Hereditary Spastic Paraplegias: Current Knowledge and Future Perspective

The Hereditary Spastic Paraplegias (HSPs) are disabling neurodegenerative disorders characterized by progressive weakness and spasticity in the lower limbs with or without additional neurological or extraneurological features. These symptoms are due to progressive degeneration, or distal axonopathy, of the corticospinal tract. Collectively, HSPs are rare conditions and their onset ranges from early childhood to more than 70 years. HSPs are genetically determined and they are among the most clinically and genetically heterogeneous human diseases. All modes of inheritance, ADHSP, ARHSP, X-linked (XHSP), and more rarely mitochondrial inheritance, have been described. Currently, 84 different spastic gait disease loci (SPG) with 67 corresponding spastic paraplegia genes (SPGs) have been identified. Notwithstanding the extreme genetic and allelic heterogeneity in HSP, recent cellular, animal, and pathological research has outlined the existence of common themes in the neurodegeneration of the corticomotor spinal tract. The analyses of the functions of HSP proteins indicate that a variety of primary molecular abnormalities underlie various genetic subtypes of HSP. Attempts to integrate functionality of diverse HSP proteins into a single underlying pathogenic mechanism seem too premature or over simplistic, but the multiple functions of several HSP proteins put forward the possibility that few patterns may impinge on the broader degeneration seen in HSP. Animal models for these disorders have been developed. They will enable investigators to further uncover the biochemical processes that cause nerve degeneration and identify and test therapy targets.

An increased focus on this disease is timely and critical. There is definitely reason to hope for treatments and therapies in coming years that will restore significant function to people affected by HSP. Thus, this Research Topic welcomes manuscripts that describe genotypes and phenotypes of the different forms of hereditary spastic paraplegias, increase our understanding of their pathogenesis, and articulate strategies to use this knowledge to deliver novel therapeutic tools. The overall aim is to offer a wide vision of our current knowledge in this topic and to underlie the future needs to develop therapies that reduce this unmet medical problem of our society.