraplegia 

Abstract Background: Spastic paraplegia type 55 (SPG55) is an autosomal recessive complicated hereditary spastic paraplegia. Here we report an SPG55 case with typical neurological phenotypes including optic atrophy, lower extremity spasticity and peripheral neuropathy. Methods: The present study involved one patient in a Chinese family. Neurological examination including the ophthalmology related examinations as well as nerve conduction velocity and a sural nerve biopsy were performed for the patient. We performed a genetic analysis of genes associated with peripheral neuropathy and spastic paraplegia using a multigene next-generation sequencing(NGS) panel and sanger sequencing. Furthermore, we cultured patient’s primary skin fibroblasts, then we examined the cytoplasmic LC3B immunofluorescence in the patient’s primary fibroblast and after two drugs (butylphthalide sodium chloride and idebenone) were used to the target the mitochondria function of the fibroblast.Results: Here we reported an SPG55 case with typical neurological phenotypes including optic atrophy, lower extremity spasticity and peripheral neuropathy. We identified a homozygous C12orf65 nonsense mutation (c.394C>T, p. R132*) in the affected patient. The mutation was associated with active autophagosome formation with increased LC3B puncta in the patient’s fibroblasts compared with an age-matched healthy individual, while the latter phenotype was normalized by Dl-3-N-butylphthalide treatment. Conclusions: This is the first pilot study to characterize the SPG55 mutation in the Chinese population; it will contribute to further research revealing the role of C12orf65 mutations in regulation of mitochondria function and autophagy.