Hereditary Spastic Paraplegias: Genetics and Clinical Features

Voluntary movement in humans is mediated by the pyramidal motor system, a tortuous central nervous system pathway comprising long corticospinal and lower motor neurons. The hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurological disorders with the defining feature of lower extremity spasticity and weakness, resulting from a length-dependent axonopathy of corticospinal upper motor neurons. HSPs are among the most genetically diverse neurological disorders, with nearly 60 distinct genetic loci; over 30 genes have already been identified. The HSPs can exist in pure forms or with a number of associated neurological and extra-neurological features. Recent studies elucidating the pathogenesis underlying HSPs have highlighted the importance of basic cellular functions, especially membrane traffic, organelle shaping, and lipid/cholesterol metabolism, in axonal development and maintenance. A small number of converging cellular pathogenic themes have been identified for the most common HSPs, and some of these pathways represent compelling targets for future therapies.