Update on the Genetics of Spastic Paraplegias

Hereditary spastic paraplegias are a genetically heterogeneous group of neurological disorders. Patients present lower limb weakness and spasticity, complicated in complex forms by additional neurological signs. We review here the major steps toward understanding the molecular basis of these diseases made over the last 10 years.

Our perception of the intricate connections between clinical, genetic, and molecular aspects of neurodegenerative disorders has radically changed in recent years, thanks to improvements in genetic approaches. This is particularly true for hereditary spastic paraplegias, for which > 60 genes have been identified, highlighting (i) the considerable genetic heterogeneity of this group of clinically diverse disorders, (ii) the fuzzy border between recessive and dominant inheritance for several mutations, and (iii) the overlap of these mutations with other neurological conditions in terms of their clinical effects. Several hypotheses have been put forward concerning the pathophysiological mechanisms involved, based on the genes implicated and their known function and based on studies on patient samples and animal models. These mechanisms include mainly abnormal intracellular trafficking, changes to endoplasmic reticulum shaping and defects affecting lipid metabolism, lysosome physiology, autophagy, myelination, and development. Several causative genes affect multiple of these functions, which are, most of the time, interconnected. Recent major advances in our understanding of these diseases have revealed unifying pathogenic models that could be targeted in the much-needed development of new treatments.